Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[N:25]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[N:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=3)=[O:22])=[C:16]([CH3:40])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41]>CO>[ClH:41].[ClH:41].[C:29]([C:27]1[CH:28]=[C:24]([NH:23][C:21]([NH:20][C:17]2[C:16]([CH3:40])=[N:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=2)=[O:22])[N:25]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2C)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2C)cc1
Reaction time: 4 h

Procedure:
Treat a 22° C. solution of 4-{5-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-6-methyl-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (Preparation 49; 63.20 g, 115.4 mmol) in MeOH (600 mL) with HCl (4 N solution in dioxane, 300 mL, 1200 mmol). Stir the mixture for 4 hours then concentrate under reduced pressure (room temperature, ca. 10 torr, 3 days) to afford 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(2-methyl-6-piperazin-1-yl-pyridin-3-yl)-urea dihydrochloride as an off-white powder (62.2 g—contains ca. 45 mol % of dioxane. LCMS(ES+): m/z=448 [M+H].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1ccc(N)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 110 °C
Yield: 99 %

Procedure:
To 3.7 mL of 2-fluoro-nitrobenzene are added 8.73 g of 4-methoxyaniline (2 equivalents). The whole is heated to 110° C. overnight. The medium is taken up in ethyl acetate, successively washed with water, a saturated solution of sodium bicarbonate and then with a saturated solution of sodium chloride. The organic phase is dried on magnesium sulfate, filtered and then concentrated under reduced pressure. With silica gel chromatography of the residue (petroleum ether/ethyl acetate: 90/10) 8.63 g of the desired product are isolated.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>N1C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=2[CH3:9])(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: Cc1occc(=O)c1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1occc(=O)c1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 58 %

Procedure:
3-Hydroxy-2-methyl-4H-pyran-4-one (0.5 g, 4.0 mmol) was reacted with 4-nitrobenzenesulfonyl chloride (0.88 g, 4.0 mmol) in 15 mL of pyridine to afford PZBG-2c in 58% yield (0.71 g, 2.3 mmol). 1H NMR (500 MHz, CDCl3) δ=8.42 (d, J=9.2 Hz, 2H), 8.31 (d, J=9.2 Hz, 2H), 7.69 (d, J=5.7 Hz, 1H), 6.34 (d, J=5.8 Hz, 1H), 2.53 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=171.8, 163.5, 154.6, 151.2, 142.3, 138.6, 130.4, 124.3, 117.6, 16.3. ESI-MS(+): m/z 312.06 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH2:11][CH:10]([CH2:13][O:14][CH3:15])[O:9]2)=[CH:4][CH:3]=1.[Br:16][CH:17]([CH2:21][Br:22])[C:18](Cl)=[O:19].[OH-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18](=[O:19])[CH:17]([Br:16])[CH2:21][Br:22])[NH:12][CH2:11][CH:10]([CH2:13][O:14][CH3:15])[O:9]2)=[CH:6][CH:7]=1
Reactant: COCC1CNC(c2ccc(Cl)cc2)O1
Reactant: O=C(Cl)C(Br)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COCC1CNC(C(=O)C(Br)CBr)(c2ccc(Cl)cc2)O1

Procedure:
To 20.8 milliliters of 25 percent w/v, p-chlorophenyl-5-methoxymethyl oxazolidine solution in 50 milliliters of benzene was added 5 grams of 2,3-dibromopropionyl chloride. To this solution was added 1.6 grams of 50% sodium hydroxide. After washing with water, drying and removal of the benzene in vacuo, there was obtained 4.8 grams of the title compound, nD30 1.5478. Analytical data supports the structure.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH:6]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4].Cl.[CH3:26][NH:27][O:28][CH3:29].C([Mg]Cl)(C)C>C1COCC1>[CH3:29][O:28][N:27]([CH3:26])[C:3]([C@H:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C@H:6]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4]
Reactant: COCOc1ccc(OCOC)c(C2CC(C)CC2C(=O)OC)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COCOc1ccc(OCOC)c([C@@H]2C[C@H](C)C[C@@H]2C(=O)N(C)OC)c1
Yield: 95.8 %

