Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[CH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](=[O:41])[C:27]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)([CH3:32])[CH2:28][S:29]2)=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:26]1([OH:41])[C:25]2[C:30](=[CH:31][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[S:29][CH2:28][C:27]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH3:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Reactant: C#CCCCCO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of 6-(t-butyldimethylsilyloxy)-1-hexyne (10.8 g, 50.9 mmol) in dry tetrahydrofiuran (100 ml) was added dropwise n-butyl lithium (30.1 ml, 48.9 mmol, 1.63M in tetrahydrofuran) at −78° C., which was then stirred at −20° C. for 1 hour. To the reaction mixture , was then added 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (8.0 g, 25.5 mmol) dissolved in tetrahydrofuran at −78 C for 30 min, and the resulting mixture was stirred at −10° C. (for 24 hours. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (12.5 g, yield: 93%).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C)[CH:32]=3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(OC)c2)cc1)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(O)c2)cc1)c1ccccc1

Procedure:
Prepared by treating 1u with boron tribromide (3 eq) in CH2Cl2 at room temperature. Yield (57%); 1H NMR (d6-DMSO) δ 12.15 (br s, 1H), 10.19 (s, 1H), 7.41-7.02 (m, 17H), 6.86 (d, J=8.0 Hz, 2H), 6.42 (d, J=15.7 Hz, 1H), 2.37 (q, J=7.4 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H); APcI m/z: 510 (M+H+)
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Br:23])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:24]([S-:26])#[N:25].[K+].BrBr>CC(O)=O.C1COCC1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]2[N:22]=[C:24]([NH2:25])[S:26][C:17]=2[C:16]=1[Br:23])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc(N)cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2nc(N)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (9 g, 21.63 mmol) in EtOH (50 ml) and EtOAc (50 ml) was added Pt/C (1.5 g), attached with a balloon of H2. More Pt/C (500 mg) was added after 3 h. Then the reaction mixture was stirred at rt for another 2 h. The reaction mixture was filtered over celite, concentrated down to give product (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) and went to next step without purification. To a solution of (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) (21.63 mmol) in HOAc/THF (80 ml, 1:1) was added KSCN at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Then Br2 was added slowly, reacted at 0° C. The reaction was quenched by adding sat. NaHSO3, extracted by EtOAc, dried over MgSO4, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 65H (2.3 g, 24% over 2 steps).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[CH3:23][C:22]([NH:26][C:27]([NH:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:7]([F:14])=[CH:8][C:9]([F:13])=[CH:10][C:11]=1[F:12])=[O:4])=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F
Product: CC(C)(C)NC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F

Procedure:
Following the procedure of Example 58 only using the product of Example 50 and t-butylisocyanate, the title compound was obtained, mp 205°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[I:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][N:15]=1>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:17]2[CH:16]=[N:15][C:14]([I:13])=[CH:19][CH:18]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: Oc1ccc(I)nc1
Product: COC(=O)c1cc(COc2ccc(I)nc2)c(C)o1

