Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])C(O)=O.[BrH:26].FF>>[F:1][C:2]([Br:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Yield: 35.6 %

Procedure:
Perfluorooctanoic acid 18.6 g (0.045 mole), 48% hydrobromic acid 9.1 g (0.054 mole) and Freon 113 (400 ml) were mixed and treated with fluorine. The solution immediately turned to dark red. When the dark red color disappeared, fluorine was terminated and the reaction mixture was poured into dilute hydrochloric acid solution. The lower phase was separated and dried over magnesium sulfate. After removing the solvent, 7.2 g (36% yield) of perfluoroheptyl bromide was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([C:50]2[C:51]([C:56](O)=[O:57])=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:47]=[CH:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:51]1[C:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:45]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: O=C(O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.95 g, 2.61 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.43 g, 2.66 mmol, 1.02 eq.) and 3-(dimethylamino)propylamine (0.32 g, 3.13 mmol, 1.2 eq.) as described. When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:15][C:16](=[O:18])[CH3:17])[CH:7]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:9]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:15][C:16](=[O:18])[CH3:17])[CH:7]=[C:8]([N:10]2[CH:11]=[CH:12][CH:13]=[CH:14]2)[CH:9]=1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1cc(N)cc(-n2cccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of N-(3-nitro-5-pyrrol-1-yl-phenyl)acetamide (7.51 g, 30.61 mmol) in ethanol (100 ml), were added iron powder (4.273 g, 76.53 mmol, 2.5 eq.) and a solution of calcium chloride (8.49 g, 76.53 mmol, 2.5 eq.) in water (100 ml). The mixture was stirred at 80° C. for 2 h and then filtered through a pad of celite. The celite pad was washed with ethyl acetate (200 ml) and the combined organic layer was washed with water (100 ml) and brine (25 ml). The solvent was evaporated and the residue was purified by column chromatography (20% ethyl acetate in hexanes) to give the compound in 87% yield (5.7 g). 1H NMR (300 MHz, DMSO-d6): δ 9.9 (s, 1H), 8.25 (s, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.05 (d, 1H), 6.8 (s, 1H), 6.5 (m, 1H), 6.3 (m, 1H), 5.15 (s, 2H), 2.02 (s, 3H).
Reaction SMILES: N#[C-].C(N(CC)CC)C.Cl[SiH](Cl)Cl.C(Cl)Cl.[F:17][C:18]1[C:19]([Si:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([N:24]=[C:25]=O)[CH:21]=[CH:22][CH:23]=1.N>>[F:17][C:18]1[C:19]([Si:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([N+:24]#[C-:25])[CH:21]=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)c1c(F)cccc1N=C=O
Agent: Cl[SiH](Cl)Cl
Agent: N
Agent: [C-]#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]c1cccc(F)c1[Si](C)(C)C
Reaction time: 0.08 h

