Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[N:20]=[N:19][C:18]=1[O:29]C)=O)(C)(C)C.[OH-].[Na+].Cl>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:29])[NH:19][N:20]=[C:21]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[CH:22]=1
Reactant: COc1nnc(-c2cnn(C)c2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cn1

Procedure:
2-[3-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester is dissolved in 8 ml dioxan and 8 ml aqueous 2N NaOH and heated by microwave irradiation for 90 min at 150° C. The solution is neutralized with aqueous HCl and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 35 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([O:32]C)=[O:31].CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC)c(F)c3)CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2,6-difluoro-4-{2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetate (0.500 g, 10.7 mmol) in 14 ml anhydrous tetrahydrofuran was added by 7 ml methanol and 7 ml water. Lithium hydroxide (0.3129 g, 5.37 mmol) was added into the reaction mixture, and the reaction was stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed under vacuum, and the remaining aqueous layer was extracted with dichloromethane (3×20 ml). The organics were combined, dried over magnesium sulphate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on Biotage column (50 g silica gel) using a gradient eluent of 0-70% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 432.3 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:38]=1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CNC(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-tert.butoxycarbonyl-aminomethyl)-aniline Rf value: 0.3 (aluminium oxide, methylene chloride/methanol=20:1) C29H29N3O5
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[CH3:12][C:13](=O)[O:14]CC>C1(C)C=CC=CC=1>[C:13]([CH:6]1[CH2:5][C:4]([CH3:11])([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])(=[O:14])[CH3:12]
Reactant: CC1(C)CCC(=O)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)C1CC(C)(C)CCC1=O
Temperature: 55 °C

Procedure:
To a suspension of NaH (2.88 g, 60% dispersion in mineral oil, 60 mmol) in toluene (25 mL), EA (6.5 mL, 66 mmol) is added. The mixture is stirred at rt for 5 min before a solution of 4,4-dimethyl-cyclohexanone (2.52 g, 20 mmol) in EA (6 mL) is added. The mixture is heated to 55° C. where a vigorous reaction starts. The white to grey suspension turns orange and becomes clear. The clear solution is poured onto ice/water and is extracted with EA. The aq. phase is acidified to pH 4-5 and extracted once more with EA. The combined organic extracts are dried over Na2SO4 and the solvent is removed in vacuo to give 2-acetyl-4,4-dimethyl-cyclohexanone (2.00 g) as a yellow oil; 1H NMR (CDCl3): δ 2.35 (t, J=7.0 Hz, 2H), 2.12 (s, 2H), 2.10 (s, 1H), 1.48 (t, J=7.0 Hz, 2H), 0.98 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12](=[O:14])[CH3:13].[Br:15]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Oc1c(C)sc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(=O)Oc1c(CBr)sc2ccccc12
Yield: 102.7 %

Procedure:
A suspension of 1.00 g (4.85 mmol) of 2-methyl-3-acetoxybenzo[b]thiophene, 1.21 g (6.78 mmol) of N-bromosuccinimide, and 10 mg benzoylperoxide was heated under reflux for 3 hours. The mixture was filtered and the filtrate was concentrated to afford 1.42 g (100%) of a pale yellow oil. NMR (CDCl3, 90 MHz) δ2.35 (s, 3H, OAc), 4.48 (s, 2H, --CH2 --Br), 7.2-7.8 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH3:25])=[C:14]([Br:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reactant: O=C1CCC(=O)N1Br
Product: CCOCc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 6, intermediate from (4R,9aR)-6-ethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-bromosuccinimide.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NCCCBr)OCc1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(NCCCN1CCC(O)(c2ccccc2)CC1)OCc1ccccc1