Procedure:
Compound (54) was prepared from compound (16) and 2-iodo-5-hydroxy-pyridine in a manner analagous to that described in Example 5(a). LC/MS System A: Rt=3.52 mins, m/z=374 (M+H) for C13H12INO4)
Reaction SMILES: OCCCN1C=C(C2C=C[C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3C=2[CH2:17][N:16](C)[C:15]3=[O:20])C=N1.NC1C(C(NC)=O)=[N:53][C:54]([Br:57])=[CH:55][CH:56]=1>>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:46]=[CH:47][C:33]([NH:32][C:24]2[N:23]=[C:22]([NH:21][C:13]3[C:14]([C:15](=[O:20])[NH:16][CH3:17])=[N:53][C:54]([Br:57])=[CH:55][CH:56]=3)[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][N:25]=2)=[C:34]([O:48][CH3:49])[CH:35]=1)(=[O:45])[O:39][CH2:40][CH3:41])[CH3:44]
Reactant: CNC(=O)c1nc(Br)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 78 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 10 with 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D, 279 mg, 1.21 mmol). The reaction mixture was concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→5% MeOH in DCM] to afford 661 mg of the title compound (78%). 1H NMR (400 MHz, CD3OD) δ 8.94-9.11 (m, 1H), 8.37 (s, 1H), 7.68 (d, J=7.1 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.07 (t, J=2.0 Hz, 1H), 6.94 (td, J=2.4, 8.2 Hz, 1H), 4.04-4.16 (m, 4H), 3.88 (s, 3H), 3.33-3.34 (m, 1H), 3.28 (s, 1H), 2.94 (s, 3H), 1.29 (t, J=7.1 Hz, 6H). MS (ESI): m/z 647.53/649.53 [M+H]+. UPLC: tR=1.49 min (UPLC-TOF: polar—2 min).
Reaction SMILES: Br[C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].[CH3:13][O-:14].[Na+]>>[CH3:13][O:14][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12]
Reactant: C[O-]
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Agent: [Na+]
Product: COc1c(O)cc(C(=O)O)cc1O
Yield: 45 %

Procedure:
Treatment of 4-bromo-3,5-dihydroxybenzoic acid (23.3 g, 0.1 mole) with sodium methoxide (18.5 g, 0.8 g atom) in an analogous procedure to that of Example 9 with a 9 hour reflux yielded 12 g (theory 18.4 g) of a white solid, m.p 238°-42° C. NMR showed this to be 45% title product and 55% starting material.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([NH2:14])[CH3:13].[Br:15][C:16]1[N:21]=[C:20](NCC2C=C3C(=CC=2)N=CC=C3)[C:19]([NH2:34])=[N:18][CH:17]=1>>[Br:15][C:16]1[N:21]=[C:20]([NH:14][CH:12]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[N:9]=[CH:8][CH:7]=[CH:6]3)[CH3:13])[C:19]([NH2:34])=[N:18][CH:17]=1
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Reactant: CC(N)c1cc2cccnc2cc1F
Product: CC(Nc1nc(Br)cnc1N)c1cc2cccnc2cc1F

Procedure:
The title compound was prepared as a white solid from 1-(7-fluoroquinolin-6-yl)ethanamine in analogy to the synthesis of compound 52.1. LCMS (method B): [MH]+=364, tR=2.38 min.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]=4[OH:19])[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]=4[OH:19])[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cccc(O)c24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3cccc(O)c23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(4-hydroxy-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 0.031 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(4-hydroxy-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.010 g, 75%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>CO>[NH:13]([C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][N:3]=1)[NH2:14]
Reactant: NN
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Solvent: CO
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cn1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-5-sulfamoylpyridine (1.0 g, 0.005 mole) was added to methanol (20 ml) and the reaction mixture was cooled to 5° C. before adding hydrazine hydrate (0.50 ml, 0.52 g, 0.01 mole). After stirring for 10 minutes at 5° C., the mixture was refluxed for 45 minutes. Additional hydrazine hydrate (1.0 ml) was added and the mixture was refluxed for approximately 12 hours. The reaction mixture was concentrated in vacuo to an oil which was slurried with 40 ml of boiling ethanol. The ethanol layer was collected by decantation and cooled in an ice bath to produce a white solid which was collected by filtration and air dried; yield, 0.69 g (73 percent).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=1[NH2:24])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC[C:27]([C:29](Cl)=[O:30])=[O:28].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=2[NH:24][C:27](=[O:28])[C:29]1=[O:30])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCC(=O)C(=O)Cl
Reactant: CCOP(=O)(CNc1c(N)cc([N+](=O)[O-])c2ccccc12)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c3ccccc3c21)OCC
Temperature: 25 °C

