Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH:23][C@@H:24]([CH2:35][CH2:36][C:37]2[NH:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:41]=2)[C:25](OCC2C=CC=CC=2)=[O:26])=[CH:14]1.C(N(CC)CC)C>C1COCC1>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]2[C@@H:24]([CH2:35][CH2:36][C:37]3[NH:38][CH:39]=[C:40]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:41]=3)[C:25](=[O:26])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:11]2=[S:12])=[CH:14]1
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1[C@H](CCc2nc(-c3ccccc3)c[nH]2)N(Cc2c[nH]c3ccccc23)C(=S)N1c1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3ylmethyl)amino]-4(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[C:22]([C:24]1[CH:25]=[C:26]([CH2:40][CH:41]=[CH:42]O)[C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:28][CH:29]=1)#[N:23]>CC#N>[C:22]([C:24]1[CH:25]=[C:26]([CH2:40][CH:41]=[CH:42][Br:20])[C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:28][CH:29]=1)#[N:23]
Reactant: COc1ccc(COc2ccc(C#N)cc2CC=CO)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc(COc2ccc(C#N)cc2CC=CBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a suspension of Ph3P (2.4 g) in 30 mL of MeCN at 0° C. was added bromine (1.5 g) and the mixture was stirred at 0° C. for 15 minutes and then warmed to ambient temperature. To the suspension of Br2PPh3 was then added 3-cyano-6-((4-methoxybenzyl)oxy)-1-(3-hydroxyprop-2-en-1-yl)benzene (2.3 g) in 20 mL MeCN drop-wise. The resulting solution was stirred at ambient temperature for 1 hour, cooled to ambient temperature and concentrated. The residue was purified on silica gel column (ethyl acetate/hexane, 1:9) to afford 3-cyano-6-((4-methoxybenzyl)oxy)-1-(3-bromoprop-2-en-1-yl)benzene (0.81 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[N:12]O)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H]>O1CCCC1.CO.[Ni]>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH2:12])[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=NO)CO2
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c1C(N)CO2
Yield: 96.5 %

Procedure:
A mixture of the above described 4-methoxy-benzofuran-3-one oxime (27.7 g, 155 mmol; HPLC 1.448 min) and Raney-Nickel (13.85 g) in tetrahydrofuran (700 mL) and methanol (700 mL) was hydrogenated at 100 bar hydrogen-pressure at 100° C. for 22 h. Filtered the catalyst off, washed with methanol and tetrahydrofuran, all volatiles very removed in vacuum to give the title compound as a brown oil (24.7 g, 98%, HPLC 0.4 min), MS (ISP) m/e=166.2 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:6][CH:5]=1
Reactant: O=C1OCCN1CCn1ncc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2cnn(CCN3CCOC3=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
A mixture of 3-[2-(6-Nitro-indazol-1-yl)-ethyl]-oxazolidin-2-one (200 mg, 0.72 mmol), iron powder (400 mg, 7.1 mmol), and ammonium chloride (20 mg, 0.37 mmol) in a 4:1 ethanol/H2O solution (5 mL) was heated to reflux for 3 hours, cooled to room temperature, concentrated under reduced pressure. The resudue was stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (120 mg, 67%). 1H NMR (300 MHz, DMSO-d6) ppm 4.03 (s, 3H), 4.42 (d, J=6.10, 1H), 6.04 (m, 1H), 7.25 (m, 1H), 7.32 (m, 1H), 7.38 (m, 1H), 7.48 (m, 2H), 7.69 (m, 1H), 7.79 (m, 1H), 8.44 (m, 1H), 9.12 (s, 1H); MS (DCI/NH3) m/z 247 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]([O:12][CH3:13])[O:10][CH3:11])=[C:4]([CH3:14])[N:3]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].O>O1CCCC1>[CH3:11][O:10][CH:9]([O:12][CH3:13])[C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH:22]=[O:23])=[N:3][C:4]=1[CH3:14]
Reactant: CN(C)C=O
Reactant: COC(OC)c1cc(C)c(Br)nc1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)c1cc(C)c(C=O)nc1C
Reaction time: 0.67 h
Yield: 35.4 %

