Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C@H:17]1([C:26]([OH:28])=O)[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:26]([C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:25])[CH2:21][CH2:22]1)=[O:28])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)CC1

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) trans-cyclohexane-1,4-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.67 g (76%) of the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].[Br-]>>[CH2:19]([O:18][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1cc(-c2ccccc2)c(OCC(=O)OC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [K+]
Product: CCCCOc1cc(-c2ccccc2)c(OCC(=O)O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared as an off white solid (0.167 g, 85%) from (5′-butoxy-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp 92–94° C.; 1H NMR (DMSO-d6) δ 0.92 (t, J=7.5 Hz, 3H), 1.38–1.49 (m, 2H), 1.65–1.74 (m, 2H), 3.64 (s, 2H), 4.02 (t, J=6.6 Hz, 2H), 6.87 (s, 2H), 7.33–7.39 (m, 2H), 7.39–7.44 (m, 4H), 7.57–7.61 (m, 4H), 12.30–12.55 (bs, 1H); IR (KBr) 3420, 3060, 2930, 2860, 2770, 2590, 1725, 1590, 1570, 1460, 1420, 1360, 1260, 1235, 1215, 1195, 1075, 1050, 1010, 925, 760, 750, 700, and 620 cm−1; mass spectrum [(+) ESI], m/z 394 (M+NH4)+; Anal. Calcd. for C24H24O4: C, 76.57; H, 6.43; N, 0.00. Found: C, 76.33; H, 6.55; N, −0.04.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[CH3:28]B1OB(C)OB(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([CH3:28])[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)[C@H]1CCCN(C(=O)C(F)(F)F)[C@H]1C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (17 mg) is added to a flask charged with a stir bar, trifluoromethanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (200 mg), trimethylboroxine (81 μL), K3PO4 (0.15 g), and 1,4-dioxane (4 mL) under argon atmosphere at room temperature. The reaction mixture is heated to 100° C. and stirred at this temperature overnight. Another portion of trimethylboroxine (40 μL) and tetrakis(triphenylphosphine)palladium(0) (17 mg) is then added and stirring is continued at 100° C. The addition of further amounts of trimethylboroxine and tetrakis(triphenylphosphine)palladium(0) is repeated after each 6 h of stirring until the starting material is completely consumed. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na2SO4) and concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol 1:0→9:1) to give the title compound. Yield: 50 mg (37% of theory); LC (method 1): tR=4.62 min; Mass spectrum (ESI+): m/z=284 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH2:14][Cl:15])=[O:12].[CH3:16][C:17]1[C@@H:34]([O:35][C:36]([C@H:38]([OH:55])[C@@H:39]([NH:46][C:47]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:48])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:33][C@:29]2([OH:56])[C:30]([CH3:32])([CH3:31])[C:18]=1[C@@H:19]([O:74][C:75]([CH3:77])=[O:76])[C:20]([C@@:22]1([CH3:73])[C@H:27]([C@@H:28]2[O:57][C:58]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)=[O:59])[C@:26]2([O:68][C:69]([CH3:71])=[O:70])[CH2:66][O:67][C@@H:25]2[CH2:24][C@@H:23]1[OH:72])=[O:21]>ClCCl>[C:75]([O:74][C@@H:19]1[C:18]2[C:30]([CH3:31])([CH3:32])[C@@:29]([OH:56])([CH2:33][C@H:34]([O:35][C:36](=[O:37])[C@H:38]([O:55][C:11]([O:13][CH2:14][Cl:15])=[O:12])[C@@H:39]([NH:46][C:47](=[O:48])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:17]=2[CH3:16])[C@@H:28]([O:57][C:58](=[O:59])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:27]2[C@:26]3([O:68][C:69](=[O:70])[CH3:71])[CH2:66][O:67][C@@H:25]3[CH2:24][C@H:23]([OH:72])[C@@:22]2([CH3:73])[C:20]1=[O:21])(=[O:76])[CH3:77]
Reactant: O=C(Cl)OCCl
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)OCCl)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.7 %

