Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH3:25])[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>ClC(Cl)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:25])[C:33](=[O:35])[CH3:34])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: CNc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-methyl-amine was diluted to 0.20 M with anhydrous dichloroethane, then delivered to an 8 mL vial via pipette (0.20 mmol). To the amine solution was added base (0.4 M triethylamine in dichloroethane, 0.40 mmol). Acetyl chloride was diluted to 0.20 M with dichloroethane, and added at rt (0.2 mmol). The reaction was shaken overnight at 50° C., then evaluated by MS. Polyamine scavenging resin was added (0.5 mmol). The solution was shaken overnight at rt, then filtered into an 8 mL vial. The reaction was concentrated using an HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). N-{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-N-methyl-acetamide was isolated in 100% purity @ 254 nm, LCMS (APCI): 479 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Al]>CO>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: O=C1CCCCC1
Agent: [Al]
Solvent: CO
Product: C1=Cc2ccccc2C(C2CCN(C3CCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.50 gram (1.8 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 6.68 gram (68.1 millimoles) of cyclohexanone, 0.49 gram of finely cut bits of aluminum foil and 15 milliliters of methanol were mixed together. To the mixture, 0.01 gram (0.04 millimole) of mercuric chloride was added and the resulting mixture stirred at ambient temperature for 24 hours at which time a TLC analysis indicated complete consumption of the starting material and formation of a new product. The reaction mixture was filtered successively through celite and silica gel to remove aluminum and mercury salts and the filtrate concentrated in vacuo to obtain a yellow oil which crystallized on trituration with acetonitrile. Recrystallization from acetonitrile produced purified 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cyclohexylpiperidine product as long, straw-colored needles of melting point 162°-164° C. in a yield of 490 milligrams (75 percent). Elemental analyses were as follows:
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:14]CCC.CI>C1COCC1>[C:1]([NH:5][S:6]([C:9]1([CH3:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)NS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of N-tert-butyl-(3-chloro)propylsulfonamide (4.3 g, 20 mmol) was dissolved in dry THF (100 mL) and cooled to −78° C. To this solution was added n-BuLi (17.6 mL, 44 mmol, 2.5 M in hexane) slowly. The dry ice bath was removed and the reaction mixture was allowed to warm to room temperature over a period of 1.5 hours. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 mL, 2.5 M in hexane) was added. The reaction mixture was warmed to room temperature, recooled to −78° C. over a period of 2 hours and a neat solution of methyl iodide (5.68 g, 40 mmol) added. The reaction mixture was allowed to warm to room temperature overnight, quenched with saturated NH4Cl (100 mL) at room temperature. It was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a yellow oil which was crystallized from hexane to provide the product as a slightly yellow solid (3.1 g, 81%): 1H NMR (CDCl3) δ 0.79 (m, 2H), 1.36 (s, 9H), 1.52 (m, 2H), 1.62 (s, 3H), 4.10 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: CC(C)C(=O)Cl
Reactant: Cn1ccc2ccc(N)cc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc2ccn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a solution of 1-methyl-1H-indol-6-amine (45 mg, 0.31 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (35 μL, 0.34 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 24.3 mg (36%) of the title compound (LCMS RT=5.73 min, MH+ 217.2)
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:12]1([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:24](Cl)=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>O1CCCC1>[CH:1]([NH:4][C:24](=[O:25])[CH:23]([O:22][C:21]1[CH:32]=[CH:33][C:18]([C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=2)=[CH:19][CH:20]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)NC(C)C
Reaction time: 5 h

Procedure:
To a solution of 5 g of isopropylamine and 5 ml of triethylamine in 100 ml of absolute tetrahydrofuran is slowly added dropwise with stirring at -5° C a solution of 13 g of α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid chloride in 25 ml of absolute tetrahydrofuran. The reaction mixture is left to stand for 5 hours at room temperature, then evaporated in vacuo to dryness. The residue is partitioned between methylene chloride and 2N hydrochloric acid. The organic phase is washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The residue yields the crude α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid isopropylamide of the formula ##STR23## (m.p. 86°-88° C after recrystallisation from petroleum ether).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][N:7]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCNCC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCN(Cc1ccccc1)CC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of the compound (27.8 g) obtained in step 2 and sodium carbonate (16.3 g) in acetonitrile (132 mL) was added benzyl bromide (14.4 g) at room temperature, and the mixture was stirred at 75° C. for 2 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane) to give N-benzyl-N-[2-(3,4-dichlorophenyl)-3-ethoxy-3-oxopropyl]-β-alanine ethyl ester (34.6 g, 99%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH2:21]>O1CCCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:21][CH3:20])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2F)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cc(C(F)(F)F)ccc2F)C1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
A stirred solution of 4.5 g (0.015 mol) of 3-[2-fluoro-5-(trifluoromethyl)phenoxyl]-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 4.0 g (0.05 mol) of 40% aqueous monomethylamine. After stirring for 16 h the reaction mixture was diluted with 200 mL of water and the oil which separated slowly solidified. The solids were collected by filtration (3.9 g) and recrystallized from benzene/ligroin, yielding 3.5 g (79.8%) of white crystals, mp 93.5°-95° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].[C:11](=O)([O-])[O-].[K+].[K+].CI>>[CH3:11][O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1cccnc1[N+](=O)[O-]
Yield: 97.4 %

