Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[NH2:8][C@@H:9]([CH2:28][C:29](=[O:42])[N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[C:14](=[O:22])[C@@:13]1([CH:25]=[C:26]=[O:27])OC)=[O:11].C(=O)([O-])O.[Na+].[Cl:48][C:49]([O:51][CH3:52])=[O:50].Cl>O1CCOCC1.O>[ClH:48].[CH3:52][O:51][C:49]([NH:8][C@@H:9]([CH2:28][C:29](=[O:42])[N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[CH2:34][CH2:35]1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[C:14](=[O:22])[C@H:13]1[CH2:25][C:26]([O:4][CH3:3])=[O:27])=[O:11])=[O:50]
Reactant: COC(=O)Cl
Reactant: CO[C@]1(C=C=O)C(=O)N(CC(=O)O)CCN1C(=O)[C@@H](N)CC(=O)N1CCN(c2ccncc2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C[C@@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](CC(=O)N1CCN(c2ccncc2)CC1)NC(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (R,S)-[4-[2-amino-4-oxo-4-[4-(pyridin-4-yl)piperazin-1-yl]butyryl]-3-methoxy-carbonylmethyl-2-oxopiperazin-1-yl]acetic acid trifluoroacetic acid salt (0.30 g) produced in Working Example 21, an aqueous solution of sodium hydrogen carbonate (0.18 g), water (3 ml) and 1,4-dioxane (3 ml) was added methyl chloroformate (0.051 ml) and the solution was stirred for 1 hour at room temperature. To the reaction solution was added 1N hydrochloric acid and the solution was adjusted to pH 3, which was then concentrated. The concentrate was purified by means of CHP-20 column chromatography (eluent:H2O→10% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.25 g) as a white amorphous powdery product.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([S:19][CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClCCl.ClC1C=CC=C(C(OO)=[O:42])C=1>O>[C:1]12([C:11]3[CH:12]=[C:13]([S:19]([CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=[O:42])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc(CSc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(CS(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
844 mg (2 mmol) of methyl 4-[3-(1-adamantyl)-4-methoxyphenylthiomethyl]benzoate and 20 ml of dichloromethane were introduced into a round-bottomed flask and 386 mg (1.9 mmol) of meta-chloroperbenzoic acid were added. The reaction medium was stirred at room temperature for two hours and was then poured into water and extracted with dichloromethane. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and ethyl ether (90/10). After evaporation of the solvents, 270 mg (30%) of the expected ester, having a melting point of 121°-2° C., were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH2:24][CH2:25][OH:26].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[OH:26][CH2:25][CH2:24][CH2:23][N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:14]1=[O:21]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: OCCCBr
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CCCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 3-bromo-1-propanol as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from diethyl ether/petroleum ether (60-95° C.). M.p. 94-97° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24]([F:35])([F:34])[F:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C(F)(F)F)c3O2)cc1
Yield: 72.3 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (10.0 g, 26.10 mmol) with 2-(trifluoromethyl)phenylboronic acid (7.43 g, 39.12 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (1.02 g, 1.30 mmol), and potassium carbonate (9.01 g, 65.19 mmol) generally according to the procedure described for Intermediate 37 provided 8.46 g (75%) of (±)-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a tan solid. mp 116-118° C.; Anal. calcd. for C23H19F3O4S: C, 61.60; H, 4.27. Found: C, 61.91; H, 4.23.
Reaction SMILES: S1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[C:13](O)(C(F)(F)F)=O>C(Cl)Cl>[CH:6]1[CH:5]=[C:4]([CH2:13][C:12]2[NH:8][CH:9]=[CH:10][CH:11]=2)[NH:3][CH:2]=1
Reactant: O=Cc1cncs1
Reactant: O=C(O)C(F)(F)F
Reactant: c1cc[nH]c1
Solvent: ClCCl
Product: c1c[nH]c(Cc2ccc[nH]2)c1
Reaction time: 0.17 h
Yield: 203.1 %