Procedure:
A deoxygenation then afforded the expected isonitrile. See Baldwin, J. E. et al., Tetrahedron, 39, 2989 (1983). Triethylamine (4.10 mL, 29.3 mmol) was added slowly at 0° C. to a 2 N solution of trichlorosilane in CH2Cl2 (8.40 mL, 16.8 mmol) followed, 5 min latter, by the compound prepared in Example (3) (2.35 g. 11.2 mmol). After 1 h 30 at 0° C. and 30 min at room temperature, the solution was saturated with NH3, filtered over Celite, washed with 5% NaH2PO4 and dried (Na2SO4). The crude obtained after evaporation of the solvent was then subjected to flash-chromatography (hexanes/AcOEt 95:5) to afford 1.42 g (66%) of a slighly purple liquid: IR (neat, cm−1) 2114, 1598, 1440, 1254, 1237, 1110, 943, 848, 793; 1H NMR (300 MHz, CDCl3) δ 0.45 (d, J=1.8 Hz, 9H), 7.01 (br t, J=8.3 Hz, 1H), 7.17 (br d, J=7.7 Hz, 1H), 7.32 (ddd, J1=J2=8.0 Hz, J3=6.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 0.1, 116.5 (d, JCF=26 Hz), 124.3, 131.6, 166.8 (d, JCF=243 Hz), 166.9; HRMS (EI) m/z calcd for C10H12FNSi (M+) 193.0723, found 193.0715; LRMS (EI) m/z 193 (M+), 178, 150, 116, 105.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH:7]=[CH:8][C:9]1[CH:19]=[N:18][C:12]2[NH:13][CH2:14][CH2:15][O:16][CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:29]>>[ClH:29].[N:18]1[C:12]2[NH:13][CH2:14][CH2:15][O:16][CH2:17][C:11]=2[CH:10]=[C:9]([CH:8]=[CH:7][C:6]([OH:20])=[O:5])[CH:19]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)COCCN2
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)C=Cc1cnc2c(c1)COCCN2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-(5,7,8,9-Tetrahydro-6-oxa-1,9-diaza-benzocyclohepten-3-yl)-acrylic acid tert-butyl ester (0.14 g, 0.49 mmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL). After stirring at room temperature for 30 min, the clear tan solution was concentrated in vacuo. The resulting oil was triturated with hexanes (20 mL) until the oil was converted to a fine off-white solid. The solid was then suspended in anhydrous HCl in dioxane (2 mL, 4.0 M), sonicated and concentrated to about 1 mL. The suspension was treated with Et2O (20 mL), sonicated, isolated by filtration and dried under vacuum. Yield: 0.11 g (87%); 1H NMR (300 MHz, DMSO-d6) δ 8.40 (br s, 3H), 8.31-8.29 (m, 2H), 7.53 (d, J=16.0 Hz, 1H), 6.51 (d, J=16.0 Hz, 1H), 4.76 (s, 2H), 3.96-3.92 (m, 2H), 3.71-3.67 (m, 2H); ESI MS m/z 221 [C11H12N2O3+H]+
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:27])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](N)=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[ClH:28].N([O-])=O.[Na+].[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35]>CC(C)=O.O>[C:1]([O:4][C:5]1[C:6]([CH3:27])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:35][CH:34]([Cl:28])[C:33]([O:37][CH2:38][CH3:39])=[O:36])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2
Reactant: C=CC(=O)OCC
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reaction time: 0.5 h

Procedure:
17.5 g of 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman (prepared as described in Preparation 50) were dissolved in a mixture of 130 ml of acetone and 30 ml of water. 13 ml of concentrated hydrochloric acid, and then 8.5 ml of water containing 4.3 g of sodium nitrite, was added dropwise to this solution in an ice bath. A further 37.3 ml of ethyl acrylate were then added dropwise, and then the reaction mixture was heated to 40°-43° C.; at this temperature, 680 mg of cuprous oxide were added slowly. After about 30 minutes, nitrogen generation finished. The reaction mixture, which had separated into two layers, was mixed with benzene to extract the organic layer. The benzene extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off and the resulting dark brown oil was subjected to silica gel column chromatography. After the first elution with a 1:1 by volume mixture of benzene and cyclohexane, the title compound was obtained from the next elution with a 2:1 by volume mixture of benzene and cyclohexane and from the subsequent elution with benzene alone.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:9]1)C1C=CC=CC=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](Cl)=[O:35]>>[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([C:34]([N:8]2[CH2:13][CH2:12][C@H:11]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C@H:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[CH2:9]2)=[O:35])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CCC1=O
Reactant: CN1CCNCC1
Product: Cc1ccccc1[C@@H]1CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1N1CCN(C)CC1

