Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.N12CCCN=C1CCCCC2>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cc2ccc(N3CCCC3)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 160 °C
Yield: 69 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456,100 mg, 0.289 mmol), pyrrolidine (60.3 uL, 0.723 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (204 uL, 1.45 mmol). The mixture was heated to 160° C. for 30 minutes and then cooled to room temperature. The reaction mixture was diluted with dichloromethane (25 mL) and washed with 0.5M HCl (3×10 mL). The combined aqueous portions were extracted with dichloromethane (15 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 10% acetone/dichloromethane as the eluent to produce 79 mg of P-582 as a pale orange semisolid in 69% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.93 (m, 4H), 3.31-3.34 (m, 4H), 3.71 (s, 3H), 3.77 (s, 2H), 6.37 (d, J=9 Hz, 1H), 6.91 (d, J=9 Hz, 1H), 7.23-7.28 (m, 2H), 7.32 (dd, J=9, 2 Hz, 1H), 7.36 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 397.1 (M+1) LC-MS: 98%
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(=O)(OC(C)(C)C)[O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:15][C:12]([O:11][C:9]([N:1]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[C:9](=[O:8])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])([CH3:13])[CH3:14]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccs1
Yield: 79.9 %

Procedure:
A solution of 2-aminothiazole (5 g, 0.05 mol), (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (27.8 g, 0.15 mol) and DMAP (100 mg) in THF (100 mL) was stirred at reflux overnight. The mixture was allowed to cool and concentrated in vacuo. The residue was chromatographed on silica, eluting with 8% ethyl acetate in hexane, to give the desired material as a white solid (12 g).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][NH2:17]>O>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:17][N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1ccccc1F
Solvent: O
Product: c1ccc(-c2n[nH]c3ccccc23)cc1
Temperature: 170 °C
Yield: 67 %

Procedure:
To 2-fluorobenzophenone (1.0 g, 5.0 mmol) was added hydrazine (5 mL) and the reaction was heated to reflux for 3 hours. The reaction was then added to water (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried with sodium sulfate (Na2SO4) and concentrated to an oil. The subsequent hydrazine adduct was heated with pyridine (20 mL) to 170° C. for 4 days. Pyridine was then removed under vacuum and the resulting oil taken up in water (100 mL) and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate layers were dried (Na2SO4) and concentrated to give the final compound (650 mg, 67% yield). 1H NMR (CDCl3) δ 10.6 (br s, 1H), 8.04–7.99 (m, 2H), 7.56–7.50 (m, 2H), 7.47–7.33 (m, 2H), 7.29–7.19 (m, 3H); ES-MS (m/z) 195 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>CC(OC)(C)C>[CH3:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][C:2]=1[NH2:1]
Reactant: CO
Reactant: CCCCOc1ccc(C(=O)O)c(N)c1
Solvent: O=S(Cl)Cl
Solvent: COC(C)(C)C
Product: CCCCOc1ccc(C(=O)OC)c(N)c1

Procedure:
A mixture of 2-amino-4-butoxybenzoic acid (2.0 g), thionyl chloride (1.2 g) and methanol (33 mL) was boiled under reflux for 24 hours. The reaction solution was diluted with MTBE and washed with sodium hydroxide solution. The organic phase was dried and concentrated. The product with the molecular weight of 223.27 (C12H17NO3) was obtained in this way; MS (ESI): 224 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH2:9]C[CH2:7][CH2:6][N:5]2[CH:17]=1.CN(C)[C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:21]>>[C:25]1([CH3:28])[CH:26]=[CH:27][C:22]([C:20]([C:17]2[N:5]3[CH2:6][CH2:7][CH2:9][CH:10]([C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])[C:4]3=[CH:3][C:2]=2[CH3:1])=[O:21])=[CH:23][CH:24]=1
Reactant: Cc1cc2n(c1)CCCCC2C(=O)OC(C)C
Reactant: Cc1ccc(C(=O)N(C)C)cc1
Product: Cc1ccc(C(=O)c2c(C)cc3n2CCCC3C(=O)OC(C)C)cc1

