Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:57])C(=O)C1>CC#N>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:57])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Solvent: CC#N
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Cl)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (56 mg, 0.083 mmol, 1 equiv) in MeCN (1 mL) was added NCS (11 mg, 0.083 mmol, 1 equiv). After 1 h, the reaction was concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (51 mg, 87%) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.40 (t, J=1.5 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.31 (s, 1H), 7.03 (d, J=10.3 Hz, 1H), 6.87 (d, J=6.8 Hz, 1H), 6.28-5.83 (m, 1H), 4.54-4.46 (m, 1H), 4.12-4.06 (m, 1H), 3.71 (s, 3H), 3.62-3.57 (m, 1H), 3.49-3.42 (m, 1H), 3.31 (br. s., 1H), 2.48 (s, 3H), 2.48-2.36 (m, 1H), 2.31 (d, J=1.3 Hz, 3H), 2.17-2.09 (m, J=6.0 Hz, 1H), 2.00-1.61 (m, 10H), 1.29 (s, 3H), 1.26 (s, 9H), 1.11 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1):706.25.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38](=[NH:55])[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:42]2>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:55]=[C:38]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[NH:44][C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:42]4)[N:37]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CCc1cc2cc(C(=N)NO)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (150 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 10 min. ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (193 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 6 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was recrystallized from ethanol to afford ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D33) (95 mg) as a light pink solid. MS (ES): C24H24ClN3O4 requires 453; found 454.0 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:13]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: COc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
1.0 mL of methylene chloride, 2.7 pit of N,N-dimethylformamide and 0.061 mL of oxalyl chloride were added to 0.11 g of 2-methoxybenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 4.0 mL of methylene chloride and 0.45 mL triethylamine containing 57 mg of tert-butyl 2-amino-4-phenoxybenzoate and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-methoxybenzamido)-4-phenoxybenzoate.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]3[N:11]([S:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)(=[O:14])=[O:13])[CH:9]([CH:10]=2)[CH2:8][C:7](=[O:25])[CH2:6]3)[CH2:3][CH2:2]1.[CH3:26][N:27]([CH:29](OC)OC)[CH3:28]>>[CH:1]1([C:4]2[CH:5]3[N:11]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)(=[O:14])=[O:13])[CH:9]([CH2:8][C:7](=[O:25])[C:6]3=[CH:26][N:27]([CH3:29])[CH3:28])[CH:10]=2)[CH2:2][CH2:3]1
Reactant: O=C1CC2C=C(C3CC3)C(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1C(=O)CC2C=C(C3CC3)C1N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
6-Cyclopropyl-8-(4-(trifluoromethyl)phenylsulfonyl)-8-azabicyclo[3.2.1]oct-6-en-3-one (1.02 g, 2.74 mmol), was dissolved in DMF-DMA (6 mL) and heated to 100° C. for 4 h. The reaction mixture was concentrated under vacuum to give compound 117. MS (ESI) 427.1 (M+H)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[CH:7]=[N:8]/[N:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:23]1([C:29](=[N:36][NH2:37])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:11]1([C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]/[N:8]=[CH:7]/[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[NH:37][N:36]=[C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: Brc1ccsc1/C=N/N=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C(=N/N=C(c1ccccc1)c1ccccc1)\c1sccc1NN=C(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 14 h
Yield: 78.8 %

Procedure:
To a mixture of (E)-1-((3-bromothiophen-2-yl)methylene)-2-(diphenylmethylene)hydrazine (15 g, 40.6 mmol, including its Z isomer) and (diphenylmethylene)hydrazine (9.57 g, 48.7 mmol) in toluene (125 mL) was added palladium(II) acetate (0.120 g, 2.031 mmol), 1,1′-bis(diphenylphosphino)ferrocene (2.252 g, 4.06 mmol) and Cs2CO3 (26.5 g, 81 mmol). The reaction mixture was stirred at 85° C. for 14 hours and was subsequently diluted with toluene (25 mL) and filtered to remove undissolved solids. The filtrate was purified by flash column chromatography. The pure product fractions were evaporated to give the title compound (15.5 g, 79%). ESI-MS m/z [M+H]+ calc'd for C31H24N4S, 485. found, 485.