Procedure:
The similar reaction as described in Reference Example 9 by using 2-nitro-3-hydroxypyridine (7.0 g), potassium carbonate (6.91 g) and methyl iodide (4.67 ml) gave the title compound (7.5 g) as crystalline powders.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]3=[O:20])[CH2:7][CH2:6]2)[O:4]CC1.CC(C)=O.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1
Reactant: O=c1[nH]c2ccccc2n1C1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 74.1 %

Procedure:
To a flask charged with 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-benzo[d]imidazol-2(3H)-one (1.100 g, 4.01 mmol) were added acetone (7.29 mL) and water (0.729 mL) followed by PPTS (1.310 g, 5.21 mmol). The resulting light brown solution was heated at reflux overnight. Water was then added to the mixture leading to an oiling out of the organics. The mixture was transferred to a separatory funnel and extracted with EtOAc (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure. The oil thus obtained was purified with a 50 g SNAP column (Biotage) ramping DCM:MeOH:NH4OH (90:10:1) in DCM from 0-35% leading to coelution of product and starting material. The mixture was used in the next step without further purification. The mixture containing 1-(4-oxocyclohexyl)-1H-benzo[d]imidazol-2(3H)-one (0.685 g, 2.97 mmol, 74.2% yield) was obtained as a brown foam. m/z (ESI) 231.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[S:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cnccc3s2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2nc3cnccc3s2)cc1
Yield: 60.3 %