Procedure:
The title compound, MS: m/e=514.3 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-o-tolyl-piperidin-4-one, N-methyl-piperazine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: O1[C:5]2([CH2:10]CC(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)C[CH2:6]2)OCC1.[C:28]12([CH2:38][O:39][C:40]3[C:52](Cl)=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42]([F:54])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.C1(B(O)O)CC1.C(/B1OC(C)(C)C(C)(C)O1)=C\C>>[C:28]12([CH2:38][O:39][C:40]3[C:52](/[CH:6]=[CH:5]/[CH3:10])=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42]([F:54])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3(CC2)OCCO3)cc1F
Agent: C/C=C/B1OC(C)(C)C(C)(C)O1
Agent: OB(O)C1CC1
Product: C/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 305/306 Step 2 and making variations as required to replace tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate and to replace cyclopropylboronic acid with trans-propenylboronic acid pinacol ester, tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate was obtained as a yellowish oil (1.20 g, quant.). To a mixture of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate (0.30 g, 0.75 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. Concentration in vacuo gave the title compound as a yellowish residue (0.260 g, quant.) which was used without further purification: MS (ES+) m/z 345.2 (M+1).
Reaction SMILES: FC1C([O:8][C:9](=O)[CH:10]([C:17]2[N:18]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][C:21]=23)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=C(F)C(F)=C(F)C=1F.[CH3:37][O:38][C:39](=[O:48])[C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[C:42]([F:47])[CH:41]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:37][O:38][C:39](=[O:48])[C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:9](=[O:8])[CH:10]([C:17]2[N:18]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][C:21]=23)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:42]([F:47])[CH:41]=1
Reactant: COC(=O)c1ccc(N)c(F)c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 4.3, [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester (example 4.2) was reacted with 4-amino-3-fluoro-benzoic acid methyl ester (CAS Reg. No. 185629-32-7) in the presence of DMAP in DMF to give the title compound as colorless oil. MS: m/e=510.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(NC(C)C)(C)C.[Li].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CCOC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[C:7]1[C:6]([F:8])=[CH:5][N:4]=[CH:3][C:2]=1[Br:1])[CH3:22]
Reactant: Fc1cncc(Br)c1
Reactant: CCOC(=O)Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a round bottom flask is added 3-bromo-5-fluoropyridine (475 mg, 2.7 mmol) in 4 ml of dry THF at −78° C., followed by the addition of lithium diisopropylamine (1.62 ml, 3.24 mmol). The reaction mixture is stirred at −78° C. for 1 hour, followed by the addition of ethyl chloroformate (586 mg, 5.4 mmol). The reaction mixture is warmed up to room temperature and stirred for 1 hour. The reaction mixture is diluted with EtOAc, washed with saturated NH4Cl/water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 670 mg of 3-bromo-5-fluoro-isonicotinic acid ethyl ester.
Reaction SMILES: [N:1]1([NH:6][S:7]([CH:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:21]N1C(=O)CCC1=O.O>O1CCCC1>[Cl:21][C:5]1[N:1]([NH:6][S:7]([CH:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH2:13][CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nn1cccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=CCCCC1S(=O)(=O)Nn1cccc1Cl
Yield: 29.9 %

Procedure:
150 mg (0.503 mmol) of ethyl 6-[N-(1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31 was dissolved in 3 ml of tetrahydrofuran, and 70 mg (0.528 mmol) of N-chlorosuccinimide was added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=2:1) and the resulting solid was further washed with isopropyl ether to give 50 mg of the title compound as a white powder (yield: 30%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([CH3:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:16]([O-])([O-])=O.[K+].[K+].IC>CN(C)C=O.O>[Br:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([CH3:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(F)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c([N+](=O)[O-])cc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 3-bromo-2-fluoro-6-methyl-5-nitrobenzoic acid (2.41 g, 8.67 mmol) in N,N-Dimethylformamide (25 ml) at room temperature and under nitrogen was added K2CO3 (2.4 g, 17.34 mmol) followed by iodomethane (0.7 ml, 11.27 mmol). The reaction mixture was stirred at room temperature for 2 hours before being diluted with deionized water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic phases were washed with saturated NaHCO3(aq) (50 ml) and then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified twice by FCC (50 g silica, Isolute cartridge, gradient of eluents; 98:2 Heptane:EtOAc to 9:1 Heptane:EtOAc) to give 2.43 g (89%) of methyl 3-bromo-2-fluoro-6-methyl-5-nitrobenzoate as a white solid. LC-MS 99%, 2.18 min (3 minute LC-MS method), m/z=no ionization, 1H NMR (500 MHz, Chloroform-d) δ ppm 8.22 (d, J=6.2 Hz, 1H), 4.00 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.Br[C:21]1[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[C:18][C:21]4[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3ccc(S(N)(=O)=O)s3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (267 mg, 1 mmol) and commercially available 5-bromothiophene-2-sulfonamide (230 mg, 1 mmol) according to general procedure II. Obtained as a light brown solid (158 mg, 44%). MS (ISP) 427.9 [(M+H)+], 429.9 [(M+2+H)+]; mp 265–266° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.O(CC)[C:10]([S-:12])=S.[K+].[ClH:16]>CN(C=O)C>[Cl:16][C:10]1[S:12][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: CCOC(=S)[S-]
Reactant: Nc1ncccc1Br
Reactant: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc2ncccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-3-bromopyridine (1.0 g, 5.8 mmol) and potassium ethyl xanthate (2.22 g, 13.9 mmol) were heated to 130° C. in DMF (5 mL) overnight. After cooling to rt, the reaction mixture was diluted with 1 M aqueous HCl (30 mL) and stirred at rt for an additional 1 h. The resulting solid was collected by filtration, washed with water (2×), and air-dried. The material was suspended in CH2Cl2 (2 mL) and sulfuryl chloride (5 mL) was added. After 2 h, water (30 mL) was added to decompose the excess sulfuryl chloride. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (2×) and brine. The EtOAc layer was discarded. The combined aqueous washes were brought to pH ˜12 with 1 N aqueous NaOH and were extracted with EtOAc (3×). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 0.933 g (95%) of the title compound as a yellow solid. LC-MS: RT=5.81 min., [M+H]+=171.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)=[CH:14][C:13]=2[OH:27])=[O:10])=[CH:4][CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:27][C:13]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH:16]=[CH:17][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cc1ccc(Br)cc1)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1O
Product: O=C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1O
Yield: 50.5 %

