Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:21]([CH3:23])[CH3:22])[CH3:20].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([Br:24])[C:3]1([CH:21]([CH3:22])[CH3:23])[CH3:20]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2Br

Procedure:
A solution of ethyl (1-oxo-2-isopropyl-2-methyl-6,7-dichloro-5-indanyloxy)acetate (3.6 g., 0.01 mole, N-bromosuccinimide (2.4 g., 0.0134 mole) and benzoyl peroxide (20 mg.) in carbon tetrachloride is refluxed four hours, cooled and filtered free of succinimide. The solvent is evaporated and the crude product is purified by column chromatography and then recrystallized from cyclohexane to afford substantially pure ethyl (1-oxo-2-isopropyl-2-methyl-3-bromo-6,7-dichloro-5-indanyloxy)acetate, m.p. 83°-85° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9]2.O>CS(C)=O>[CH2:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:5][C:1]#[N:2])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: ClCc1ccc2c(c1)CCC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, partial solution of NaCN (11.4 g, 0.232 mol) in DMSO 75 mL) was added 5-chloromethylindan (35.2 g, 0.211 mol) dropwise over 45 minutes. (The internal temperature was maintained below 65° C.). The resulting mixture was stirred at room temperature overnight. H2O (250 mL) was added and the mixture was extracted with ether. The organic phase was washed with H2O (200 mL), 6N HCl (100 mL), H2O (200 mL), saturated aqueous NaHCO3 (100 mL), and saturated aqueous NaCl, dried (MgSO4), and concentrated. The crude product was distilled under reduced pressure (0.6 mm) to give 28.1 g (85%) as a colorless oil, b.p. 131°) C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:26][CH2:25]2)=[C:20]([C:34]([F:37])([F:36])[F:35])[CH:19]=1.B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:6]5[CH:7]=[N:8][C:9]6[C:4]([CH:5]=5)=[CH:3][CH:2]=[CH:11][CH:10]=6)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:19][C:20]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)(=[O:33])[CH2:31][CH3:32]
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
To a solution of compound 5.2 ethyl 6-chloro-4-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)quinoline-3-carboxylate (1 g, 1.6 mmol, lequiv.) in dioxane (5 mL) at room temperature was sequentially added 3-qunionline boronic acid 5.3 (350 mg, 2 mmol, 1.1 equiv.), PdCl2(Ph3P)2 (130 mg, 0.19 mmol, 0.1 equiv.), t-Bu-Xphos (78 mg, 0.19 mmol, 0.1 equiv.) and Na2CO3 (1N, 5.5 mL, 5.5 mmol, 3 equiv.). The mixture was degassed, sealed under argon, and heated overnight at 100° C. Upon cooling to room temperature, the mixture was diluted with EtOAc (20 mL), filtered through celite, and washed with EtOAc (20 mL×2). The resulting solution was concentrated and the residue was purified via flash chromagraphy (CH2Cl2:MeOH=30 :1) to afford the desired product 5.4 ethyl 4′-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylate (360 mg; 31%). LC-MS: (M+H): 535.20
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]([CH2:11][C:12]23[CH2:19][CH2:18][CH2:17][N:16]2[C:15](=[O:20])[N:14]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:13]3=[O:29])=[CH:9][CH:8]=1)=[O:6]>CO.O.O>[Cl:28][C:23]1[CH:22]=[C:21]([NH:14][C:15]([N:16]2[CH2:17][CH2:18][CH2:19][C@@:12]2([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([OH:4])=[O:6])=[CH:31][CH:30]=2)[C:13]([OH:1])=[O:29])=[O:20])[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C[C@@]2(C(=O)O)CCCN2C(=O)Nc2cc(Cl)cc(Cl)c2)cc1
Temperature: 45 °C
Yield: 87.2 %

Procedure:
NaOH (0.406 g) was added to a solution of 5-(4-methoxycarbonylbenzyl)-3-(3,5-dichlorophenyl)-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.601 g) in MeOH/H2O (20 mL/4 mL) and the mixture was heated at 45° C. for 18 hours. The reaction mixture was cooled, acidified, diluted with water and extracted with EtOAc. The extract was washed with water, brine, dried (MgSO4), filtered, and concentrated. The residue was recrystallized from EtOAc/hexane (1:1) to give N-[N-(3,5-dichlorophenyl)carbamoyl]-2-(4-carboxybenzyl)proline (0.529 g). mp. 144.6° C.; MS (m/z) 459 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1.C(Cl)Cl>[C:27]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Reaction time: 60 h