Procedure:
To a solution of 2-bromo-5-dimethoxymethyl-3,6-dimethylpyridine (382 mg, 1.47 mmol) in tetrahydrofuran (6 mL) were added n-butyllithium (1.6 mol/L; 1,4 mL, 2.2 mmol) and dimethylformamide (0.23 mL, 3.0 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 40 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (6:1 hexane/ethyl acetate) to afford 5-dimethoxymetyl-3,6-dimethyl-2-pyridinecarboxaldehyde (109 mg, 35%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C@H:26]([C:52]([O:54]C)=[O:53])[CH2:27][C:28]1[N:32]=[CH:31][N:30]([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=1.Cl.[NH:57]1[C:61](=[O:62])[CH2:60][CH2:59][C@H:58]1[C:63](O)=[O:64].CCN(C(C)C)C(C)C>CN(C=O)C>[NH:57]1[C:61](=[O:62])[CH2:60][CH2:59][C@H:58]1[C:63]([NH:25][C@H:26]([C:52]([OH:54])=[O:53])[CH2:27][C:28]1[N:32]=[CH:31][N:30]([C:33]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=1)=[O:64]
Reactant: COC(=O)[C@@H](N)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)O)N1
Yield: 99.3 %

Procedure:
According to the general procedure for HBTU promoted coupling, 4.7 g (10.5 mmol) H-His(Trt)-OMe.HCl, 4.54 g (10.8 mmol) HBTU, 2.69 g (10.5 mmol) Pyr-OH and 8.3 ml (26.3 mmol) DIPEA were reacted in a CYTOS® Lab System in anhydrous DMF at total flow of 26.7 ml/min and a residence time of 1.2 min to yield 5.3 g of crude Pyr-His(Trt)-OH which was used in the next step without purification. Yield based on HPLC: 81%.
Reaction SMILES: C([O:3][C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]=[CH2:12])[C:6](=O)[CH:5]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:10]([CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH:5]=[CH:6]1)[CH:11]=[CH2:12]
Reactant: C=CCC1CCC(OCC)=CC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCC1C=CC(=O)CC1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of (+)-3-ethoxy-6-(2-propenyl)-2-cyclohexen-1-one (300 mg, 1.7 mmol) in dry ether was added to a solution of LAH (30 mg, 0.8 mmol) in dry ether at 0° C. and the mixture was stirred for 1 hour. The reaction was quenched with 2M HCl and stirred for 30 minutes and then extracted with ether. The ethereal extracts were washed with saturated NaHCO3, dried over anhydrous MgSO4 and the solvent was removed under vacuum. The yellow liquid obtained was purified using 20% ethyl acetate/hexane mixture to get the final product as a pale yellow liquid (0.15 g, 65%). Rf (20% ethyl acetate/hexane) 0.56. 1H NMR (300 MHz, CDCl3): ∂ 1.68-1.78 (m, 1H), 2.10-2.18 (m, 1H), 2.2-2.3 (m, 2H), 2.34-2.42 (m, 1H), 2.48-2.56 (m, 2H), 5.1 (d, J=12.5 Hz, 2H), 5.76-5.86 (m, 1H), 6.0 (dd, J=2.4, 10.2 Hz, 1H), 6.9 (d, J=10.2 Hz, 1H). (ESI, Pos) m/z 159.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][N:10](C(OCC1C=CC=CC=1)=O)[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[C:1]([O:5][C:6]([C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C12CCC1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C12CCC1CNC2
Yield: 121.2 %

Procedure:
To a solution of 360 mg (1.02 mmol) of 1-tert-butoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in methanol (20 ml) was added 400 mg of 20% palladium hydroxide-carbon, followed by vigorous stirring in an atmosphere of hydrogen gas. After removing insoluble material by filtration through celite, the resulting filtrate was concentrated to give 243.8 mg of the title compound as a crude product.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH2:41][C:42]23[C:48]([F:50])([F:49])[CH:47]2[CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH2:41][C:42]34[C:48]([F:50])([F:49])[CH:47]3[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3(F)F)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-4-(((1RS,6SR)-7,7- difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoate (stereochemistry arbitrarily assigned), the title compound was obtained as a yellow oil (0.23 g, 81%): MS (ES+) m/z 341.0 (M−55).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[CH2:9]([C:11]1[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=1[NH:19][C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])=[S:21])[CH3:10]>ClCCl>[CH3:27][C:23]([N:22]1[C:2](=[O:8])[C:3](=[O:5])[N:19]([C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[CH2:9][CH3:10])[C:20]1=[S:21])([CH3:26])[CH2:24][CH3:25]
Reactant: CCc1cc(C#N)ccc1NC(=S)NC(C)(C)CC
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CCc1cc(C#N)ccc1N1C(=O)C(=O)N(C(C)(C)CC)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Ethyl chlorooxoacetate (0.82 mL, 7.3 mmol) was added dropwise to a stirring solution of 1-(2-ethyl-4-cyanophenyl)-3-(1,1-dimethyl-propyl)-thiourea (1.0 g, 3.65 mmol) in dichloromethane (30 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated to afford a residue which was triturated with diethyl ether and hexanes to afford 0.71 g (59%) of 4-[3-(1,1-dimethyl-propyl)-4,5-dioxo-2-thioxo-imidazolidin-1-yl]-3-ethyl-benzonitrile as a yellow solid: mp 172.8–173.3° C.; 1H NMR (DMSO-d6): δ 7.92 (s, 1H), 7.80 (d, 1H), 7.52 (d, 1H), 2.50 (m, 2H), 2.19 (m, 2H), 1.76 (2s, 6H), 1.08 (t, 3H), 0.85 (t, 3H); IR (KBr) 3400, 2950, 2260, 1775 cm−1; MS (m/z) 329 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]2[C:12](=[O:13])[CH:11]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1csc(N)n1
Product: Cc1csc2nc(CCl)cc(=O)n12
Yield: 85.3 %