Reaction SMILES: Cl.CO[C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1>C(O)C>[CH2:7]([N:6]1[CH2:5][C:4](=[O:14])[CH:24]([C:23](=[O:27])[CH3:22])[C:25]1=[O:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C1CC(=O)O1
Reactant: COC(=O)CNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C1C(=O)CN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
N-Benzylglycine methyl ester hydrochloride (23.0 g) is dissolved in ethanol (180 ml) and thereto is added triethylamine (11.1 g) under ice-cooling and further added dropwise diketene (9.2 g). The mixture is stirred at room temperature for 1 hour and distilled to remove the solvent. The residue is dissolved in chloroform, washed with water, 10% hydrochloric acid, and water in this order, dried and then distilled to remove the solvent. The residue is dissolved in xylene (360 ml) and the solution is added dropwise to a solution of sodium methoxide [which is prepared from metal sodium (2.6 g) and methanol (180 ml)], and the mixture is stirred at 80° C. for 2.5 hours while distilling off methanol. After cooling, the reaction mixture is extracted with water. The extract is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and distilled to remove the solvent. The residue is recrystallized from n-hexane-isopropyl ether-diethyl ether to give 1-benzyl-3-acetyl-2,4-dioxopyrrolidine (20.33 g, 87.7%). m.p. 74°-75° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([CH3:15])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:13]([O:12][C:10]1[C:9]([CH3:15])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=1)[CH3:14]
Reactant: CCOc1cc(COC(C)=O)ncc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(CO)ncc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.4 g of (4-ethoxy-5-methyl-2-pyridyl)methyl acetate were dissolved in 46 ml of ethanol. 23 ml of 3N sodium hydroxide solution were then added dropwise thereto and the mixture was stirred at room temperature for a further 3 hours. The ethanol was subsequently removed in vacuo, whereupon the residual aqueous solution was extracted three times with 100 ml of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from petroleum ether and there was obtained 4-ethoxy-5-methyl-2-pyridylmethanol of melting point 99°-101°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=O)=O)=CC=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of 2-fluoro-4-chloro-5-hydroxynitrobenzene (7.1 g, 37.1 mmol) and potassium carbonate (5.1 g, 37.1 mmol) in acetonitrile (300 ml) was stirred for 2 hours at a refluxing temperature. Cyclopentyl p-toluenesulfonate (10.3 g, 40.8 mmol) was added thereto, followed by stirring further for 2 hours under refluxing. After completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture, 1N hydrochloric acid (800 ml) was added thereto, and the mixture was extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with an aqueous solution of sodium bicarbonate and water, dried, and the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxynitrobenzene as a yellow solid (8.93 g, 34.3 mmol, 92.6% yield).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12]1=[O:23])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:8]([C:9]([N:11]2[C@H:15]([CH3:16])[C@H:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:13][C:12]2=[O:23])=[O:10])[CH2:7][C:6]([OH:32])=[O:5])=[CH:30][CH:29]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC(=O)O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A solution of (3S)-3-(4-Chlorobenzyl)-4-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-4-oxo-butyric acid tert-butyl ester (5.1 g, 11 mmol) in DCM (100 mL) was treated with TFA (50 mL) and stirred at room temperature for 1 hour. The solution was concentrated in vacuo, taken up into toluene and then conc. in vacuo. Placed on high vacuum for 6 hours to give (3S)-3-(4-Chlorobenzyl)-4-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-4-oxo-butyric acid (4.5 g, 100%.) 1H NMR (CDCl3, 400 MHz) δ 7.44-7.37 (3H, m), 7.31-7.21 (6H, m), 5.48 (1H, d, J 6.9 Hz), 4.70-4.63 (1H, m), 4.50-4.42 (1H, m), 3.05 (1H, dd, J 13.3 and 6.2 Hz), 2.89 (1H, dd, J 17.7 and 10.6 Hz), 2.63 (1H, dd, J 13.2 and 9.0 Hz), 2.43 (1H, dd, J 17.6 and 4.4 Hz), 0.86 (3H, d, J 6.6 Hz.)