Procedure:
In like manner, condensing isopropyl 2-methyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-9-carboxylate with N,N-dimethyl-p-toluamide there is obtained isopropyl 5-p-toluoyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-1-carboxylate (XI, R=CH3, L=p-CHR=iC3H72, n=2).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][C:34]([OH:36])=O.C(N(C(C)C)C(C)C)C.[C:46]([C:50]1[O:54][C:53]([C:55]2[C:56]([NH2:74])=[N:57][CH:58]=[C:59]([C:61]3[N:65]([CH2:66][CH3:67])[N:64]=[C:63]([CH:68]4[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]4)[N:62]=3)[N:60]=2)=[N:52][N:51]=1)([CH3:49])([CH3:48])[CH3:47]>C(#N)C>[NH2:74][C:56]1[N:57]=[CH:58][C:59]([C:61]2[N:65]([CH2:66][CH3:67])[N:64]=[C:63]([CH:68]3[CH2:69][CH2:70][N:71]([C:34](=[O:36])[CH2:33][CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[CH2:72][CH2:73]3)[N:62]=2)=[N:60][C:55]=1[C:53]1[O:54][C:50]([C:46]([CH3:47])([CH3:48])[CH3:49])=[N:51][N:52]=1
Reactant: O=C(O)CCOC1CCCCO1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C2CCN(C(=O)CCOC3CCCCO3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 106 g, 279.51 mmol), was added portionwise to a stirred solution of 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (44.3 g, 254.10 mmol) and N-ethyl-N-isopropylpropan-2-amine (89 mL, 508.21 mmol) dissolved in acetonitrile (600 mL) at 25° C. The resulting solution was stirred at 25° C. for 20 min then 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (101 g, 254.10 mmol) was added portionwise washing the last portion into the mixture as a slurry in acetonitrile (300 mL). After stirring for 1 hour the precipitate was collected by filtration, washing with acetonitrile and drying in vacuo to afford 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one (128 g, 91%) as a beige solid. The filtrate was diluted with DCM (600 ml), washed with water, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of 2 to 2.5% 7N ammonia in methanol with dichloromethane. A second crop of the desired product (40 g, 72.2 mmol, 28.4%) was obtained as a cream solid which was combined with the first crop: 1H NMR Spectrum: (DMSO-d6) 1.29-1.48 (16H, m), 1.48-1.75 (4H, m), 1.83-1.99 (2H, m), 2.48-2.68 (2H, m), 2.68-2.79 (1H, m), 2.87-2.99 (1H, m), 3.07-3.19 (1H, m), 3.32-3.42 (1H, m), 3.47-3.6 (1H, m), 3.64-3.75 (1H, m), 3.75-3.84 (1H, m), 3.84-3.95 (1H, m), 4.24-4.39 (1H, m), 4.47-4.6 (3H, m), 7.84 (2H, s), 8.79 (1H, s): Mass Spectrum [M+Na]+=577.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)(=O)C>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[NH:11][C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[N:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc3ccsc23)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 19.8 %

Procedure:
To a solution of 2-Chloro-N-mesitylthieno[3,2-d]pyrimidin-4-amine (51.4mg, 0.17 mmol), TFA (0.11 mL, 1.36 mmol) in TFE (1 mL) was added 4-aminobenzonitrile (80.2 mg, 0.68 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC to afford the product as a white solid (13 mg, 20%):
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:14])[NH:22][CH3:21])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.6 mmol), methylamine (0.25 mL, 2M in THF) and DIPEA (0.29 mL, 1.6 mmol) in DMF (2 mL). MS (LC-MS): 633.0 [2M]+; tR (HPLC conditions c): 4.55 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=O)[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.Cl>C1COCC1.CO>[CH3:1][C:2]1([CH3:16])[CH2:7][NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc2O1