Procedure:
A mixture of 4-hydroxy-4-phenylpiperidine (5 g, 0.0282 mol), N-benzyloxycarbonyl-3-bromopropylamine (8.445 g, 0.031 mol), and potassium carbonate (7.795 g, 0.0564 mole) in acetone (200 mL) was stirred and refluxed for 12 hours. Acetone was evaporated at reduced pressure, the residue was treated with ice-cold water (400 mL) and extracted with CH2Cl2 (4×120 mL). Solvent was evaporated from the combined dried (sodium sulfate) extracts and the residue was found to be almost pure desired product (9.5 g, 91%) by tlc and 1H-NMR and was used as such without any further purification.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:13][C:14](=[O:26])[C:15]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[N:18][C:16]=3[N:17]=2)=[CH:7][C:6]=1[CH3:27].C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:29][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:13][C:14](=[O:26])[C:15]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[N:18][C:16]=3[N:17]=2)=[CH:7][C:6]=1[CH3:27]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one (0.50 g, 1.34 mmol) in anhydrous DMF (6 mL) was added carbon tetrabromide (0.53 g, 1.61 mmol) and triphenylphosphine (0.42 g, 1.61 mmol). The reaction mixture was stirred at 25° C. for 16 hours. DMF was removed under vacuum and dichloromethane (200 mL) was added. The organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was removed and the residue was washed with ether (100 mL) to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid. Yield: 0.23 g (40%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH2:30])=[CH:28][C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][C:8]3[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCc2ccc3c(c2)OCO3)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(1,3-benzodioxol-5-yl)methanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz, CD3CN): δ 0.97 (t, 3H), 1.39-1.48 (m, 2H), 1.72-1.80 (m, 2H), 3.67 (t, 2H), 4.05 (d, 2H), 5.91 (s, 2H), 6.26-6.34 (m, 2H), 6.64 (d, 1H), 7.32-7.48 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:26]=[C:25]([CH:27]3[CH2:29][CH:28]3[C:30]([OH:33])([CH3:32])[CH3:31])[N:24]([CH3:34])[C:23]=2[CH:35]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:19]4[CH:20]=[CH:21][C:22]5[N:26]=[C:25]([CH:27]6[CH2:29][CH:28]6[C:30]([OH:33])([CH3:31])[CH3:32])[N:24]([CH3:34])[C:23]=5[CH:35]=4)[C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ccc2oc(-c3ccc(Cl)cc3)cc12
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(Br)cc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)cc21
Temperature: 190 °C
Yield: 19644.6 %

Procedure:
A mixture of 2-(4-chlorophenyl)furo[3,2-c]pyridin-4(5H)-one (100 mg), 2-((1RS,2SR)-2-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclopropyl)propan-2-ol (151 mg), N,N′-dimethylethylenediamine (0.043 mL), copper(I) iodide (78.0 mg), potassium carbonate (169 mg) and DMSO (3.0 mL) was heated at 190° C. for 1 hr under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate to give the title compound (37.9 g) as a pale red solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: C1CCN(C2CCC3(CC2)OCCO3)OC1
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(1,4-dioxaspiro[4.5]decan-8-yl)-1,2-oxazinane (350 mg, 1.54 mmol) from above step A, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (×4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:32]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=4)=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:32][C:5]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: COc1cc(CCc2ccc3c(c2)CCN3CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc(OC)c1OC
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: COc1cc(CCc2ccc3c(c2)CCN3CC(N)(CO)CO)cc(OC)c1OC
Yield: 68 %

Procedure:
When the product of Step D was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 68% yield, as a creamy solid. 1H-NMR (CDCl3) 1.77 (broad s, 4H+H2O); 2.79 (s, 4H); 2.96 (tr, 2H, J=8.3 Hz); 3.07 (s, 2H); 3.44 (tr, 2H, J=8.3 Hz); 3.57-3.61 (m, 4H); 3.82 (m, 9H); 6.38 (s, 2H); 6.55 (d, 1H, J=7.95 Hz); 6.9 (d, 1H, J=7.95 Hz); 7.03 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1COCC1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-nitroaniline (4-7) (10.0 g, 72 mmol) and anhydrous potassium carbonate (20 g, 1.44 mmol) in anhydrous THF (240 mL) and benzoyl chloride (9.1 mL, 78 mmol) was stirred at RT overnight. The resultant solution was poured into 10% aq. HCl (200 mL) and cooled to 0° C. The yellow solid precipitated was filtered, washed successively with water (200 mL) and hexane (200 mL). Further drying under vacuum overnight provided the required 4-nitro-N-benzoylaniline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:6][CH:7]=1.B([C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)=[CH:3][C:4]=1[C:23]1[O:24][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:26][N:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nnc(-c2ccccc2)o1
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1-c1nnc(-c2ccccc2)o1
Temperature: 110 °C
Yield: 54.5 %

