Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[CH3:31][NH2:32]>CO>[CH3:31][NH:32][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: CN
Solvent: CO
Product: CNc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 130 °C
Yield: 50 %

Procedure:
A mixture of 6-chloro-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 17) (250 mg, 0.59 mmol) and methylamine (4 ml of a 2M in methanol, 8.0 mmol) was heated at 130° C. for 90 minutes in a sealed vessel under microwave irradiation. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/trifluoroacetic acid (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (126 mg, 50%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)=[CH:10][N:9]=1.C(N(CC)CC)C>O1CCCC1>[Cl:7][C:8]1[N:9]=[C:10]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=2)=[CH:12][N:13]=1
Reactant: COC(=O)Cc1ccc(-c2cnc(Cl)nc2Cl)cc1
Reactant: COC(=O)CS
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CSc1nc(Cl)ncc1-c1ccc(CC(=O)OC)cc1
Reaction time: 4 h

Procedure:
Methyl thioglycolate (0.18 ml) was added to a solution of the product from step (iii) (0.6 g) and triethylamine (0.56 ml) in tetrahydrofuran (10 ml) at room temperature. The mixture was stirred for 4 hours and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 20-30% ethyl acetate in isohexane. Yield 0.7 g.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[C:10]([CH3:29])=[N:11][C:12]3[C:17]([N:18]=2)=[C:16]([C:19]2[NH:23][C:22]4[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=4[CH:20]=2)[CH:15]=[CH:14][CH:13]=3)[CH2:3]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][C:10]1[C:9]([NH:8][C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:3]2)=[N:18][C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]1[NH:23][C:22]2[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=2[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](NS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 9.8 %

Procedure:
A mixture of (R)-2-(3-(((1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483, 52 mg, 0.133 mmol), methanesulfonyl chloride (41.4 μL, 0.533 mmol), and triethylamine (74.2 μL, 0.533 mmol) in DCM (1.33 mL) was stirred at 0° C. for 5 min; the reaction mixture was warmed to RT and stir for 1 h when product was observed via LCMS. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-5% 2 M ammonia in MeOH/DCM to give N-((1R,3S)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinoxalin-2-yl)amino)cyclohexyl)methanesulfonamide (489, 6 mg, 0.013 mmol, 10% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.36 (m, 2H) 1.37-1.51 (m, 2H) 1.59 (d, J=6.65 Hz, 3H) 1.99-2.06 (m, 1H) 2.16-2.23 (m, 1H) 2.39 (d, J=11.15 Hz, 1H) 2.52-2.57 (m, 1H) 2.59 (s, 3H) 3.00 (s, 3H) 3.48-3.59 (m, 1H) 3.99-4.10 (m, 1H) 4.54 (d, J=7.04 Hz, 1H) 4.68 (q, J=6.98 Hz, 1H) 4.97 (d, J=6.65 Hz, 1H) 5.68 (s, 1H) 6.92 (d, J=1.37 Hz, 1H) 7.42 (t, J=7.82 Hz, 1H) 7.69-7.74 (m, 1H) 7.91-7.97 (m, 1H) 12.29 (br. s., 1H). MS (ESI, pos. ion) m/z: 469.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[F:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[F:19])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C(C)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(OCCCC(=O)O)cc1F
Yield: 78.2 %