Procedure:
Cool a suspension of 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acid methyl ester (2.4 g, 7.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.4 g, 14.2 mmol) in anhydrous THF (60 mL) to −10° C. in an NaCl/ice bath. Add isopropyl magnesium chloride (2.0 M in THF, 14.2 mL, 28.4 mmol) and stir the reaction for 30 min. Quench the reaction with saturated ammonium chloride. Add EtOAc and wash with brine. Dry the organic solution (Na2SO4), filter and concentrate in vacuo to yield 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acid methoxy-methyl-amide 9a (2.5 g, 6.8 mmol, 96%) as a pale yellow oil. 1H NMR (δ, 400 MHz, CDCl3): 6.95 (d, 1H, J=8.8 Hz), 6.92 (d, 1H, J=3.0 Hz), 6.79 (dd, 1H, J=8.8, 3.0 Hz), 5.16-5.03 (m, 4H), 3.80 (m, 1H), 3.64 (m, 1H), 3.50 (s, 3H), 3.46 (s, 3H), 3.43 (s, 3H), 2.74 (s, 3H), 2.13-2.05 (m, 2H), 1.95-1.79 (m, 3H), 1.19 (d, 3H, J=6.2 Hz). HRMS calcd. 368.2073; found (electrospray, M+1) 368.2065.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]1>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH:13]=1
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na]
Solvent: CO
Product: O=C(O)C1CC=C(c2cc3ccccc3[nH]2)CC1
Yield: 28.8 %

Procedure:
To 50 mL of methanol is added sodium (3.32 g, 144.3 mmol). After the metal has dissolved indole (2.89 g, 24.6 mmol) and methyl 4-oxocyclohexanecarboxylate (5.0 g, 32.0 mmol) are added. The mixture is heated to reflux for 3 hours. The methanol is removed under reduced pressure and the residue partitioned between water and methylene chloride. The organic layer is discarded. The aqueous layer is acidified to pH 5 and extracted with three portions of methylene chloride. The combined organics are dried over sodium sulfate and evaporated to give 4-indolyl-3-cyclohexenecarboxylic acid (1.71 g). The material is hydrogenated in methanol (75 mL) under 50 psi of hydrogen int he presence of 5% palladium on carbon (0.5 g). After filtration and removal of solvent, the product is obtained as a mixture of diastereomers.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1>C(O)C>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:19][NH:18][C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:23])[F:22])=[CH:21][CH:20]=2)[CH3:2])=[CH:5][CH:6]=1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1ccncc1
Solvent: CCO
Product: CC(=NNC(=O)c1ccc(C(F)(F)F)cc1)c1ccncc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A mixture of 2.97 gm (0.0245 mole) of 4-acetylpyridine, 5.0 gm (0.0245 mole) of 4-trifluoromethylbenzhydrazide and 100 ml of absolute ethanol is refluxed for 6 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point, cooled to room temperature and chilled. The crystals which separate are collected, washed with water and dried to yield 6.29 gm (84%) of the title compound having a melting point of 198.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:20])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([O:34][C:35]([F:38])([F:37])[F:36])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:20])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=3[O:34][C:35]([F:36])([F:37])[F:38])(=[O:32])=[O:31])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C)cc1C1(O)C(=O)Nc2ncc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3cc(C)ccc3OC)c3cc(Cl)cnc32)c(OC(F)(F)F)c1
Yield: 26.1 %

Procedure:
With 1.18 g of the compound obtained in Step 118-5 and 1.24 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 565 mg of the title compound (brown gummy substance) was obtained by a similar method to Example 2.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:21][NH2:22]>CCO>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:21][NH2:22])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(F)cc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(F)cc2)CC1
Yield: 90.9 %

