Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:12])[C:7]([NH:9][CH2:10][CH3:11])=[O:8].Cl>C(O)(=O)C>[CH2:4]([N:5]1[CH:11]=[CH:10][N:9]=[C:7]([OH:8])[C:6]1=[O:12])[CH3:3]
Reactant: CCNC(=O)C(=O)NCC(OC)OC
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ccnc(O)c1=O
Reaction time: 1 h
Yield: 79.9 %

Procedure:
67.5 g (330 mM) of N-(2,2-dimethoxyethyl)-N′-ethylethanediamide and 2 ml of concentrated hydrochloric acid in 390 ml of acetic acid were refluxed under stirring for 1 h. The solvent was removed under vacuum to give an oil, which was further purified by silica gel column chromatography, using dichloromethane/methanol (95/5) as eluant to give 37 g of 1-ethyl-3-hydroxy pyrazine-2(1H)-one, as an oil. Yield: 79.5%.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:51]1([CH2:57][NH:58][CH2:59][CH:60]=[CH2:61])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)(=O)C>[O:12]=[C:10]([N:58]([CH2:57][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:59][CH:60]=[CH2:61])[CH2:9][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reactant: C=CCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN(Cc1ccccc1)C(=O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-(phenylmethyl)glycine (D88, 1.06 g, 4.0 mmol), DIPEA (1.38 ml, 8.0 mmol) and TBTU (1.61 g, 5.0 mmol) in dry DMF (8 ml) was stirred at room temperature for 30 min. Then N-(phenylmethyl)-2-propen-1-amine (D87, 647 mg, 4.4 mmol) was added and stirring was continued for another 2 h. After reaction was completed, ethyl acetate was added and the organic layer was washed with water and brine. The residue was purified via flash chromatography to give the title compound (1.50 g, 95%). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.4-7.2 (m, 10H), 5.8-5.5 (m, 1H), 5.2-5.0 (m, 2H), 4.7-4.3 (m, 4H), 4.1-3.7 (m, 4H), 1.5 (s, 9H); MS: (ES/+) m/z: 295 [M-BOC+], C24H30N2O3 requires 394.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](O)[CH2:17][OH:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:8]1([C:6]2([C:5]3[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=3)[O:18][CH2:17][CH2:16][O:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C2(c3ccccc3)OCCO2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a round-bottom flask were added 4-methylbenzophenone (11, 5.0 g, 25.5 mmol, 1.0 equiv.), ethylene glycol (57 mL, 1020 mmol, 40.0 equiv.), para-toluenesulfonic acid monohydrate (147 mg, 0.77 mmol, 0.03 equiv.), and toluene (65 mL, 0.4 M). The biphasic reaction mixture was stirred vigorously at reflux with a Dean-Stark trap for 4 days. The reaction mixture was cooled to room temperature. The reaction mixture was washed with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Mg504, filtered, and concentrated. Recrystallization from hexanes yielded 12 (4.58 g, 75%) as a white solid. 1H-NMR (500 MHz, CDCl3) δ 7.58-7.55 (m, 2H), 7.45-7.40 (d, 2H, J=8.0 Hz), 7.38-7.35 (m, 2H), 7.33-7.30 (m, 1H), 7.18 (d, 2H, J=8.0 Hz), 4.09 (s, 4H), 2.37 (s, 3H). 13C-NMR (125 MHz, CDCl3): δ 142.2, 139.1, 137.7, 128.7, 128.0, 127.9, 126.1, 126.0, 109.4, 64.8, 21.1.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:15]=2)=[CH:9][C:8]=1[CH3:37])C.[OH-].[Na+].Cl>C(O)C>[CH2:33]([O:32][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:38])=[O:3])=[C:8]([CH3:37])[CH:9]=2)[CH:19]=[C:18]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:17]=1)[CH:34]([CH3:36])[CH3:35]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (190 mg; 0.34 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 110 mg (61%). HPLC-MS: m/z: 525.1 (M+H)+; Rt: 2.55 min.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])C.S(Cl)(Cl)=O.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>Cl.C(O)C.CCOCC>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[F:22][C:23]1[CH:24]=[C:25]([F:29])[CH:26]=[CH:27][C:28]=1[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)C1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Solvent: CCOCC
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Temperature: 55 °C
Yield: 57.4 %

