Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([C:36]([F:39])([F:38])[F:37])([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:41]([O:43][C:44](=[O:52])[CH2:45][C:46]1[N:47]=[C:48](Br)[S:49][CH:50]=1)[CH3:42].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:41]([O:43][C:44](=[O:52])[CH2:45][C:46]1[N:47]=[C:48]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:4][CH3:5])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:35])([C:36]([F:38])([F:39])[F:37])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:1][CH3:2])=[CH:7][C:8]=2[CH3:21])[S:49][CH:50]=1)[CH3:42]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCOC(=O)Cc1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1csc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
Degassed N,N-dimethylformamide (0.25 mL) was added to (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 22.9 mg, 0.0401 mmol), (2-bromo-thiazol-4-yl)-acetic acid ethyl ester (Example 42; 17.8 mg, 0.071 mmol), tetrakis(triphenylphosphine)palladium (0) (5.9 mg, 0.0051 mmol) and potassium phosphate (19.2 mg, 0.0904 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 95 to 105° C. for five hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/dichloromethane=1/4) to give the title compound (9.7 mg, 39%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[P:13]([O-:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[CH2:15]([O:14][P:13]([O:17][CH2:18][CH3:19])([C:6]([OH:12])([CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:20])[CH3:16]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)C(=O)CCN(C)C
Product: CCOC(=O)C(O)(CCN(C)C)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A mixture of 8.05 g (0.05 mole) of ethyl 4-(N,N-dimethylamino)-2-oxobutanoate in 31 g (0.225 mole) of diethyl phosphite is stirred at 20°-30° for 3-5 days. The excess diethyl phosphite is removed on a rotary evaporator under high vacuum at a bath temperature of 50°-70° to yield the crude product as a viscous oil. This is purified by chromatography on silica gel using chloroform/methanol as eluant.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:44][C:45]([OH:47])=[O:46]>CN(C=O)C>[C:45]([CH2:44][O:23][C:22]([C:21]1[C:16]2[N:15]=[C:14]([C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1)=[O:24])([OH:47])=[O:46]
Reactant: O=C(O)CCl
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)OCC(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
50 mg (0.08 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid were dissolved in 6 mL DMF. Subsequently 27.6 mg KI, 126.5 mg (0.88 mmol) K2CO3 and 62.8 mg (0.64 mmol) chloro-acetic acid were added. The resulting mixture was stirred for 8 h at 60° C. Further 92 mg K2CO3 and 62.8 mg (0.64 mmol) chloro-acetic acid were added. After further 8 h at 60° C. the reaction mixture was concentrated under removed pressure. The remaining residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give pure 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid carboxymethyl ester as a white amorphous solid. The corresponding dihydrochloride was obtained by treatment with a 0.1 M HCl-solution and following lyophilization.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.[CH2:32]([NH2:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>>[CH2:32]([NH:34][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1)[CH3:33]
Reactant: CCN
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCNc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCOCC3)cc2OC)o1
Yield: 86 %

Procedure:
As described for example 106, 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine (100 mg, 0.23 mmol) using ethylamine instead of dimethylamine hydrochloride and potassium carbonate was converted to the title compound (88 mg, 86%) which was obtained as a white solid. MS: m/e=448.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[C:27]([F:30])([F:29])[F:28])[CH2:22]Br.O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([C:27]([F:28])([F:29])[F:30])=[C:19]([F:18])[CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)c(F)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (8.9 g, 42.3 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.69 g, 42.3 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-fluoro-4-(trifluoromethyl)benzyl bromide (9.0 g, 42.3 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) and recrystallized from diisopropyl ether-hexane to give ethyl 3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-oxopropionate (10.8 g, 66%).
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[CH:6]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][S:16]([CH2:19][CH2:20][NH:21][C:22]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:23])(=[O:18])=[O:17])[CH2:11][CH2:10]1)([CH3:8])[CH3:7]>>[C:3]([CH2:2][N:15]([CH:12]1[CH2:13][CH2:14][N:9]([CH:6]([CH3:8])[CH3:7])[CH2:10][CH2:11]1)[S:16]([CH2:19][CH2:20][NH:21][C:22]([C:24]1[S:25][C:26]([Cl:29])=[CH:27][CH:28]=1)=[O:23])(=[O:17])=[O:18])(=[O:4])[NH2:5]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: NC(=O)CCl
Product: CC(C)N1CCC(N(CC(N)=O)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[carbamoylmethyl-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 48 mg (2 equiv.) 2-chloro-acetamide and 100 mg (0.25 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[carbamoylmethyl-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(Cl)c(C#N)c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 2-chloro-5-fluoro-benzonitrile (1 g, 6.43 mmol), K2CO3 (2.66 g, 19.3 mmol) and 1-methyl-piperazine (1.02 g, 10.26 mmol) in DMSO (14 ml) was stirred at 100° C. overnight and then further 1-methyl-piperazine (1.02 g, 10.26 mmol) was added. The mixture was stirred at 100° C. overnight and then partitioned between water and Et2O. The organic phase was extracted with 1 M HCl and the aqueous layer was brought to basic conditions with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4 and evaporated in vacuo to give 1 g of 2-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1([CH:18]2[O:20][CH:19]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[OH:20][CH:19]([CH:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: CCOC(=O)C1OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(O)C(Oc1ccc(Cl)cc1[N+](=O)[O-])c1ccccc1
Yield: 32.6 %