Procedure:
4-(4-Acetyl-3-fluorophenoxy)butanoic acid, ethyl ester (20 mg, 0.0745 mmol) is dissolved in 1 mL of methanol/water (3:2) and treated with 30.91 mg (0.22 mmol) of potassium carbonate according to the procedure described for Example 4 to give 14 mg (82%) of 4-(4-acetyl-3-fluorophenoxy)butanoic acid as a white powder: m.p. 110°-111° C.; The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 1710, 1670, 1610 cm-1 ; MS m/e calculated for C12H13 O4FNa: 263.0695, found 263.0699.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[N:25]=[C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:31][CH2:30][CH:29]([C:26]3[S:27][CH:28]=[C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[F:17])[N:25]=3)[CH2:34][CH2:33]2)=[O:16])[O:4][N:3]=1
Reactant: Fc1ccccc1-c1csc(C2CCNCC2)n1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCC(c3nc(-c4ccccc4F)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 6 h
Yield: 30.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (109 mg, 0.377 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperidine (90 mg, 0.343 mmol) and diisopropylethylamine (0.120 ml, 0.686 mmol) in dimethylsulfoxide (1.5 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (42.0 mg, 30.6%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]3[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[C:6]([Cl:26])[CH:5]=[CH:4][C:3]=1[N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]([O:34]CC)=[O:33].[OH-].[Na+]>O1CCOCC1>[C:32]([C:28]1[N:27]([C:3]2[CH:4]=[CH:5][C:6]([Cl:26])=[C:7]([CH2:8][O:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[C:19]=3[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]4[N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)[C:2]=2[Cl:1])[CH:31]=[CH:30][CH:29]=1)([OH:34])=[O:33]
Reactant: CCOC(=O)c1cccn1-c1ccc(Cl)c(COc2cccc3c(-n4cccn4)cc(C)nc23)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(=O)O)c3Cl)c2n1
Yield: 79.2 %

Procedure:
To a solution of 1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]-2-ethoxycarbonylpyrrole (395 mg) in 1,4-dioxane (5 ml) was added 1N sodium hydroxide solution (1.8 ml), and the mixture was refluxed for 2 days. The solvent was removed in vacuo and the residue was dissolved in water. The aqueous solultion was washed with diethyl ether and adjusted to pH 5 with 1N hydrochloric acid. The mixture was extracted with chloroform, and the extract was dried over magnesium sulfate and evaporated in vacuo to give 2-carboxy-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (296 mg) as amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH:17](OCC)(OCC)[O:18][CH2:19][CH3:20].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:10](=[CH:17][O:18][CH2:19][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1ccc(I)cc1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccc(I)cc1Cl
Yield: 89.8 %

Procedure:
md) 53.7 g of ethyl 3-(2-chloro-4-iodo-phenyl)-3-oxo-propionate are heated to boiling under reflux for 4 hrs. with 40 g of triethyl orthoformate and 46.1 g of acetic anhydride. The volatile constituents are distilled off in a water-jet vacuum and finally in a high vacuum. 55.9 g (90%) of ethyl 2-(2-chloro-4-iodo-benzoyl)-3-ethoxy-acrylate are obtained as a yellowish oil. Mass spectrum: peaks inter alia at 408 (M+, 4%), 373 (67%), 342 (14%), 335 (100%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.C([O:12][C:13](=[O:25])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]#[CH:24])(C)(C)C.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:25])=[O:12])=[C:17]([C:23]#[C:24][C:2]2[S:3][C:4]([Cl:7])=[CH:5][CH:6]=2)[CH:18]=1
Reactant: Clc1ccc(Br)s1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc(Cl)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-chlorothiophene (Aldrich, 163 mg; 0.82 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 200 mg; 0.75 mmol), dichlorobis(triphenylphosphine)palladium(II) (33 mg; 0.04 mmol), copper(I) iodide (8.6 mg; 0.04 mmol) was degassed during two minutes under nitrogen then THF (3 mL) and triethylamine (208 μL; 1.50 mmol) were added and reaction mixture was stirred at 60° C. for 16 hours. The solvent was evaporated and the residue was treated with an HCl solution (4 N in dioxane, 3.7 mL). After stirring for 16 hours, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown sticky solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:9][C:4]2[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-chloropyridin-3-amine (1.535 g, 7.399 mmol, Asymchem Laboratories, Morrisville, N.C.) was dissolved in pyridine (20 mL), and 4-acetylbenzenesulfonyl chloride (2.436 g, 11.14 mmol) was added. The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (110 C-115 C) and stirred under nitrogen for 2 hours. The reaction was then cooled to room temperature, concentrated, and poured into a biphasic solution of water (40 mL) and DCM (50 mL). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter plug (DCM to 20:1 DCM/MeOH) to afford 4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide. MS (ESI positive ion) m/z: 389 (M+1, 79Br), 391 (M+1, 81Br). Calcd. for C13H10BrClN2O3S: 388 (79Br), 390 (81Br).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]([Cl:23])([Cl:22])[C:18](=N)OC>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:18]([C:17]([Cl:23])([Cl:22])[Cl:16])[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:4]=2[CH:3]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COCCCCNc1cc(F)ccc1N
Solvent: CC(=O)O
Product: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Fluoro-2-(4-methoxybutylamino)aniline (4.28 g) was dissolved in acetic acid (100 ml), methyl 2,2,2-trichloroethanimidate (2.49 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (6.53 g).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:11][Mg]Br>CCOCC>[OH:10][C:1]1([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=C1CCc2ccccc21
Solvent: CCOCC
Product: CC1(O)CCc2ccccc21
Yield: 87.5 %

