Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]1[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:3]([CH2:12][C:13]2[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=2)[C:4]2[C:9](/[C:10]/1=[N:28]/[C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(CN2C(=O)C(=O)c3ccccc32)o1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CN2C(=O)/C(=N\c3cccc(C(F)(F)F)c3)c3ccccc32)o1
Temperature: 140 °C
Yield: 22.6 %

Procedure:
A mixture of ethyl 5-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]-2-furoate (60 mg, 0.200 mmol) and 3-trifluromethylaniline (32 mg, 0.200 mmol) was heated at 140° C. for 2 h. The residue was dissolved in CHCl3 (1 mL) and purified by preparative TLC using EtOAc/hexane 6:4), giving the desired product (20 mg, 23%)
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C1(C)C=CC=CC=1.[CH2:14]([O:25][C:26]1[CH:27]=C([CH:32]=[CH:33][CH:34]=1)C(O)=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.C(Cl)Cl>[CH2:14]([O:25][C:26]1[CH:27]=[C:1]([CH:32]=[CH:33][CH:34]=1)[C:2]([Cl:4])=[O:3])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCOc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCOc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
1 mL of oxalyl chloride (11.5 mmol) and two drops of anhydrous DMF are added under argon to 93 mg of toluene-dried acid 22 (318 μmol) dissolved in 20 mL of anhydrous DCM. The medium is stirred at room temperature for two hours, and then concentrated to give 99 mg of a yellow oil, i.e. a yield of 99%.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(N([CH2:23][CH3:24])CC)C.[C:25](Cl)(=[O:35])[C:26]1[CH:34]=[CH:33][CH:32]=[C:28]([C:29](Cl)=[O:30])[CH:27]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:25](=[O:35])[C:26]2[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:24]4[CH:23]=[CH:15][CH:10]=[CH:11][CH:12]=4)=[O:7])=[CH:16][CH:17]=3)=[O:30])[CH:27]=2)=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccc(OC(=O)c2cccc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)c2)cc1

Procedure:
Into a 500 ml four-neck flask equipped with a condenser tube and a thermometer are charged 56 g of benzyl p-hydroxybenzoate, 25 g of triethylamine and 160 ml of toluene. A suspension of 25 g of isophthalic dichloride in 100 ml of toluene is added dropwise with stirring while maintaining the mixture at 0°-3° C. over 3 hours. After addition, the mixture is further allowed to react at 0°-3° C. for 1 hour. Thereafter, the resulting reaction product is collected by filtration to obtain white crystals. The crystalline product is washed with 1500 ml of water twice and then with 1000 ml of methanol twice and subsequently, recrystallized from a mixture solvent of hexane-chloroform (1:1) to give di(p-benzyloxycarbonylphenyl)isophthalate melting at 105°-107° C. as white crystals.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[C:5]=1[F:17].[AlH4-].[Li+]>O1CCCC1>[F:17][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)OC)c1F
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1cccc(CO)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid methyl ester (16, 3.80 g, 13.8 mmol) in 133 mL of tetrahydrofuran, lithium tetrahydroaluminate (20.0 mL, 1.00 M in tetrahydrofuran, 20.0 mmol) was added under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature for 8 hours, followed by addition of 10 g of NaSO4.10H2O. After 12 hours, the reaction was filtered, the filtrate concentrated under vacuum and purified with silica gel column chromatography eluting with 5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a white solid (17, 3.0 g, 87.9%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].C([O:16][C:17]([CH:19]1[CH:21]([CH:22]=O)[C:20]1([CH3:25])[CH3:24])=[O:18])C>C(O)C>[C:8]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:22][C@H:21]1[C@H:19]([C:17]([OH:18])=[O:16])[C:20]1([CH3:25])[CH3:24])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)[C@@H](C=C(C#N)c2ccccc2)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenylacetonitrile is added to a stirred solution of sodium ethoxide in absolute ethanol (prepared from 1.1 g sodium and 100 ml of ethanol). Next, a solution of 3-formyl-2,2-dimethyl-cyclopropanecarboxylic acid ethyl ester (8.5 g) in absolute ethanol (15 ml) is added over 5 minutes. The reaction mixture is stirred for 12 hours at room temperature and then heated on a steam bath for 0.5 hour. The alcohol is removed in vacuo, and the residue washed with water (250 ml) and ether (150 ml). The aqueous layer is acidified with concentrated hydrochloric acid. The resulting cream colored slurry is filtered and the isolated product dried. The product is dissolved in ether and precipitated with hexane to afford 6.1 g of white crystals, m.p. 186°-188° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N1CCOCC1)C.Cl.[CH2:45]([O:47][C:48](=[O:52])[C@H:49]([CH3:51])[NH2:50])[CH3:46]>O1CCCC1>[CH2:45]([O:47][C:48](=[O:52])[C@H:49]([CH3:51])[NH:50][C:25](=[O:27])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:46]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
13.3 g of Nα -tert.butoxycarbonyl-Nε -benzyloxycarbonyl-L-lysine were dissolved in 100 ml of tetrahydrofuran and the solution was cooled to -20° C. 4.58 ml of isobutyl chloroformate and 4.48 ml of N-ethylmorpholine were then added. After stirring at -20° C. for 2 minutes 5.37 g of L-alanine ethyl ester hydrochloride and 4.48 ml of N-ethylmorpholine were added and the mixture was allowed to come to room temperature, whereafter it was stirred for 4 hours. The solvent was removed by evaporation and the residue was partitioned between 200 ml of ethyl acetate and 100 ml of water. The organic phase was washed in sequence twice with 25 ml of 10% citric acid solution each time, twice with 25 ml of saturated sodium hydrogen carbonate solution each time, once with 25 ml of water and once with 25 ml of saturated sodium chloride solution, dried and evaporated. The resulting gum crystallized from ethyl acetate/n-hexane. There were obtained 13 g (77%) of Nα -tert.butoxycarbonyl-Nε -benzyloxycarbonyl-L-lysyl-L-alanine ethyl ester. Rf (chloroform/methanol 9:1) 0.73.
Reaction SMILES: CO[C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])[CH3:17]>C(#N)C.C(N(CC)CC)C>[NH2:14][C:13]1[C:10]([C:11]#[N:12])=[C:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:22]([CH2:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])[C:20]=1[C:19]([O:18][CH3:16])=[O:23]
Reactant: CCOC(=O)CCN
Reactant: COC(=C(C#N)C#N)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCn1c(C(=O)OC)c(N)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After dissolving (methoxyphenylmethylene)methane-1,1-dicarbonitrile (15.10 g) and β-alanine ethyl ester hydrochloride (15.11 g) in acetonitrile (300 mL), triethylamine (23.00 mL) was added and the mixture was stirred for 10 minutes at room temperature. After confirming complete consumption of the (methoxyphenyl-methylene)methane-1,1-dicarbonitrile by thin-layer chromatography (hexane/ethyl acetate=3/1), the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. Acetonitrile (700 mL) and anhydrous cesium carbonate (53.65 g) were added to the residue. Methyl bromoacetate (16.00 mL) was added thereto and the mixture was heated to reflux for 40 minutes. After cooling the mixture to room temperature, it was allowed to stand, the supernatant was separated by decantation, and the solvent was distilled off under reduced pressure. The residue was combined with the solid portion remaining after decantation, ethyl acetate and water were added, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was passed through a chromatography column packed with a small amount of silica gel (elution with dichloromethane), for removal of the highly polar impurities, to obtain the title compound as a crude product (35.31 g).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:11][C:10](=[O:12])[NH:9][CH2:8]2)[C:3]1=[O:13].[H-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:9]1[C:10](=[O:12])[CH2:11][C:4]2([C:3](=[O:13])[N:2]([CH3:1])[C:6](=[O:7])[CH2:5]2)[CH2:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1C(=O)CC2(CNC(=O)C2)C1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC2(CC(=O)N(Cc3ccccc3)C2)C1=O
Reaction time: 1 h

Procedure:
A solution of 1.82 g (10 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione in 20 ml N,N-dimethylformamide was added gradually under a nitrogen atmosphere to 0.050 g (10.4 mmol) of 50% oil suspension of sodium hydride which had been previously washed twice with toluene and covered with 10 ml N,N-dimethylformamide. After stirring one hour there was added 1.40 g (11 mmol) of benzyl chloride and stirring was continued overnight at room temperature. After concentrating to a small volume in vacuo, the residue was diluted with 40 ml water and extracted twice with dichloromethane. The combined organic phase was washed with water, dried over magnesium sulfate, and evaporated to give a solid. Crystallization from toluene:hexane to affore 1.74 g of the title compound, mp 157°-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[NH:16])[NH:7]OC=CC(OCC)=O)=[C:4]([F:19])[CH:3]=1.CC([O:24]C)(C)C.[C:26]1([O:32][C:33]2[CH:38]=CC=CC=2)C=CC=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[NH:7][CH:28]=[C:27]([C:26]([O:32][CH2:33][CH3:38])=[O:24])[N:16]=2)=[C:4]([F:19])[CH:3]=1
Reactant: COC(C)(C)C
Reactant: CCOC(=O)C=CONC(=N)c1ccc(Br)cc1F
Reactant: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c(-c2ccc(Br)cc2F)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 (300 g, 0.91 mol, 1 eq) in diphenyl oxide (900 mL, 3 vol) was stirred at 190° C. under N2 for 1 h and checked by LC-MS (no 25 remaining) Cooled the mixture to rt and TBME (600 mL, 2 vol of 25) was added, and then PE (1.8 L, 6 vol of 25) was dropwise added to separate out solids. The mixture was stirred at rt for 20 min, and filtered to give 160 g wet cake. The wet cake was washed with PE (1 L) and dried to afford 120 g ethyl 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylate 26 with 92% LC purity as brown solids.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:11]1([CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(C)C(C)(C)C(=O)CCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)C(C)(C)C(=O)Cn1cncn1
Temperature: 40 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
162.5 g (1 mol) of 1-chloro-3,3,4-trimethylpentan-2-one are added dropwise to a suspension of 84 g (1.2 mols) of 1,2,4-triazole and 165.6 g (1.2 mols) of potassium carbonate in 1 liter of ethanol. The mixture is stirred for 15 hours at 40° C., the inorganic precipitate is filtered off under suction, the solvent is distilled off, the precipitate is taken up in 500 ml of methylene chloride, the organic phase is extracted with 1 liter of water, the aqueous phase is extracted with 500 ml of methylene chloride, the methylene chloride phases are combined, and the combined phases are extracted with twice 1 liter of water. The solvent is distilled off from the organic phase. 154.6 g (79.3% of theory) of 1-(1,2,4-triazol-1-yl)-3,3,4-trimethylpentan-2-one are obtained as a colorless oil of refractive index nD20 =1.4827. ##STR16##
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].N12CCCN=C1C[CH2:17][CH2:16][CH2:15][CH2:14]2.BrC(CC)C>CN(C=O)C>[CH:15]([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])([CH2:16][CH3:17])[CH3:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCC(C)Br
Product: CCC(C)ON1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
N-hydroxylphthalimide (18.4 mmol, 3.0 g) was dissolved in anhydrous DMF (20 mL) under nitrogen. To the stirring solution, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (27.6 mmol, 4.13 mL) was injected followed by 2-bromobutane (22.1 mmol, 2.41 mL) and the reaction was warmed to 55° C. After stirring for 18 hour, the reaction was cooled to room temperature and concentrated to a red oil. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution, distilled water, brine and dried over magnesium sulfate. The solvent was removed under vacuum providing 3.57 g (89%) of a yellow solid. Rf: 0.8 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.80 (2H,m), 7.73 (2H,m), 4.31 (1H,m), 1.81 (1H,m), 1.64 (1H,m), 1.32 (3H,d), 1.03 (3H,t).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Cl[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>CCOC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: COC(=O)CCCl
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCn1cc(I)cn1
Temperature: 50 °C

Procedure:
To a mixture of 4-iodopyrazole (1.000 g, 5.155 mmol), Cs2CO3 (2.016 g, 6.186 mmol), and DMF (20 mL, 0.2 mol) was added methyl 3-chloropropanoate (758.1 mg, 6.186 mmol) at 0° C. The reaction was heated to 50° C. for 1 h. The material was transferred to a separatory funnel, diluted with EtOAc, and washed with water several times to remove DMF. The organic layer was dry-loaded onto silica gel, and column chromatography was used for purification, eluting with 3:1 Hexanes/EtOAc, affording the title compound as a clear liquid. MS (ES+): m/z=280.95 (100) [MH+]. HPLC: tR=2.91 min (ZQ3, polar—5 min).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([O:23][CH3:24])=[O:22].C(Cl)Cl.C(N(CC)C(C)C)(C)C.[NH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][N:39]=1>O>[CH3:24][O:23][C:21]([C:4]1[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:37][C:38]1[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][N:39]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: Nc1nccc2ccccc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CNc2nccc3ccccc23)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
In a 10 mL round-bottomed flask, methyl 3-(bromomethyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (50 mg, 0.123 mmol) was combined with methylene chloride (5 mL) to give a colorless solution. To this solution, N,N-diisopropylethylamine and 1-aminoisoquinoline were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 25 mL H2O and extracted with ethyl acetate (1×25 mL). The organic layer was washed with 1 M HCl (1×10 mL), saturated aqueous NaHCO3 (1×10 mL), and H2O (1×10 mL). The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 5% to 40% ethyl acetate in hexanes), giving 7-chloro-3-(isoquinolin-1-ylaminomethyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (4 mg, 7%). MS calcd. for C27H20ClN3O3 [(M+H)+] 470.1, obsd. 470.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:32][C:33]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
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: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)ncnc2c1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
To a mixture of 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Intermediate KKKK; 0.07 g, 0.147 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (0.049 mg, 0.220 mmol) and potassium carbonate (0.101 g, 0.734 mmol) in Dioxane (Solvent Ratio: 3, Solvent Volume: 0.734 ml) and Water (Solvent Ratio: 1.000, Solvent Volume: 0.245 ml) was added Pd (PPh3)4 (17 mg, 0.015 mmol), degassed with nitrogen and irradiated in microwave at 100° C. for 1 h. The aqueous layer was discarded and the reaction mixture was filtered through SPE and concentrated. To this was then added DCM (1 ml) and TFA (1 ml) and the reaction was stirred for 2 h. The crude mixture was purified using reverse phase HPLC to obtain 4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (16 mg, 23% yield) as white solid. m/z (ESI) 470.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C.O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:15]1[CH:16]=[C:11]([C:9]2[N:8]=[C:5]3[N:4]([CH:10]=2)[N:3]=[C:2]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[C:26]([F:37])([F:36])[F:25])[CH:7]=[CH:6]3)[CH:12]=[CH:13][C:14]=1[CH3:24])=[O:23]
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: OB(O)c1cnccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2cn3nc(-c4cnccc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Yield: 24.3 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.034 g, 0.1 mmol), [4-(trifluoromethyl)-3-pyridyl]boronic acid (0.038 g), bis(triphenylphosphine)palladium(II) dichloride (7 mg), Na2CO3 (0.032 g), and isopropanol-water (1 mL, 3:1). The mixture is heated at 80° C. for 16 hr, cooled, concentrated, taken up in 1:1 EtOAc and CH2Cl2, filtered, concentrated onto celite and purified by silica gel chromatography (10-100% EtOAc in Hexanes) to give the title compound (0.011 g, 25% yield). LCMS m/z=454.5 [M+H]+, tR=2.47 min. (compound same as Example 364)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1.C1(C)C(C)=CC=CC=1.N([C:25]1[NH:26][CH2:27][CH2:28][N:29]=1)[N+]([O-])=O>CC(C)=O>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[Cl:10])[CH:3]([OH:12])[CH2:2][NH:1][C:25]1[NH:29][CH2:28][CH2:27][N:26]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1ccc(Cl)c(Cl)c1
Temperature: 160 °C

Procedure:
To a stirred solution of 8 parts of α-(aminomethyl)-3,4-dichlorobenzyl alcohol in 4.5 parts of xylene are added 5.2 parts of 2-(nitramino)-2-imidazoline. The whole is heated in an oil-bath at a temperature of about 160°C. till a clear melt is obtained (about 15 minutes). After cooling to about 60°C., the melt is dissolved in acetone and allowed to crystallize. The precipitated product is filtered off and recrystallized from 20 parts of 4-methyl-2-pentanone, yielding 3,4-dichloro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol; m.p. 148°C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:20]N1C(=O)CCC1=O.O>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCn2ccc(C(N)=O)c2C1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)cc(C(N)=O)c2C1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution under nitrogen of 21.1 g (79.6 mmol) of tert-butyl 8-carbamoyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 600 ml of dichloromethane, cooled to −40° C., is added dropwise a solution of 10.6 g (79.6 mmol) of N-chlorosuccinimide in 200 ml of dichloromethane over about 40 minutes. Stirring is continued for 6 hours at a temperature of −40° C., 150 ml of water are then added and the reaction medium is allowed to warm to room temperature. The product is isolated by filtration and is washed with water to give 17.5 g of tert-butyl 8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a whitish solid after drying under reduced pressure at 40° C. in the presence of phosphorus pentoxide.