Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].C(Cl)Cl.[Si](OS([C:28]([F:31])(F)F)(=O)=O)(C)(C)C>O>[CH2:1]([O:3][C:4](=[O:16])[CH:28]([F:31])[CH:6]([CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH3:2]
Reactant: CCOC(=O)C=CCOCc1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(COCc1ccccc1)C(F)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 119.4 %

Procedure:
In a 10 mL flask with 4-benzyloxy-but-2-enoic acid ethyl ester (0.1 g, 0.45 mmol) inside, dry CH2Cl2 3 mL was added under argon. This was cooled to 0° C., TMSOTf (0.08 mL, 0.45 mmol) was added drop by drop. After stirring for 10 min, ethyl α-fluoro silyl enol ether (0.08 g, 0.45 mmol) was added dropwisely at 0° C. This was left stirring at 0° C. for 1.5 hr, at room temperature for 5 hr and refluxing for 25 hr. After cooling to room temperature, H2O was added and the aqueous phase was extracted with CH2Cl2 three times and the combined organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product which was purified by silica gel flash chromatography (Hexane: EtOAc=6:1, Rf==0.42) to give 87.7 mg (59.3%) of the product. 1H NMR (CDCl3, 400 MHz): δ 1.18-1.32 (m, 6H), 2.32-2.54 (m, 2H), 2.77-2.98 (m, 1H), 3.44-3.57 (m, 2H), 4.07-4.30 (m, 4H), 4.45-4.54 (m, 2H), 4.96-5.09 (dd, J=48, 3.2, 1H, minor isomer), 5.10-5.22 (dd, J=48, 3.2, 1H, major isomer), 7.24-7.36 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 14.23, 30.96-31.02 (d, J=6.0), 32.63, 38.51-38.70 (d, J=19), 60.87, 61.73, 67.94-67.99 (d, J=5.0), 68.60-68.63 (d, J=3.0), 73.29-73.35 (d, J=6.0), 86.96-88.81 (d, J=185), 87.54-89.40 (d, J=186), 127.77, 127.87, 128.54, 137.99-138.04 (d, J=5.0), 168.92-169.42 (t, J=25.8), 171.80-171.85 (d, J=5.0). MS (FAB): expected for C17H23FO5 (M+H)+ 327.36. Found 327.16020. IR (neat) νmax 2983, 2938, 2907, 2872, 1760, 1734, 1455, 1374, 1208, 1183, 1090, 1029, 739, 699.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=S)=[CH:14][CH:13]=1)#[N:11]>>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:5][C:19]=1[NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: NCc1ccccc1N
Product: N#Cc1ccc(NC2=Nc3ccccc3CN2)cc1

Procedure:
The title compound (MS: m/e=249.0 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 4-cyanophenylisothiocyanate.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:4][CH:3]=1.C(=O)=O>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCCC[C@@H]1Oc1ccc(Br)nc1
Agent: O=C=O
Solvent: CO
Product: CC(C)S(=O)(=O)N[C@H]1CCCC[C@H]1Oc1ccc(Br)nc1