Procedure:
A solution of 25.05 g (0.190 mol) of 1-indanone in 250 ml of anhydrous ether was added over 45 min to a solution of 81.0 ml (0.243 mol) of 3.0M methyl magnesium bromide in ether under N2 whilst stirring magnetically. After completion of the addition, the reaction was heated to reflux for 40 min, allowed to cool, then quenched with 30 ml of saturated ammonium chloride solution. The ether layer was decanted from a white solid, washed with water (2×100 ml), then with saturated sodium chloride solution (100 ml), dried (K2CO3) and evaporated in vacuo to leave 24.64 g (88%) of the title product as an orange oil. NMR δ(CDCl3) 1.57 (3H, s), 2.16-2.24 (2H, m), 2.77-2.89 (1H, m), 2.97-3.09 (1H, m) 7.23-7.38 (4H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[CH3:42])[O:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([N:30]=[C:31]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[N:32]=2)[CH:29]=1>CN(C)C=O.CN(C)C(=O)C>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:41]([CH3:42])=[C:20]([NH:19][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:21]=4)=[CH:29][N:28]3[N:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Cn1nccc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)c1ccnn1C
Yield: 46.8 %

Procedure:
In the same manner as in Example 55 and using 1-methyl-1H-pyrazole-5-carboxylic acid (86.0 mg, 0.686 mmol), tetrahydrofuran (5 mL), thionyl chloride (118 μL, 1.36 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (125 mg, 47%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].[Br:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([O:11][CH2:16][C:15]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:14]=1[Br:13])=[O:10]
Reactant: Clc1cccc(Br)c1CBr
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1c(Cl)cccc1Br
Yield: 98 %

Procedure:
1 cis/trans 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylic acid (2.3 g), 2-bromo-6-chlorobenzylbromide (2.85 g) and potassium carbonate (1.6 g) were stirred together in acetone (30 ml) under reflux for 6 hours. The reaction mixture was cooled, diluted with water, and extracted three times with 50 ml portions of diethyl ether. The combined ether extracts were washed with water and with aqueous sodium bicarbonate solution (three times), dried over magnesium sulphate and evaporated to give the orange title product (4. g, 98%) m.p. 61°-67° C.
Reaction SMILES: [CH:1]([NH:5][C:6]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH2:3][CH3:4])[CH3:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[CH:1]([NH:5][C:6]([CH2:8][CH:9]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(=O)C=CC(=O)OC
Reactant: NCCCCCCO
Product: CCC(C)NC(=O)CC(NCCCCCCO)C(=O)OC
Reaction time: 8 h

Procedure:
To methyl 3-(sec-butylcarbamoyl)acrylate from the above reaction at room temperature was added the 6-amino-1-hexanol (13.7 g, 117 mmol) and the resulting mixture was stirred overnight to give the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Reactant: c1cncc(B2OCCCO2)c1
Product: O=[N+]([O-])c1ccc(Cl)c(-c2cccnc2)c1
Yield: 68.7 %

