Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH2:5][NH:6][C:7]([NH:9][CH3:10])=[O:8].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:42][C:43]1[CH:48]=[C:47]([C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[CH:46]=[CH:45][C:44]=1[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C>[C:57]([O:56][C:55]([NH:54][C:44]1[CH:45]=[CH:46][C:47]([C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)=[CH:48][C:43]=1[NH:42][C:15]([C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][NH:6][C:7]([NH:9][CH3:10])=[O:8])[C:3]([O:2][CH3:1])=[O:20])=[CH:19][CH:18]=1)=[O:17])=[O:61])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N
Reactant: CNC(=O)NCC(C(=O)OC)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)NCC(C(=O)OC)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h

Procedure:
4-[2-Methoxy-1-({[(methylamino)carbonyl]amino}-methyl)-2-oxoethyl]benzoic acid (350 mg, 1.25 mmol), EDCI (312 mg, 1.63 mmol), and HOBT (220 mg, 1.63 mmol) were combined in DMF (15 mL) and stirred for 10 minutes before adding tert-butyl [2-amino-4-(3-thienyl)phenyl]carbamate (398 mg, 1.37 mmol). The reaction was then stirred at 55° C. for 24 h. The solvent was evaporated, and the resulting residue was dissolved in EtOAc, washed (water, brine), dried (MgSO4), and concentrated. Flash chromatography on silica (0-5% MeOH/CH2Cl2) afforded methyl 2-[4-({[2-[(tert-butoxycarbonyl)amino]-5-(3-thienyl)phenyl]amino}carbonyl)phenyl]-3-{[(methylamino)carbonyl]amino}propanoate as a white solid. MS (ESI) calcd [M+H]+ 553.2, found 553.2.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[N:4][C:5]([N:10]3[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCN[C@H](C)C2)c1C
Temperature: 110 °C
Yield: 77.2 %

Procedure:
To a round bottom flask is added 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (500 mg, 2.07 mmol), 4-fluorophenylboronic acid (580 mg, 4.15 mmol) sodium carbonate (440 mg, 4.15 mmol), toluene (16 mL) and water (8 mL). The reaction mixture is purged with nitrogen for 20 min. Tetrakis(triphenylphosphine) palladium (50 mg, 0.103 mmol) is added and the mixture is heated to 110° C. for 18 h. The reaction mixture is concentrated and partitioned between ethylacetate and water. It is extracted with ethylacetate twice and the combined organic phases are dried with sodium sulfate and concentrated. It is purified by column chromatography (0-25% methanol/methylene chloride) to give 480 mg of 3-(4-fluoro-phenyl)-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (83%).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][CH:10]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[H][H]>[Pd].C(O)C>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH:10]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11]2)=[O:8])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(C(=O)NC2CCN(C3CCCCC3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(C(=O)NC2CCN(C3CCCCC3)C2)cc1

