Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[O:34])[CH3:23])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:22]([CH3:23])[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([OH:6])=[O:34])=[O:35])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CN(CCOc1ccccc1C=O)C(=O)OC(C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCOc1ccccc1C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 124.1 %

Procedure:
A solution of sodium chlorite (2.85 g; 31.5 mmol; 5.5 eq.) and sodium dihydrogenphosphate (2.47 g; 20.6 mmol; 3.6 eq.) in water (25 mL) was added dropwise to a mixture of 2-methyl-2-butene (5.7 mL) and [2-(2-formyl-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.6 g; 5.73 mmol; 1 eq.) in 1,4-dioxane (25 mL). The reaction mixture was stirred at room temperature for 1.5 hour. After dilution with EA, the solution was washed with 1M HCl, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (2.1 g, 93%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.66-7.59 (dd, J=7.7, 1.8 Hz, 1H), 7.52-7.42 (m, OH), 7.16-7.10 (d, J=8.4 Hz, 1H), 7.03-6.94 (td, J=7.5, 1.0 Hz, 1H), 4.18-4.07 (m, 1H), 3.54-3.48 (t, J=5.4 Hz, 2H), 2.96-2.86 (d, J=11.7 Hz, 3H), 1.42-1.31 (m, 9H).
Reaction SMILES: [CH3:1][CH2:2][CH3:3].C=CC.[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:2]([CH3:3])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC
Reactant: c1ccccc1
Solvent: C=CC
Product: CC(C)c1ccccc1

Procedure:
An integrated process is disclosed for (i) catalytically cracking (FCC) a heavy hydrocarbon feedstock, (ii) obtaining a combined propane/propylene stream, and (iii) reacting the propylene of the combined propane/propylene stream with benzene to produce a cumene product stream. The integrated process comprises contacting a heavy hydrocarbon feedstock with a hydrocarbon cracking catalyst in a fluidized reactor zone to produce a hydrocarbon effluent stream that includes propane and propylene. The process then further comprises separating the combined propane/propylene stream from the hydrocarbon effluent stream, passing the combined propane/propylene stream to an alkylation reactor, and reacting at least some of the propylene of the combined propane/propylene stream with benzene in the alkylation reactor to produce cumene.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]([F:21])([F:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[I-].[NH3:24].C1(S(O)(=O)=O)C=CC=CC=1>C(OC(C)C)(=O)C.CS(C)=O>[C:5]1([S:8]([OH:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1.[F:20][C:13]([F:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:12][NH2:24]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)c2ccccn2)cc1
Reactant: N
Agent: O=S(=O)(O)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)C
Product: NCC(F)(F)c1ccccn1
Temperature: 80 °C

Procedure:
10 g of 2,2-Difluoro-2-pyridin-2-ylethyl 4-methylbenzenesulfonate (J) obtained in step 3, 5 g of NaI, 20 mL of DMSO and 90 mL of aqueous ammonia were taken in a 500 mL autoclave vessel. The reaction mixture was heated to 80° C. and a pressure of 15 to 17 kg of ammonia maintained for 30-40 hours. The volume of the reaction mass was reduced by vacuum distillation. The RM was washed with 60 mL of IPE. The pH of the RM was adjusted to 10-14 by adding a 50% NaOH solution and extracted three times with 60 mL of MDC. The combined MDC layers were washed with brine, dried over sodium sulphate and distilled under vacuum (crude weight=8 g). The crude mass obtained was dissolved with 10 mL of MDC, and to this 4.5 g benzene sulphonic acid (BSA) dissolved in 30 mL isopropyl acetate (IPAc) was added dropwise over a period of 30 minutes with stirring at RT. The RM was stirred for 30 minutes at RT. The solid obtained was filtered and washed with IPAc and dried under vacuum, resulting in 5 g of the titled compound (Yield=49.5%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10]Br>C(Cl)(Cl)(Cl)Cl>[Br:10][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[S:1][CH:5]=1
Reactant: BrBr
Reactant: c1ccc2sccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1csc2ccccc12
Yield: 48.4 %

