Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.O.[NH2:22]N.Cl.C[N:26]([CH3:35])CCCN=C=NCC.O>CN(C=O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[C:4]([C:18]4[O:20][CH:35]=[N:26][N:22]=4)=[CH:3][C:2]([OH:1])=[CH:17][C:6]=3[CH:7]=2)=[CH:11][CH:12]=1
Reactant: NN
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2cc3cc(O)cc(-c4nnco4)c3o2)cc1
Temperature: 25 °C
Yield: 2.3 %

Procedure:
Compound 24 (0.6 g, 2.2 mmol) in DMF (3–5 mL) and hydrazine monohydrate (0.25 mL, 5 mmol) was treated with EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (0.64 g, 3.3 mmol) and the reaction allowed to stir at rt for several hours. The reaction was worked up by adding water and extracting twice with EtOAc; The combined EtOAc extracts were washed with brine and dried over MgSO4. The EtOAc was concentrated to render 125 mg of the crude acyl hydrazide which was used as is for the next step. The crude acyl hydrazide from the previous step was treated with 3–5 mL of triethyl orthoformate and catalytic p-toluenesulfonic acid and heated to reflux for 30 minutes. The reaction mixture was allowed to cool to rt and was poured into 2 N HCl aq, extracted with EtOAc, washed with 2 N HCl aq, saturated NaHCO3 aq, brine, and dried over MgSO4. Filtration and concentration followed by chromatography on silica gel (1:19 MeOH/CH2Cl2) gave 15 mgs of 138: MP=260–266° C.; 1H NMR (DMSO-d6) δ 9.94 (brs, 1 H), 9.75 (br s, 1 H), 9.45 (s, 1 H), 7.79 (d, 2 H, J=8.7 Hz), 7.33 (d, 1 H, J=2.4 Hz), 7.20 (s, 1 H), 7.18 (d, 1 H, J=2.4 Hz), 6.92 (d, 2 H, J=8.7 Hz); MS 295 (M+H)+.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][C@H:14]([N:18]2[C:24](=[O:25])[CH2:23][CH2:22][NH:21][C@H:20]([CH3:26])[CH2:19]2)[CH2:15][O:16][CH3:17])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[C:31]([NH:35][C:36]([N:21]2[CH2:22][CH2:23][C:24](=[O:25])[N:18]([C@H:14]([CH2:15][O:16][CH3:17])[CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:7][CH2:6]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:19][C@H:20]2[CH3:26])=[O:37])[CH:32]=[CH:33][CH:34]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)NCCC1=O
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2cccc(C(F)(F)F)c2)CCC1=O
Yield: 39 %