Procedure:
2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one was added to BH3-THF complex (Aldrich) in THF with ice cooling. The mixture was heated to reflux for 2 h then carefully diluted with 12 mL of MeOH and heated to reflux for an additional 1 h. Concentrated HCl (12 mL) was added and heated to reflux for 1 h. The mixture was concentrated and the resulting solid was suspended in a dilute aqueous solution of NaOH (1 M) and extracted with EtOAc (100 mL×4). The organic layers were washed with H2O and dried over MgSO4. Evaporation of solvent gave a yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccc(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (61 mg, 78%), MS (ISP) m/z=313.6 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[C@@H:13]2[C@@H:9]([O:10]C(C)(C)[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([Cl:40])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:7]1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.O>[CH2:1]([NH:3][C:4]([C@@H:6]1[C@@H:13]([OH:12])[C@@H:9]([OH:10])[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([Cl:40])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of (3aS,4S,6R,6aR)-6-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid ethylamide (Step D1) in TFA/water (2:1) is stirred at RT overnight. The reaction mixture is concentrated in vacuo to afford the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 2-(2-amino-4-trifluoromethylphenoxy)benzoate (19.2 g, 0.062 mol) and 2N sodium hydroxide (65 mL, 0.13 mol) in tetrahydrofuran (100 mL) was warmed to 50° C. while stirring under argon for 3 h. The tetrahydrofuran was evaporated, and the aqueous solution was acidified with dilute HCl, extracted with ethyl acetate, dried over anhydrous MgSO4, filtered and evaporated. The crude product was recrystallized from EtOAc/hexane to give the title compound as a white crystalline solid. 1H NMR (250 MHz, CD3OD) δ7.91 (d, 1H), 7.50 (dd, 1H), 7.22 (dd, 1H), 7.11 (d, 1H), 6.97 (d, 1H), 6.86 (d, 1H), 6.78 (d, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>O1CCCC1.C(O)C>[Br:13][C:9]1[N:8]=[C:7]([CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
Add n-butyl lithium (16.2 mL, 2.5 M in hexanes, 40.5 mmol) dropwise to a solution of 2,6-dibromopyridine (8.00 g, 33.8 mmol) in tetrahydrofuran (100 mL) at −78° C. Stir 30 minutes then add dimethylformamide (12.3 g, 169 mmol) via syringe. Allow solution to warm to ambient temperature then pour it into a solution of sodium borohydride (17.85 g, 338 mmol) in ethanol (50 mL) at −10° C. After 10 minutes, remove the cooling bath. After 1 hour at ambient temperature, add water and 1N hydrochloric acid (gas evolution), then add saturated sodium bicarbonate solution until the mixture is neutralized. Extract the aqueous phase with ethyl acetate, dry over sodium sulfate, filter and concentrate under reduced pressure. Dissolve the residue in diethyl ether and add an excess of hydrogen chloride (2N in diethyl ether). Decant the organic phase and add saturated sodium bicarbonate solution to the residue. Extract with ethyl acetate (3×), dry over sodium sulfate, filter and concentrate under reduced pressure to afford the title compound as a brown oil (2.73 g, 14.5 mmol): MS (m/z): 189 (M+1).
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[C:6]1([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][C:16]=2[CH:23]=[O:24])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(-c2csc3ccccc23)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1sc2ccccc2c1-c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (62.5 ml of 1.6M solution in hexane, 0.1 mole) was added dropwise to a stirred solution of 3-phenylbenzo[b]thiophene (21.0 g, 0.1 mole) in tetrahydrofuran (150 ml) at -70° C. The solution was stirred at -70° C. for 30 minutes and dimethylformamide (10 ml, 0.13 mole) was added. The resulting mixture was stirred at -70° C. for 30 minutes and then allowed to warm to ambient temperature. After a further hour the reaction was quenched by the addition of dilute hydrochloric acid (100 ml, 2M) and the tetrahydrofuran removed under reduced pressure. The resulting oil was extracted into diethyl ether, the ethereal extract washed with water, dried over potassium carbonate and concentrated.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C:5]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([O:24]CC4C=CC=CC=4)=[CH:19][C:18]=3[Cl:32])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H][H]>[Pd]>[CH3:1][C:2]1([CH3:33])[O:6][C:5]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([OH:24])=[CH:19][C:18]=3[Cl:32])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1
Reactant: [H][H]
Agent: [Pd]
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(O)cc3Cl)c2O1