Procedure:
A solution of 20 g. (0.067 mole) of 4-cyano-N-(1-cyclohexyl-3-pyrrolidinyl)benzamide in 400 ml. of 95% ethanol and 19.24 g. (0.202 mole) of concentrated hydrochloric acid containing 2.0 g. of palladium on charcoal (10%) was shaken at room temperature in three atmospheres of hydrogen for five hours. The filtered mixture was concentrated at reduced pressure and the residue was partitioned between dilute sodium hydroxide and chloroform. The dried chloroform solution was concentrated at reduced pressure and the residue was recrystallized from ethyl acetate to give 8.0 g. (40%) of product which melted at 125°-129° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([C:28]([OH:34])([CH2:32][CH3:33])[C:29](O)=[O:30])[CH3:27].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:26]([C:28]([OH:34])([CH2:32][CH3:33])[C:29]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([NH:13][CH2:12][C:11]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:30])[CH3:27]
Reactant: CCC(O)(CC)C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(O)(CC)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (100 mg, 0.27 mmol), 2-ethyl-2-hydroxybutanoic acid (36 mg, 0.27 mmol), and NMM (30 μL, 0.27 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (144 mg, 0.326 mmol). The mixture was stirred at ambient temperature for 72 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient of 95:5 to 0:100 (water:CH3CN, 0.1% TFA) over 30 min with a flow rate of 18 mL/min. After concentration of desired fractions in vacuo, 1-(2-ethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide was obtained an amorphous solid (55 mg; HPLC RT=3.32 min, method A; LC-MS m/z=482.2; 1H NMR, 400 MHz, CDCl3, 7.25 ppm (m, 3H), 7.2 ppm (m, 1H), 7.1 ppm (br s, 1H), 5.45 ppm (br s, 1H), 4.55 ppm (m, 2H), 4.3 ppm (m, 3H), 3.7 ppm (m, 2H), 2.2 ppm (m, 2H), 2.0 ppm (m, 2H), 1.8 ppm (m, 2H), 1.7 ppm (m, 2H), 1.4 ppm (s, 9H), 0.8 ppm (m, 6H)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:18][C:19]([C:21]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[O:23][N:22]=1)=O.N1C=CC=CC=1>C(O)C>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:24]1[O:23][N:22]=[C:21]([C:19]2[N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[S:16][CH:18]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CCl)C1=NOC(c2ccccc2F)C1
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1
Temperature: 77 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butoxycarbonylpiperidine-4-carbothioamide (1 g, 4.10 mmol) in ethanol (10 mL) was added 2-chloro-1-[4,5-dihydro-5-(2-fluorophenyl)-3-isoxazolyl]ethanone (i.e. the product of Step A) (0.99 g) followed by pyridine (0.34 mL, 4.10 mmol). The reaction mixture was heated at 77° C. for 3 h, and then stirred at room temperature overnight. Ethanol was removed from the reaction mixture, and the remaining residue was diluted with ethyl acetate (50 mL). The organic layer was separated, washed with water, saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated under reduced pressure. The resulting oil was purified by column chromatography on silica gel to provide the title compound as a pale yellow sticky oil (1.11 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:19]>CN(C=O)C>[CH3:19][O:15][CH:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:11]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-ol (120 mg, 0.57 mmol) in 5 mL of DMF was added 10 equivalent of sodium hydride (228 mg, 5.7 mmol, 60% in mineral oil). The mixture was stirred at 23° C. for 15 min followed by the addition of 10 equivalent of iodomethane (355 uL, 5.7 mmol). The reaction was continually stirred for 2 h and then extracted with ethyl acetate and water. The organic phase was dried and solvent was evaporated. The residue was purified on a flash chromatography column with EtOAc/hexanes to afford 2-(3-methoxy-pyrrolidin-1-yl)-5-nitro-pyridine. LRMS calcd for C10H13N3O3 (m/e) 223, obsd 224 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]([OH:25])=[O:24])=[C:14]([CH3:26])[N:13]=1.O1CCOCC1.Cl>CCOCC>[ClH:10].[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N:2]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]([OH:25])=[O:24])=[C:14]([CH3:26])[N:13]=2)[CH3:1])=[CH:5][CH:6]=1
Reactant: Cc1nc(Cl)c2ccccc2c1CC(=O)O
Reactant: CNCc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1nc(N(C)Cc2ccc(Cl)cc2)c2ccccc2c1CC(=O)O

Procedure:
N-Methyl-4-chlorobenzylamine (1.40 g., 9.0 mmol) and 1-chloro-3-methyl-4-isoquinoline acetic acid (770 mg., 3.0 mmol), prepared as in Example 8, were refluxed in 20 ml. p-dioxane for 16 hr. The cooled reaction mixture was partitioned between 200 ml ether and 50 ml 1 N sodium hydroxide. The ether rafinate was extracted with 2×30 ml 1 N sodium hydroxide. The combined basic phases were acidified to pH 6.5 with 6 N hydrochloric acid and extracted with 3×75 ml ethyl acetate. This organic phase was dried over magnesium sulfate, filtered, and vacuum evaporated to an oily residue. Chromatography of this on silica gel eluted with ethyl acetate gave an oil. The title compound was prepared from this oil by treatment with hydrochloric acid gas in ether, filtrate, and drying in vacuo; 52 mg. (4%), m/e 354.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:17]=[N:18][C:19]([CH2:22]Br)=[CH:20][CH:21]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>C1(C)C(C)=CC=CC=1>[CH2:26]([O:25][P:24]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][N:18]=1)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)nc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCOP(=O)(Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1)OCC
Temperature: 140 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of di-tert-butyl[6-(bromomethyl)pyridin-3-yl]imidodicarbonate (Compound 260C, 3.0 g, 7.7 mmol) in dry xylene (100 mL) was added a triethyl phosphite (6.0 g, 36 mmol). The reaction mixture was stirred at 140° C. for 4 h, then concentrated. The residue was purified by column chromatography to give the desired compound (2.5 g, yield: 92%) as a liquid. 1H NMR (CDCl3, 400 MHz): δ=1.34 (t, J=7.6 Hz, 6H), 1.39 (s, 18H), 3.43 (d, J=22.0 Hz 2H), 4.09-4.18 (m, 4H), 7.43 (dd, J=2.0, 8.0 Hz, 1H), 7.67 (s, 1H), 8.33 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[N:22]=3)[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.CCO>[OH:28][CH2:27][C:23]1[N:22]=[C:21]([C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C=O)n3)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(CO)n3)c2)cc1