Reaction SMILES: [C:1]([C:8]1[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH:15]([C:19](=[NH:21])[NH2:20])[C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:24]1([CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH:15]([C:19](=[NH:21])[NH2:20])[C:16]([N:27]2[CH2:26][CH2:25][N:24]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH2:28]2)=[O:18])=[O:13])=[CH:22][CH:23]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: O=C(CN1CCNCC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)NC(C(=N)N)C(=O)O)cc1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)NC(C(=N)N)C(=O)N2CCN(CC(=O)OCc3ccccc3)CC2)cc1

Procedure:
4-(4-Amidinobenzamidoacetyl)piperazin-1-ylacetic acid, FAB 348, is obtained analogously from 4-(4-BOC-amidinobenzamidoacetyl)piperazin-1-ylacetic acid (FAB 448; obtainable by condensing 4-BOC-amidinobenzamidoacetic acid with benzyl piperazin-1-ylacetate to give benzyl 4-(4-BOC-amidinobenzamidoacetyl)piperazin-1-ylacetate and hydrogenolyzing the benzyl ester group).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:51])([CH3:50])[CH2:38][CH2:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([O:40][CH2:39][CH2:38][C:37]([CH3:51])([CH3:50])[CH3:36])[CH:46]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CC(C)(C)CCOc1cccc(B(O)O)c1
Product: CC(C)(C)CCOc1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)c1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 3-(3,3-dimethyl-butoxy)phenylboronic acid (45 mg, 0.2 mmol, prepared according to general procedure H) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[3′-(3,3-dimethyl-butoxy)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: ClC(OC(Cl)C)=O.[CH2:8]([N:15]1[CH2:20][CH2:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([F:29])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(CC1C2[C:37](=[N:38]C=CC=2)[NH:36]C=1)C>ClCCl.C1(C)C=CC=CC=1>[F:29][C:17]1[CH2:16][N:15]([CH2:8][C:9]2[C:10]3[C:37](=[N:38][CH:13]=[CH:12][CH:11]=3)[NH:36][CH:14]=2)[CH2:20][CH2:19][C:18]=1/[CH:21]=[CH:22]/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: FC1=C(/C=C/c2ccccc2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: FC1=C(/C=C/c2ccccc2)CCN(Cc2c[nH]c3ncccc23)C1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
1-Chloroethyl chloroformate (0.048 ml, 0.44 mmol) was added dropwise to a solution of (E)-1-benzyl-3-fluoro-4-(2-phenylethenyl)-1,2,5,6-tetrahydropyridine (0.1002 g, 0.342 mmol) in dichloromethane (2 ml) at -8° C. The mixture was stirred at -8° C. to 0° C. for 1 hour, concentrated in vacuo, the residue redissolved in methanol (5 ml) and heated at reflux for fifteen minutes. The reaction mixture was evaporated and the residue partitioned between saturated aqueous potassium carbonate (25 ml) and dichloromethane (2×25 ml). The organic extracts were washed with brine (25 ml), combined, dried (MgSO4) and concentrated in vacuo. The residue and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.0606 g, 0.346 mmol) were suspended in toluene (5 ml) and the mixture stirred at reflux for 12 hours. The toluene was evaporated and the product purified by flash chromatography, eluting with dichloromethane/methanol/ammonia (120:8:1), to afford the title compound (0.0585 g, 51%). Recrystalisation from methanol gave buff needles, m.p. 218°-221° C. (dec.); δH (DMSO-d6) 2.35 (2H, m, tetrahydropyridinyl CH2), 2.64 (2H, m, tetrahydropyridinyl CH2), 3.16 (2H, br s, tetrahydropyridinyl CH2), 3.80 (2H, s, ArCH2N), 6.52 (1H, d, J 16.4Hz, CH=CHPh), 7.05 (1H, dd, J 7.8, 4.7Hz, 5-H), 7.14 (1H, d, J 16.4Hz, CH=CHPh), 7.23 (1H, m, ArH), 7.32 (2H, m, ArH), 7.42 (1H, s, 2-H), 7.48 (2H, m, ArH), 8.05 (1H, dd, J 7.8, 1.4Hz, 