Procedure:
Separation of the enantiomers comprising cis-N-{2-[(6-bromopyridin-3-yl)oxy]cyclohexyl}propane-2-sulfonamide (7.96 g, 21.1 mmol) was carried out by chiral chromatography. Column: Chiralpak® AD-H, 2.1×25 cm, 5 μm; Mobile phase: 70:30 carbon dioxide: methanol; Flow rate: 65 g/min. The first-eluting compound was enantiomer [N-{(1R,2S)-2-[(6-bromopyridin-3-yl)oxy]cyclohexyl}propane-2-sulfonamide] and the second-eluting peak provided desired product N-{(1S,2R)-2-[(6-bromopyridin-3-yl)oxy]cyclohexyl}propane-2-sulfonamide upon removal of solvent in vacuo. Yield: 3.13 g, 8.30 mmol, 39%. The absolute stereochemistry of these enantiomers was assigned by analogy to Example 5.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([CH:21]=[C:22]([C:24]4[CH:29]=[C:28]([NH:30][C:31]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH:27]=[CH:26][C:25]=4[Cl:38])[N:23]=3)[CH:20]=2)=[CH:11][CH:10]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:38][C:25]1[CH:26]=[CH:27][C:28]([NH:30][C:31]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:32])=[CH:29][C:24]=1[C:22]1[N:23]=[C:18]2[N:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([NH:7][CH3:6])=[CH:14][CH:13]=3)=[CH:20][N:19]2[CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cnc3nc(-c4cc(NC(=O)N5CCCC5)ccc4Cl)cn3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(-c2cnc3nc(-c4cc(NC(=O)N5CCCC5)ccc4Cl)cn3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl(4-(2-(2-chloro-5-(pyrrolidine-1-carboxamido)phenyl)imidazo[1,2-a]pyrimidin-6-yl)phenyl)(methyl)carbamate was treated with 5% TFA in DCM and was stirred overnight at room temperature. At completion, the reaction mixture was concentrated in vacuo and the residue was redissolved in methanol. Purification of the compound was done via mass-triggered reverse phase column chromatography preparative system (15% to 65% (B)). m/z (ESI) for 26: 447.2 (M+H+), 1H NMR (600 MHz, DMSO-D6) δ 9.17 (d, J=2.6, 1H), 8.88 (d, J=2.6, 1H), 8.5, 362 (s, 1H), 8.46 (m, 2H), 7.73 (m, 1H), 7.52 (d, J=8.6, 2H), 7.40 (d, J=8.8, 1H), 6.68 (d, J=8.7, 2H), 5.97 (s, 1H), 3.40 (s, 4H), 2.73 (d, J=5.0, 3H), 1.86 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Br)cc4)nc23)CC1
Yield: 32.9 %

Procedure:
Beginning with 0.090 gm (0.39 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.128 gm (0.59 mMol) 4-bromobenzoyl chloride, 0.053 gm (23%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([NH:5][C@@H:6]1[CH2:31][CH2:30][N:9]2[C:10]3[CH:23]=[CH:22][C:21](C4N=NN(C)N=4)=[CH:20][C:11]=3[C@H:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@H:8]2[CH2:7]1)=[O:4].[N+:34]([O-])([OH:36])=[O:35]>C(Cl)Cl>[F:1][C:2]([F:32])([F:33])[C:3]([NH:5][C@@H:6]1[CH2:31][CH2:30][N:9]2[C:10]3[CH:23]=[CH:22][C:21]([N+:34]([O-:36])=[O:35])=[CH:20][C:11]=3[C@H:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@H:8]2[CH2:7]1)=[O:4]
Reactant: C[C@@H]1c2ccccc2[C@H]2C[C@H](NC(=O)C(F)(F)F)CCN2c2ccc(-c3nnn(C)n3)cc21
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: C[C@@H]1c2ccccc2[C@H]2C[C@H](NC(=O)C(F)(F)F)CCN2c2ccc([N+](=O)[O-])cc21

Procedure:
A solution of 10 (8═H, R2═COCF3; 76 mg, 0.2 mmol) in DCM (1.5 mL) was cooled to 0° C. and fuming nitric acid (21 μl, 0.5 mmol) was added in portions. The ice/water bath was removed and the reaction mixture turned red. After 10 min the reaction was quenched with aqueous NaHCO3, extracted with DCM, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (Heptane:Ethyl acetate=7:3) followed by preparative HPLC. Freeze-drying from acetonitrile/H2O afforded rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-nitrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide) (10, R8═NO2, R2═COCF3; 6 mg, 7%. Data: (m/z)=420 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([OH:14])(=O)=[O:12])=[N:2]1.P(Cl)(Cl)([Cl:17])=O>>[CH:8]1[CH:9]=[C:4]2[C:3]([CH2:10][S:11]([Cl:17])(=[O:14])=[O:12])=[N:2][O:1][C:5]2=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cc1noc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)Cc1noc2ccccc12