Procedure:
Dissolve benzo[b]thiophene (23 g, 0,170 mmol) in carbon tetrachloride (80 mL). Add, by dropwise addition, a solution of bromine (26.85 g, 0,168 mmol) in carbon tetrachloride (30 mL) and stir at room temperature for 2 days. Quench with a 1M solution of sodium thiosulfate and separate the organic phase. Extract the aqueous phase with carbon tetrachloride, combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by distillation to give 3-bromobenzo[b]thiophene as a pale yellow liquid (17.33 g, 48%); bp 64°-72° C. @ 0.02 mm Hg.
Reaction SMILES: C1(=O)OCCC1.[NH2:7][CH2:8][C:9](O)=O.[N:12]1([CH2:18][C:19]([OH:21])=O)[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(CN)O>>[O:21]1[CH2:9][CH2:8][N:7]=[C:19]1[CH2:18][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]
Reactant: O=C(O)CN1CCCC1=O
Reactant: NCC(=O)O
Solvent: O=C1CCCO1
Solvent: NCCO
Product: O=C1CCCN1CC1=NCCO1

Procedure:
--[(2-oxazolin-2-yl)methyl]-2-pyrrolidone, for example, can be obtained by condensation of pyrrolidone and chloroacetic acid to form 2-pyrrolidone acetic acid, where m =I in the above formula (II), or, alternatively, by condensing butyrolactone with glycine, and the starting carboxylic acid condensed with ethanolamine and cyclodehydrated to form 1-[(2-oxazolin-2-yl)methyl]-2-pyrrolidone.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([N:10]1[C:14]2[CH2:15][C:16](=[CH:19]O)[C:17](=O)[C:13]=2[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[C:14]2[CH2:15][C:16]3[CH:19]=[N:2][NH:1][C:17]=3[C:13]=2[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C(=CO)Cc2c1cnn2Cc1ccccc1
Reactant: NN
Solvent: CO
Product: c1ccc(Cn2ncc3c2Cc2cn[nH]c2-3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
Hydrazine (0.07 ml) was added dropwise to an ice-cold solution of 0.5 g of 1-benzyl-5,6-dihydro-5-hydroxymethylene-4(1H) cyclopentapyrazolone in 25 ml of methanol. The solution was heated at reflux for 2 hours and then cooled to room temperature and stirred for 16 hours. An additional 0.07 ml of hydrazine was added and the solution was heated at reflux for 8 hours. Removal of the solvent under reduced pressure gave 1-benzyl-4,7-dihydro-1H-cyclopenta-[1,2-c:3,4-c']dipyrazole as an orange-red solid (86% yield) melting at about 61°-72° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]1([C:13]2[O:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:7]1([C:13]2[O:22][C:21]3[CH2:20][CH2:19][CH2:18][N:17]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:16][C:15]=3[CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(-c2cc3c(o2)CCCNC3)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1CC1)N1CCCc2oc(-c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1.8 g. of cyclopropylcarbonyl chloride in 50 ml. of dry chloroform is added dropwise to a cooled mixture of 3.1 g. of 2-phenyl-4,6,7,8-tetrahydrofuro[3,2-c]azepine and 1.7 g. of triethylamine in 50 ml. of dry chloroform. After addition, the reaction mixture is stirred at ambient temperature for 20 hours, washed with water and dried. The chloroform is removed and the residue is triturated with n-hexane to produce a solid product. The product is recrystallized from n-hexane to give 2-phenyl-5-cyclopropylcarbonyl-4,6,7,8-tetrahydrofuro[3,2-c]azepine, m.p. 108°-110°C.
Reaction SMILES: [O:1]=[C:2]([NH:11][NH:12][C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])[CH2:3][CH2:4]C1C=CC=CN=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][S:37]CCC(NN)=O.ClC1C=CC2OC3C=CC=CC=3CN(C(Cl)=O)C=2C=1>>[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][S:37][CH2:4][CH2:3][C:2]([NH:11][NH:12][C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])=[O:1]
Reactant: O=C(CCc1ccccn1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: NNC(=O)CCSCc1ccco1
Agent: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCSCc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,41oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)thio]-1-oxopropyl]hydrazide (13) was prepared in the manner 8-chlorodibenz[b,f]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(2-pyridinyl)propyl]hydrazide (6) was prepared, as described above in Example 6, from 3-[(2-furanylmethyl)thio]propanoic acid, hydrazide (12), prepared as described above in Example 12, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, on a 10 mmol scale. The yield was quantitative. Analysis calculated for C22H20N3O4SCl (M.W. 457.94): C, 57.70; H, 4.40; N, 9.18; Cl, 7.74; S, 7.00. Found: C, 57.59; H, 4.36; N, 9.01; Cl, 7.95; S, 7.07.
Reaction SMILES: [C:1]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][O:23][CH3:24])=[CH:18][C:17]([O:25][Si](C(C)C)(C(C)C)C(C)C)=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:1]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][O:23][CH3:24])=[CH:18][C:17]([OH:25])=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(O)cc3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
530 mg of 3-benzoyl-6-triisopropylsilyloxy-4-methoxymethyl-beta-carboline was dissolved in 7.5 ml of absolute tetrahydrofuran and stirred for 0.5 hour under argon at room temperature after adding 1.1 ml of a 1.1 molar tetrabutylammonium fluoride solution in tetrahydrofuran. After adding ethyl acetate, the organic phase was washed with saturated common salt solution, dried and concentrated by evaporation. 315 mg of the title compound was obtained after absorptive precipitation with ethyl acetate/petroleum ether, melting point 258° C.
Reaction SMILES: [Na].Br[CH:3]([CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)(C)(C)C.C1C=CC=CC=1>[Cl:15][C:14]([Cl:17])([Cl:16])[CH2:13][CH:3]1[C:4]([CH3:12])([CH3:11])[CH:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Cl)(Cl)Cl
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: CCOC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Yield: 85.9 %

