Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19]C3CCCCO3)[CH:14]=[C:15]([CH2:16]OC)[C:7]1=2)[CH3:2].B(Br)(Br)[Br:28].C(O)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][Br:28])[C:7]1=2)[CH3:2]
Reactant: BrB(Br)Br
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(COC)c21
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(CBr)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [1-hydroxy-4-methoxymethyl-6-(tetrahydro-pyran-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester from step 1.10. (870 mg, 1.37 mmol) in DCM (10 mL) was added boron tribromide (0.46 mL, 3.02 mmol) slowly under −78° C. The reaction mixture was allowed to stir at room temperature for 1 h. Ethanol was added slowly and the solvent was removed under vacuum. The crude product was used for next step without further purification. 1H NMR (300 MHz, CD3CN) δ 7.13 (s, 1H), 7.01 (s, 1H), 5.62 (dd, 1H), 4.42-4.63 (dd, 2H), 4.14 (q, 2H), 3.18-3.24 (dd, 1H), 2.40-2.51 (m, 1H), 1.22 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]([NH2:29])=[NH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:28]=[C:27]([NH:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[Cl:19])[N:29]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N=C(N)Nc1ccccc1Cl
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Product: O=C1Cc2cnc(Nc3ccccc3Cl)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(2-chlorophenyl)guanidine were converted to I-12 (26%): HRMS Calcd. for C18H12Cl2N4O: 371.0466, Found 371.0467.
Reaction SMILES: [CH3:1][C:2]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17](=[O:25])OC2C=CC=CC=2)[CH:12]=1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[O:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[O:49][C:50]1[CH:51]=[C:52]([NH:53][C:17]([NH:16][C:13]2[CH:12]=[C:11]([C:2]([CH3:1])([CH3:10])[CH2:3][N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9]3)[O:15][N:14]=2)=[O:25])[CH:54]=[CH:55][CH:56]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(CN1CCOCC1)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)CN5CCOCC5)on4)c3)c2cc1OC
Temperature: 25 °C
Yield: 17.9 %

Procedure:
A stirred solution of phenyl 5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-ylcarbamate (22 mg), N,N-diisopropylethylamine (12 mg, 0.093 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (15 mg, 0.051 mmol) in THF (0.5 mL) was heated at 60° C. for 15 h. The reaction mixture was cooled to rt and partitioned between saturated aqueous sodium carbonate and dichloromethane. The organic layer was separated and concentrated under reduced pressure to give the crude product. Purification via preparative TLC afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-yl)urea (5 mg, 1% over three steps) as a solid. 1H NMR (400 MHz, CDCl3) δ 9.35 (brs, 1H), 8.65 (brs, 2H), 7.66 (s, 1H), 7.57 (s, 1H), 7.29-7.41 (m, 3H), 7.01 (m, 1H), 6.10 (s, 1H), 4.09 (s, 6H), 3.63-3.66 (m, 4H), 2.40-2.70 (m, 6H), 1.32 (s, 6H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[C:7]([NH:9][C:10](=O)[C:4]2=[N:3][CH:2]=1)=O.[OH-].[K+].CS(O)(=O)=O.O[CH2:20][CH2:21][N:22]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][N:24]=[C:23]1[CH3:30].OCCN1C([N+]([O-])=O)=CNC1(C)CS([O-])(=O)=O>CN(C)C=O.CO>[CH3:30][C:23]1[N:22]([CH2:21][CH2:20][N:9]2[CH2:7][C:5]3[C:4](=[N:3][CH:2]=[CH:1][N:6]=3)[CH2:10]2)[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][N:24]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: O=C1NC(=O)c2nccnc21
Agent: CC1(CS(=O)(=O)[O-])NC=C([N+](=O)[O-])N1CCO
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ncc([N+](=O)[O-])n1CCN1Cc2nccnc2C1
Reaction time: 8 h

Procedure:
To a solution of 1.80 parts by weight of 2,3-pyrazinedicarboximide which was prepared according to the procedure described in Helvetica Chemica Acta 41 (1958) p. 512 in 40 parts by volume of dry dimethylformamide is added 17.0 parts by volume of methanol containing 0.85 parts by weight of potassium hydroxide pellets. The combination of these two solutions results in the formation of a precipitate. To this mixture is then added in one portion a slightly warm solution of 3.01 parts by weight of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole methanesulfonate (preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazolemethanesulfonate is described in U.S. Pat. No. 3,770,763) in 40.0 parts by volume of dimethylformamide. The mixture turns dark blue in color, then upon swirling turns green in color and eventually turns yellow in color. The mixture is then heated on a steam bath for 4 hours at an internal temperature of 70°-85° C. After cooling, the mixture to room temperature the insoluble material is separated by filtration, rinsed with dimethylformamide and air dried. The mother liquor is rinsed into a round bottom flask, concentrated to a volume of about 40 parts, then diluted to a volume of 100 parts with water and allowed to stand overnight. The resulting solid material which separates out of this liquor is separated by filtration, washed with water and air dried to afford a product, in the form of brown needles, melting at 231°-234° C. This product is then taken up in 8.0 parts by volume of warm dimethylformamide; activated carbon is added to the solution and the solution is then filtered. The filtrate is diluted with 20 parts by volume of water and then seeded. The resulting crystals are separated by filtration, washed with methanol and air dried to afford 6-[2-(2-methyl-5-nitro-1H-imidazole-1-yl)ethyl]-5H-pyrrolo[3,4-b]pyrazine-5,7(6H-dione), melting at 232°-234° C. This compound is represented by the following structural formula ##STR7##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][N:20]1[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[CH:21]1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][N:20]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[CH:21]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: ClCn1cnc(Cl)c1Cl
Reactant: Oc1ccc(Oc2cccc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc(OCn3cnc(Cl)c3Cl)cc2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
At room temperature (about 20° C.), 4.9 g of 4-(6-chloro-2-pyridinyloxy)-phenol in 40 ml of anhydrous dimethylformamide is dripped into 0.6 g of 100% strength sodium hydride in 20 ml of anhydrous dimethylformamide. The mixture is subsequently stirred for 30 minutes at 50° C., and then 4.2 g of 1-chloromethyl-4,5-dichloroimidazole in 20 ml of anhydrous dimethylformamide is dripped in at room temperature. This mixture is stirred for 2 hours at 60° C. and overnight at room temperature. It is then stirred into 200 ml of ice water and the solution is extracted three times with methyl tert-butyl ether. The organic phase is washed with 5% strength sodium hydroxide solution and water, and dried, and the solvent is evaporated off under reduced pressure. The crude product obtained is recrystallized from toluene. There is obtained 6.6 g of 1-[4-(6-chloro-2-pyridinyloxy)-phenoxymethyl]-4,5-dichloroimidazole; m.p.: 94°-98° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]([C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:14][CH:13]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>C(Cl)Cl>[CH3:28][O:27][C:23](=[O:26])[CH2:24][CH2:25][N:19]([CH2:18][CH2:17][O:16][C:15]1[CH:21]=[CH:22][C:12]([N:4]2[C:3]([Cl:2])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]3)=[N:5]2)=[CH:13][CH:14]=1)[CH3:20]
Reactant: CNCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CCN(C)CCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
A mixture of the product from step 2 (0.1 g, 0.27 mmol), methyl acrylate (0.15 g, 1.7 mmol) in methylene chloride (2 mL) was stirred at room temperature for 24 h. After the inorganic salts were filtered off, the solvent was removed in vacuo. The crude product was purified by a column chromatography on silica gel eluting with 5% methanol in methylene chloride to afford the ester (100 mg, 60%) MS (APCI) m/z 388 (M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[CH:23][C:11]([CH2:12][O:13][C:14]([CH3:22])([C:18]([F:21])([F:20])[F:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+:26]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([CH3:22])([C:18]([F:19])([F:20])[F:21])[C:15]([O-:17])=[O:16])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1.[Na+:26]
Reactant: CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)[O-])C(F)(F)F

Procedure:
A mixture of (±)-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid (0.36 g.), N aqueous sodium hydroxide (1.0 ml.) and water (3.0 ml.) is stirred until no more of the acid dissolves. The mixture is filtered, the filtrate is washed with ether and evaporated in vacuo. The residue is crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80° C.) to give (±)-sodium 2[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (0.3 g.) m.p. 271°-272° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11](Cl)(=O)C>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ncc(Br)cn1
Solvent: CO
Product: COC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid (3.22 g, 15.9 mmol) in MeOH (50 mL) at room temperature was added acetyl chloride (4.0 mL, 56.3 mmol). The reaction mixture was heated to reflux for 15 min, cooled to room temperature and concentrated under reduced pressure. The reaction mixture was diluted with saturated NaHCO3 (30 mL) and EtOAc, and transferred to a separatory funnel. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated to give methyl 5-bromopyrimidine-2-carboxylate (2.30 g, 10.6 mmol, 67% yield) as a white solid. LC/MS (ESI+) m/z=216.9 (M+H). Calculated for C6H5BrN2O2 216.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C([N-]C(C)C)(C)C.[Li+].[CH:27]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:32]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:33])[C:9]1=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C2CCCC2)C1=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 42.7 %

Procedure:
2-Oxopyrrolidine-1-carboxylic acid t-butyl ester (9.3 g, 50.4 mmol) was dissolved in THF (60 mL, 800 mmol) under nitrogen and was then cooled at −78° C. 2M Lithium diisopropylamide in heptane/THF/ethylbenzene (34 mL) was added over 40 minutes, and the resulting mixture was stirred for 1.5 hours at −78° C. Cyclopentanecarbonyl chloride (6.1 mL, 50 mmol) was dissolved in THF (4.0 mL, 49 mmol) and slowly added dropwise via syringe to the mixture over 30 minutes, then stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and the mixture stirred at room temperature for 30 minutes. The mixture was extracted with EtOAc (200 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×75 mL), then saturated aqueous NaCl. The aqueous layers were combined and re-extracted with EtOAc (75 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was then placed on high vacuum for 10 minutes to yield a crude oil. The oil was dissolved in 50% AcOH/H2O and purified by preparative HPLC (10-70% MeCN/H2O; 0.05% TFA; over 80 minutes on a 2″ column at 40 mL/min). The fractions were collected and lyophilized to yield 3-cyclopentanecarbonyl-2-oxopyrrolidine-1-carboxylic acid t-butyl ester (6 g) as a yellow solid. MS m/z: [M+H]+ calcd for C15H23NO4, 281.3; found 282.2.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14]2.[N:28]1([C:33](=[O:36])[CH:34]=[CH2:35])[CH2:32][CH2:31][CH2:30][CH2:29]1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C>[O:36]=[C:33]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)/[CH:34]=[CH:35]/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14]2
Reactant: C=CC(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc2C1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)N1CCc2cc(/C=C/C(=O)N3CCCC3)ccc2C1
Temperature: 110 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
DIPEA (1.44 ml, 8.36 mmol) was added to a solution of 125a (650 mg, 2.09 mmol), 125b (287 mg, 2.29 mmol), Pd-(OAc)2 (46 mg, 0.21 mmol) and P(o-tol)3 (127 mg, 0.42 mmol) in propionitrile/DMF (8 ml/2 ml) and the reaction mixture was purged with nitrogen for 10 minutes, then was heated at 110° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was cooled to 20-35° C. and filtered on celite. The filtrate was concentrated and resultant residue diluted with water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (30 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 50% ethyl acetate/pet ether as an eluent to get the desired compound as an off-white solid (400 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J=6.8 Hz, 2H), 7.41 (d, J=15.7 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.94 (d, J=15.7 Hz, 1H), 4.56-4.46 (m, 2H), 3.63 (t, J=6.6 Hz, is 2H), 3.55 (t, J=5.9 Hz, 2H), 3.41-3.34 (m, 2H), 2.79 (t, J=5.9 Hz, 2H), 1.96-1.88 (m, 2H); 1.87-1.76 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15](Cl)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1.[OH-].[Na+].[NH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([NH2:21])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1
Reactant: N
Reactant: CC(C(=O)Cl)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(N)=O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 0.5 h

Procedure:
3 g (10 mmoles) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionyl chloride are stirred into 30 ml of concentrated aqueous ammonia solution. Stirring is continued for a further half hour at room temperature; adjustment to pH 12 is effected with sodium hydroxide solution, followed by extraction with ether, drying of the ethereal phase and concentration. 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionamide (m.p. 131°-132° C.) is obtained.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=1)=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)c1ccc(F)cc1

Procedure:
L14. (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with 4-fluoro-benzoic acid in analogy to experiment A1 to give (2S,4R)-1-(4-fluoro-benzoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 484.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[Cl:22][C:23]1[CH:33]=[CH:32][C:31]([S:34](=[O:40])(=[O:39])[NH:35][CH:36]2[CH2:38][CH2:37]2)=[CH:30][C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>C(Cl)Cl>[Cl:22][C:23]1[CH:33]=[CH:32][C:31]([S:34](=[O:40])(=[O:39])[NH:35][CH:36]2[CH2:38][CH2:37]2)=[CH:30][C:24]=1[C:25]([NH:27][C:28]([N:13]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:29])=[O:26]
Reactant: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Product: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(S(=O)(=O)NC3CC3)ccc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
To a solution of tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate 14, 1.5 g, 5.08 mmol) in DCM (20 mL) was added 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (1.6 g, 5.32 mmol). The reaction mass was stirred at RT for 2 h. Excess of solvent was removed under vacuum to afford 0.500 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.50 (m, 4H), 1.41 (s, 9H), 2.11 (m, 1H), 3.68-3.75 (m, 6H), 7.59 (d, J=8.7 Hz, 1H), 7.78-7.87 (m, 4H), 8.10 (m, 2H), 8.27 (s, 1H), 8.95 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.CC([O-])=O.[K+]>CC(N(C)C)=O.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:18]1[N:14]([CH3:13])[N:15]=[N:16][CH:17]=1)=[CH:11][CH:10]=2
Reactant: Cn1ccnn1
Reactant: Clc1cc2cc(Br)ccc2cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1nncc1-c1ccc2cnc(Cl)cc2c1
Reaction time: 1 h
Yield: 31.1 %

Procedure:
A suspension of 6-bromo-3-chloroisoquinoline (60 mg, 0.25 mmol), 1-methyl-1H-1,2,3-triazole (41 mg, 0.50 mmol), Pd(OAc)2 (2.22 mg, 9.9 umol) and KOAc (49 mg, 0.50 mmol) in DMA (4 mL) was stirred at 1500 under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water and dried with Na2SO4 and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 40% EtOAc in cyclohexane to afford the title compound as a white solid (19 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@@H:12]2[O:22][CH2:23][CH3:24])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[O:22][CH2:23][CH3:24])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)c2cc(Cl)c(C)[nH]2)[C@@H](OCC)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCO[C@H]1CNCC[C@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Yield: 37.5 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate (Intermediate 34, 1.6 g, 4.48 mmol), potassium hydroxide (1.76 g, 31.37 mmol), and hydrazine hydrate (1.6 mL, 31.37 mmol) in ethylene glycol (180 mL) was stirred for 40 h at 120° C. The reaction mixture was poured in to water (120 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated in vacuo to yield the crude product which was triturated with water (30 mL) to afford 4-chloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide 480 mg (37%) as solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:13]([CH2:15][C:16]1[N:20]=[C:19]([CH3:21])[O:18][N:17]=1)#[C-:14]>>[CH3:1][C:2]1[C:3]2[N:4]([CH:14]=[N:13][C:15]=2[C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [C-]#[N+]Cc1noc(C)n1
Reactant: Cc1nc2ccccc2nc1O
Product: Cc1nc(-c2ncn3c2c(C)nc2ccccc23)no1

Procedure:
M.p. 192°-193° C., from 3-methyl-2-quinoxalinol and 3-isocyanomethyl-5-methyl-1,2,4-oxadiazole. (Compound 8)
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.O.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: Nc1cccc(B(O)O)c1
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: O
Solvent: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Yield: 82.2 %

Procedure:
The title compound (230 mg, 82%) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (270 mg, 0.803 mmol, prepared in example 1), 3-aminobenzeneboronic acid monohydrate (150 mg, 0.968 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), 2 M sodium carbonate (290 mg in 1.4 mL water) and 1,4-dioxane (5.5 mL) in a manner analogous to the procedure described in Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][NH:10][C:11](=O)[C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+:30]>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:30]=[C:11]([C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([CH3:15])[CH3:14])[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)c1ccc(Br)cn1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(Br)cn2)c[nH]1
Temperature: 130 °C
Yield: 62.9 %

Procedure:
In a sealed tube, a mixture of (S)-tert-butyl 1-(2-(5-bromopyridin-2-yl)-2-oxoethylamino)-3-methyl-1-oxobutan-2-ylcarbamate (0.1 g) and ammonium acetate (0.186 g) in xylene was heated at 130° C. for 3 hrs. The reaction was diluted with EtOAc, washed with sat. NaHCO3, water and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil. The residue was purified by silica chromatography (0-100% EtOAc in hexane) to yield (S)-tert-butyl 1-(4-(5-bromopyridin-2-yl)-1H-imidazol-2-yl)-2-methylpropylcarbamate (0.06 g) as a pale yellow solid. LC/MS (Cond. N-1): [M+H]+ 395.17, RT=3.06 min.