Procedure:
1,2-Benzisoxazole-3-methanesulfonic acid (1) (1.00 g, 4.7 mmol) was mixed with xylenes (10 mL) and phosphorous oxychloride (1.0 mL, 11 mmol) and heated to reflux until the reaction was complete. The mixture was filtered through CELITE™ and evaporated to dryness to yield 1,2-benzisoxazole-3-methanesulfonyl chloride (2) as a light brown solid. It was dissolved in ethyl acetate (10 mL), cooled in an ice-bath and treated with ammonia. Work-up analogous to example 2 gave pure zonisamide.
Reaction SMILES: [CH2:1]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][C@H:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[N+:45]([O-])=O)[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][CH:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[N+:23]([O-])=O.C(Cl)(Cl)Cl.CO>CO>[CH2:3]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[NH2:23])[CH2:2][CH2:1][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][CH:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[NH2:45]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=C1CC(CO)N(C(=O)c2cc(N)c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3N)cc2OC)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A mixture of the diol 76 (0.98 g, 1.49 mmol) and SnCl20.2H2O (3.36 g, 14.9 mmol) in MeOH (35 mL) was heated at reflux and the progress of the reaction monitored by TLC (90% CHCl3/MeOH). After 45 minutes, the MeOH was evaporated in vacuo and the resulting residue was cooled (ice), and treated carefully with saturated NaHCO3 (120 mL). The mixture was diluted with EtOAc (120 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give a brown solid. Flash chromatography (95% CHCl3/MeOH) afforded the pure bis-amine 77 as an orange solid (0.54 g, 61%): [α]19D=−31.8° (c=0.30, CHCl3); 1H NMR (270 MHz, CDCl3) δ6.74 (s, 2Harom), 6.32 (s, 2Harom), 5.00 (br s, 2H, NCH2C═CH2), 4.93 (br s, 2H, NCH2C═CH2), 4.54 (br s, 2H, NCHCH2OH), 4.24-4.14 (m, 4H, OCH2CH2CH2O), 3.98-3.50 (m, 14H, NCHCH2OH, NCH2C═CH2 and OCH3), 2.76 (dd, 2H, J=8.61, 15.91 Hz, NCH2C═CH2CH2), 2.46-2.41 (m, 2H, NCH2C═CH2CH2), 2.33-2.28 (m, 2H, OCH2CH2CH2O); 13C NMR (67.8 MHz, CDCl3) δ171.0 (NC═O), 151.0 (Cquat), 143.5 (Cquat), 141.3 (Cquat), 140.6 (Cquat), 112.4 (C—Harom), 111.9 (Cquat), 107.8 (NCH2C═CH2), 102.4 (C—Harom), 65.2 (OCH2CH2CH2O), 65.0 (NCHCH2OH), 59.8 (NCHCH2OH), 57.1 (OCH3), 53.3 (NCH2C═CH2), 34.4 (NCH2C═CH2CH2), 29.0 (OCH2CH2CH2O); MS (FAB) (Relative Intensity) 596 (M+., 13), 484 (M—NCH2CCH2CH2CHCH2OH, 14), 389 (10), 371 (29), 345 (5), 224 (8), 206 (44), 166 (100), 149 (24), 112 (39), 96 (34), 81 (28); IR (NUJOL™) 3600-3000 (br, OH), 3349 (NH2), 2922, 2852, 2363, 1615, 1591 (NH2), 1514, 1464, 1401, 1359, 1263, 1216, 1187, 1169, 1114, 1043, 891, 832, 761 cm−1. (2S,4R)&(2S,4S)-1,1′-[[(Propane-1,3-diyl)dioxy]bis[(2-amino-5-methoxy-1,4-phenylene)carbonyl]]bis[2-(hydroxymethyl)-4-methylpyrrolidine] (77).
Reaction SMILES: N1C=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3]C=1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[CH:34]=[CH:33][C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:33]=[CH:34][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:36][C:21]=2[NH:20][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([CH:4]([CH3:3])[CH3:5])[CH2:12][CH2:11]2)=[O:15])=[N:27][CH:28]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)C2CCN(C(C)C)CC2)c1