Yield: 88.1 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (200 mg, 0.54 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added benzoyl chloride (94 μL, 0.81 mmol). Upon complete addition the reaction mixture was stirred for 60 h, then quenched with 10% aqueous HCl (15 mL). The mixture was partitioned between H2O (35 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with NaHCO3 (35 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a colourless solid (225 mg, 88%): 1H NMR (400 MHz, CDCl3, □ in ppm) 8.05 (dm, J=7.2 Hz, 2H), 7.91 (dm, J=7.2 Hz, 2H), 7.62 (tt, J=1.2, 7.4 Hz, 1H), 7.55-7.41 (m, 5H), 7.39 (d, J=8.6 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.81 (pentet, J=6.3 Hz, 1H), 5.38 (d, J=7.6 Hz, 1H), 5.21 (dd, J=5.9, 7.4 Hz, 1H), 2.31 (s, 3H), 1.50 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.CN.[C:16]([BH3-])#[N:17].[Na+].Cl>CO.O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:16][NH2:17])[CH2:7][CH2:6]2
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCC(CN)C2
Yield: 41.9 %

Procedure:
A solution of 6-methoxy-3,4-dihydro-1H-naphthalen-2-one (176 mg, Aldrich, U.S.A.), acetic acid (0.57 mL), methylamine (2.0 M in tetrahydrofuran, 5.0 mL), and sodium cyanoborohydride (64 mg) was stirred in 5 mL methanol for 20 h. The solution was acidified to a pH<2 with concentrated hydrochloric acid, diluted with water to a volume of 50 mL, and extracted with 50 mL of dichloromethane. The aqueous phase was made basic (pH>10) by the addition of 1 M sodium hydroxide and extracted with two 50 mL aliquots of dichloromethane. The basic dichloromethane extracts were dried in vacuo to yield 80 mg of (6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)methylamine.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:14]=1[CH:15]=[N:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:40][NH:41]2)C1C=CC=CC=1)C>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:13]([CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][C:4]([NH:41][CH3:40])=[O:24])=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ncc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ncc12

Procedure:
3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide CXCIX was prepared from 3-(7-methoxy-1H-indazol-4-yl)-3-phenyl-propionic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4). Part of the crude 3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide CXCIX was used without further purification for the next step. A second portion of3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide was purified on chiral HPLC by multiple injections onto 20×250 mm Chiralpak AD preparative column using a mixture of 70/30 hexane/EtOH at 7 ml/min in order to separate the enantiomers CXCIX-A and CXCIX-B.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[N:29]([CH2:35][CH:36]1[CH2:38][CH2:37]1)[CH:28]=[C:27]2[C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.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>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:37][CH2:38]3)[CH:28]=[C:27]4[C:39]([O:41][CH3:42])=[O:40])[CH:7]=2)=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Temperature: 80 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.24 g) [prepared as described in US2005020590], the product of step iii) (4.3 g), tetrakis(triphenylphosphine)palladium(0) (1.5 g) and potassium carbonate (3.54 g) in DMF (50 mL) was heated to 80° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate and evaporated. The crude product was purified (SiO2, 50 to 70% ethyl acetate in isohexane as eluent) to yield the sub-title compound (2.5 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[N:13]=[C:12]2[NH:25][C:26]1[S:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[N:30]=1)C1C=CC=CC=1.C1(C(=CC=CC=1)O)O.COC.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[N:30]=[C:26]([NH:25][C:12]3[C:11]4[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=4)[N:15]=[C:14]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:13]=3)[S:27][CH:28]=2)=[CH:32][CH:33]=1
Reactant: Clc1ccc(-c2csc(Nc3nc(-c4cccnc4)nc4ccc(OCc5ccccc5)cc34)n2)cc1
Agent: COC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: O
Product: Oc1ccc2nc(-c3cccnc3)nc(Nc3nc(-c4ccc(Cl)cc4)cs3)c2c1
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of N-(6-(benzyloxy)-2-(pyridin-3-yl)quinazolin-4-yl)-4-(4-chlorophenyl)thiazol-2-amine and catechol, dimethyl ether (0.16 g, 1.15 mmol) was added methanesulfonic acid (4.0 mL). The mixture was stirred for 1 hr and was then poured into water. The slurry was added to a stirring sat. NaHCO3(aq), solution slowly and allowed to stir for 30 min. The precipitate was filtered to give a brown solid which was washed with methanol to give 4-(4-(4-chlorophenyl)thiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol (0.23 g, 91.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>ClCCl>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])=[CH:7][N:6]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2CC2)cn1