Procedure:
In a 1 liter round bottom flask, a solution of ethyl-N-benzyl-3-pyrrolidine carboxylate (21.8 g, 11.7 mmol) in 140 ml of 6N HCl was heated at reflux for 2.5 hours. The solution was cooled and the solvent was removed to dryness with a vacuum pump. The residue was then treated with thionyl chloride (100 ml) for 16 hours at room temperature. After the reaction, the excess thionyl chloride was vacuum stripped to dryness (60° C., 4 hours). To the residue in the flask was added 1,3-difluorobenzene (30 g, 26 mmol) followed by aluminum chloride (25 g, 18.7 mmol) in portions at room temperature. When the mixture turned homogeneous (in about 10 minutes) it was then heated at 55° C. for 1 hour. After the reaction was complete, excess 1,3-difluorobenzene was removed under reduced pressure. The residue was partitioned between ice/water and dichloromethane (700 ml) and basified with 50% NaOH solution to pH 10. The dichloromethane solution was washed with water and brine, then dried over anhydrous MgSO4. The solvent was stripped and the crude oil (31 g) was purified by flash chromatography over a silica gel column. The pure product thus obtained weighed 26 g (74%) as a yellow oil. An analytical sample was prepared by dissolving 4.2 g of the oil in ethanol and treating with an ethanol solution of oxalic acid (1.33 g, 14.8 mmol). To the mixture was added ether dropwise to cause crystallization. Recrystallization from ethanol and ether gave 2.63 g of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxalate as white crystals, m.p.=114°-116° C.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].C1COCC1.[F:37][C:38]1[CH:39]=[C:40]([Mg]Br)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]>ClC1C=CC=CC=1>[F:37][C:38]1[CH:39]=[C:40]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)=[O:9])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(F)c3)sc2c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone (1.5 g, 3.6 mmol)(see U.S. Pat. No. 5,420,349) in chlorobenzene (15 mL) was cooled to 0° and treated with a 0.73 M THF solution of 3-fluoro-4-methoxyphenylmagnesium bromide (16.0 mL, 11.7 mmol)(prepared from 4-bromo-2-fluoroanisole, catalytic iodine, and magnesium turnings in THF). The mixture was allowed to warm to ambient temperature and when the starting material was consumed, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (2x), and brine (2x), dried (sodium sulfate), and concentrated. The residue was purified via chromatography (silica gel, 5-10% MeOH in CH2Cl2) to provide 0.79 g (44%) of the title compound as a brown oil: 1H NMR d 1.44 (m, 2H), 1.59 (m, 4H), 2.48 (m, 4H), 2.74 (t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.09 (t, J=6.0 Hz, 2H), 6.77-6.83 (m, 3H), 6.96 (dd, J=2.3 Hz, 8.9 Hz, 1H), 7.11-7.19 (m, 2H), 7.31 (d, J=2.3 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H); 13C NMR d 24.4, 26.1, 55.3, 55.9, 56.4, 57.9, 66.5, 104.7, 113.5, 114.6, 115.3, 116.7, 117.0, 124.4, 125.5, 126.7, 126.8, 130.5, 131.6, 132.6, 134.1, 140.4, 140.9, 148.0, 148.1, 153.8, 158.1, 163.5, 193.2; MS (FD) m/e 519 (M+); Anal. calc'd. for C30H30FNO4S: C, 69.34; H, 5.82; N, 2.69. Found: C, 69.63; H, 5.89; N, 2.64.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[CH:11][C:10]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=3)=[CH:7][CH:6]=2)[N:9]=[C:10]([C:20]([OH:29])([C:21]([F:22])([F:24])[F:23])[C:25]([F:26])([F:27])[F:28])[CH:11]=1
Reactant: OC(c1cc(-c2ccccc2Cl)n(-c2ccc(Br)cc2)n1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3nc(C(O)(C(F)(F)F)C(F)(F)F)cc3-c3ccccc3Cl)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A mixture of 2-[1-(4-bromophenyl)-5-(2-chlorophenyl)-1H-pyrazol-3-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol (100 mg, 020 mmol), 3-methanesulfonyl-phenylboronic acid (48 mg, 0.24 mmol), K2CO3 (83 mg, 0.60 mmol), Cl2Pd(dppf).DCM (16 mg, 10 mol %) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 3 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to give the title compound (94 mg, 82%) as a white solid. 1H-NMR (DCM-d2): δ 8.12 (m, 1H), 7.92 (m, 1H), 7.87 (m, 1H), 7.67 (m, 1H), 7.61 (d, 2H), 7.33-7.47 (m, 6H), 6.74 (s, 1H), 5.25 (s, 1H), 3.07 (s, 3H); MS(ES): 575 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:13]2[C:9]=1[C:10](=[O:24])[N:11]([CH3:23])[CH2:12]2)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:13]2[C:9]=1[C:10](=[O:24])[N:11]([CH3:23])[CH2:12]2
Reactant: CN1Cc2c(CN3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1Cc2c(CN3CCCC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl[2-methyl-3-oxo-7-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 109B) was added DCM (0.5 mL) and TFA (0.5 mL, 6 mmol). The solution was stirred at room temperature for 20 minutes. The crude product was dried in vacuo and used directly in next step without further purification. MS (ES+): m/z 246.31 (100) [MH+]; HPLC: tR=0.29 min (UPLC, Analytical).
Reaction SMILES: [CH2:1](C1C=C2C(COC2=O)=CC=1)[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][C:24]2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([O:35][CH3:36])[C:27](Br)=[CH:26][CH:25]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(B(CC)CC)C>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][C:24]2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([O:35][CH3:36])[C:27]([CH2:1][CH3:2])=[CH:26][CH:25]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccc(Cl)cc2)ccc(Br)c1OC
Reactant: CCc1ccc2c(c1)C(=O)OC2
Agent: CCB(CC)CC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccc(Cl)cc2)ccc(CC)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from ethyl 6-(4-chlorobenzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 84) and triethyl borane.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:6]=1.N.[CH3:21][N:22]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:6]=1)#[N:22]
Reactant: Cc1cc(-n2cc(I)nc2C)cc2ccc(=O)[nH]c12
Reactant: CN1CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Product: Cc1cc(-n2cc(C#N)nc2C)cc2ccc(=O)[nH]c12
Reaction time: 2 h