Procedure:
Using a similar procedure to that described in Example 275, 1-(4-pyridinyl)piperidin-4-ylcarboxylic acid (2.0 g, 9.7 mmol), thionyl chloride (1.4 m L, 19 mmol), and 2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (2.8 g, 9.2 mmol) afforded, after purification by column chromatography (SiO2: 5 to 10% [2.0 N ammonia in methanol]:methylene chloride), 0.40 g (9%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([F:1])[CH:7]=1)=[O:17]
Reactant: COc1ccccc1F
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCCCCBr)cc1F
Yield: 93.4 %

Procedure:
2-Fluoroanisole (1.18 g), 6-bromohexanoyl chloride (2.0 g) and aluminum chloride (1.31 g) were reacted and treated in the same manner as in Preparation Example 105 to give 2.65 g of 6-bromo-1-(3-fluoro-4-methoxyphenyl)-1-hexanone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([C:19]1[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=1)=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 16.5 g. of 3-cyanobenzoyl chloride were added to 80 ml. of methylene chloride. The temperature was brought to approximately 0° C. by means of an external ice bath and kept cold while 20 g. of aluminum chloride were added in portions. A solution of 10.8 g. of anisole in 20 ml. of methylene chloride were added to the reaction solution. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into a mixture of ice water/hydrochloric acid and extracted with ethyl acetate. The layers were separated and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was crystallized from toluene/hexane to which a small amount ethyl acetate had been added to provide 7.7 g. of the desired subtitle intermediate, m.p. 85°-88° C.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:3]2[CH2:4][C:5]3[C:10]([C:2]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:20])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)C2Cc3ccccc3C2=O)cc1
Reactant: Br[Mg]c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccccc3C2)cc1
Yield: 57 %