Procedure:
A suspension of 4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine-6-carboxaldehyde (8.93 mmol) in a mixture of 70 mL of THF and 70 mL of absolute EtOH is treated with 1 g of NaBH4 and then heated to reflux for 15 minutes under N2. After cooling, the organic solvents are removed, the residue is heated for 30 minutes at reflux in dilute NaHCO3, cooled, filtered, washed with H2O, then dried to give the desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[I:17]I>C(Cl)Cl.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Fe+2].[N+]([O-])([O-])=O>[I:17][C:15]1[CH:14]=[CH:13][C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[C:3]([CH2:1][CH3:2])[CH:16]=1
Reactant: II
Reactant: CCc1ccccc1OCCN1CCCC1
Agent: [Fe+2]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CCc1cc(I)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A finely triturated mixture of 0.8 g of silica gel (0.2-0.5 mm) and 0.41 g (1.00 mmol) of iron (II) nitrate nonahydrate was added to a solution of 0.44 g (2.01 mmol) of 1-[2-(2-ethylphenoxy)ethyl]pyrrolidine and 0.28 g (1.10 mmol) of iodine in 5 mL of DCM and the mixture was stirred for 12 hours at RT. The reaction mixture was filtered and the filtrate was evaporated down in vacuo. The residue was purified by column chromatography (silica gel, DCM/MeOH/sat. aqueous ammonia 9:1:0.1). Yield: 0.286 g (41% of theoretical); C14H20INO (M=345.219); calc.: molpeak (M+H)+: 346; found: molpeak (M+H)+: 346; HPLC-MS: 6.74 minutes (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[N:21]/[O:22][CH2:23][C:24](O)=[O:25])=[C:16]([CH3:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[F:44][C:45]([F:49])([F:48])[CH2:46][NH2:47]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:29])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[N:21]/[O:22][CH2:23][C:24]([NH:47][CH2:46][C:45]([F:49])([F:48])[F:44])=[O:25])=[C:16]([CH3:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of [1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-meth-(E)-ylideneaminooxy]-acetic acid (i.e. the product of Step 2, 200 mg) in CH2Cl2 (12 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (130 mg). After 15 min, 2,2,2-trifluoroethyl amine (64 μL, 80 mg) and N,N-4-dimethylaminopyridine (80 mg) was added and the mixture was stirred at room temperature over night. After concentration in vacuum, the residue was purified by flash chromatography on silica gel to obtain the title compound (100 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: Brc1ccc(-c2nc[nH]c2-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccc(Br)cc2)c1-c1ccc(Br)cc1
Yield: 71.2 %

Procedure:
4,5-Di-(4-bromophenyl)imidazole (2.13 g) was treated with ethyl 8-bromooctanoate (2 g) and K2CO3 (0.5 g) in 2-butanone as described in Example 9 to give ethyl 8-(4,5-di-(4-bromophenyl)imidazol-1-yl)-octanoate (2.2 g, 52%) as a pale yellow oil.; Found: C, 55.13; H, 5.19; N, 5.18; Br; 28.76%; C28H28Br2N2O2 requires: C, 54.76; H, 5.15; N, 5.11; Br, 29.15%
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([C:25]([C:27]2[CH:36]=[C:35]([CH3:37])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C:22]1[N:23]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:19]=[C:20]([C:25]([C:27]2[CH:36]=[C:35]([CH3:37])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[N:21]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
65 mg (0.30 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 91 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL DMF at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[F:31])[CH2:17][CH2:16]1)=[O:14].[CH:32]1([O-:37])[CH2:36][CH2:35][CH2:34][CH2:33]1.[Na+]>>[CH:32]1([O:37][C:4]2[C:3]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=4[F:31])[CH2:19][CH2:20]3)=[O:14])=[C:2]([F:1])[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(F)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1
Reactant: [O-]C1CCCC1
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(OC4CCCC4)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1

