Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][CH2:30][S:31][CH3:32])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:43])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:43])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CSCCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 61 in dichloromethane (2 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (˜85%)(0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane. The product fractions are combined and recrystallized from ethyl acetate-methanol-hexanes to afford 0.07 gm of the title compound as a white solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:22](Cl)(=[O:31])[C:23]1[C:24]([O:29][CH3:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(Cl)Cl>[C:2]([O:6][C:7](=[O:14])[C@@H:8]([NH:9][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH:10]([CH3:11])[CH2:12][CH3:13])([CH3:4])([CH3:5])[CH3:3]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)[C@H](NC(=O)c1ccccc1OC)C(=O)OC(C)(C)C
Yield: 47.5 %

Procedure:
L-Isoleucine tertbutyl ester hydrochloride (500 mg, 2.23 mmol) was dissolved in CH2Cl2 (10 ml). Triethylamine (600 g, 6.0 mmol) and 2-anisoyl chloride (456 mg, 2.68 mmol) were added. After 18 h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 60% Pet. ether, 40% ethyl acetate) to give a colourless oil identified as the title compound (341 mg, 1.06 mmol, 48%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([N:17]3[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:18]3)[CH:11]=2)=[CH:6][C:5]=1F)(=O)[CH3:2].Cl.CON.C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C.[NH2:54][NH2:55]>COCCOC.CCO>[NH2:16][C:14]1[N:13]=[C:12]([N:17]2[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:18]2)[CH:11]=[C:10]([C:7]2[CH:6]=[C:5]3[C:4]([C:1]([CH3:2])=[N:54][NH:55]3)=[CH:9][CH:8]=2)[N:15]=1
Reactant: NN
Reactant: CC(=O)c1ccc(-c2cc(N3C[C@@H](C(=O)NCc4ccccc4)CC[C@H]3C)nc(N)n2)cc1F
Agent: CON
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]c2cc(-c3cc(N4C[C@@H](C(=O)NCc5ccccc5)CC[C@H]4C)nc(N)n3)ccc12
Temperature: 120 °C
Yield: 10.1 %

Procedure:
Into a sealed tube, (3S,6R)-1-[6-(4-acetyl-3-fluorophenyl)-2-amino-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (90 mg, 0.195 mmol), O-methylhydroxylamine hydrochloride (16.3 mg, 0.20 mmol), and K2CO3 (32.3 mg, 0.234 mmol) were stirred together in DME (3 mL) for 4 hours at 57° C. The reaction mixture was filtered, and the filtrate containing the oxime intermediate was concentrated in vacuo to 2 mL. Then EtOH (3 mL), Hunig's base (0.05 mL, 0.27 mmol), and hydrazine anhydrous (0.013 mL, 0.410 mmol) were added, and the resulting yellow mixture was heated overnight at 120° C. in an oil bath. The solution turned black. LCMS showed mainly product. The black solid was filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (9 mg) as a light yellow solid. LC-MS (ES) m/z=456 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.32 (m, 4H), 1.75-1.91 (m, 3H), 1.97-2.12 (m, 1H), 2.41-2.53 (m, 1H), 2.60 (s, 3H), 3.11-3.27 (m, 1H), 4.33-4.50 (m, 2H), 4.56-4.74 (m, 1H), 6.59 (s, 1H), 7.23-7.41 (m, 5H), 7.54-7.63 (m, 1H), 7.96 (m, 1H), 7.94 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:21].[ClH:28].[N:23]1([CH2:22][C@H:9]2[NH:8][CH2:12][C@H:11]([NH:13][C:14]([C:16]3[S:17][C:18]([Cl:21])=[CH:19][CH:20]=3)=[O:15])[CH2:10]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N[C@H]1CN[C@H](CN2CCCC2)C1)c1ccc(Cl)s1
Reaction time: 18 h

Procedure:
17.4 To a stirred solution of 134 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester at r.t. in 3.4 ml dioxane under an argon atmosphere were added 1.6 ml 4 M HCl in dioxane. The mixture was then stirred for 18 h. The resulting white suspension was concentrated to leave 139 mg 5-chloro-thiophene-2-carboxylic acid ((3R,5S)-5-pyrrolidin-1-ylmethyl-pyrrolidin-3-yl)-amide dihydrochloride as off-white solid. MS 314.3 ([M+H]+)
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[CH3:26][C:22]1[N:21]=[C:20]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc([Sn](C)(C)C)c2ccccc12
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(-c2ccc(C(=O)O)c3ccccc23)n1