Procedure:
DIPEA (0.026 g, 46.0 mmol, 4.0 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8] (0.04 g, 23.0 mmol, 4.0 eq) in dry dichloromethane under an argon atmosphere at 0° C. To the above reaction mixture at 0° C., a solution of paclitaxel 14114 (0.10 g, 11.7 mmol, 1.0 eq) in dry dichloromethane (y ml) was added. The reaction mixture was stirred at room temperature for 16 h. reaction progress was monitored by TLC. After 16 h the reaction mixture was diluted with dichloromethane (25 ml), washed with a 10% solution of NaHCO3 (15 ml), brine (10 ml), and then dried over anhydrous Na2SO4. Evaporation of the solvents under vacuum gave a white solid, (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate [315], (0.08 g, 70%)
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]2([OH:24])[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(#N)C>[Pt].C(O)(C)C>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][C:17]1([OH:24])[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CN1CCC(O)(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)CC1
Agent: [Pt]
Solvent: CC(C)O
Solvent: CC#N
Product: CN1CCC(O)(CNc2c(N)c(Cl)nc3ccccc23)CC1

Procedure:
A mixture of 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}-1-methylpiperidin-4-ol (14.05 g), 5% platinum on carbon (1.1 g), acetonitrile (280 mL), and isopropanol (84 mL) was placed under hydrogen pressure on a Parr apparatus overnight. The reaction mixture was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to provide crude 4-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}-1-methylpiperidin-4-ol. This material was dissolved in 240 mL of acetonitrile.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CN(C(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-trifluoromethylphenylboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (42%, light brown crystals).
Reaction SMILES: [C:1](=[O:17])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1([CH3:6])[CH2:5][CH2:4]1.[F:18][C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[O:35][C:32]2=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:6][C:3]1([O:2][C:1]([N:41]2[CH2:42][CH2:43][CH:38]([C:36]3[O:35][C:32]4=[CH:33][N:34]=[C:29]([C:20]5[CH:21]=[CH:22][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:24][C:19]=5[F:18])[CH:30]=[C:31]4[CH:37]=3)[CH2:39][CH2:40]2)=[O:17])[CH2:4][CH2:5]1
Reactant: CC1(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(OC(=O)N2CCC(c3cc4cc(-c5ccc(S(C)(=O)=O)cc5F)ncc4o3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Methyl-cyclopropyl 4-nitrophenyl carbonate (48 mg) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (75 mg) and N,N-diisopropyl-ethylamine (32 μL) in tetrahydrofuran (1 mL) at room temperature. The mixture is stirred at room temperature overnight. The solution is concentrated and the residue is taken up in ethyl acetate. The resulting mixture is washed with 1 M aqueous NaOH solution (3×), water, and brine. The organic phase is dried (Na2SO4) and concentrated. The residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: [N+](=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[O:5][CH2:4]1)=[N-].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][CH:3]([O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[C:12]2=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=C1COc2ccc(OCc3ccccc3)cc2C1=O
Reactant: COc1ccc(O)cc1
Agent: [Rh]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)cc1
Temperature: 25 °C
Yield: 5.4 %

Procedure:
A solution of 76 g of 3-diazo-6-benzyloxy-4-chromanone and 76 g of p-methoxyphenol in 450 ml of toluene was heated to 110° C. in an oil bath. Rhodium (II) acetate dimer (225 mg) was added in one portion. After nitrogen evolution ceased (5 minutes), the reaction was allowed to cool to room temperature, diluted with ethyl acetate and washed with 10% sodium hydroxide to remove excess phenol. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by column chromatography on silica gel eluting with dichloromethane to give 5.5 g of present title product; mp 98°-100° C.; 1H-NMR (CDCl3) delta (ppm) 3.85(s, 3H), 4.45-4.65 (m, 2H), 5.0-5.2 (m, 3H), 6.5-7.6 (m, 12H)
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14](/[CH:19]=[CH:20]/[C:21]2[N:26]=[N:25][C:24]3O[C:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=4[O:30][C:23]=3[CH:22]=2)[CH:15]=[C:16]([F:18])[CH:17]=1.O.O1CCC[CH2:37]1>>[CH2:1]([O:8][C:24]1[N:25]=[N:26][C:21](/[CH:20]=[CH:19]/[C:14]2[CH:15]=[C:16]([F:18])[CH:17]=[C:12]([F:11])[CH:13]=2)=[CH:22][C:23]=1[O:30][CH2:29][C:31]1[CH:32]=[CH:33][CH:34]=[CH:28][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(F)cc(/C=C/c2cc3c(nn2)Oc2ccccc2O3)c1
Reactant: C1CCOC1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Fc1cc(F)cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Reaction time: 0.17 h