4-H), 8.20 (1H, dd, J 4.7, 1.4Hz, 6-H) and 11.51 (1H, br s, NH); m/z (CI+, NH3) 334 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:35]([O:37][C:38](Cl)=[O:39])[CH3:36]>ClCCl>[CH2:35]([O:37][C:38](=[O:39])[NH:2][C@H:3]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:11]2[C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)=[O:27])[CH2:5][CH2:4]1)[CH3:36]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.3 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was suspended in dichloromethane (2 ml) under nitrogen at room temperature and triethylamine (153 μl, 1.09 mmol) was added followed by ethylchloroformate (39 μl, 0.4 mmol). The reaction was stirred at room temperature for 1.5 h and the mixture was quenched with sat. sodium bicarbonate solution (3 ml). The organic phase was separated and the aqueous phase was washed with dichloromethane (2×3 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) and the product was triturated with diethylether (3 ml) to give (cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid ethyl ester (64 mg) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][N:9]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)O1>COCCOC.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>[C:36]([O:35][C:34]([NH:33][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:12]2[C:11]([Cl:15])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=2)=[CH:29][CH:28]=1)([CH3:32])[CH3:31])=[O:40])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1ncc(Cl)c(Cl)n1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Yield: 81.7 %

Procedure:
2M aqueous Na2CO3 (4.7 ml, 9.4 mmol) was added to a solution of 2,4,5-trichloropyrimidine [Chesterfield, J.; McOmie, J. F. W.; Sayer, E. R.; J. Chem. Soc. (1955) 3478-3481] (1.18 g, 6.44 mmol), tert-butyl N-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]1-methylethyl}carbamate (1.55 g, 4.29 mmol) and tetrakis(triphenylphosphine)palladium (O) (150 mg, 0.13 mmol) in ethyleneglycol dimethylether (20 ml) under N2 and the mixture heated to reflux for 6 h. The reaction was diluted with H2O (30 ml) and extracted with ethyl acetate (3×50 ml), the combined ethyl acetate extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 15% ethyl acetate in hexane) to give 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine as a white solid (1.34 g). δH (d6DMSO) 8.62 (1H, s), 7.90 (2H, d, J 8.6 Hz), 7.54 (2H, dt, J 8.7, 2.1 Hz), 5.02 (1H, bs), 1.65 (6H, s) and 1.37 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].Cl>ClCCl>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:5][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cccc(Cl)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
[step 1] 3-Chloro-2-nitroaniline (2.0 g, 11.6 mmol) was dissolved in dichloromethane, triethylamine (2.6 mL, 18.5 mmol) and 2-methoxyacetyl chloride (1.4 mL, 15.1 mmol) were added, and the mixture was stirred at 70° C. for 18 hr. To the mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted 3 times with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 v/v-50/50 v/v) to give N-(3-chloro-2-nitrophenyl)-2-methoxyacetamide (1.7 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:27])=[CH:24][N:23]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NC(=O)c1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to tert-butylamine via Procedure G. Crude methyl 6-(tert-butylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 250 mg of 6-(tert-butylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(tert-butylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N2-tert-butyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. MS (Q1) 409 (M)+.