Reaction time: 1 h

Procedure:
5-Amino-2-methoxy pyridine (12.4 grams, 0.10 mole) and 10 milliliters (ml) of pyridine were mixed together in 200 ml dichloromethane in a reaction flask. 9.1 ml (0.10 mole) of cyclopropane carboxylic acid chloride was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and temperature rose to 34° C. The reaction was allowed to stand for one hour at room temperature, after which the reaction mixture was washed with 200 ml of 5% sodium hydroxide and 100 ml water. The resulting organic phase was separated and dried over anhydrous magnesium sulfate. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated in vacuo to give a solid that was triturated with hexane to yield 16.7 grams, after drying. The product was identified by IR and NMR as the title compound, having a melting point of 130°-131° C. This compound will be referred to as Compound 1.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH:18]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Cl:28])([CH3:16])[C:14](=[O:29])[CH:13](Br)[CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=O)C.[OH2:31].[OH-].[Na+].Cl>N1C=CC=CC=1>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:18]1[CH2:17][C@@:15]2([CH3:16])[C@@H:11]([CH2:12][CH:13]([OH:31])[C:14]2=[O:29])[C@H:10]2[C@H:19]1[C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=1[CH2:8][CH2:9]2
Reactant: O
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2C(CCCCCCl)C[C@]2(C)C(=O)C(Br)C[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: C[C@]12CC(CCCCCCl)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC(O)C2=O

Procedure:
A solution of 15.3 g of crude 3-acetoxy-16-bromo-11-(5-chloropentyl)-estra-1,3,5(10)-trien-17-one in 237 ml of pyridine is mixed with 79 ml of water and then with 50 ml of sodium hydroxide solution (1N) and stirred for 24 hours at room temperature. Then, 25 ml of hydrochloric acid (2N) is added, it is evaporated to the dry state in a vacuum, diluted with 11 of ethyl acetate, washed with hydrochloric acid (2N), washed neutral with water, washed with common salt solution, dried on sodium sulfate and evaporated to the dry state in a vacuum. 4.2 g of crude 11-(5-chloropentyl)-3,16-dihydroxy-estra-1,3,5(10)-trien-17-one is obtained, and after chromatography on silica gel with hexane/ethyl acetate, 2.5 g of pure 11-(5-chloropentyl)-3,16-dihydroxy-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Sn](C)(C)C)=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:36][C@H:35]([CH2:37][N:38]3[CH:42]=[C:41]([CH3:43])[N:40]=[N:39]3)[O:34][C:33]2=[O:44])=[CH:28][CH:27]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:36][C@H:35]([CH2:37][N:38]5[CH:42]=[C:41]([CH3:43])[N:40]=[N:39]5)[O:34][C:33]4=[O:44])=[CH:28][CH:27]=3)=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)cc3)C(=O)O2)nn1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc([Sn](C)(C)C)cc2)=NO1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO[Si](C)(C)C(C)(C)C)C5)cc4)cc3)C(=O)O2)nn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]4,5-dihydroisoxazole (0.70 g, 1.6 mmol), (5R)-3-(4-iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (0.5 g, 1.29 mmol), tri-2-furyl phosphine (0.06 g, 0.26 mmol) and tris(dibenzylideneacetone)palladium (0) (0.12 g, 0.13 mmol) were dissolved in 1,4-dioxane (5 ml) and degassed three times. The mixture was then heated to 90° C. and stirred for 18 hr. LCMS indicated that the reaction was not yet complete, so it was cooled and an additional (0.12 g, 0.13 mmol) of tris(dibenzylidene acetone) palladium (0) was added, the mixture degassed and reheated to 110° C. for 3 hours, and 25° C. for 40 hours. The solution was concentrated in vacuo and purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent giving 0.2 g of the desired product as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].