Procedure:
Under ice-cooling, to a solution (20 mL) of benzyl alcohol (580 mg) in tetrahydrofuran was added 60% sodium hydride (220 mg), and the mixture was stirred for 10 min. To the mixture was added a solution (10 mL) of 3-[(E)-2-(3,5-difluorophenyl)vinyl][1,4]benzodioxino[2,3-c]pyridazine (700 mg) in tetrahydrofuran, and the mixture was stirred at 60° C. for 4 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3,4-bis(benzyloxy)-6-[(E)-2-(3,5-difluorophenyl)vinyl]pyridazine (710 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN(C(O[N:18]1[N:26]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([N:54]2[CH2:59][CH2:58][CH:57]([NH:60][C:61]([C:63]3[NH:64][C:65]([CH3:70])=[C:66]([Cl:69])[C:67]=3[Cl:68])=[O:62])[CH2:56][CH2:55]2)[N:53]=1)[C:48]([OH:50])=O.NN>CN(C=O)C>[Cl:68][C:67]1[C:66]([Cl:69])=[C:65]([CH3:70])[NH:64][C:63]=1[C:61]([NH:60][CH:57]1[CH2:56][CH2:55][N:54]([C:52]2[CH:51]=[C:47]([C:48]([NH:18][NH2:26])=[O:50])[CH:46]=[C:45]([Cl:44])[N:53]=2)[CH2:59][CH2:58]1)=[O:62]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NN)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.1 %

Procedure:
Diisopropylethylamine (0.043 ml, 0.25 mmol), HATU (0.048 g, 0.12 mmol) and HOAT (0.017 g 0.12 mmol) were added to a stirred solution of 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinic acid (Example 153; 0.055 g, 0.12 mmol) in DMF (2 ml). The resultant solution was stirred for 5 mins and hydrazine (0.04 ml, 0.12 mmol) was added. The mixture was stirred at room temperature for 14 h, partitioned between water and EtOAc. The layers were separated and the organic layer was washed with water two more times. The organic phase was dried over magnesium sulfate and concentrated to give the title compound (30 mg).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:19]2)C=CC=CC=1.O>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH:20]2[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:21]2)=[CH:24][CH:25]=1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reaction time: 18 h

Procedure:
A solution of 52.09 g (0.527 mole) of phosgene in 500 ml of methylene chloride was stirred with 73 g (0.53 mole) of potassium carbonate under nitrogen atmosphere for 30 min, then treated with 146.3 g (0.439 mole) of 1-diphenylmethyl-3-(4-fluorophenoxy)azetidine in 300 ml of methylene chloride added dropwise. After stirring for 18 hr, the reaction mixture was treated with 200 ml of water added slowly. The aqueous phase was separated and the organic solution dried by filtration through Whatman phase separating filter paper then concentrated in vacuo to a pale amber oil. Trituration of the oil with 30/60 petroleum ether yielded a crude tacky solid, 89.3 g (88.6%). A portion of this solid was recrystallized from 30/60 petroleum ether yielding a fine white crystalline product, m.p. 44°-52° C. A second recrystallization from isopropyl ether yielded fine white crystals, m.p. 57°-58.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:10])=[O:9].[CH:32]1([NH:35][C:36](=[O:45])[C:37](=[O:44])[C@@H:38]([NH2:43])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]1>>[Cl:28][C:24]1[CH:25]=[C:26]([F:27])[C:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]3[C:29]([NH:43][C@@H:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:37](=[O:44])[C:36]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:45])=[O:31])=[O:17])[CH2:19][CH2:20]2)=[N:22][CH:23]=1
Reactant: CC(C)C[C@H](N)C(=O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-5-methyl-2-oxo-hexanoic acid cyclopropylamide in step 1. MS (m/e)=667.15 [M+H+].
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([F:21])([F:20])[CH2:9][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=1)(=O)=O.[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C(O)(=O)C>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:28]2[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=2)[C:8]([F:21])([F:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=S(=O)(OC1=CCN(Cc2ccccc2)CC1(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(C2=CCN(Cc3ccccc3)CC2(F)F)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a mixture of 1-benzyl-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.13 g), 4-hydroxyphenylboronic acid (0.43 g) and sodium carbonate (1.01 g) in DMF (10 mL) was added dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) (73 mg) under nitrogen atmosphere. The reaction mixture was stirred at 90° C. for 3 hr. The reaction mixture was added to water, and the mixture was adjusted to pH=5 with acetic acid, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (725 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].O>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: Brc1ccccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A flask was charged with 2-bromopyridine (1.21 mL, 12.66 mmol) and triethylamine (40 mL) and sparged with nitrogen for 15 min. To this was added ethynyltrimethylsilane (1.97 mL, 13.92 mmol) and the reaction was purged 15 min longer. To this was added copper(I) iodide (0.121 g, 0.633 mmol), and Pd(PPh3)2Cl2 (0.444 g, 0.633 mmol). Reaction stirred at room temperature for 72 h. The reaction was diluted with ethyl acetate (60 mL) and poured into water. The black heterogeneous emulsion was filtered through a plug of celite and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%-->15% EtOAc/Hex) gave 1.73 g (78%) as a dark oil. 1H-NMR (CDCl3, 500 MHz) δ 8.58 (m, 1H), 7.66 (ddd, J=7.9, 7.9, 1.8, 1H), 7.47 (m, 1H), 7.24 (ddd, J=7.6, 4.9, 1.2, 1H), 0.29 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 150.1, 143.2, 136.1, 127.4, 123.1, 103.8, 94.9, −0.2. Mass spec.: 176.14 (MH)+.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[Br:24][C:25]1[CH:37]=[CH:36][C:28]([CH:29]=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C@H:29]2[C@H:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]2([CH3:4])[CH3:3])=[CH:36][CH:37]=1
Reactant: CCOC(=O)C=Cc1ccc(Br)cc1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CCOC(=O)[C@H]1[C@H](c2ccc(Br)cc2)C1(C)C
Yield: 54 %