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted phenol, for example, the known compound 2,6-dichloro-4-phenylmethoxyphenol, was reacted under basic conditions with a haloalkane derivative of a desired carbon chain length, for example 1-bromo-4-chlorobutane, to attach the bridging group B, thereby affording the corresponding 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene (A). Intermediate (A) was then reacted under basic conditions with, for example, the known compound 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol, to attach moiety D, as well as the benzo-fused ring, affording the corresponding 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (B). Intermediate (B), for example 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene, as set forth above, was then reduced with hydrogen gas in the presence of a catalyst, for example 10% palladium on carbon, providing the corresponding 4-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dichlorophenol (C). Intermediate (C) was then reacted under basic conditions with, for example, 1,1,1,3-tetrachloropropane, which simultaneously dehydrohalogenates, thereby introducing the moiety —E—G—C(R4)═C(R5)(R5) into the molecule to provide Compound 12, a novel compound of formula I. Example 1 set forth below, provides a detailed method to how Compound 12 shown in Scheme 1 was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[NH2:21]>>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:21][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 24.2 %

Procedure:
Using 2-methoxy-5-sulfamoylbenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 142.6 mg (0.339 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1) and 35.6 mg (0.848 mmol) of LiOH--H2O in 12 ml of THF/water (4:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the hexane fraction extracted with 5% aqueous NaOH. The aqueous layers were combined and acidified with 1M HCl, and then extracted with EtOAc and Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.91 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.47 (2H, s), 7.23 (4H, q, J=8.1 Hz), 7.01 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.33 (2H, d, J=4.8 Hz), 1.30 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][N:10]2C(=O)C3=CC=CC=C3C2=O)=[C:7]([C:21]([O:23]CC)=[O:22])[O:6][N:5]=1)[CH3:2].[ClH:26]>[OH-].[Na+]>[ClH:26].[NH2:10][CH2:9][C:8]1[C:4]([O:3][CH2:1][CH3:2])=[N:5][O:6][C:7]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1onc(OCC)c1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1noc(C(=O)O)c1CN
Yield: 82 %

Procedure:
A solution of ethyl 3-ethoxy-4-phthalimidomethylisoxazole-5-carboxylate in 1 M NaOH was boiled under reflux for 45 min. The mixture was cooled, added concd HCl and extracted with diethylether (3×400 ml). The organic extracts were concentrated in vacuo, added 1 M HCl (600 mL) and boiled under reflux for 1 h. After cooling the mixture was washed with diethylether (3×600 mL) and concentrated in vacuo to give a crude product which was recrystallized (acetic acid) to yield the title compound (1.5 g, 82%): mp 215-216° C. (dec).
Reaction SMILES: [NH2:1][CH:2]1[CH2:16][O:15][C:5]2=[CH:6][CH:7]=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][CH:29]=O.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][CH2:29][NH:1][CH:2]1[CH2:16][O:15][C:5]2=[CH:6][CH:7]=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1
Reactant: O=CCCc1c[nH]c2ccc(F)cc12
Reactant: NC1COc2ccc3c(c2C1)C(=O)NCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCc2ccc3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Reaction time: 2 h

Procedure:
To a mixture of 9-amino-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one (46) (130 mg, 0.596 mmol), 3-(5-fluoro-1H-indol-3-yl)propanal ((2), 113 mg, 0.596 mmol) in acetic acid (70 μl) and methanol (20 ml) was added NaBH3CN (75 mg, 1.19 mmol) in portions. The resulting mixture was stirred for 2 hr. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with 1N NaOH and saturated NaCl before being dried over with Na2SO4. Concentration of organic solution gave the crude compound, which was purified on silica gel (100% EtOAc) to give the desired compound, which was treated with 1 equivalent of etherate HCL to form HCl salt for title compound. MS (APPI) m/z 394.4.