Procedure:
This compound was synthesized from 2-amino-4-methyl thiazole (5.0 g, 43.710 mmol) and ethyl chloroacetoacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 8.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.67 (s, 3H), 4.53 (s, 2H), 6.27 (s, 1H), 7.05 (s, 1H); ESI-MS (m/z) 215.39 (M+H)+.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[C:5]1([O:12][CH3:13])[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7].[OH-].[Na+]>O.O1CCOCC1>[F:3][CH:2]([F:4])[O:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[O:12][CH3:13]
Reactant: COc1ccccc1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1OC(F)F
Yield: 71.9 %

Procedure:
About 58 g of chlorodifluoromethane are passed into a solution of 55.5 g of guaiacol and 130 g of sodium hydroxide in 300 ml of water and 300 ml of dioxane at 60° C. The mixture is filtered at 10° C. and the organic layer is separated off, dried with anhydrous potassium carbonate and distilled. 56 g (73%) of 1-difluoromethoxy-2-methoxybenzene of boiling point 75°-76° C./0.9 kPa are obtained.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([F:9])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br>>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:7]1[C:6](=[O:8])[C:5]([F:9])=[CH:4][N:3]=[C:2]1[Cl:1]
Reactant: O=c1[nH]c(Cl)ncc1F
Reactant: BrCc1ccccc1Br
Product: O=c1c(F)cnc(Cl)n1Cc1ccccc1Br
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield from 2-chloro-5-fluoro-3H-pyrimidin-4-one and 2-bromobenzyl bromide according to the procedure for Example 1B. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 1H, J=1.2 Hz), 7.62 (dd, 1H, J=7.6, 1.2 Hz), 7.17-7.30 (m, 2H), 6.78 (d, 1H, J=7.6 Hz), 5.52 (s, 2H). MS (ES) [m+H] calc'd for C11H7N2OFClBr, 317, 319; found 317, 319.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:18][N:19]3[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]4[CH2:30][CH2:29]4)[C:20]3=[O:31])[N:10]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2=[CH:4][CH:3]=1>[Pd]>[CH:28]1([N:21]2[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:19]([CH2:18][C:9]3[N:10]([CH2:11][CH2:12][CH2:13][C:14]([F:15])([F:17])[F:16])[C:5]4[C:6]([N:8]=3)=[N:7][CH:2]=[CH:3][CH:4]=4)[C:20]2=[O:31])[CH2:30][CH2:29]1
Reactant: O=c1n(Cc2nc3nc(Cl)ccc3n2CCCC(F)(F)F)c2cnccc2n1C1CC1
Agent: [Pd]
Product: O=c1n(Cc2nc3ncccc3n2CCCC(F)(F)F)c2cnccc2n1C1CC1

Procedure:
Compound 41 was prepared by Pd catalysed reduction of compound 39.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)C.[Cl:24][C:25]1[CH:26]=[C:27]([C@H:32]2[C@@H:38]([CH:39]=O)[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].C[Si](C=[N+]=[N-])(C)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:24][C:25]1[CH:26]=[C:27]([C@H:32]2[C@@H:38]([CH:39]=[CH2:1])[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [Rh]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=C[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of chlorotris(triphenylphosphine)rhodium (I) (0.12 g) and triphenylphosphine (1.5 g) in tetrahydrofuran (5 ml) was added 2-propanol (0.44 ml), and tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-formyl-1,4-oxazepane-4-carboxylate (2.0 g) was added. To the reaction mixture was added trimethylsilyldiazomethane (2 M diethyl ether solution, 5.2 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.1 g).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OCC)=[NH:19])[CH3:9].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:8]([O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:19])=[N:33][NH:32][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:9]
Reactant: NNC(=O)c1ccccc1
Reactant: CCOC(=N)CCCCCCC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCCCCC(N)=NNC(=O)c1ccccc1
Reaction time: 12 h
Yield: 65 %