Procedure:
Isopropyltriphenylphosphonium iodide (8.65 g, 20.0 mmol) and ethyl 4-bromo-cinnamate (5.10 g, 20.0 mmol) were reacted as described under General Procedure B to furnish the title compound (3.21 g, 54%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 2.62 (d, J=5.5 Hz, 1H), 1.91 (d, J=5.5 Hz, 1H), 1.36 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 0.91 (s, 3H).
Reaction SMILES: [OH-:1].[Na+].Br[C:4]([CH3:32])([CH3:31])[C:5]([C:7]1[CH:30]=[CH:29][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[C:19]([CH3:27])([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH3:20])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)=[O:6]>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].ClCCl.O>[OH:1][C:4]([CH3:32])([CH3:31])[C:5]([C:7]1[CH:30]=[CH:29][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[C:19]([CH3:27])([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH3:20])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: [OH-]
Reactant: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1
Yield: 96.8 %

Procedure:
5.31 g (0.0664 mol) of 50% NaOH and 175 mg of 50% BTEAC were added to a solution of 17.5 g (0.0369 mol) of 1-{4-[4-(2-bromo-2-methyl-propionyl)-phenoxy]-phenyl}2-methyl-2-morpholin-4-yl-propan-1-one in 35 ml of dichloromethane. The reaction was refluxed for 3 hours, adding 175 mg of BTEAC every hour, then diluted with 20 ml of dichloromethane and 20 ml of water. The organic phase was separated, washed with brine, and dried with sodium sulphate, filtered and evaporated in vacuum obtaining 14.7 g of an oil.
Reaction SMILES: [O:1]=[C:2]1[N:15]([CH:16]2C[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH2:14][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[CH:12]=[CH:13][C:5]=2[CH2:4][C@H:3]1[NH:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1)=[O:31].FC(F)(F)C(O)=O>ClCCl>[O:48]=[C:39]1[N:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:30]([NH:29][C@H:3]3[C:2](=[O:1])[N:15]([CH:16]4[CH2:17][CH2:18][NH:19][CH2:20]4)[CH2:14][C:6]4[C:7]5[CH:8]=[N:9][NH:10][C:11]=5[CH:12]=[CH:13][C:5]=4[CH2:4]3)=[O:31])[CH2:33][CH2:34]2)[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(C2CCNC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
(R)-tert-butyl 4-(8-oxo-7-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-7,8-dihydroazepino[3,4-e]indazol-9(3H,6H, 10H)-yl)piperidine-1-carboxylate (45 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.25 mL) was added to the mixture. Reaction stirred at room temperature for 1.5 hour. Reaction mixture was concentrated in vacuo. C18 preparatory HPLC purification afforded the title compound as yellow solid in 52% yield. High resolution MS m/e (M+H)+=543.2830.