Procedure:
The title compound was prepared from D7 and 2-bromo-6-methylpyridine using a similar method to Description 8 (45%), followed by hydrolysis of the methyl ester using 1M NaOH solution (69%) to afford a white solid.
Reaction SMILES: S([O-])(O)=O.[Na+].[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:17]=O)[NH:13][C:12]=1[CH3:19])=[O:10])[CH3:7].[NH2:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([C:17]2[NH:20][C:21]3[CH:22]=[C:23]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:32]=[CH:33][C:34]=3[N:35]=2)[NH:13][C:12]=1[CH3:19])=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(C)[nH]c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)c1C
Temperature: 120 °C
Reaction time: 10 h
Yield: 85.6 %

Procedure:
Sodium hydrogen sulfite (101 mg) and the 5-formyl-2,4-dimethyl-pyrrole-3-carboxylic acid ethyl ester (146 mg) obtained in Example 53 (1) were added to an N,N-dimethylacetamide (5 ml) solution of 3,4-diaminobenzophenone (160 mg). The mixture was heated to 120° C. and stirred for 10 hours. The reaction mixture was allowed to cool to room temperature, and then a 5% sodium carbonate (6 ml) was added and stirred at room temperature. The precipitate was collected by filtration to afford 5-(5-benzoylbenzimidazole-2-yl)-2,4-dimethylpyrrole-3-carboxylic acid ethyl ester (248 mg, 85%) as a light yellow solid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][OH:17])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][O:17][S:28]([CH3:27])(=[O:30])=[O:29])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCO)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCOS(C)(=O)=O)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethanol (2.00 g, 6.65 mmol) in CH2Cl2 (66 mL) at 0° C. were added dropwise Et3N (1.02 mL, 7.31 mmol) and methanesulfonyl chloride (0.57 mL, 7.3 mmol). The reaction was stirred at 0° C. for 1 h, and was diluted with CH2Cl2 (40 mL). The resulting mixture was washed with aq. sat. NH4Cl (2×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (2.55 g, quantitative yield) that was used further without purification. LC-MS: tR=1.13 min; ES+: 379.29.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][CH2:9][C@@H:10]([OH:27])[C@@H:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2].[C:30](ON1C(=O)CCC1=O)([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31].CCN(CC)CC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C@@H:10]([OH:27])[C@@H:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[CH:28][CH:29]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CNCc1ccc(C#N)cc1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CN(Cc1ccc(C#N)cc1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl (2S,3R)-4-(4-cyanobenzylamino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (600 mg, 1.5 mmol) in CH2Cl2 (30 mL) was treated with Teoc-OSu (762 mg, 3.0 mmol, 2.0 equiv) and Et3N (304 mg, 3.0 mmol, 2.0 equiv). The mixture was allowed to stir overnight at rt. LC-MS analysis showed that all of the free amine had been consumed. The solution was washed with water, 1.0 M aq HCl, and brine, then over dried over Na2SO4, filtered and evaporated to leave tert-butyl (2S,3R)-4-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate. NMR analysis showed that the compound was of sufficient purity to use in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][S:9]([C:12]1[CH:13]=[C:14]([CH:25]=[C:26]([F:28])[CH:27]=1)[C:15]([O:17]CC1C=CC=CC=1)=[O:16])(=[O:11])=[O:10]>>[Cl:8][S:9]([C:12]1[CH:13]=[C:14]([CH:25]=[C:26]([F:28])[CH:27]=1)[C:15]([OH:17])=[O:16])(=[O:10])=[O:11]
Reactant: O=C(OCc1ccccc1)c1cc(F)cc(S(=O)(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(F)cc(S(=O)(=O)Cl)c1
Yield: 82.1 %