Procedure:
3-Bromo-4-chloronitrobenzene (5.17 g, 21.9 mmol) was reacted with pyridine-3-boronic acid-1,3-propanediol cyclic ester (4.27 g, 26.2 mmol) over 24 h, as described in Example 62. The resulting crude residue was purified by column chromatography on silica, using 50% diethyl ether in dichloromethane as the eluent, to yield 3-(2-chloro-5-nitrophenyl)pyridine (3.53 g, 69%): δH (360 MHz, CDCl3) 7.42-7.48 (1H, m), 7.70 (1H, d, J 8.7), 7.81 (1H, dt, J 8.0 and 1.8), 8.17-8.27 (2H, m), 8.68-8.77 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10](N2[C@@H](C(C)C)COC2=O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].OO.[OH-].[Li+].S([O-])([O-])=[O:33].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10]([OH:11])=[O:33])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S([O-])[O-]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A solution of 3-[2(R)-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (560 mg, 1.40 mmol) in tetrahydrofuran (30 mL) and water (10 mL) cooled to 0° C. was treated with a 30% aqueous hydrogen peroxide solution (0.7 mL) and lithium hydroxide (117 mg, 2.80 mmol). The reaction was stirred at 0° C. for 1 h. At this time, the reaction was quenched with an aqueous sodium sulfite solution (0.71 g, 5.6 mmol in 4 mL) followed by the addition of a 0.5N aqueous sodium bicarbonate solution (13 mL). The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (60 mL) and extracted with methylene chloride 3×20 mL). The aqueous layer was then acidified to pH=2 with a 5N aqueous hydrochloric acid solution and then was extracted with ethyl acetate (4×25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2(R)-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (203 mg, 48%) as clear colorless oil.
Reaction SMILES: [C:1]1([S:7]([NH:10][N:11]=[C:12](Cl)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>O1CCCC1>[C:1]1([S:7]([NH:10][N:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])[N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(NN=C(Cl)c1ccccc1Br)c1ccccc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=NNS(=O)(=O)c2ccccc2)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 124.8 %

Procedure:
To a stirred solution, under nitrogen, of α-chloro-2-bromobenzaldehyde phenylsulfonylhydrazone (271.1 g; 720 mmol) in tetrahydrofuran (THF; 2 L), was added dropwise N-methylpiperazine (159.7 g; 1600 mmol). The reaction was stirred at ambient temperature for three hours, and then permitted to stand at ambient temperature for 16 hours. The reaction was chilled in an ice bath, and then filtered to remove the piperazine hydrochloride that was formed. The filtrate was concentrated to yield a brown gum. The gum was triturated with hot acetonitrile, the mixture was cooled in an ice bath, and when cold, was filtered to remove unwanted side product. The filtrate was then concentrated to afford 392.9 g of a brown gum of crude 1-[[(phenylsulfon-yl)hydrazono]-(2-bromophenyl)methyl]-4-methylpiperazine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][NH:11]C(=O)OC(C)(C)C)(=[O:7])=[O:6].O1CCOCC1.[ClH:29]>C(OCC)(=O)C>[ClH:29].[CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][NH2:11])(=[O:6])=[O:7]
Reactant: COCCS(=O)(=O)c1ccccc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)c1ccccc1CN
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(Step 4) tert-Butyl {2-[(2-methoxyethyl)sulfonyl]benzyl}carbamate obtained in Step 3% (15.0 g) was dissolved in ethyl acetate (91 ml), and 4N hydrogen chloride-1,4-dioxane solution (34.2 ml) was added at 0° C. The mixture was stirred at room temperature for 12 hr, and the precipitated crystals were collected by filtration, and washed with ethyl acetate to give 1-{2-[(2-methoxyethyl) sulfonyl]phenyl}methanamine hydrochloride (10.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:11][CH:12]=2)[C:25]#[N:26])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1C
Reactant: C[Si](C)(C)C#N
Product: Cc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3,4-dimethylbenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 91%).
Reaction SMILES: [C:1]1([CH2:11][CH2:12]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1>CN(C)P(N(C)C)(N(C)C)=O>[C:1]1([CH2:11][CH2:12][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCc1cccc2ccccc12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCc2cccc3ccccc23)cc1
Temperature: 110 °C

Procedure:
A solution of 4.7 g. of 2-(α-naphthyl)ethyl bromide and 6.6 g. of ethyl p-aminobenzoate in 50 ml. of hexamethylphosphoramide is stirred and heated at 110° C. for 16 hours. The mixture is cooled, diluted with 50 ml. of water and filtered to give a crude product, which is recrystallized from ethanol. Recrystallization gives ethyl 4-[2-(α-naphthyl)ethylamino]benzoate as white crystals, m.p. 104°-106° C.