Procedure:
A mixture of 6-(4-Iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.55 g), cuprous cyanide (0.27 g) and palladium acetate (0.03 g) in 1-methyl-2-pyrrolidone (5 cm3) was heated and stirred at 175° for 2 hours. The cooled mixture was poured into aqueous ammonia solution (30 cm3 ; S.G. 0.880) and extracted with dichloromethane (3×100 cm3). The combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform. Combination and evaporation of the appropriate fractions afforded the title compound, m.p. >350°, (0.22 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[C:30]2[CH3:38])[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[C:30]2[CH3:38])[CH2:28][CH2:29]1)=[O:23]
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1cc(C)ccc1C)CC2
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 52.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.053 g, 0.105 mmol) obtained in step 2 and ethanesulfonamide (0.057 g, 0.587 mmol), the title compound (0.033 g, 52%) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:12]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:17]=[CH:16][C:15]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[O:10])=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere, 3-anisoyl chloride (195 g) and biphenyl (190 g) were stirred in dichloromethane (1.4 L). The flask was placed in an ice bath and to it was added anhydrous aluminum chloride (172 g) in portions, each spaced 10 minutes apart. After the aluminum chloride addition was complete the reaction mixture was heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture was slowly poured into a beaker containing a 10% aqueous solution of hydrochloric acid (1.5 L) and ice while stirring vigorously. A separatory funnel was used to separate the organic and aqueous layers. The recovered organic layer was then washed with deionized water three times with 1 liter each time, hereinafter designated as (3×1 L), dried over sodium sulfate and concentrated by rotary evaporation. Crystals formed while sitting overnight and were collected by vacuum filtration. A recrystallization was then performed by dissolving the crystals in a solution of 10% methanol/90% dichloromethane and subsequently removing nearly all of the solvent by rotary evaporation. Crystals formed while sitting overnight and were collected by vacuum filtration yielding 153 g of [1,1′-biphenyl]-4-yl(3-methoxyphenyl)methanone.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH2:31]([N:39]([CH2:44][CH:45]1[CH2:47][O:46]1)[S:40]([CH3:43])(=[O:42])=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(O)C>[CH2:31]([N:39]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:44][CH:45]([OH:46])[CH2:47][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCN(CC1CO1)S(C)(=O)=O
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Solvent: CCO
Product: CCCCCCCCN(CC(O)CN1CCN(CC(=O)OCC)CCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1)S(C)(=O)=O