Procedure:
The compound was prepared in analogy to example 358 from (2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone and sodium cyclopentanolate. MS (m/e): 560.5 (MNH4+, 43%)
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[O:31]1CCCC1>>[CH2:1]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC(CCCCCCCCC)OCc1ccccc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: CCCCCCCCCC(CCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A solution of 9.3 g of 4-benzyloxy-1-tridecene in 40 ml of tetrahydrofuran was added, dropwise, under nitrogen, to 70.4 ml of 9-borabicyclo[3.3.1]nonane (0.5M solution in hexane). The reaction mixture was stirred at room temperature for 3 hrs. and quenched by the sequential addition of 18 ml of ethanol, 6 ml of 6N sodium hydroxide, and 12 ml of 30% hydrogen peroxide. The reaction mixture was heated at 50° for 2 hrs. and then allowed to stand at ambient temperature overnight. Upon standing the mixture separated into aqueous and organic phases. The aqueous phase was saturated with potassium carbonate and the organic phase was separated, washed with 30 ml of a 10% aqueous solution of sodium sulfite and 30 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous potassium carbonate, and concentrated. The residue was taken up in 20% diethyl ether/hexane, filtered, and concentrated to an oil. Flash chromatography of the oil on silica gel using hexane diethyl ether (2:1 by volume) as the eluent yielded 7.7 g (80%) of 4-benzyloxytridecan-1-ol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=O)=[C:5]2[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].COC1C=CC(P2SP(C3C=CC(OC)=CC=3)[S:32]2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[S:32])[NH2:13])=[C:5]2[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COc1ccc(P2SP(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Product: NC(=S)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
Reaction of 5-chloro-3-phenylsulfonylindole-2-carboxamide with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane (Lawesson's reagent) according to the procedure of Example 18 gave the title compound. Chromatographic purification on silica gel was carried out using 30% ethyl acetate-methylene chloride, followed by 50% ethyl acetate-methylene chloride. The pure product had mp 207°-210° C. Anal. calcd for C15H11ClN2O2S2 : C, 51.35; H, 3.16; N, 7.98. Found: C, 50.84; H, 3.08; N, 8.04. NMR (DMSO-d6) δ12.90 (1H, s), 10.71 (1H, s), 10.70 (1H, s), 8.0-8.6 (2H, m), 7.84 (1H, d, J=2 Hz), 7.54-7.66 (3H, m), 7.46 (1H, d, J=8.5 Hz), 7.30 (1H, dd, J=8.5, 2 Hz).
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([NH:29][C:30]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:31])[C:24]=4[Cl:28])[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:40])[CH:4]=1)#[N:2].Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>>[C:46]([O:45][C:43](=[O:44])[CH2:42][N:14]([C@H:11]1[CH2:12][CH2:13][N:9]([CH2:8][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[S:7][CH:6]=2)[C:10]1=[O:40])[S:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[C:24]=2[Cl:28])[CH:19]=1)(=[O:17])=[O:16])([CH3:49])([CH3:48])[CH3:47]
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4c(Cl)c(NC(=O)OCc5ccccc5)ccc4c3)C2=O)cs1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN([C@H]1CCN(Cc2csc(C#N)c2)C1=O)S(=O)(=O)c1ccc2c(Cl)c(NC(=O)OCc3ccccc3)ccc2c1

Procedure:
The title compound is prepared from N-Cbz-6-amino-5-chloro-naphthalene-2-sulfonic acid-[1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using tert-butyl bromoacetate in place of benzyl bromide. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc/CH2Cl2 to 10% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=[O:15])[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:8]1(=[O:15])[C:9]2[CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]3[O:14][C:10]=2[CH2:11][CH2:12][CH2:13]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CCCC2=C1C1CCCCC1O2

Procedure:
A solution of cyclohexanone (5.28 mL, 50.9 mmol), cyclohexane-1,3-dione (5.89 g, 50.9 mmol), and p-toluenesulfonic acid monohydrate (0.485 g, 2.55 mmol) in xylene (600 mL) was heated at reflux under a Dean Stark trap for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate in hexanes to provide the title compound: 1H NMR (CDCl3) δ 1.21-1.31 (m, 2H), 1.43-1.57 (m, 3H), 1.72-1.83 (m, 1H), 1.96-2.08 (m, 4H), 2.33 (t, 2H), 2.41 (t, 2H), 2.96-3.06 (m, 1H), 4.61-4.69 (m, 1H); MS (DCl/NH3) m/z 193 (M+H)30.