Procedure:
To a solution of 46 mg of sodium in a mixture of 12 ml of t-butanol and 6 ml of benzene was added, at room temperature, 709 mg of ethyl 4-bromo-6,6,6-trichloro-3,3-dimethylhexanoate. The mixture was treated as described in Example XII A to produce 470 mg (86% yield) of ethyl 2-(β,β,β-trichloroethyl)-3,3-dimethylcyclopropanecarboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:31]([NH:35][S:36](Cl)(=[O:38])=[O:37])([CH3:34])([CH3:33])[CH3:32]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([O:11][S:36](=[O:38])(=[O:37])[NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Reactant: CC(C)(C)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OS(=O)(=O)NC(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added 1.10 g (3.20 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR), Et2O (50 mL), and 0.90 mL (6.40 mmol) of NEt3, in that order. The solution was cooled to 0° C. To this solution was rapidly added a solution of 1.10 g (6.40 mmol) of (tert-butyl amino)sulfonyl chloride (Matler, W. L., Comer, W. T., and Deitchman, D., Journal of Medicinal Chemistry, 1972,15 (5), 538-541) in Et2O (10 mL). A precipitate ensued and the reaction was allowed to stir for 30 minutes. Another two equivalents of (tert-butyl amino)sulfonyl chloride (1.10 g, 6.40 mmol) in Et2O (10 mL) and NEt3 (0.90 mL, 6.40 mmol) were added, and the reaction mixture was stirred for another 30 minutes. The reaction was quenched with brine and the organics extracted with Et2O. The organics were dried (MgSO4) and concentrated. The residue was submitted to flash chromatography (EtOAc:CHCl3 1:9) to yield the title compound. 1H NMR (CDCl3) δ 1.23 (s, 9 H), 1.46 (s, 9 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 4.63 (br s, 1 H), 7.23 (s, 1 H), 7.26 (s, obscured by CDCl3, 1 H), 7.42 (d, 2 H), 7.46 (d, 2 H).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCCN1CCC(c2cccc(Cl)c2)CC1
Reactant: ON=C1CCCCCC1
Product: Clc1cccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)c1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(3-chlorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(3-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: F[C@@H]1CCNC1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:32][C@@H:33]([CH2:37][CH3:38])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:32][C@@H:33]([CH2:37][CH3:38])[C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: CC[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol) in CH2Cl2 (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed by the addition of (S)-2-hydroxybutanoic acid (105 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one (300 mg, 95%). LC/MS: m/z 407.5 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.92 (d, J=7.0 Hz, 1H), 4.28 (q, J=6.5 Hz, 1H), 3.89 (m, 8H), 2.52 (s, 3H), 1.67 (m, 1H), 1.51 (m, 1H), 0.91 (t, J=7.4 Hz, 3H)
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH2:20])=[NH:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:9])[F:8].CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=O.[OH-].[Na+]>CC(O)C>[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:20]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH:25]=[CH:24][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:8])[F:9]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccc(Cl)cc3)n2)c1
Temperature: 25 °C