Procedure:
A trifluoroacetic acid (18 mL) solution of benzyl 3-(chlorosulfonyl)-5-fluorobenzoate (2.30 g) was stirred at 60° C. for 18 hours. The oily substance floating on the liquid surface was removed, and the solution part was decanted and evaporated under reduced pressure. Hexane was added to the residue, then this was sonicated for 10 minutes. The resulting solid was collected by filtration to obtain 3-(chlorosulfonyl)-5-fluorobenzoic acid (1.37 g). EI: 238
Reaction SMILES: [C:1]1([C:7](=[O:15])[C:8]([O:10][Si](C)(C)C)=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[CH:17][C:18](=C)[CH3:19]>>[C:7]([C:8]1([OH:10])[CH2:19][CH2:18][CH:17]=[CH:16][CH2:9]1)(=[O:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(O[Si](C)(C)C)C(=O)c1ccccc1
Reactant: C=CC(=C)C
Product: O=C(c1ccccc1)C1(O)CC=CCC1

Procedure:
If the 1-phenyl-2-trimethylsiloxyprop-2-en-1-one is reacted with isoprene instead of butadiene, an analogous procedure gives an oily product which, after bulb tube distillation (150°/0.06 mm Hg), gave the following analysis:
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][O:4][CH2:5][CH:6](O)[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:17][CH:6]([CH2:5][O:4][CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)COCC(O)CN1CCCC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)COCC(Cl)CN1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
Dry hydrogen chloride gas was bubbled into an ice-cooled solution of 107.7 g (0.5 mole) of α-[(2,2-dimethylpropoxy)methyl]-1-pyrrolidineethanol (the product of Example 3a) in 110 ml of dry toluene until 20.05 g (0.55 mole) was taken up. This solution was added to a stirred ice-cooled suspension of 109.4 g (0.525 mole) of phosphorous pentachloride in 60ml of dry toluene (argon atmosphere) at a rate to keep the reaction temperature between 10°-15° C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred for 1.5 hr. The reaction mixture was added to a stirred ice-cooled solution of 385 ml (4.5 mole) of 45% potassium hydroxide and 700 ml of ice at a rate to keep the reaction temperature between 25°-35° C. The reaction mixture was stirred for 0.5 hr then extracted with toluene. An immiscible oil formed between the layers. The oil was partitioned between dichloromethane and water. The dichloromethane layer and the toluene layer above were combined, dried and concentrated to dryness to give 84.3 g of oil. The oil was distilled (65°-86° C. at 0.35 mm) to give 76.63 g of oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Br:11])[C:5]=1[O:12][CH3:13])([O-])=O.[Sn]>>[NH2:1][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Br:11])[C:5]=1[O:12][CH3:13]
Reactant: COc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Agent: [Sn]
Product: COc1c(N)cc(Cl)cc1Br
Yield: 97.4 %