Procedure:
In a foil-covered 250-mL three-necked flask, equipped with a magnetic stirrer and N2 inlet, was placed 5-thiazolecarboxaldehyde (1, 0.88 g, 7.81 mmol) (Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. Synthesis 1987, 998-1001), CH2Cl2 (30 mL), and pyrrole (6 mL, 87 mmol). The reaction mixture was stirred for 10 min, then TFA (0.25 mL, 3.2 mmol) was added. After a stirring period of 2 h at room temperature, the reaction mixture was transferred to a separatory funnel and washed with saturated aqueous NaHCO3 (50 mL), H2O (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and adsorbed onto silica gel (3 g). Purification by column chromatography (gradient elution 33-67% EtOAc/hexanes) provided dipyrromethane 2 (0.95 g, 52%) as a gray solid: 1H NMR (300 MHz, CDCl3) δ 5.74 (s, 1 H), 6.02 (m, 2 H), 6.17 (m, 2 H), 6.70 (m, 2 H), 7.58 (s, 1 H), 8.19 (br s, 2 H), 8.68 (s, 1 H).
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(NC1SC=C(C(=NOC)C(O)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(OC[C:56]1[CH2:65][S:64][C@@H:59]2[C@H:60](N)[C:61](=[O:62])[N:58]2[C:57]=1[C:66]([OH:68])=[O:67])=O>CC(N(C)C)=O.C(Cl)Cl>[S:64]1[C@@H:59]2[CH2:60][C:61](=[O:62])[N:58]2[C:57]([C:66]([OH:68])=[O:67])=[CH:56][CH2:65]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12

Procedure:
The process of claim 1 comprising reacting at low temperature in dimethylacetamide, in the presence of triethylamine, tosyl chloride and the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid and reacting the resulting product with 7-amino-cephalosporanic acid in methylene chloride in the presence of triethylamine to obtain the syn isomer of 3-acetoxymethyl-7-[2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]2[CH2:24][C:23](=O)[O:22][C:20](=[O:21])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]([CH2:24][C:23]2[NH:9][C:4]3[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17].[ClH:10]
Reactant: Nc1ccc(I)cc1N
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(Cl)c(Cl)c1

Procedure:
By a procedure similar to that of example 1.4, starting from 4-iodo-1,2-phenylenediamine and 3-(3,4-dichlorophenyl)glutaric anhydride, 3-(3,4-dichlorophenyl)-4-(5-iodo-2-benzimidazolyl)butanoic acid•HCl was obtained as off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 24 h
Yield: 53 %

Procedure:
Under an argon atmosphere, 4-bromo-4′-hydroxybiphenyl (3.0 g, 12 mmol), 1-bromopentane (3.6 g, 24 mmol), and potassium carbonate (1.66 g, 12 mmol) were dissolved in acetone (60 mL) and stirred under a reflux condition for 24 hours. After they reacted with each other, liquid separation and extraction were performed with water and chloroform. After an organic layer was dried with anhydrous sodium sulfate and filtered, the solvent was distilled off under a reduced pressure. After the obtained reaction mixture was separated and purified with a silica gel column chromatography using chloroform as a moving bed, the mixture was purified by a recrystallization method using chloroform and hexane. Thereby, a white solid of 4-Bromo-4′-pentyloxybiphenyl (A1) was obtained (1.99 g, yield: 53%). The obtained product (A1) was identified by using a 1H-NMR method. 1H-NMR (CDCl3, 400 MHz) δ=7.53-7.51 (d, 2H), 7.48-7.46 (d, 2H), 7.42-7.40 (d, 2H), 7.00-6.95 (d, 2H), 4.01-3.98 (t, 2H), 1.81 (m, 2H), 1.42 (m, 4H), and 0.94 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N+:17]#[C-:18])#[C-:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O>Cl(O)(=O)(=O)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:24]2[N:1]=[C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]3[C:10]=2[NH:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N+:17]#[C-:18])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C=O)cc1OC
Reactant: [C-]#[N+]CCCCCC[N+]#[C-]
Reactant: Cc1ccnc(N)c1
Agent: [O-][Cl+3]([O-])([O-])O
Product: [C-]#[N+]CCCCCCNc1c(-c2ccc(OC)c(OC)c2)nc2cc(C)ccn12

Procedure:
Compound (24) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-4-methylpyridine solution (0.1 M, DCM), 0.575 ml of 1,6-diisocyanhexane solution (0.2 M, DCM), 0.500 ml of 3,4-dimethoxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([C:18](=[O:20])[CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.CC(C)([O-])C.[K+].C(OCC)C>C(O)(C)(C)C.O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][C:10]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([C:18](=[O:20])[CH3:19])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[CH:24][CH:23]=1
Reactant: CC(=O)C(CCc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: ClCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC(=O)C(CCc1ccc(Cl)cc1)(Cc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Yield: 321.5 %