Procedure:
To a stirred mixture of 4-chloro-2-nitrophenol (11.68 g, 67.32 mmol), ethyl 3-phenyloxirane-2-carboxylate (9.61 g, 50.00 mmol) in ethanol (200 mL) was added portionwise 60% sodium hydride (738 mg, 20.00 mmol) and the red mixture stirred at reflux for 3 days. The solvent was removed in vacuo. The residue was dissolved in chloroform and extracted three times with 10% aqueous potassium carbonate. The organic layer was washed with water and brine, dried, filtered and evaporated to afford a brown residue. The residue was dissolved in a minimal volume of chloroform and precipitated by adding diethyl ether to afford the title compound (5.970 g,33%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ1.16 (t, 3H, J=7.0 Hz), 4.09 (q, 2H, J=7.0 Hz), 4.29 (t, 1H, J=7.0 Hz), 5.63 (d, 1H, J=7.0 Hz), 6.09 (d, 1H, J=7.0 Hz), 7.19-7.60 (m, 7H), 7.97 (d, 1H, J=2.6 Hz). MS APCI, m/z=388 (M+Na).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH3:8][C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][C:5]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7]
Reactant: C1CCNCC1
Reactant: CC(C)(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CCC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,4-Dimethylvaleric acid (348 g), piperidine (291 mL) and DMF (1.7 L) were mixed. To the mixture were added HOBt.H2O (450 g) and WSC.HCl (563 g) at ice temperature. After the mixture was stirred at RT overnight, water (1.7 L) was added to the reaction mixture at ice temperature and the mixture was extracted with toluene (500 mL, and 400 mL×2). The organic layer was washed with aqueous 10 w/v % sodium carbonate (1 L) and water (1 L), then concentrated in vacuo to give the title compound (508 g) as a crude product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:25])[C:10](=[O:24])[N:11]([CH:21]([CH3:23])[CH3:22])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:26].[H][H]>[Pd].CO>[F:30][C:29]1[CH:28]=[CH:27][C:4]([CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([OH:25])[C:10](=[O:24])[N:11]([CH:21]([CH3:22])[CH3:23])[C:12]=3[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]2=[O:26])=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: [Pd]
Solvent: CO
Product: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (95 mg, 0.22 mmol; Example 13) and 10% palladium on charcoal (0.11 g) in methanol (5 mL) was stirred under a balloon of hydrogen gas at room temperature overnight. The reaction mixture was filtered, and the filtrate concentrated under vacuum. The residue was subjected to preparative HPLC purification on C-18 reverse stationary phase column eluting with a gradient of water—acetonitrile in the presence of 0.1% trifluoroacetic acid. Collection and lyophilization of appropriate fractions provided the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=C2CCCCCC2)c2ccc(Br)cc2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(C(=C2CCCCCC2)c2ccc(Br)cc2)c1
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a cold (5° C.) solution of {(4-bromophenyl)[3-(methyloxy)phenyl]methylidene}cycloheptane (192) (0.557 g, 1.5 mmol) in CH2Cl2 (50 mL) was added BBr3 (0.425 mL, 4.5 mmol) slowly. The reaction mixture was stirred between 5° C. and 20° C. for 4 h and then carefully poured into water (100 mL). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×50 mL) and the combined organic layer dried (Na2SO4). Concentration and purification by flash column chromatography gave 0.44 g (82%) of compound 193 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=8.4 Hz, 2H), 7.17 (dd, J1=7.8 Hz, J2=7.8 Hz, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.74 (br d, J=7.5 Hz, 1H), 6.69 and 6.67 (dd, J1=2.4 Hz, J2=8.1 Hz, 1H), 6.62 (app t, J=1.8 Hz), 4.71 (s, 1H), 2.32 (br, m, 4H), 1.59 (br s, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: Fc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Ferric chloride (0.5 g) was added to a mixture of 4-bromo-3-fluoro-benzenesulfonyl chloride (2.5 g) and fluorobenzene (3 ml) and then stirred at reflux for 18 hours. The flask was cooled to room temperature and the residue was partitioned between aqueous NaHCO3 and DCM. The DCM layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallised from ethanol to give buff coloured crystals.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([OH:16])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]([NH2:32])([CH3:31])[CH3:30]>O1CCCC1.C(OCC)(=O)C>[CH3:3][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:16])[CH3:1]
Reactant: CC(C)N
Reactant: CC(C)Oc1c(C(=O)O)oc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1oc2ccccc2c1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 1.14 mmol) and 1,1'-carbonyldiimidazole (240 mg, 1.48 mmol) in 7 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and i-propylamine (0.58 mL, 6.84 mmol) is added and the reaction mixture is stirred at room temperature for 30 minutes. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:2 to 1:1) provides 3-(1-methylethoxy)-N-(1-methylethyl)-2-benzofurancarboxamide in 72% yield as a yellow oil.
Reaction SMILES: C(S([CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31](=[O:33])[CH3:32])[S:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:34])[CH2:6]1)=O)C.C(Cl)(=O)C([Cl:38])=O>C(Cl)Cl>[Cl:38][CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31](=[O:33])[CH3:32])[S:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:34])[CH2:6]1
Reactant: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1S(=O)CC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl

Procedure:
A solution of 1.2 g p-nitrobenzyl 2-(4-ethylsulfinyl-2-oxo-1-azetidinyl)-3-acetylthio-3-(2-ethoxyethylthio)-acrylate in 50 ml methylene chloride was cooled to -50° C. under a nitrogen atmosphere. Oxalyl chloride (0.196 ml) was added dropwise at -50° C., then the reaction mixture was allowed to warm to -15°. After 1 hour at -15° C. the methylene chloride solution was washed with 20 ml saturated aqueous sodium bicarbonate solution and 20 ml water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (1.2 g). The crude title compound was used without further purification. The NMR spectrum of a deuterochloroform solution showed peaks at 1.23(m,3H); 2.3-3.72(c,11H); 5.23(m,2H); 5.7-6.32(c,1H); 7.52(m,2H); and 8.2(m,2H) ppm. The infrared spectrum of a chloroform solution had absorption bands at 5.6 and 5.78 microns.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].F[C:28](F)(F)C1C=C(N2CCN(CCO)CC2)C=CC=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH2:19][CH3:28])=[O:17]
Reactant: OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12
Product: CCOC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12

Procedure:
Using the procedure of Example 13, methyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate and 2-[-4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethanol were reacted to obtain 2-[4-3-trifluoromethylphenyl)-piperazin-1-yl]-ethyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluorobenzoate. The said product was dissolved in absolute ethanol and an ethanolic solution of hydrogen chloride was added thereto followed by anhydrous ether. The mixture crystallized was vacuum filtered and the product was washed with anhydrous ether and was dried to form the desired hydrochloride salt melting at 230°-240° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][S:12][CH3:13])=[CH:7][CH:6]=1)[OH:4].[S:16](Cl)([C:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:24]([N:25]([CH3:27])[CH3:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].C1N2CCN(CC2)C1.O>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[CH:3]([O:4][S:16]([C:19]1[C:31]2[C:23](=[C:24]([N:25]([CH3:27])[CH3:26])[CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:6]=[CH:7][C:8]([S:11][S:12][CH3:13])=[CH:9][CH:10]=1
Reactant: CSSc1ccc(C(O)C(F)(F)F)cc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O
Product: CSSc1ccc(C(OS(=O)(=O)c2cccc3c(N(C)C)cccc23)C(F)(F)F)cc1
Reaction time: 4 h
Yield: 28.4 %

Procedure:
2,2,2-Trifluoro-1-(4-methyldisulfanyl-phenyl)-ethanol (6) (12 mg, 0.047 mmol) and dansyl chloride (15 mg, 0.057 mmol) were dissolved in dry CH2Cl2 (0.2 mL). A solution of DABCO (63 mg, 0.56 mmol) dissolved in dry CH2Cl2 (0.1 mL) was added dropwise to the above solution. After 4 hours at room temperature, the reaction was poured into H2O (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with H2O (3×30 mL), followed by brine (1×30 mL) and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation. Flash chromatography on silica gel using 0-15% acetone/hexanes to yield Compound 1 as a yellow solid (6.5 mg, 28%). 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J=8.5 Hz, 1H), 8.2 (d, J=8.7 Hz, 1H), 8.07 (d, J=7.3 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 5.59 (q, J=6.3 Hz, 1H), 2.84 (s, 6H), 2.37 (s, 3H); 19F NMR (376 MHz, CDCl3): δ −76.3 (d, J=6.3 Hz). HRMS calc'd for C21H21F3NO3S3: 488.0636. found: 488.0647.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[NH:28][C:25]2[S:26][CH:27]=[C:23]([S:22][CH3:21])[N:24]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CSc1csc(N)n1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1csc(NC(=O)c2cccc(OC(C)=O)c2)n1
Temperature: 25 °C
Yield: 121.4 %

Procedure:
Into a solution of 511 (0.815 g, 4.10 mmol) and dry THF (25.0 mL) was added triethylamine (0.572 mL, 4.10 mmol), followed by a solution of the 508 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL). The reaction was stirred at room temperature. After stirring overnight, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed once with water, three times with saturated aqueous. sodium bicarbonate solution, and once with brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 85 (1.28 g, >100%) as a red foam. The crude product was dissolved in dichloromethane. Silica gel was added to the dichloromethane solution and the suspension was concentrated in vacuo. The residue was loaded on top of a 90 g silica gel cartridge and eluted down the column using a solution of 20% ethyl acetate in hexane. Appropriate fractions of the major product were combined and concentrated in vacuo to give 85 (0.614 g, 58%) as a tan solid. This material was used in the next step without further purification.