Procedure:
2-Amino-4-chloro-6-bromoanisole was prepared by the same procedure described for Step 3 of Preparation 2a except using 2-nitro-4-chloro-6-bromoanisole (16.2 g) and tin (14.5 g). Workup provided 2-amino-4-chloro-6-bromoanisole (14.0 g, 97%). 1H NMR (300 MHz, CDCl3) δ6.88 (d, J=2.4 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3) δ142.9, 141.9, 130.2, 121.4, 117.1, 114.6, 59.6.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([Cl:24])[CH:18]=[C:17]2[Cl:25].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([Cl:24])[C:18]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)=[C:17]2[Cl:25]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Clc1cc(Cl)c2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (1.40 mL, 9.96 mmol) in THF (12 mL) cooled to 0° C. was added n-butyllithium (2.5 M solution in hexanes, 3.80 mL, 9.50 mmol) dropwise via syringe. The reaction mixture was stirred at 0° C. for 10 minutes then cooled to −78° C. at which time a separate solution of 6-bromo-2,4-dichloroquinoline (1.80 g, 6.51 mmol, Intermediate 44: step b) in THF (29 mL) was added dropwise via syringe. The mixture was stirred at −78° C. for 30 minutes followed by the addition of 4-(bromomethyl)benzonitrile (1.52 g, 7.74 mmol) in THF (5 mL). After an additional 10 minutes of stirring at −78° C., the reaction was transferred to an ice bath and warmed to ambient temperature over 5 hours. The reaction was quenched with water and the aqueous phase was extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% EtOAc-Hexanes) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:12][CH2:13][C:14]([N:16]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH:17]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[NH:12][CH2:13][C:14]([N:16]2[CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:25][CH:17]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.9 cm3 of 3-methoxyphenyl isocyanate is added to a solution of 2 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate in 20 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 20 hours at a temperature in the vicinity of 25° C. After evaporation of the solvent under reduced pressure at a temperature in the vicinity of 45° C., the crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (95/5 by volume)]. The fractions containing the expected product are combined, then concentrated to dryness under reduced pressure. After recrystallization in acetonitrile, 1.9 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-methoxyphenyl)ureido]acetyl}-5-phenylprolinate melting at 174° C., are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:20])[CH2:4][CH2:3]1.[O:21]1[C:30]2[CH:29]=[C:28]([CH:31]=O)[N:27]=[CH:26][C:25]=2[O:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>>[O:21]1[C:30]2[CH:29]=[C:28]([CH2:31][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=5[O:13][CH2:12][C:11]4=[O:20])[CH2:4][CH2:3]3)[N:27]=[CH:26][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: NC1CCN(CCN2C(=O)COc3ccccc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccccc2N1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one (Intermediate 97), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to give the product as a off-white solid, 81 mg (16%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].N1CCOCC1>C1COCC1.CS(C)=O.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.35 mmol) in anhydrous THF (4 ml) and anhydrous DMSO (0.4 ml) was treated with Pd(PPh3)4 (61 mg, 0.053 mmol). The mixture was degassed under gentle vacuum, morpholine (308 uL, 3.5 mmol) was added, and left to stir at rt under nitrogen for 4 hours. The yellow 10 solution was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down an amino-propyl SPE (5 g), eluting with MeOH followed by 5% AcOH/MeOH. The product fractions were combined and concentrated in vacuo to afford the title compound as an off white solid (30 mg, 35%). NMR; δH (400 MHz, d6-DMSO) 0.89 (t, 3H, J=7.5 Hz), 1.23-1.34 (m, 2H), 1.55-1.65 (m, 2H), 3.85 (t, 2H, J=7 Hz), 11.17 (s, 1H), 14.37 (br.s, 1H); m/z 243.3 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]=[C:26]=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:27]
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: COC(=O)c1ccc(N)c(O)c1
Product: COC(=O)c1ccc(NC(=O)Nc2ccccc2-c2ccccc2)c(O)c1
Yield: 51.1 %

Procedure:
The urea was prepared from 2-hydroxy 4-carbomethoxy aniline (0.167 g, 1 mmol) and 2-phenyl phenyl isocyanate (1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound (0.185 g, 50%). EI-MS m/z 363 (M−H)−
Reaction SMILES: C(OC(=O)[NH:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:35]=[CH:36][N:37]([CH3:39])[CH:38]=4)=[CH:30][CH:29]=3)=[C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][C:18]3=[O:26])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)C=C.O=O.C(NCC)C>ClCCl.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>[NH2:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:35]=[CH:36][N:37]([CH3:39])[CH:38]=4)=[CH:30][CH:29]=3)=[C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][C:18]3=[O:26])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: C=CCOC(=O)NC1(c2ccc(C(Nc3ccc(-c4cn(C)cn4)cc3)=C3C(=O)Oc4ccccc43)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=O
Solvent: ClCCl
Solvent: CCNCC
Product: Cn1cnc(-c2ccc(NC(=C3C(=O)Oc4ccccc43)c3ccc(C4(N)CC4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.58 g of allyl(1-{4-[[4-(1-methyl-1H-imidazol-4-yl)phenylamino]-(2-oxobenzofuran-3-ylidene)methyl]phenyl}cyclopropyl)carbamate was dissolved in 20 mL of dichloromethane. The solution was freed from oxygen using argon. Then at RT, 0.52 mL of diethylamine and 0.058 g of tetrakis(triphenylphosphine)palladium (0) were added. The mixture was stirred for 2 hours at RT, the suspension was evaporated down with silica gel and chromatographed with dichloromethane/methanol (97:3) on silica gel 70 at a flow rate of 30 mL/min. The clean fractions were combined, evaporated down to the residue, dissolved in dichloromethane, filtered, and combined with diisopropyl ether. The dichloromethane was distilled off, the crystals formed were suction filtered and washed with diisopropyl ether. Yield: 0.26 g of yellow crystals, melting point 190° C.-191° C., as base. Rf value: 0.51 (dichloromethane/methanol (9:1)).