[NH:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:12]([C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[NH:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:12]([C:22]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:23])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an aqueous solution containing 6.80 g of H-Gly-OH and 9.20 g of sodium hydrogen carbonate, under ice-cooling condition, was added 120 ml of THF solution containing 27.5 g of Boc-Ser(Bzl)-OSu, and the mixture was stirred at room temperature overnight.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1([O:20][C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:20])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.2.). Starting with 6 g (24.80 mmol) of 1-(5-bromo-2-pyridyl)piperazine, obtained in step 3.2., and 10.88 g (48.52 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate, prepared in step 1.1. of Example 1, and after chromatography on silica gel, eluting with a 15/85 and then 30/70 mixture of ethyl acetate and cyclohexane, 6.70 g of product are obtained in the form of an oil that crystallizes to a white solid.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:2]=1.C(N(CC)CC)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[Cl:7][C:6]1[CH:1]=[CH:2][C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])=[C:4]([O:8][C:34](=[O:35])[CH2:33][O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(COCc1ccccc1)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of triclosan (7.53 grams, 26 mmol) and triethylamine (8.2 grams, 81 mmol) in acetone (50 mL) at 0° C. was added benzyloxy acetyl chloride (10 grams, 54.2 mmol) drop wise. The reaction mixture was stirred at room temperature for 18 hours. Solids were filtered off and poured onto cold water (100 mL). Crude 4 was extracted into chloroform, washed with 5% sodium bicarbonate solution (2×50 mL), and water (2×50 mL). The chloroform layer was dried over sodium sulphate and distilled off to get crude 4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7](Br)[CH:6]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1B(O)O)=[O:16]>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[CH:21]=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:17]=2[CH:15]=[O:16])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(Br)c1
Reactant: COc1ccc(C=O)c(B(O)O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2cc(OC)ccc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-4-methoxy-phenyl)-acetic acid methyl ester and 2-formyl-5-methoxyphenylboronic acid.
Reaction SMILES: Br[C:2]1[N:3]([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][N:6]=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(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>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:2]1[N:3]([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3Br)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3cccs3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of 3-[3-(2-bromoimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (22 mg, 0.0431 mmol; see example 11 (b)) in toluene (5 mL) and ethanol (0.5 mL) was added 2-thienyl boronic acid (27.6 mg, 0.216 mmol), Pd(PPh3)4 (3.0 mg, 2.59 μmol) and NaOH (0.17 mL, 0.26 mmol, 1.5 M aq), and the reaction mixture stirred for 4 h at 90° C. Another portion of 2-thienyl boronic acid (27.6 mg, 0.216 mmol) and Pd(PPh3)4 (3.0 mg, 2.6 mmol) was added and the reaction was stirred overnight at 90° C. The reaction mixture was diluted with EtOAc (30 mL) and washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:hexane (7:3) as eluent to give the sub-title compound in 90% yield (20 mg, 0.039 mmol).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([C:15](Cl)=[O:16])[S:11][N:10]=1.Cl>O1CCCC1>[C:1]([CH:3]([C:15]([C:12]1[S:11][N:10]=[C:9]([Cl:8])[C:13]=1[Cl:14])=[O:16])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C(=O)c1snc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of methyl cyanoacetate (1.98 g) in unhydrous tetrahydrofuran (20 ml) 60% sodium hydride (1.6 g) was added at a temperature below 10° C. To the reaction mixture a solution of 3,4-dichloro-5-isothiazolecarbonyl chloride (4.30 g) in unhydrous tetrahydrofuran (15 ml) was added dropwise at the same temperature. After finishing the addition, the reaction mixture was stirred at room temperature for 2 hours and 1N-aqueous hydrochloric acid (10 ml) was added. After extraction with ethyl acetate and drying the organic phase with unhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain methyl 2-cyano-3-(3,4-dichloro-5-isothiazolyl)-3-oxopropanoate (4.7 g) as pale yellow crystals. mp 119-122° C.