Procedure:
2-(4-nitrophenyl)thiazolo[4,5-c]pyridine (2.57 g, 0.01 mol), iron powder (2.8 g, 0.05 mmol) and NH4Cl (4.32 g, 0.08 mol) were refluxed in CH3OH/H2O (4:1, 200 mL) for 6 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was washed with water (30 ml) to give 4-(thiazolo[4,5-c]pyridin-2-yl)benzenamine as a white solid (1.37 g, Yield: 60%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[NH:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:8]([C:10](ON1C(=O)CCC1=O)=[O:11])[CH3:9].CN1CCOCC1>CN(C=O)C>[NH:7]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:8]([C:10]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:11])[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
L-Alanine (3.57 g, 40 mmol) was dissolved in 18.8 ml of Triton B (40 mmol), evaporated to dryness, and the oily residue re-evaporated twice with DMF (30 ml each). The salt obtained was stirred with 11.45 g of Boc-Ala-OSu (40 mmol) in 40 ml DMF, with 4 ml of NMM added, for 20 hours. The solvent was removed and the residue taken up in 10% HOAc (100 ml). The product was extracted into EtOAc (4 times 100 ml), washed twice with a small volume of H2O, dried over Na2SO4, evaporated to a small volume, and treated with petroleum ether until cloudiness developed. A crystalline product formed on storage in the refrigerator overnight: Yield, 8.2 g (76.3%); mp 115°-118°.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:22][CH3:23])[CH2:6][C:5]([CH2:13]OS(C(F)(F)F)(=O)=O)([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH2:4]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-:41]>C1COCC1>[F:41][CH2:13][C:5]1([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH2:6][C:3]([O:22][CH3:23])([O:2][CH3:1])[CH2:4]1
Reactant: [F-]
Reactant: COC1(OC)CC(COS(=O)(=O)C(F)(F)F)(C(=O)OC(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC1(OC)CC(CF)(C(=O)OC(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of Intermediate 302A (1.8 g, 4.94 mmol) in THF (30 mL) was added TBAF (5.93 mL, 5.93 mmol, 1M in THF) at −78° C. and the reaction mixture was stirred at RT for 1 h. It was then quenched with ice-cold water and extracted with ethyl acetate (3×25 mL). The combined organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (4 g REDISEP® column, eluting with 25% ethyl acetate in hexanes). Fractions containing the product were combined and evaporated to afford the Intermediate 302B as a pale yellow liquid (0.8 g, 69%). 1H NMR (400 MHz, chloroform-d) δ ppm 5.06 (s, 1H), 4.51-4.72 (m, 2H), 3.15 (s, 6H), 2.56 (dd, J=13.55, 2.01 Hz, 2H), 2.21 (d, J=14.06 Hz, 2H), 1.26 (d, J=6.02 Hz, 6H).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[C:12]1[CH2:17]Cl.[NH3:20].[I-].[K+]>O1CCCC1.CO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]2[N:11]3[C:15]([CH3:16])=[N:14][N:13]=[C:12]3[CH2:17][NH:20][C:3](=[O:19])[C:4]=2[CH:9]=1
Reactant: N
Reactant: COC(=O)c1cc(Cl)ccc1-n1c(C)nnc1CCl
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(=O)NC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A stirred solution of 5-chloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzoic acid methyl ester (VIb)(300 mg., 1 mmole) in tetrahydrofuran (THF) (10 ml.) was cooled, under nitrogen, in an ice bath and treated with 8 ml. of a saturated solution of ammonia in methanol. The mixture was kept in the ice bath for 20 minutes and at ambient temperature for one hour. At this time there was no reaction by thin layer chromatography (TLC). The mixture was therefore treated with potassium iodide (166 mg., 1 mmole) and kept at ambient temperature for 18 hours. It was concentrated in vacuo, and the residue was mixed with water and extracted with chloroform. The extract was washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from a methanol/ethyl acetate mixture to give 0.169 g., melting point 253.5°-255.5° and 0.026 g., melting point 251°-252.5°. The mixture melting point with that of an authentic sample of the titled compound (VIIa) was 261.5°-264.5°. The first crop was recrystallized from a methanol/ethyl acetate mixture, seeding with an authentic sample, to give 0.110 g., melting point 262°-264°. This was identical to the authentic sample of (VIIa) by ir comparison.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:33]([CH:32]=[CH2:31])(=[O:35])=[O:34])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Nc3ccc(N)cc3)c2cc1OC
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1ccc(Nc2ncnc3cc(OC)c(OC)cc23)cc1
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of dichloromethane (10 mL), compound 41 (100 mg, 0.337 mmol) and triethylamine (141 μL, 1.02 mmol) was cooled to 0° C. 2-chloro-1-ethane sulfonyl chloride (32 μL, 0.304 mmol) was added and the reaction was allowed to proceed for 1 hour prior to removal of a precipitate and addition of saturated sodium bicarbonate (10 mL) and extraction with dichloromethane (2×10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (24 mg, 20% yield): 1H NMR (400 MHz, DMSO) δ 10.81 (br, 1H), 10.13 (s, 1H), 8.75 (s, 1H), 8.02 (s, 1H), 7.58 (d, J=8.9, 2H), 7.25 (m, 3H), 6.83 (dd, J=16.4, 10.0, 1H), 6.15 (d, J=16.5, 1H), 6.07 (d, J=10.0, 1H), 3.99 (s, 3H), 3.98 (s, 3H); 13C NMR (100 MHz, DMSO) δ 157.93, 156.16, 150.10, 149.26, 136.23, 135.75, 132.76, 127.82, 125.54, 120.00, 107.16, 103.16, 100.51, 56.55, 56.45; [M+H]+ calculated for C18H18N4O4S 387.1, found 387.4.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]#[N:15])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].[CH3:31][N:32]=[C:33]=[S:34]>O>[CH3:31][NH:32][C:33](=[S:34])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)([C:14]#[N:15])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN=C=S
Reactant: N#CC(CCCc1ccccc1)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=S)C(C#N)(CCCc1ccccc1)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a tetrahydrofuran solution containing 1.78 g (6.6 mmole) of 2-(4-chlorophenyl)-5-phenylvaleronitrile was added a tetrahydrofuran solution containing 0.77 g (6.9 mmole) of potassium tert-butoxide at 0° C. After stirring for 30 minutes, a tetrahydrofuran solution containing 0.5 g (6.8 mmol) of methyl isothiocyanate was added to the mixture and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography to obtain 1.19 g (yield: 52.4 %) of N-methyl-2-(4-chlorophenyl)-2-cyano-5-phenylthiovaleroamide as a crystal.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35](I)[CH:34]=3)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:14]>>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:41])[C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[C:37]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][N:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:38]=3)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: C#Cc1cnc2cnccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-a]pyrazine and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1. The product was obtained as a solid: 544 m/z (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:38][CH:39]([Cl:43])[C:40](Cl)=[O:41]>ClCCl>[Cl:38][CH:39]([Cl:43])[C:40]([N:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:15]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)NCCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylcarbamate (230 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane with triethylamine (120 μL, 0.82 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (120 mg, 0.82 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield tert-butyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylcarbamate. 1H NMR (CDCl3): 7.99 (d, 1H), 7.82 (br s, 1H), 7.62 (m, 1H), 7.48-7.30 (m, 4H), 6.78 (s, 1H), 5.82 (s, 1H), 4.95 (m, 1H), 3.95 (m, 2H), 3.43 (m, 2H), 1.42 ppm (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:14][C:10]1[CH:9]=[C:8]([C:3]2[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1-c1cccc(F)c1
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(-c2ccccc2N=C=S)c1

Procedure:
Reaction of 2-amino-3'-fluorobiphenyl (10 g) and thiophosgene (9.2 g) in a mixture of dioxane (15 ml) and water (70 ml) at ambient temperature for 1.5 hours yielded 3'-fluoro-2-biphenylylisothiocyanate as a brown oil.