Procedure:
Add triethylamine (5.6 mL, 40 mmol) to a solution of 7-ethoxycarbonimidoylheptanoic acid ethyl ester (11.0 g, 41 mmol) and benzoic acid hydrazide (5.5 g, 40 mmol) in ethanol (110 mL) at room temperature under nitrogen and stir the mixture for 12 hours. Remove the solvent under reduced pressure, dissolve the residue in ethyl acetate (200 mL), wash with saturated NaHCO3 (200 mL) and brine (200 mL) solutions, and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 8-amino-8-(benzoylhydrazono)octanoic acid ethyl ester (8.3 g, 64%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH:31]=[CH:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:30]=4)=[O:2])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(C=Cc2ccccc2)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C=Cc4ccccc4)cc3)(CC1)CC2
Yield: 27.5 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminostilbene (66.4 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-styrylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (21.3 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:11])=[CH:8][C:7]=1[O:24][CH3:25]>>[OH:5][C:6]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)=[O:11])=[CH:8][C:7]=1[O:24][CH3:25]
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)ccc1O
Reactant: O=[N+]([O-])O
Product: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3.2 ml of 65 percent nitric acid are added dropwise within 10 minutes at 20° to 12.8 g of 4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone (dissolved in 160 ml of acetic acid). After stirring for 1.5 hours, the reaction mixture is poured into 600 ml of ice-water, and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzophenone of melting point 172°.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH3:10])[O:7][C:6]=1[CH3:11])(OC)=[O:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:11][C:6]1[O:7][C:8]([CH3:10])=[CH:9][C:5]=1[CH2:1][OH:2]
Reactant: COC(=O)c1cc(C)oc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(CO)c(C)o1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a stirred solution of 3-carbomethoxy-2,5-dimethylfuran (2.5 g, 16.2 mmol) in methylene chloride (distilled from CaH) at -20° C., under N2, was added 2.5 eq of DIBAL (1M in CH2Cl2). After 1 h, the dry ice/acetonitrile bath was removed and 60 mL of 10% HCl was added dropwise. The organic layer was separated, dried over MgSO4, and evaporated. The residue was chromatographed (silica gel, 60% ether/hexane) to yield 1.3 g of 2,5-dimethyl-3- hydroxymethylfuran.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(-c3cccc(S(C)(=O)=O)c3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 3-methylsulfonylphenylboronic acid.
Reaction SMILES: [OH:1][C:2]1[C:17]([CH2:18][CH:19]([CH3:33])[CH2:20][Si:21]([CH3:32])([O:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].C1CCCCC=1>[Pd].C(O)C>[OH:1][C:2]1[C:17]([CH2:18][CH:19]([CH3:33])[CH2:20][Si:21]([CH3:32])([O:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(Cc1cccc(C(=O)OCc2ccccc2)c1O)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(Cc1cccc(C(=O)O)c1O)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Yield: 78.6 %

Procedure:
A mixture of the above crude oil of benzyl 2-hydroxy-3-[2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyl]benzoate (11.61 g, 0.023 mol), ethanol (40 ml), cyclohexene (12 ml) and 10% palladium-on-charcoal (1.2 g) was maintained at reflux for 1 hour. The mixture was cooled and rinsed with ethanol. The liquids were concentrated and the pale yellow oil obtained was purified by chromatography on silica under pressure (eluent: 80/20/0.2 CH2Cl2 /ethyl acetate/acetic acid) to give 7.5 g (yield: 78%) of 2-hydroxy-3-[2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]-propyl]benzoic acid in the form of a colourless oil.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([C:14]([N:19]1[C:23](=[O:24])[CH:22]=[C:21]([NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[CH2:33][OH:34])[C:20]1=[O:35])([CH3:18])[CH:15]([CH3:17])[CH3:16])#[N:13]>C(Cl)Cl.CCOCC>[C:12]([C:14]([N:19]1[C:23](=[O:24])[CH:22]=[C:21]([NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[CH:33]=[O:34])[C:20]1=[O:35])([CH3:18])[CH:15]([CH3:16])[CH3:17])#[N:13]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2cc(Cl)ccc2CO)C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2cc(Cl)ccc2C=O)C1=O
Yield: 91.7 %

Procedure:
Pyridinium chlorochromate (4.4 g, 0.0204 mol) in methylene dichloride (20 ml) is added rapidly to a methylene chloride (20 ml) solution of N-(1-cyano-1,2-dimethylpropyl)-2-(5-chloro-2-hydroxymethylanilino)maleimide (4.75 g, 0.0136 mol). After 2 hours the dark reaction mixture is diluted with ether (20 ml) and a yellow precipitate is formed and is filtered off. This solid is redissolved in ethyl acetate:methylene chloride (1:1) and is passed through a silica gel column to give a yellow solid 4.31 g, (92%) with mp 80° C. (dec.).