Procedure:
In analogy to the procedure described for intermediate 58F, (R)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 65H) and 3-(trifluoromethyl)phenyl isocyanate gave the title compound in 39% yield as orange solid. MS: 527.3 (MH+).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:19][CH:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:21]([F:24])([F:23])[F:22])[C:8]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.C[Si]([C:35]#[CH:36])(C)C.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.[Cu](I)I.O>[C:35]([C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:19][CH:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:21]([F:24])([F:22])[F:23])[C:8]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:14])=[O:15])=[N:9]2)=[CH:4][CH:3]=1)#[CH:36]
Reactant: CCCS(=O)(=O)Nc1nc2cc(I)ccc2nc1OC(c1cccnc1)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1ccc2nc(OC(c3cccnc3)C(F)(F)F)c(NS(=O)(=O)CCC)nc2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
Compound 77 (70.0 mg, 0.127 mmol) obtained in Example 74 was dissolved in DMF (2.00 mL). To the solution were added trimethylsilylacetylene (0.089 mL, 0.634 mmol), triethylamine (0.088 mL, 0.634 mmol), copper iodide (I) (9.66 mg, 0.051 mmol), and tetrakis (triphenylphosphine)palladium (29.3 mg, 0.025 mmol), and the mixture was stirred at 120° C. for 30 minutes. Water was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. Washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/3). The obtained purified product was dissolved in THF (1.80 mL). Tetrabutylammonium fluoride (1.0 mol/L solution in THF, 0.107 mL, 0.107 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/1) to give Compound 79 (25.7 mg, 46% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][NH:11][CH2:10]2)[O:6][N:5]=1)[CH3:2].C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>ClCCl>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:35])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc(C2CNCC(c3ccc(CC(F)(F)F)cc3)C2)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 52 mg (0.14 mmol) of the compound from Example 61A in dichloromethane (1.6 ml) was admixed with 0.07 ml (49.7 mg, 0.49 mmol) of triethylamine and then, at 0° C., 28 mg (0.14 mmol) of 4-nitrophenyl chloroformate were added. The mixture was stirred at 0° C. for 2 h, then warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 75.8 mg (95% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([O:22][CH2:23][C:24]([CH2:28][OH:29])([CH3:27])[CH2:25][OH:26])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:34](Br)[C:35]#[CH:36].C(Cl)Cl>C1COCC1.O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C:24]([CH2:28][O:29][CH2:36][C:35]#[CH:34])([CH3:27])[CH2:25][OH:26])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=2)=[CH:9][CH:10]=1
Reactant: C#CCBr
Reactant: COc1ccc(C(OCC(C)(CO)CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C#CCOCC(C)(CO)COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
1-O-(4,4′-dimethoxytrityl)-2-hydroxymethyl-2-methyl-1,3-propanediol 16 (620 mg, 1.47 mmol) was dissolved in anhydrous THF (6 mL) and sodium hydride (60% in oil, 590 mg, 14.7 mmol) was added. After 10 min stirring, propargyl bromide (80% in toluene, 650 mL, 5.9 mmol) was added and the mixture was stirred at RT for 1 h. Then CH2Cl2 was added (100 mL) and 2 mL of water. Organic layer was washed with water (2×100 mL) and dried over Na2SO4. After evaporation the residue was purified by flash chromatography using an increasing amount of ethyl acetate (10% to 50%) in cyclohexane containing 1% of triethylamine.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:16]=O>CCOCC>[N:1]1([CH2:16][NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: C=O
Reactant: NC1CCCC1
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCOCC
Product: c1ccc2c(c1)nnn2CNC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To the mixture of 36 g (0.3 mole) of benzotriazole and 30 mL (0.3 mole) of cyclopentylamine in 1400 mL of ether was added dropwise 22 mL (0.3 mole) of 37% aqueous formaldehyde. The reaction mixture was stirred at room temperature overnight. The solution was dried over calcium chloride, filtered and concentrated under pressure. Hexane was added under ice-cooled bath and the resulting solid was collected by filtration and washed with hexane dried to give 58.6 g of benzotriazol-1-ylmethyl-cyclopentyl-amine as a white solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10]>>[C:1]1([C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][O:10]1)=[O:8]
Reactant: OCc1ccccc1
Reactant: CO
Product: O=C1OCc2ccccc21

Procedure:
The procedure as described in F is repeated, except that 50 ml of benzyl alcohol are used instead of methanol, to give a phthalide compound of the formula ##STR17## m.p. 183°-184° C.
Reaction SMILES: C([CH2:8][NH:9][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH3:28])=[O:26])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][C:13]1=[O:24])C1C=CC=CC=1.Br.C(O)(=O)C.BrBr.[CH3:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH2:8]([N:9]1[CH2:10][CH2:11][C:12]2([C:25]([O:27][CH3:28])=[O:26])[C:13](=[O:24])[CH:14]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][C:21]=12)[C:38]1[CH:37]=[CH:36][CH:41]=[CH:40][CH:39]=1
Reactant: CCCCCC
Reactant: COC(=O)C1(CCNCCc2ccccc2)C(=O)CCc2ccc(OC)cc21
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: COC(=O)C12CCN(Cc3ccccc3)C(Cc3ccc(OC)cc31)C2=O
Reaction time: 0.5 h

Procedure:
A solution of IV hydrobromide (0.13 m.) in 350 ml. acetic acid was treated dropwise with a solution of bromine (0.13 m) in 50 ml. acetic acid. After stirring for 1/2 hour, the reaction was diluted with 1.5 1. "Skellysolve B" (essentially n-hexane) and cooled. The precipitated residue was separated by decantation and washed with cold "Skellysolve B". The residue was taken up in methylene chloride and treated with dilute ammonium hydroxide until basic. The layers were separated and the aqueous layer extracted two times more with methylene chloride. The combined extracts were dried (MgSO4) and concentrated. The residue was taken up in acetone and allowed to crystallize with stirring. The crystals were collected to give V (69%). The analytical sample was recrystallized from methanol; mp 158°-160° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:22])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]1[C:12]([C:13]2[C:14]([CH3:22])=[CH:15][CH:16]=[CH:17][C:18]=2[NH2:19])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(N)c1-c1nnnn1Cc1ccccc1
Reaction time: 4 h
Yield: 100.2 %