Procedure:
A slurry of 13.25 g (50 mmol) of 1-oxo-2-(4-methoxybenzoyl)indane in a mixture of 300 mL of ether and 300 mL of benzene was prepared. To the slurry was added 35.66 g (197 mmol) of phenylmagnesium bromide. The resulting mixture was heated to reflux for sixteen hours and poured into a mixture of ice and sulfuric acid. The mixture was allowed to separate and the organic layer was removed. The organic extract was washed with a bicarbonate solution, dried over sodium sulfate, filtered, and concentrated to a red oil. A small amount of ether was added to the oil and a crystalline precipitate formed. The crystals were removed by filtration. The filtrate was concentrated to dryness and the product crystallized from methanol to yield 9.3 g of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(C4CCCCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(C4CCCCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:12]\[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)/[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:9]([Cl:21])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C(=C/c1ccco1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(=Cc1ccco1)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A suspension of (E)-2-(4-bromophenyl)-3-furan-2-ylacrylic acid (Preparation 9, 4.10 g, 14.0 mmol) and oxalyl chloride (2.5 mL, 28.0 mmol) in anhydrous CH2Cl2 (100 mL) was treated with a catalytic amount of anhydrous DMF (25 μL). The resulting solution was stirred at 20° C. for 4 h, then the solvents were removed under reduced pressure. CH2Cl2 (50 mL) was added to the residue, then the solvents were evaporated off under reduced pressure to give 2-(4-bromophenyl)-3-furan-2-ylacryloyl chloride as a brown solid. A solution of this acid chloride (343 mg, 1.1 mmol) in anhydrous THF (1 mL) was added to a solution of 5-chlorothiazol-2-ylamine hydrochloride (171 g, 1.0 mmol) and NEt3 (0.56 mL, 4.0 mmol) in anhydrous THF (1 mL). The suspension was stirred for 16 h at 20° C., then the solvents were removed under reduced pressure. The residue was partitioned between CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was washed with H2O (5 mL) and brine (5 mL), before being concentrated. The resulting solid was recrystallised from MeOH to furnish the title compound: RTA=4.39 min; m/z (ES+)=410.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Reactant: Fc1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCc3cccc(F)c3F)cccn12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A suspension of 500 mg of ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate, 0.35 ml of 2,3-difluorobenzylbromide, and 650 mg of potassium carbonate in 8.6 ml of N,N-dimethylformamide (DMF) was stirred at 60° C. for 1 hour. The reaction mixture was left to be cooled to room temperature and water was then added thereto. The resulting solid was collected by filtration and washed with water. The solid was washed with diisopropyl ether to obtain 650 mg of ethyl 8-[(2,3-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:16][CH2:17][CH2:18][CH3:19])([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[C:23]([O:27][C:28](=[O:41])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([S:37](=[O:40])(=[O:39])[NH2:38])[CH:31]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH2:16]([C:12]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:3]2[NH:36][C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:28](=[O:41])[O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:31][C:32]=3[S:37](=[O:39])(=[O:40])[N:38]=2)[C:13]1=[O:14])[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCCCC1(C)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A solution of Example 27F (0.296 g, 0.885 mmol) and (4-amino-3-sulfamoyl-phenyl)-carbamic acid tert-butyl ester (0.280 g, 0.973 mmol) in toluene (40 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the title compound (0.430 g, 92%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.53 (m, 1 H) 0.69 (m, 3 H) 0.87 (m, 1 H) 1.08 (m, 2 H) 1.46 (m, 9 H) 1.55 (m, 3 H) 2.01 (m, 1 H) 2.20 (m, 1 H) 7.60 (m, 5 H) 8.13 (m, 2 H) 9.83 (m, 1 H) 13.93 (m, 1 H). MS (ESI−) m/z 524 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:18])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O-])([O-])=O.[K+].[K+].[Br:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[C:28]=1[F:35]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:18])[N:4]([CH2:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][Br:25])[C:28]=2[F:35])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1[nH]ccc(OCc2ccc(F)cc2F)c1Br
Reactant: Fc1c(CBr)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(CBr)c1F
Temperature: 110 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (from Step 3, Example 74) (0.3 g, 0.95 mmol) in DMF (26 mL) was added K2CO3 (0.26 g, 1.9 mmol) and 2,6-bis(bromomethyl)fluorobenzene (1.6 g, 5.7 mmol), and the reaction mixture was stirred at 110° C. for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with a 50% aqueous solution of brine, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organics were washed with water, dried (Na2SO4), filtered, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 99:1 to 95:5 methylene chloride/methanol) afforded 3-bromo-1-(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as an off-white solid (0.24 g, 49%): 1H NMR (300 MHz, CDCl3) δ 7.55-7.40 (m, 3H), 7.35-7.25 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.80 (m, 2H), 6.14 (d, J=6 Hz, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 4.50 (s, 2H).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([OH:21])=[O:20])(=O)=O)C=CC=CC=1.[CH3:22]O>[OH-].[Na+]>[CH3:22][O:21][C:19]([C:11]1[NH:10][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1)=[O:20]
Reactant: CO
Reactant: O=C(O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc2cccnc2[nH]1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
0.495 g (1.64 mmol) of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid was dissolved in 5 mL of methanol and 3 mL of 2N aqueous sodium hydroxide. The reaction was stirred at 40° C. for 8 h. The solvent was removed under reduced pressure. Residual volatiles were removed by twice codistilling with toluene. The residue was suspended in methanolic hydrochloric acid and stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure.