Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=1.[CH:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:36][S:33]([CH:30]3[CH2:32][CH2:31]3)(=[O:35])=[O:34])=[O:14])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 34.7 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.3 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (87 mg, 0.45 mmol), 4-dimethylaminopyridine (55 mg, 0.45 mmol), cyclopropane sulfonamide (109 mg, 0.9 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (52 mg, 35%) as a light yellow solid: LC/MS m/e calcd for C26H33N3O5S (M+H)+: 500.6, observed: 500.2.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3>C1COCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][C:20]([CH3:1])([OH:29])[CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3
Reactant: O=C(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 0 °C
Yield: 89 %

Procedure:
Methylmagnesium bromide (92 μl, 3.0 M in THF) was added to an ice-cooled solution of title compound of example 103, step 1, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-one (86 mg, 0.18 mmol) in anhydrous THF (1.8 ml). The reaction was stirred in the gently warming ice bath for 6 hours, and then quenched by addition of water. The crude mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, water and then brine. The organic layer was dried over Na2SO4, filtered and condensed. Some unreacted starting material was precipitated from ˜50% acetone/hexanes. The condensed filtrate was carried forward. Yield=89%. MS (ESI), m/z: calculated 486.98. found 531.7 (M+HCOO−).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:35][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)=[O:24])[C:20](=[O:21])[N:13]3[CH:12]([C:36](O)=[O:37])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:61][CH:62]([CH2:77][C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C:63](=[O:76])[CH2:64][O:65][C:66](=[O:75])[C:67]1[C:72]([CH3:73])=[CH:71][CH:70]=[CH:69][C:68]=1[CH3:74].C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([N:10]2[CH2:35][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)=[O:24])[C:20](=[O:21])[N:13]3[CH:12]([C:36]([NH:61][CH:62]([CH2:77][C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C:63](=[O:76])[CH2:64][O:65][C:66](=[O:75])[C:67]3[C:72]([CH3:73])=[CH:71][CH:70]=[CH:69][C:68]=3[CH3:74])=[O:37])[CH2:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(N)CC(=O)OC(C)(C)C
Reactant: O=C(NC1CCCCC2CN(S(=O)(=O)c3ccccc3)CC(C(=O)O)N2C1=O)c1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)C1CN(S(=O)(=O)c2ccccc2)CC2CCCCC(NC(=O)c3nccc4ccccc34)C(=O)N21

Procedure:
To a solution of 2-benzenesulfonyl-6-[(isoquinoline-1-carbonyl)-amino]-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carboxylic acid, 111, (124 mg, 0.23 mmol) in dichloromethane is added EDCl (191 mg, 1 mmol), HOBt (135 mg, 1 mmol), 2,6-dimethyl-benzoic acid 3-amino-4-tert-butoxycarbonyl-2-oxo-butyl ester (200 mg, 0.62 mmol), and triethylamine (0.15 mL, 1 mmol). After consumption of the starting material, the reaction is diluted with EtOAc and washed with water, 1N HCl, saturated NaHCO3, and brine. The organic layer is concentrated in vacuo and the crude residue obtained is used directly in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:27])[CH:33]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Reactant: OB(O)c1cccc(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: CCO
Solvent: COCCOC
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(O)c1
Temperature: 130 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2087 μmol) and 3-hydroxyphenylboronic acid (1.55 eq) in a mixture of DME/EtOH:1/1 (8 ml) were added Na2CO3 (4 eq) and Pd tetrakis (0.05 eq.). The reaction mixture was flushed with Ar and was heated in the microwave at 130° C. for 1.5 hours. The reaction mixture was cooled to RT, diluted with 1N NaHCO3 and extracted with EtOAc. The organic layer was extracted with 1N NaHCO3 and the combined aqueous layers were acidified with citric acid and 1N HCl. The aqueous layer was extracted with EtOAc, the organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by recrystallization from EtOAc.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.[OH-].[Li+]>C1COCC1>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1csc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1csc(Br)n1
Temperature: 70 °C

Procedure:
A mixture of methyl 2-bromo-1,3-thiazole-4-carboxylate (4.2 g, 18.9 mmol), THF (120 mL) and 1N lithium hydroxide (50 mL) was heated at 70° C. for 1 h. The organic solvent was removed in vacuo. The residual aqueous solution was cooled to 0-5° C. and acidified to pH1 with 1N HCl solution. The tile compound was obtained by filtration, as a white solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[C:15]2[C:19]([CH:20]=[CH:21][CH:22]=1)=[N:18][N:17]([CH3:23])[C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25].[Cl:28][CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:28][CH2:29][CH2:30][O:13][C:14]1[C:15]2[C:19]([CH:20]=[CH:21][CH:22]=1)=[N:18][N:17]([CH3:23])[C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25]
Reactant: OCCCl
Reactant: Cn1nc2cccc(O)c2c1S(N)(=O)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc2cccc(OCCCl)c2c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
3.8 g (22 mmol) of diethylazo dicarboxylate was added to a solution containing 5 g (22 mmol) of 4-hydroxy-2-methyl-2H-indazole-3-sulfonamide, 1.8 g (22 mmol) of 2-chloroethanol and 5.8 g (22 mmol) of triphenylphosphine in 50 ml of THF, and the mixture was stirred at room temperature for 20 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, then concentrated and purified by column chromatography (hexane/ethyl acetate=2/1) to obtain 1.66 g (yield: 26%) of the desired product. Melting point: 177°-179° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12](=O)[CH2:13]Br)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[N:16]=[C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1C(=O)CBr
Reactant: Nc1ncccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N)sc1-c1cn2cccnc2n1
Yield: 27.5 %

Procedure:
A solution of ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (5.9 g), 2-aminopyrimidine (5.7 g) and triethylamine (8.4 ml) in ethanol (100 ml) was refluxed for 6 hours. The reaction mixture was evaporated in vacuo. To the residue was added a mixture of water and ethyl acetate, and the resulting mixture was acidified to pH 0.5 with conc. hydrochloric acid. The separated aqueous layer was treated with charcoal and filtered. To the filtrate was added ethyl acetate and the resulting mixture was adjusted to pH 7.0 and 20% aqueous potassium carbonate. The precipitate was collected by filtration, washed successively with water, ethyl acetate and ethanol, and dried over phosphorus pentoxide to give 2-(2-amino-4-ethoxycarbonyl-5-thiazolyl)imidazo[1,2-a]pyrimidine (1.6 g). mp 282° C. (dec.)
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14](N)=[CH:15][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.N([O-])=O.[Na+].[BrH:22]>>[Br:22][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:8][C:9]=2[CH:15]=1
Reactant: Br
Reactant: Nc1ccc2[nH]c(CN3CCCC3)nc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2[nH]c(CN3CCCC3)nc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.10 g (14.3 mmol) 2-pyrrolidin-1-ylmethyl-1H-benzimidazol-5-ylamine is suspended in 32.2 mL 48% hydrobromic acid and 32.2 mL water and the solution is cooled to 0° C. 2.5 M sodium nitrite solution (1.68 g in 9.7 mL water) is slowly added dropwise, so that the internal temperature does not exceed 5° C. The reaction is stirred for 10 min at 0° C. and then 3.50 g (24.37 mmol) CuBr in 11.3 mL 48% hydrobromic acid is added dropwise. The reaction is heated to 60° C. and stirred for one hour at this temperature. The solvent is eliminated i.vac. and the residue triturated with isopropanol. The precipitate is suction filtered and washed with isopropanol. The purification is carried out by column chromatography on silica gel (MeOH/NH3 9:1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C1N2CC[N:20](CC2)[CH2:19]1.CS(C)=O.[C-]#N.[K+]>O>[CH:12]1([C:10]2[S:9][C:4]3[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:19]#[N:20])[C:3]=3[CH:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CN2CCN1CC2
Reactant: Cc1nc(Cl)c2cc(C3CCCCC3)sc2n1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(C#N)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 860.8 %

Procedure:
To a mixture of 4-chloro-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (27.3 g), DABCO (1.2 g) and DMSO (150 mL) was slowly added an aqueous solution (14 mL) of KCN (8 g), followed by stirring at room temperature for 15 hours. To the reaction mixture was added water (150 mL) under ice-cooling, followed by stirring. The precipitate was collected by filtration and dissolved in chloroform. To the organic layer were added MgSO4, activated carbon (2 g), and basic silica gel (100 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (23.7 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=C1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:18]([OH:20])=O)=[C:14]([CH2:16][CH3:17])[N:15]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1NCC#N>O1CCCC1>[CH3:10][C:11]1[S:12][C:13]([C:18]([NH:3][CH:4]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)[C:5]#[N:1])=[O:20])=[C:14]([CH2:16][CH3:17])[N:15]=1
Reactant: c1c[nH]cn1
Reactant: CCc1nc(C)sc1C(=O)O
Reactant: N#CCNc1cccs1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCc1nc(C)sc1C(=O)NC(C#N)c1cccs1
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of imidazole (2.72 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2-methyl-4-ethyl-5-thiazolecarboxylic acid (1.65 g; 10 mmol) was added thereto at once, and stirring was continued for 30 minutes. To the mixture was added dropwise a solution of 2-(2-thienyl)aminoacetonitrile (1.65 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude oil. The oil was purified by silica-gel column chromatography (eluent:n-hexane:ethyl acetate=2:1 volume) to give crude crystals. Recrystallization from n-hexane/ethyl acetate gave 1.74 g of 2-(2-methyl-4-ethylthiazole-5-carboxamido)-2-(2-thienyl)acetonitrile as colorless crystals. m.p., 137°-138° C. Yield, 60%.
Reaction SMILES: Cl.[C:2]([N:4]=[C:5]([NH:26][CH2:27][CH:28](OC)OC)[NH:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([O:20][CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH:11]=1)[CH3:9])#[N:3].C1COCC1.[OH-].[Na+]>O1CCOCC1.O>[F:18][CH:17]([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([CH3:9])[CH2:7][N:6]2[CH:28]=[CH:27][NH:26][C:5]2=[N:4][C:2]#[N:3])=[CH:11][C:12]=1[O:20][CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1
Reactant: COC(CNC(=NC#N)NCC(C)c1ccc(OC(F)F)c(OC2CCOC2)c1)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: CC(Cn1cc[nH]c1=NC#N)c1ccc(OC(F)F)c(OC2CCOC2)c1
Yield: 15.7 %

Procedure:
HCl 0.5 N (0.0162 mol) was added dropwise to a solution of intermediate 12 (0.0108 mol) in 1,4-dioxane (20 ml), stirred and cooled in an ice-bath. The reaction mixture was stirred for 2 days at RT. (As an alternative, 1,4-dioxane may be replaced by THF and the reaction mixture may be refluxed for 1 hour instead of stirring 2 days at RT). The reaction mixture was treated with water, alkalized with a dilute NaOH solution, then extracted with ethylacetate. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by open column chromatography over silica gel (eluent: CH2C2 /2-propanone 96/4; CH2Cl2 /CH3OH 96/4) and twice by HPLC over silica gel (1. Eluent: CH2Cl2 /CH3OH 96/4 and 2. Eluent: CH2Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 0.64 g (15%) of (±)-[1-[2-[4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]phenyl]-propyl]-1,3-dihydro-2H-imidazol-2-ylidene]cyanamide (compound 2; mp. 67.8° C.).
Reaction SMILES: N1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[O:7])C=CN=C1.CI.C(N(CC)CC)C.[CH2:33]([O:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:44]=[C:43]([CH2:51][OH:52])[C:42]=1[CH3:53])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[C:17]1([CH2:16][CH2:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:52][CH2:51][C:43]3[C:42]([CH3:53])=[C:41]([O:40][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:44]=3)=[O:7])[CH2:9][CH2:10]2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(CO)nc2ccccc2c1OCc1ccccc1
Reactant: O=C(CCc1ccccc1)N1CCN(C(=O)n2ccnc2)CC1
Solvent: CI
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(COC(=O)N2CCN(C(=O)CCc3ccccc3)CC2)nc2ccccc2c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a solution of 1-(1H-imidazol-1-ylcarbonyl)-4-(3-phenylpropanoyl)piperazine (1.03 g) in acetonitrile (20 mL) was added dropwise methyl iodide (1.40 mL) and triethylamine (2.20 mL) at room temperature, followed by stirring at 60° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, and then [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (300 mg) was added thereto, followed by dropwise addition of triethylamine (0.50 mL) and stirring at 70° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain [4-(benzyloxy)-3-methylquinolin-2-yl]methyl 4-(3-phenylpropanoyl)piperazine-1-carboxylate (405 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([C:44]2[N:49]3[CH:50]=[CH:51][N:52]=[C:48]3[N:47]=[CH:46][CH:45]=2)[CH:38]=1>CS(C)=O.C(OCC)(=O)C.O>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=3[O:2][CH3:1])[C:19]3[S:23][N:22]=[CH:21][N:20]=3)(=[O:8])=[O:9])=[C:11]([F:18])[CH:12]=2)=[C:39]([C:44]2[N:49]3[CH:50]=[CH:51][N:52]=[C:48]3[N:47]=[CH:46][CH:45]=2)[CH:38]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(Cl)cc1-c1ccnc2nccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccnc4nccn34)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a stirred mixture of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.89 g, 2.0 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in dimethylsulfoxide (15 mL) at ambient temperature was added 4-chloro-2-(imidazo[1,2-a]pyrimidin-5-yl)phenol (0.45 g, 2.0 mmol). The mixture was stirred at ambient temperature for 16 h and diluted with ethyl acetate (50 mL) and water (20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 80-100% gradient of ethyl acetate in hexanes to afford 4-(4-chloro-2-(imidazo[1,2-a]pyrimidin-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.47 g). This solid was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 2 h at ambient temperature and concentrated in vacuo. The residue was triturated in a mixture of ethyl ether and ethyl acetate to afford 4-(4-chloro-2-(imidazo[1,2-a]pyrimidin-5-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a colorless solid in 53% yield (0.55 g): 1H NMR (300 MHz, DMSO-d6) δ8.94 (d, J=4.2 Hz, 1H), 8.52 (s, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.07 (d, J=1.2 Hz, 1H), 7.91-7.69 (m, 3H), 7.61 (d, J=4.2 Hz, 1H), 7.56-7.47 (m, 1H), 7.43 (d, J=8.7 Hz, 1H); MS (ES+) m/z 520.7 (M+1), 522.7 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1>>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(N)nc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (13 mg, 16%), MS (ISP) m/z=318.5 [(M+H)+], mp 332° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH2:19][C@H:18]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17]2)=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][CH2:19][C@H:18]([S@@:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[O:37])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](Sc3ccccn3)C2)cc1
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H]([S@](=O)c3ccccn3)C2)cc1
Yield: 80 %

Procedure:
A solution of 378 (15 mg, 0.04 mmol) and mCPBA (6 mg, 0.04 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by flash chromatography using the gradient EtOAc to 5% MeOH in DCM as an eluent, to afford the title compound (13 mg, 80% yield). 1H NMR (CDCl3) δ 1H NMR (CDCl3) δ 8.63 (m, 1H), 8.58 (m, 1H), 7.6-8.0 (m, 10H), 7.40 (m, 2H), 7.25 (m, 1H), 7.05 (m, 2H), 6.85 (m, 3H), 6.58 (d, J=8.8 Hz, 2H), 6.50 (d, J=11.1 Hz, 2H), 3.7-4.0 (m, 6H), 3.2-3.5 (m, 4H), 2.4-2.8 (m, 3H), 2.95 (m, 1H). LRMS: (calc) 406.1; (found) 407.1 (M+H1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].O.[CH:12]([NH2:14])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([Cl:10])[CH:6]=2)[N:1]=[CH:12][N:14]=1
Reactant: NC=O
Reactant: N#Cc1cc(Cl)ccc1N
Solvent: O
Product: Nc1ncnc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 2-amino-5-chlorobenzonitrile (1.07 g, 7.0 mmol) in formamide (20 ml) was heated at 180° C. for 6 hours. After cooling to room temperature, water (30 ml) was added to the reaction mixture. The precipitate was collected by filtration, washed with water and dried over P2O5, yielding the title compound as a grey solid (1.2 g, yield: 95%) which was characterized by its mass spectrum as follows: MS (m/z): 180 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:22]([O:24]C)=[O:23])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:29][CH3:30].Cl>O1CCCC1.O>[CH2:29]([N:18]([CH:19]([CH3:21])[CH3:20])[C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:22]([OH:24])=[O:23])=[CH:12][CH:11]=2)[CH3:30]
Reactant: CCI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)C)nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C(C)C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(isopropylamino)quinoxaline-6-carboxylate (95 mg, 0.28 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (23 mg, 0.96 mmol) and stirred for 10 minutes. Subsequently, iodoethane (43.7 mg, 0.28 mmol) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (25 mL) and the pH adjusted to 6 with hydrochloric acid (3N). The product precipitated and was filtered to afford 3-(ethyl(isopropyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (28.4 mg, 29%).