Procedure:
1-Benzyl-5-(2-methyl-6-nitrophenyl)-1H-tetrazole (Intermediate 17, 0.1 g) was dissolved in ethyl acetate (20 mL) under a nitrogen atmosphere. Palladium on carbon (10%, 0.1 g) was added and the nitrogen atmosphere was replaced by hydrogen. The mixture was stirred for 4 hours and then filtered through celite. The solvent was removed by evaporation under vacuum to give the title compound as a white solid (0.09 g).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1([CH2:11][CH2:12][CH:13]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:5]1([CH2:11][CH2:12][CH2:13][NH:4][CH2:3][CH2:1][OH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=CCCC1CCCCC1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OCCNCCCC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethanolamine (0.44 g, 7.1 mmol) in DCM (15 mL) at 0° C. was added a solution of 3-cyclohexylpropionaldehyde (1.0 g, 7.1 mmol) in DCM (10 mL) followed by sodium triacetoxyborohydride (1.67 g, 7.86 mmol). The resulting mixture was warmed to room temperature. After 2.5 hours the desired product was observed by mass spectrometric analysis. The reaction mixture was stirred overnight, then diluted with DCM (50 mL), washed with saturated sodium bicarbonate (2×50 mL), and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give a clear oil (1.0 g) which was used in the next step without further purification. ((m/z): [M+H]+ calcd for CHH23NO, 186.20; found, 186.0).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C@@H:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O.CN1CCOCC1.[ClH:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30][NH2:31])=[CH:23][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:28][CH2:29][CH2:30][NH:31][C:4](=[O:6])[C@@H:3]([N:2]([CH3:1])[CH3:11])[CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:23][CH:22]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A solution of (S)-2-dimethylamino-4-methyl-pentanoic acid (433 mg, 2.72 mmol), N-methylmorpholine (0.275 mL, 2.50 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (809 mg, 2.72 mmol) in dry DMF (12 mL) was treated with Triton® B (1.80 mL, 3.96 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.). The clear solution was cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.03 g, 2.72 mmol) was then added. After stirring at 0° C. for 30 minutes, the cooling bath was removed, and the stirring was continued at ambient temperature for 15 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether, white precipitate forms and was removed by filtration. The filtrate was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (5% MeOH in 1:1 EtOAc/hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 361 mg (30%) of the pure titled compound as a white foam; mp 60-72° C. APCI-MS m/z 403.3 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C[O:13]CCOCCN(CCOCCOC)CCOCCOC.ClC1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[C:37]([CH:44]([O:47][CH3:48])[O:45][CH3:46])[CH:36]=1>CC(N(C)C)=O.CC(O)=O>[CH3:46][O:45][CH:44]([O:47][CH3:48])[C:37]1[CH:36]=[C:8]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:13])[CH:40]=[CH:39][C:38]=1[N+:41]([O-:43])=[O:42]
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Phenyl-acetonitrile (0.0793 mol) in DMA (100 ml) was stirred at room temperature and 50% NaH (0.0793 mol) was added portionwise. The mixture was stirred at room temperature until the evolution of H2 had ceased. TDA-1 (0.004 mol) was added and 4-chloro-2-dimethoxymethyl-1-nitro-benzene (0.0793 mol) in DMA (30 mL) was added dropwise. The mixture was stirred at 60° C. and at 100° C. overnight. 50% NaH (0.0793 mol) was added again and the mixture was stirred further at room temperature. The mixture was poured carefully on ice/water and brought to about pH 6-7 with CH3COOH. The product was extracted with CH2Cl2. The organic layer was dried (MgSO4) and evaporated. DMA was evaporated by use of high vacuum pump to yield the title compound as a residue.
Reaction SMILES: N1C=CC=CC=1.[P:7]([Cl:10])(Cl)[Cl:8].[CH:11]([NH:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>CCOCC>[Cl:8][P:7]([Cl:10])[N:14]([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)NC(C)C
Reactant: ClP(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)N(C(C)C)P(Cl)Cl
Temperature: -70 °C
Yield: 36.3 %