Procedure:
100 mg of (2-amino-4-nitro-1-naphthylamino)-methanephosphonic acid diethyl ester is dissolved in a few ml of tetrahydrofuran and treated with 95 microliters of distilled ethyloxalyl chloride and 118 microliters of triethylamine at ice-bath temperature. The solution is stirred first to room temperature and then the reaction is allowed to be completed at 55° oil bath temperature. The batch is concentrated by evaporation, taken up in ethyl acetate and washed with brine, dried and spun in. The crude product is chromatographed on silica gel with ethanol as mobile solvent. 76 mg or 67% of theory of product is obtained as polar fraction. NMR (DMSO,Delta in ppm): 1.03 (6H tr), 3.8 (4H dq), 4.93 (2H d), 7.73 (2H dd), 8.2, 8.35, 8.47 each 1H.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)=[CH2:3].CN1C=CN=C1.[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C1(C)C=CC=CC=1>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:3])[CH2:1][CH:21]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]
Reactant: C=C(C)c1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1(C)c1ccc(C(C)=O)cc1
Yield: 21.6 %

Procedure:
To a stirred solution of 1-[4-(1-methylethenyl)phenyl]ethanone (711 mg, 4.44 mmol, trans) (Org. Lett., 2002, 4(1), 107-109), N-methylimidazole (1.06 ml, 13.3 mmol) and Co(TPP)(89 mg, 0.13 mmol) in toluene (10 ml) was added ethyl diazoacetate (0.65 ml, 6.21 mmol) in one portion at ambient temperature. The same procedure as described in Example 2H was performed to give the title compound (236 mg, 22%) as dark yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=[C:30]([CH:39]=O)[CH:29]=3)=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=[C:30]([CH2:39][NH:15][CH2:14][CH2:13][N:10]4[CH2:9][CH2:8][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:12][CH2:11]4)[CH:29]=3)=[CH:24][CH:23]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Product: c1ccc(N2CCN(CCNCc3cc(-c4ccc(C5CCCCC5)cc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 71.2 %

Procedure:
Compound 12 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-(4-cyclohexylphenyl)-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [F:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH:5]1[C:9](=[O:10])[O:8][CH:7]([CH:11]([NH:19][C:20]([C:22]2[CH:31]=[N:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[OH-:34].[Li+]>O1CCCC1>[F:1][C:2]([CH3:32])([CH3:33])[CH2:3][CH2:4][CH:5]([CH2:6][CH:7]([OH:34])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:9]([OH:8])=[O:10]
Reactant: CC(C)(F)CCC1CC(C(Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)O
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid {1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide (4 g, 8.90 mmol) in tetrahydrofuran was added lithium hydroxide (1 M in water, 28 mL) and stirred for 2 hours. The reaction was then concentrated, and concentrated from benzene (2×) to give the title compound (4.2 g, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:14](OC(=O)C)(=[O:16])C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.C(O)=O>[CH:14]([O:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1)=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: c1ccncc1
Product: C=C1CC(OC=O)CCC2=C(C)CCC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
2.67 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene were treated at 0° firstly with half of a mixture of 4.08 g of acetic anhydride, 1.84 g of formic acid and 37 mg of pyridine. The mixture was stirred for 24 hours at room temperature and with exclusion of light. Then the other half of the reagent was added and the mixture stirred for further 24 hours. The solution was poured on to a mixture of ice and sodium carbonate and worked up in a conventional manner. The crude product so obtained (3.18 g) was distilled under high vacuum and yielded 2.70 g (87%) of pure 6-formyloxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.005 50°; IR(film):νmax = 3120, 1728, 1645, 1460/45, 1190/82, 1015/1000, 905/900 cm-1. The compound smells woody, cedar-like, slightly ionone-like.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C@@H:10]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[CH3:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C@H:11]1[CH2:12][CH2:13][CH2:14][NH2+:9][C@H:10]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(CO[C@H]2CCC[NH2+][C@H]2c2ccccc2)c1C
Reaction time: 2 h