Procedure:
A mixture of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (198.7 mg, 0.3841 mmol), 4-boronobenzoic acid (63.74 mg, 0.3841 mmol) and Na2CO3 (81.42 mg, 0.7682 mmol) was suspended in MeCN (3.213 mL)/water (3.213 mL) and degassed (nitrogen/vacuum cycles). The reaction was then treated with tetrakis(triphenylphosphine)palladium(0) (44.39 mg, 0.03841 mmol), degassed again and heated at 110° C. in the microwave for 30 minutes. The reaction was treated with water (0.5 mL) and heated in the microwave at 110° C. for a further 30 minutes. The reaction mixture was washed with DCM, the aqueous phase acidified to pH1 (by addition of 1M HCl), and resulting precipitate filtered off and washed with water to give the product as an orange solid (75 mg, 55% Yield). MS (ES+) 359.14.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[F:14][C:15]([F:25])([F:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>C1COCC1>[F:14][C:15]([F:24])([F:25])/[C:16](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:3]\[C:1]#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C/C=C(/c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (6.1 g, 34.5 mmol) in 15 mL of THF was added sodium hydride (60% content, 1.4 g, 34.5 mmol). The mixture was stirred at room temperature. for 2 hours. 2,2,2-Trifluoro-1-phenylethanone (3 g, 17.2 mmol) was added and the mixture was stirred for 4 hours. After evaporation of THF, the residue was taken up in ethyl acetate (100 mL) and quenched with water (50 mL). The organic phase was washed with water (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (petrol ether: ethyl acetate=10:1) to afford the title compound (1.5 g, yield 29%) as an oil. LC-MS: m/z 198 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH3:27])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.90 min; Mass spectrum (ESI+): m/z=471 [M+Na]+.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[O:7][C:6]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:5][CH2:4]1.[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Br)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][S:1][CH2:2][CH:3]2[O:7][C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:5][CH2:4]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OC(CS)CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)O2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 64 (1.0 g, 0.003 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (described in U.S. Pat. No. 4,565,882, Example 14) (1.1 g, 0.0033 mol) and anhydrous potassium carbonate (1.6 g) in methyl ethyl ketone (15 ml). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 1.54 g (90%) of the product as an oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([CH2:23][OH:24])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][N:12]=[C:11]([CH:23]=[O:24])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of 0.54 g (1.7 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinemethanol in 15 ml of acetone was added 1.5 mg (17 mmol) of manganese dioxide and the mixture was stirred overnight at room temperature. The mixture was then filtered over a silica gel column (70-250 mesh), and the aldehyde eluated with acetone. Evaporation of the eluent and trituration of the residue with petroleum ether furnished 0.3 g of the title compound, melting point 104.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][CH3:13])=[N:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+].[Cl:20][C:21]1[N:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34]Cl)[C:23](=[O:27])[N:24]([CH3:26])[N:25]=1>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][CH3:13])=[N:10][O:11][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:22]2[C:23](=[O:27])[N:24]([CH3:26])[N:25]=[C:21]2[Cl:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cn1nc(Cl)n(-c2ccccc2CCl)c1=O
Reactant: CSC(=NO)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
The product from Step C (2.07 g) was dissolved in 10 mL of tetrahydrofuran and 10 mL of 1.0 M potassium t-butoxide in THF was added dropwise. After the addition was complete, the mixture was stirred 15 min, and then the title compound of Step E (2.06 g) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with 20 mL of water and extracted with three 30 mL portions of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give 3.53 g of the title compound of Step F as an oil. 1H NMR (CDCl3): δ 7.5 (m,5H), 7.25 (m,2H), 5.34 (d,1H), 5.18 (d,1H), 3.49 (s,3H), 2.08 (s,3H). The crude product contained minor amounts of impurities and solvent, but the material was not further purified before Step G.
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O.C1COCC1>[C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2nn(C(C)(C)C)c3ccnc(OC)c23)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of methyl 4-(1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (1.88 g) in a mixed solvent of methanol (30 mL)/THF (30 mL)/water (25 mL) was added 1N aqueous sodium hydroxide solution (5.44 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. The residue was washed with water, and dried in vacuum to give the title compound (1.50 g).
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[S-:10][C:11]#[N:12].[NH4+]>C1C=CC=CC=1>[CH2:1]([O:3][P:4]([N:12]=[C:11]=[S:10])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CCOP(=O)(Cl)OCC
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCOP(=O)(N=C=S)OCC

Procedure:
The title compound is prepared by the method of M. Kulka [Canadian Journal of Chemistry, 37, 525(1959)]by allowing diethylphosphorchloridate and ammonium thiocyanate to react in benzene; b.p. 76° C. to 83° C./0.5 Torr; nD25 1.4758.