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 5.27 g (20 mmol) of N-octyl-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2b), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[N:21]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([C:22]2[CH2:23][CH2:24][N:25]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:26][CH:27]=2)[N:21]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Ethanesulfonyl chloride (16.30 mg, 12.01 μL, 0.1268 mmol) was added to a solution of 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (60 mg, 0.1153 mmol) and DIPEA (44.71 mg, 60.26 μL, 0.3459 mmol) in N,N-dimethylformamide (1 mL) and the resulting solution stirred at ambient temperature. Analysis after 30 minutes showed SM still remaining therefore the reaction was treated with further ethanesulfonyl chloride (4 μL, 0.04222 mmol). The mixture was allowed to stir for a further 10 minutes and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×), DCM (2×), dried (MgSO4), filtered and concentrated. The mixture was triturated with DCM and the resultant yellow solid dried under vacuum at 50° C. (44.33 mg, 57% Yield).
Reaction SMILES: N1(N[C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])CCOCC1.[NH2:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[C:47]([C:52]([OH:54])=[O:53])[CH:46]=[CH:45]2>>[CH:33]1([N:14]2[C:13]3[CH:39]=[CH:40][C:10]([C:8]([NH:41][C:42]4[CH:43]=[C:44]5[C:49](=[CH:50][CH:51]=4)[CH:48]=[C:47]([C:52]([OH:54])=[O:53])[CH:46]=[CH:45]5)=[O:9])=[CH:11][C:12]=3[N:16]=[C:15]2[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=[N:20]3)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Reactant: O=C(NN1CCOCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: O=C(O)c1ccc2cc(NC(=O)c3ccc4c(c3)nc(-c3ccc5nc(-c6ccccc6)cnc5c3)n4C3CCCCC3)ccc2c1
Yield: 53 %

Procedure:
The general procedure described for Compound 574 was used with 6-amino-naphthalene-2-carboxylic acid (18.7 mg), producing 15 mg of the title compound (53% yield). MS: 618.30 (M+H+) HPLC Procedure A, retention time=16.24 min.
Reaction SMILES: [C:1]([C:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=1)([CH3:6])[CH3:5])([OH:3])=O.[N:18]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1)=[C:19]=[S:20].C(N(CC)CC)C>CCO>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:18]2[C:1](=[O:3])[C:4]([CH3:6])([CH3:5])[N:7]([C:8]3[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=3)[C:19]2=[S:20])=[CH:22][C:23]=1[C:29]([F:30])([F:31])[F:32])#[N:26]
Reactant: CC(C)(Nc1ccc(C(=O)O)c(F)c1)C(=O)O
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 2.2 %

Procedure:
4-(1-Carboxy-1-methyl-ethylamino)-2-fluoro-benzoic acid (241 mg, 1 mmol), 4-isothiocyanato-2-trifluoromethylbenzonitrile (342 mg, 1.5 mmol) and triethylamine (343 mg, 3.4 mmol) were mixed in EtOH (5 mL) and the solution was stirred for 10 days at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 1M aqueous HCl, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography eluting with ethyl acetate to obtain 4-[3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-2-fluoro-benzoic acid (10 mg) as an off white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([CH2:18][C:19]([OH:21])=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:16][CH:17]=1)[C:13](=[O:15])[O:21][C:19](=[O:20])[CH2:18]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)ccc1C(=O)O
Solvent: CC(=O)Cl
Product: O=C1Cc2cc(OCc3ccccc3)ccc2C(=O)O1
Yield: 100 %

Procedure:
A mixture of 8 g of 4-(benzyloxy)-2-(carboxymethyl)benzoic acid and 30 ml of acetyl chloride was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, added with ether, and collected by filtration to obtain 7.50 g of 6-(benzyloxy)-1H-isochromene-1,3(4H)-dione as a dark brown solid.