Procedure:
Synthesized according to General Procedure C: 51f (3.0 g, 10.7 mmol, 1.0 equiv.), anhydrous hydrazine (1.4 mL, 42.8 mmol, 4.0 equiv.), EtOH (20 mL, 0.5 M). 46f (2.59 g, 91.1%) was obtained as a white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.15 (br s, 1H), 7.22-7.19 (m, 2H), 6.95-6.91 (m, 2H), 3.84 (br s, 2H), 3.40 (s, 2H), 3.01 (s, 2H), 2.47 (br s, 4H), 2.39 (br s, 4H). 13C-NMR (125 MHz, CDCl3) δ 170.5, 162.0 (d, JC-F=243.6 Hz), 133.7 (d, JC-F=2.8 Hz), 130.6 (d, JC-F=8.3 Hz), 115.1 (d, JC-F=21.1 Hz), 62.0, 60.6, 53.7, 53.0. 19F-NMR (470 MHz, CDCl3) δ −118.9. HRMS (ESI): 267.1630 (M+1); calcd. for C13H20FN4O: 267.1621.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21][CH3:22])=[N:17][CH:18]=3)[N:13]([CH3:23])[C:12]2=[O:24])=[C:4]([CH3:25])[CH:3]=1.Cl>CCO.[Fe]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([CH3:25])=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21][CH3:22])=[N:17][CH:18]=3)[N:13]([CH3:23])[C:12]2=[O:24])[CH:6]=1
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc([N+](=O)[O-])c(F)cc1C)C2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(N)c(F)cc1C)C2
Temperature: 50 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (3 g, 8.26 mmol) was added to a solution of HCl (1.6 g, 16.5 mmol) in EtOH (50 ml) followed by iron power (4.6 g, 80 mmol), and the resulting mixture was stirred at 50° C. for 6 hours. The mixture was filtered and the filtrate was neutralized with saturated Na2CO3 solution to pH 8 and the mixture was extracted with EtOAc (3×150 mL). The combined extracts were washed with brine, dried Na2SO4) and evaporated to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.9 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1 H), 6.89 (d, J=12.4 Hz, 1H), 6.65 (d, J=8.8 Hz, 1 H), 5.01 (s, 2 H), 4.62 (d, J=14.8 Hz, 1 H), 4.44 (d, J=14.8 Hz, 1 H), 3.24 (s, 3 H), 2.48 (s, 3 H), 1.92 (s, 3 H); MS (ESI) m/z: 334.1 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8](C)=[C:7]([NH2:12])[CH:6]=1)[C:2](C)=[O:3].[NH2:13]C1C=CC=CC=1OC>>[NH2:12][C:7]1[CH:6]=[C:5]([NH:1][C:2]([NH2:13])=[O:3])[CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccccc1N
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Product: NC(=O)Nc1cccc(N)c1

Procedure:
4-acetamino-2-aminotoluene or -2-aminoanisole;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][CH:19]=O>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:18]=[CH:19][N:16]=2)[C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: Nc1nc(Br)ccc1OCc1ccccc1
Product: Brc1ccc(OCc2ccccc2)c2nccn12
Yield: 88 %

Procedure:
A mixture of 3-benzyloxy-6-bromopyridin-2-ylamine (1.0 g, 3.6 mmol) and chloroacetaldehyde (1.2 mL, 50 wt. % in water) in IMS (12 mL) was stirred at reflux for 1 hour, then concentrated under reduced pressure. The residue was partitioned between an aqueous saturated solution of sodium bicarbonate and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:Et2O, gradient 0:100 to 1:99) to give 8-Benzyloxy-5-bromo-imidazo[1,2-a]pyridine as an beige solid (960 mg, 88%). LCMS (Method H) RT 3.08 min; [M+H]+ 303 (79Br) and 305 (81Br)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])/[CH:5]=[C:6](/[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Br:23])[CH:14]=1)\[C:7]1[O:8][C:9]([CH3:12])=[N:10][N:11]=1)[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([Br:23])[CH:14]=1)[C:7]1[O:8][C:9]([CH3:12])=[N:10][N:11]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(/c1cc(Br)cc(C(F)(F)F)c1)c1nnc(C)o1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1cc(Br)cc(C(F)(F)F)c1)c1nnc(C)o1
Reaction time: 8 h
Yield: 35.3 %

Procedure:
11.2 g (27.64 mmol) (Z)-3-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-acrylic acid ethyl ester is dissolved in 200 ml acetic acid and 14.1 g Zinc dust (215.6 mmol, 7.8 mmol) is added slowly over a period of 30 minutes. The temperature of the reaction mixture is not allowed to reach >30° C. during the addition of the zinc dust. The resulting mixture is allowed to stir overnight. After filtration 200 ml EtOAc and 200 ml water are added and the organic phase is separated and washed with brine. After removal of the solvent the crude material is purified by column chromatography on silica gel using heptane/EtOAc=3:1 as eluent. 3.97 g of 3-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid ethyl ester (yield=35%) are isolated.
Reaction SMILES: [CH:1]1([C:4]2([C:10]#[N:11])[CH2:8][CH2:7][NH:6][C:5]2=[O:9])[CH2:3][CH2:2]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:12][C:13]1[N:18]=[C:17]([N:6]2[CH2:7][CH2:8][C:4]([CH:1]3[CH2:3][CH2:2]3)([C:10]#[N:11])[C:5]2=[O:9])[CH:16]=[CH:15][N:14]=1
Reactant: N#CC1(C2CC2)CCNC1=O
Reactant: Clc1ccnc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: N#CC1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a mixture of 3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (18 g) obtained in Step C of Example 103, 2,4-dichloropyrimidine (17 g), cesium carbonate (76 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.1 g) in tetrahydrofuran (300 mL) was added tris(dibenzylideneacetone)dipalladium(0) (2.1 g), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (23 g).
Reaction SMILES: [C:1]([C:5]1([CH2:11][CH2:12][CH3:13])[CH:9]=[CH:8][CH:7]([CH3:10])[O:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CCOCC>[C:1]([C:5]1([CH2:11][CH2:12][CH3:13])[CH2:9][CH2:8][CH:7]([CH3:10])[O:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC1(C(C)(C)C)C=CC(C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Product: CCCC1(C(C)(C)C)CCC(C)O1
Yield: 126.8 %

Procedure:
At ambient temp., a suspension of 2.91 g (10.4 mmol) of 2-tert-butyl-5-methyl-2-propyl-2,5-dihydrofuran and 1.06 g (1.00 mmol) of 10% palladium on activated charcoal in 60 mL of dry ether was hydrogenated for 4 h in a Parr apparatus at 2.5 bar hydrogen pressure. The catalyst was filtered off over a pad of Celite, and the solvent evaporated. The resulting residue was distilled in a Kugelrohr apparatus to provide at 75-85° C./20 mbar 2.43 g (80%) of the title compound as a colorless odoriferous liquid.
Reaction SMILES: [CH3:1][N:2]([C@@H:12]([C:24](=[O:39])[N:25]([CH3:38])[C@@H:26]([C:34](=[O:37])[NH:35][CH3:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:3](=[O:11])/[CH:4]=[CH:5]/[CH2:6][C:7]([NH2:10])([CH3:9])[CH3:8].C(O)(=O)C.[Si:44]([O:51][C@H:52]([CH3:55])[CH:53]=O)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].C([BH3-])#N.[Na+]>CO>[Si:44]([O:51][C@H:52]([CH3:55])[CH2:53][NH:10][C:7]([CH3:8])([CH3:9])[CH2:6]/[CH:5]=[CH:4]/[C:3]([N:2]([C@H:12]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:24]([N:25]([C@H:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]([NH:35][CH3:36])=[O:37])[CH3:38])=[O:39])[CH3:1])=[O:11])([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:46])[CH3:45]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N
Reactant: C[C@H](C=O)O[Si](C)(C)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide (318 mg, 0.60 mmol) was dissolved in methanol (20 ml) and glacial acetic acid (0.48 ml, 8.4 mmol). 3 Å mol sieves (9 g) and a solution of (2R)-2-(tert-butyldimethylsilyloxy)propanal (1.33 g, 7.06 mmol) in methanol (10 ml) were added successively. Sodium cyanoborohydride (220 mg, 3.53 mmol) was added as a solid. The reaction mixture was stirred at room temperature for 45 min, before a second batch of sodium cyanoborohydride (220 mg, 3.53 mmol) was added. The reaction mixture was stirred for 16 h at room temperature. The mol sieves was filtered off through a plug of celite. The celite was washed with methanol (200 ml). The solvents of the combined filtrates were removed in vacuo. The residue was dissolved in 1 N sodium hydroxide solution (50 ml) and tert-butyl methyl ether (50 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (35 g), using ethyl acetate/heptane/triethylamine (20:10:1) as eluent, to give 99 mg of (2R)-2-(N-((2R)-2-(N-((2E)-5-((2R)-2-(tert-butyldimethylsilyloxy)propylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-N-methyl-3-phenylpropionamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[I:13]>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Cl)c(I)cc1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 1-chloro-2-iodo-5-methoxy-4-nitrobenzene (113 g, 0.361 mol) in acetic acid (1 L) and water (50 mL) at 50° C., Fe (50.5 g, 0.903 mol) was added and the resulting mixture was stirred at 50° C. for 2 h. The mixture was allowed to cool to room temperature and then poured into ice-water. The precipitate was collected by filtration and rinsed with water. This crude product was dissolved with ethyl acetate (1 L) and filtered. The filtrate was washed with saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (87 g, 85% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([P:8]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])([O:10][CH2:11][CH2:12][S:13]([CH2:16][C@@H:17]([C:26]([OH:28])=[O:27])[NH:18]C(OC(C)(C)C)=O)(=[O:15])=[O:14])=[O:9])[CH2:5][CH2:6][Cl:7].Cl.C(OCC)C>C(OCC)(=O)C>[Cl:32][CH2:31][CH2:30][N:29]([P:8]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][Cl:7])([O:10][CH2:11][CH2:12][S:13]([CH2:16][C@@H:17]([C:26]([OH:28])=[O:27])[NH2:18])(=[O:14])=[O:15])=[O:9])[CH2:33][CH2:34][Cl:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N[C@@H](CS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
3-[[2-[[Bis [bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-N-tert-butoxycarbonyl-L-alanine, 1.82 g (2.91 mmol), was dissolved in 18 mL ethyl acetate, and to this solution was added hydrogen chloride, 1.75 mL of 2 M solution in diethyl ether (3.5 mmol); and the resulting mixture stirred under nitrogen overnight at room temperature. HPLC analysis of the reaction mixture showed that the reaction was incomplete (20.8% product), so an additional 0.9 equivalents of hydrogen chloride solution was added and the reaction mixture stirred for an additional 4 days, resulting in the formation of a slurry. HPLC analysis of the reaction mixture showed 99.7% product and 0.3% starting material. The slurry was filtered under nitrogen, washed with ethyl acetate, and dried under nitrogen for 3 hours to give 3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-L-alanine, compound 70A, as the hydrochloride salt, off-white solid, 0.90 g (55% yield). HPLC analysis of the product showed a purity of 99.7%. 1H NMR: δ 8.50-9.10 (bs, 3H), 4.43 (m, 1H), 4.32 (m, 2H), 3.93-3.97 (m, 1H),
Reaction SMILES: [Zn](CC)CC.ICI.N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:33]1[CH2:37][O:36]C[CH2:34]1>CCCCCC.C1(C)C=CC=CC=1.O>[CH2:10]([C@@H:33]1[CH2:34][C@H:37]1[OH:36])[CH2:11][CH2:12][CH:13]=[CH2:14]
Reactant: c1ccncc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[Zn]CC
Agent: [F-]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCCC[C@@H]1C[C@H]1O
Temperature: 20 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution (0.45 M) of the preceding compound in hexane was treated with a solution (15%) of Et2Zn (1.2 eq) in toluene, and the resulting solution was cooled in an ice bath. Diiodomethane (1.2 eq) was added dropwise, then the solution was stirred for 1 h before being warmed to 20° C. Pyridine (6 eq) was added, and the slurry was stirred for 15 min then poured onto petroleum ether. The mixture was filtered repeatedly through CELITE until a transparent solution was obtained. This mixture was concentrated at 100 mbar, and the solution that remained (that contained trimethyl{[(trans)-2-pent-4-en-1-ylcyclopropyl]oxy}silane, toluene and pyridine) was further diluted with THF. The mixture was cooled to 0° C. then treated dropwise with a solution (1 M) of TBAF (1.2 eq) in THF. After 10 min, the mixture was allowed to warm to 20° C., and after a further 1 h was poured into H2O. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine then dried. Removal of the volatiles afforded a residue that was purified by flash chromatography (eluent 0-66% Et2O/petroleum ether) to furnish the title compound (71%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.85-5.75 (m, 1H), 5.00 (dd, J=17.1, 1.6 Hz, 1H), 4.94 (br d, J=10.4 Hz, 1H), 3.20 (apparent dt, J=6.4, 2.5 Hz, 1H), 2.10-2.04 (m, 2H), 1.52-1.44 (m, 2H), 1.29-1.19 (m, 1H), 1.15-1.07 (m, 1H), 0.95-0.87 (m, 1H), 0.71-0.66 (m, 1H), 0.31 (apparent q, J=6.0 Hz, 1H).