Procedure:
300 ml abs. ether, 81 ml anhydrous pyridine and 87.5 ml PCl3 (1 Mol) are pre-cooled with stirring to -70° C. in a 2 l three-neck, round-bottomed flask with a 500 ml dropping funnel, KPG stirrer, thermometer and acetone/dry ice bath. 142 ml diisopropylamine (1 Mol) in 250 ml abs. ether are added dropwise to it within 2 hours and the temperature is maintained at ca -60° to -65° C. After completing the addition, the thickened pulpy reaction mixture is allowed to reach room temperature and is diluted with about 600 ml abs. ether to make it more easily stirrable. After a further 3 hours stirring at room temperature the precipitate which forms is aspirated over a glass filter and washed several times with ether. After drawing off the ether at normal pressure, it is freed of unreacted PCl3, diisopropylamine and pyridine in a water-jet vacuum and then the remaining oil is fractionally distilled under an oil-pump vacuum (Kp 46° C./0.35 Torr). 73.4 g of the phosphane is obtained which corresponds to 36% of the theoretical yield.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1=S)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:28]([O:27][C:25]([N:8]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 14 h
Yield: 64 %

Procedure:
To 50 ml of a dichloromethane solution of 2.984 g (9.90 mmol) of 1-benzyl-3-[(1R,2S )-2-t-butoxycarbonylcyclopropyl]pyrrolidine (isomer B1) was added 2.83 ml (19.82 mmol) of benzyl chloroformate at room temperature, and the mixture was stirred at the same temperature for 14 hours. To the reaction mixture was further added 1.98 ml (13.86 mmol) of benzyl chloroformate, followed by refluxing for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 2.188 g (64.0%) of the title compound as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2.[OH-].[Na+]>CN(C)C=O>[CH2:13]([O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)c(O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(C=O)c(O)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2,4-Dihydroxy-5-methoxybenzaldehyde (6.0 g), benzyl bromide (9.7 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.6 g) in N,N-dimethylformamide (30 ml) were heated at 100° C. under nitrogen for 5 hours. After cooling to room temperature, 1 N NaOH was added and the mixture washed with ethyl acetate. The water phase was acidified with HCl and the precipitate was filtered.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:12](/[C:14](=[C:8]1/[CH2:7][CH2:6][C:5]2[C:9]/1=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)/[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCc2ccc(F)cc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C#N)=C1\CCc2ccc(F)cc21

Procedure:
The mixture of compound 6-Fluoro-indan-1-one (5 g, 0.03 mol), and ethyl cyanoacetate (5 g, 0.05 mol), ammonium acetate (25 g, 0.33 mol) and glacial acetic acid (50 ml) in toluene (205 ml) was refluxed with a Dean Stark water trap for 4 h. The mixture was concentrated in vacuo, the residue washed by water and EtOH three times to afford the the compound (8.00 g, y=97.96%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[C:23]([O:27][C:28](=[O:37])[NH:29][CH:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:37])[NH:29][CH:30]1[CH2:31][CH2:32][CH:33]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:34][CH2:35]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: CC(C)(C)OC(=O)NC1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([OH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])=[O:19]>O>[C:7]([O:15][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])=[O:19])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCC(=O)c1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.25 h

Procedure:
Potassium carbonate (19 g) was added to a stirred suspension of benzoic acid (34 g) in water (600 ml) and the mixture was warmed gently on a steam bath. After 15 minutes, 2-bromo-2'-nitroacetophenone (68 g) and industrial methylated spirit (1 1) were added. The resultant mixture was heated under reflux for 2 hours, stirred without external heating for 1 0 minutes and then rapidly cooled to 0°-5° in an ice/salt bath with agitation. The mixture was kept at this temperature for 90 minutes and the product was collected by filtration and washed with water to give the novel compound 2-(2-nitrophenyl)-2-oxoethyl benzoate, m.p. 77-80°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:17][CH3:18])[N:10]=[C:9]([S:19][CH3:20])[N:8]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:17][CH3:18])[N:10]=[C:9]([S:19][CH3:20])[N:8]=1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SC)nc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)O)cc1Cl

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-methoxy-2-methylthiopyrimidine (prepared in the above (1)) 271 mg, a 2.0M aqueous sodium hydroxide solution 3.53 ml, water 2 ml and dimethyl sulfoxide 6 ml is stirred at 65° C. for 14 hours. After cooling the reaction mixture is neutralized with a 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo and the resulting powder is triturated with isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder, 210 mg. mp 167–170° C.