Procedure:
The resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) prepared as described in Example 197 was reacted with 4-trifluoromethyl-phenyl boronic acid (56.7 mg, 0.3 mmol) as generally described in Example 197 to afford (26.9 mg, 50%) the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:33][C:28]2[CH:29]=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(N)(C)C>C(#N)C>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:33][CH:28]([CH3:29])[CH3:27])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(NCc2ccccc2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cccc(NCc2ccccc2)c1
Yield: 60.1 %

Procedure:
A solution of 3-benzylamino-benzoic acid (500 mg, 1.5 mmol), HATU (832 mg, 2 mmol), diisopropylethylamine (0.38 ml, 2 mmol) and isopropylamine (0.19 ml, 2 mmol) in acetonitrile was heated to 50° C. for 16 hrs. On cooling, solvents were removed in vacuo and the residue partitioned between dichloromethane and water (50 ml/50 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/dichloromethane 0% to 50% v/v) to afford the title compound as a white solid (242 mg). HPLC retention time 2.69 min. Mass spectrum (ES+) m/z 269.9 (M+H).
Reaction SMILES: [PH2](O)=O.ClC([O:7][CH2:8][CH3:9])=O.[PH2:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:15][Si](Cl)(C)C.[PH2](=O)O[Si](C)(C)CCC>C1COCC1.CC(C)=O.C(N(CC)CC)C>[OH:7][C:8]([PH:10](=[O:11])[O:12][CH2:13][CH3:14])([CH3:9])[CH3:15]
Reactant: CCO[PH2]=O
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)Cl
Agent: CCC[Si](C)(C)O[PH2]=O
Agent: O=[PH2]O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCO[PH](=O)C(C)(C)O
Reaction time: 1 h

Procedure:
Hypophosphorous acid (100%, 2.0 g, 0.03M) and ethyl chloroformate (3.3 g, 0.03M) are stirred under nitrogen at room temperature in THF (40 ml). Triethylamine (3.03 g, 0.03M) is carefully added with cooling over 1 hour. 31P nmr shows that there is 85% conversion to ethyl hypophosphite (31P nmrδ=16 ppm). Trimethylsilyl chloride (3.3 g, 0.3M) is added followed by triethylamine (3.03 g, 0.03M). The mixture is stirred for 1 hour, when conversion to ethyltrimethylsilyl phosphinate (31P nmrδ=149 ppm) is complete. Acetone (5 ml) is added and the mixture is stirred for 1 hour at 60° C. The mixture is then cooled, quenched with water and washed with methylene chloride. The aqueous phase is evaporated and the residual gum is stirred with ether. Evaporation of the ether gives ethyl (1-hydroxy-1-methylethyl)phosphinate after distillation.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:29])[C:11]([OH:28])([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH2:2]2.[Br:30][CH2:31][C:32]([NH:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1)=[O:33]>C(#N)C>[Br-:30].[OH:28][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:10]([O:9][C@@H:3]1[CH:4]2[CH2:7][CH2:8][N+:1]([CH2:31][C:32](=[O:33])[NH:34][C:35]3[CH:39]=[CH:38][O:37][N:36]=3)([CH2:6][CH2:5]2)[CH2:2]1)=[O:29]
Reactant: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1
Reactant: O=C(CBr)Nc1ccon1
Solvent: CC#N
Product: COc1cccc(C(O)(C(=O)O[C@H]2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2cccc(OC)c2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of hydroxy-bis-(3-methoxy-phenyl)-acetic acid (R)-(1-aza-bicyclo[2.2.2]-oct-3-yl) ester (Intermediate K) (0.25 g, 0.63 mmol) in acetonitrile (10 ml) is added 2-bromo-N-isoxazol-3-yl-acetamide (0.15 g, 0.73 mmol) and the reaction mixture stirred at room temperature for 3 hours. The resulting precipitate is removed by filtration and the mother liquor is left at room temperature for 72 hours to crystallise. The crystals are filtered and dried in vacuo to yield the titled compound as a solid.