Procedure:
539 mg (2.15 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to a solution of 450 mg (2.15 mmol) of 3-dimethylamino-1-(4-chloro-phenyl)-2-propen-1-one in 5.5 ml of 2-propanol. After the addition of 94.5 mg (2.36 mmol) of sodium hydroxide, the reaction mixture is boiled under reflux for 29 h. After cooling to RT, the product is isolated by filtration and washed with 1-propanol and water. After drying at 60° under HV, N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(4-chloro-phenyl)-2-pyrimidineamine is obtained; Rf =0.45 (methylene chloride:methanol =98:2), MS: 397 (M+), m.p. 133°-135°.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].Cl[Si](C)(C)C.Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>CN(C=O)C.C(N(CC)CC)C>[OH:6][CH2:1][CH2:2][CH2:3][C:4]#[C:5][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: C#CCCCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCO)c21
Temperature: 70 °C

Procedure:
Using Method I above, 4-pentyn-1-ol (40 mg, 0.57 mmol) (Aldrich) was dissolved, under argon, in 3 mL DMF and 2 mL triethylamine, and to this solution was added chlorotrimethylsilane (0.13 mL, 1 mmol) (Aldrich). The reaction was stirred at room temperature for 1 h, at which time (Z)-4-bromo-1,3-dihydro-3-1(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) was added and the solution was degassed for 15 min by bubbling argon through the solution. (Ph3P)2PdCl2 (15 mg) (Aldrich) and Cul (7 mg) (Aldrich) were added and the reaction was heated at 70° C. for 14 h. The reaction mixture was then poured into 25 mL 1 N HCl and the yellow precipitate was filtered off. The product was purified via flash column chromatography to obtain (Z)-1,3-dihydro-4-(5-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 55 mg, 45%).
Reaction SMILES: [O:1]1CCCC1.[Si:6]([O:13][C@@H:14]([C@@H:16]1[C@@H:19]([C@@H:20]([CH3:40])[C:21](C2C=C(C)C=CC=2S(NC2CCCCC2)(=O)=O)=[O:22])[NH:18][C:17]1=[O:41])[CH3:15])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH-].[Na+]>O>[Si:6]([O:13][C@@H:14]([C@@H:16]1[C@@H:19]([C@@H:20]([CH3:40])[C:21]([OH:22])=[O:1])[NH:18][C:17]1=[O:41])[CH3:15])([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:7])[CH3:8]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCC2)c(C(=O)[C@H](C)[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O
Reaction time: 3 h
Yield: 69 %

Procedure:
To a tetrahydrofuran solution (2:1, 3.5 ml) of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-N-cyclohexyl-p-toluenesulfonamide (218 mg, 0.4 mmol, β:α=88:12), 0.5N aqueous sodium hydroxide (1.8 ml) was added dropwise at room temperature, followed by stirring for 3 hours at the same temperature. To the reaction mixture, 5 ml of water was then poured and the resulting mixture was washed with methylene chloride. The aqueous layer was acidified to pH 2 with 2N-hydrochloric acid. The crystals so precipitated were collected by filtration, washed with water, and then dried under reduced pressure, whereby 84 mg (β:α=89:11) of the colorless title compound was obtained (yield: 69%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C

Procedure:
A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10-24 hours. The reaction mixture was cooled to 60° C. and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil, which was carried on in the next step without purification.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[O:9]=[C:7]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)SC/C(=C\c1ccccc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(=O)SC/C(=C\c1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Yield: 78 %

Procedure:
The (Z)-2-acetylthiomethyl-3-phenylpropenoic acid described in Example 1 (step B) is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 78% (after recrystallization in ether) m.p. 80° C. IR: 3380, 1720, 1670, 1630, 1600 cm-1 1H NMR (CDCl3): 7.60 (s, 1H); 7.45 to 7.15 (m, 10H); 6.90 (broad t, 1H; 5.15 (s, 2H); 3.95 (s, 2H); 3.65 (q. app., J:6.1 Hz); 2.65 (t, 2H, J=6.1 Hz); 2.35 (s, 3H). Microanalysis: C22H23NO4S Calc. % C=60.48 H=5.83 N=3.52 Found. % C=66.29 H=5.78 N=3.51
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.CO.[NH3:15]>>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH2:15])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N)n1
Yield: 84 %

Procedure:
A solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in methanol (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65° C. for 18 h. The reaction was cooled down and the solid filtered off and washed with water (2×100 ml). The solid was dried in the vacuum oven at 40° C. overnight to afford the product as a bright yellow solid (52.14 g, 84% purity by NMR, 74%).