Procedure:
Ethyl acetate (10 ml) was saturated with hydrogen chloride by passing HCl gas for 5 min and a solution of 0.254 g of (2S,3S )-1-t-butoxycarbonyl-3-((2,3-dimethylphenyl)methoxy)-2-phenylpiperidine (prepared according to Description 3d) in 7 ml of ethyl acetate was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residual white solid was washed with ether, filtered and dried to obtain 0.23 g of (2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenylpiperidinium hydrochloride. 1H NMR (DMSO-d6) δ 1.6-1.9 (3H, m), 1.75 (3H, s), 2.15 (3H, s), 2.2 (1H, m), 3.05 (1H, m), 3.25 (1H, m), 3.84 (1H, s), 4.05 (1H, d, J=14 Hz), 4.45 (1H, d, J=14 Hz), 4.48 (1H, s), 6.95-7.5 ( 8H, m), 8.8 (1H, br s), 9.4 (1H, br s).
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([CH:45]=2)[C:43]#[N:44])O1>>[C:43]([C:42]1[CH:45]=[C:38]([C:2]2[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:23]=2)[CH:39]=[N:40][CH:41]=1)#[N:44]
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(C(F)(F)C(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 208.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.08 min, m/z=504.4 [M+H]+, m/z=502.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.80-1.92 (m, 1H) 2.86 (d, J=11.25 Hz, 1H) 3.16-3.28 (m, 2H) 3.39 (m, J=9.29 Hz, 1H) 4.21 (br. s, 1H) 4.89 (d, J=3.18 Hz, 1H) 7.67 (d, J=8.80 Hz, 2H) 8.01 (d, J=8.56 Hz, 2H) 8.11 (d, J=2.20 Hz, 1H) 8.38-8.43 (m, 1H) 8.81 (d, J=2.20 Hz, 1H) 8.91 (d, J=1.96 Hz, 1H) 9.03 (d, J=1.96 Hz, 1H) 10.34 (s, 1H).
Reaction SMILES: C1C=CC=CC=1.[F:7][C:8]1[CH:23]=[CH:22][C:11]2[O:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=O)[CH2:16][C:10]=2[CH:9]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:7][C:8]1[CH:23]=[CH:22][C:11]2[O:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[CH:16][C:10]=2[CH:9]=1
Reactant: O=C1Cc2cc(F)ccc2Oc2ccccc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CN1CCN(C2=Cc3cc(F)ccc3Oc3ccccc32)CC1
Reaction time: 4 h

Procedure:
A solution of 6.44 g. of titanium (IV) chloride in 25 ml. of benzene is added dropwise over a period of 15 minutes with cooling to a solution of 9.12 g. of 2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-one and 18 g. of 1-methyl-piperazine in 100 ml. of benzene in such a manner that the temperature does not exceed 25° C. The mixture is subsequently stirred for 4 hours at reflux. The resulting mixture is cooled and poured into a solution of 10 g. of sodium bicarbonate in 100 ml. of water. The precipitated titanium dioxide is removed by filtration and washed carefully with benzene and chloroform. The benzene solution and the chloroform solution are washed four times with water, combined, dried over sodium sulfate, evaporated in vacuo, and there is obtained crude, crystalline 1-[2-fluoro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[CH3:37][O:38][C:39]1[C:44](B(O)O)=[CH:43][CH:42]=[CH:41][N:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:22][CH:23]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:44]4[C:39]([O:38][CH3:37])=[N:40][CH:41]=[CH:42][CH:43]=4)=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ncccc1B(O)O
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)cc3c2C)C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(-c4cccnc4OC)cc3c2C)C2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 89.8 %

Procedure:
To a solution (15 mL) of ethyl 3-{[(4-{[(5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (0.53 g) synthesized in Example A174(3) in N,N-dimethylacetamide were added (2-methoxypyridin-3-yl)boronic acid (0.29 g), potassium carbonate (0.27 g) and tetrakistriphenylphosphine palladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give ethyl 3-[{[4-({cyclohexyl[5-(2-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.50 g, 89%) as a pale-yellow oil. The obtained oil was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.47 g, quantitative) as a colorless solid.