Procedure:
1.94 g of tert-butyl 2-{2-(4-chlorophenyl)ethyl}-3-oxobutanoate was dissolved in 10 ml of tert-butanol, and 0.17 g of p-chlorobenzyl chloride and 0.90 g of potassium tert-butoxide were added thereto. The mixture was heated and refluxed for 1 hour. Then, ethyl ether and water were added to the reaction solution for liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and then the solvent was distilled off under reduced pressure. The residue was subjected to medium pressure liquid chromatography (hexane/ethyl acetate=9/1) to obtain 1.43 g (yield: 52%) of tert-butyl 2-(4-chlorobenzyl)-2-{2-(4-chlorophenyl)ethyl}-3-oxobutanoate.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][O:10][C:11](=[O:42])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@@H:19]2[CH2:24][NH:23][CH2:22][CH2:21][N:20]2[C:25](=[O:40])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)=[CH:14][C:13]=1[OH:41].C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:9][O:10][C:11](=[O:42])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@@H:19]2[CH2:24][NH:23][CH2:22][CH2:21][N:20]2[C:25](=[O:40])[C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=2)=[CH:14][C:13]=1[O:41][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.5 %

Procedure:
tert-Butyldimethylsilyl chloride (2.34 g) was added to a solution of 4-[[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-piperazin-2-yl]methyl]-2-hydroxybenzoic acid methyl ester (2.56 g), 4-(dimethylamino)pyridine (126 mg) and triethylamine (2.51 ml) in dichloromethane (50 ml) at room temperature. After stirring at room temperature for 15 hours, additional triethylamine (2.51 ml) and tert-butyldimethylsilyl chloride (2.34 g) were added and the whole mixture was stirred for further 1 day. Water (200 ml) was added to the mixture, and the resulting mixture was extracted with dichloromethane. The organic extracts were washed with water and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol to give 4-[[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]piperazin-2-yl]-methyl]-2-(tert-butyldimethylsilyloxy)benzoic acid methyl ester (1.72 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O>>[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:2]1[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccccc3Cl)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 2-chlorophenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccnc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccnc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-fluoro-3-nitropyridine (2.5 g, 17.6 mmol), 4-fluorobenzyl-amine (4.40 g, 35.2 mmol), and N,N-diisopropyl-N-ethylamine (4.55 g, 35.2 mmol) in anhydrous acetonitrile (30 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue partitioned between water and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 15% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the 2-(4-fluorobenzylamino)-3-nitropyridine intermediate as yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.CN1C[CH2:35][CH2:34][C:33]1=[O:37].C(Cl)(=O)CC>O>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([NH:3][C:33](=[O:37])[CH2:34][CH3:35])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Reactant: CN1CCCC1=O
Agent: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (200 mg), pyridine (1 ml) and N-methylpyrrolidone (3 ml) was added propionyl chloride (78 mg) and the mixture was stirred at 60° C. for 1 hour. To the cooled mixture was added water, and the precipitate was collected by filtration and dissolved in chloroform. This organic solution was washed with water and brine respectively, dried with magnesium sulfate and concentrated in vacuo. The residue was collected by filtration and washed with ethyl acetate to give 3-bromo-8-(2,6-dichloro-3-propionylaminobenzyloxy)-2-methylimidazo [1,2-a]pyridine (158 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH2:19][CH:20]1[CH2:26][O:25]C(C)(C)[O:23][CH2:22][CH:21]1[OH:29].C(=O)([O-])[O-].[Na+].[Na+].CO>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([NH:19][CH:20]([CH:21]([OH:29])[CH2:22][OH:23])[CH2:26][OH:25])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: CC1(C)OCC(N)C(O)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NC(CO)C(O)CO)c1I
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride (12.0 g, 19.8 mmol) was dissolved in dioxane (40 ml). 6-Amino-2,2-dimethyl-1,3-dioxepane-5-ol (3.20 g, 19.8 mmol) and sodium carbonate (2.10 g, 19.8 mmol) were added and the mixture heated to reflux for 10 h. The reaction mixture was cooled, methanol (100 ml) and water (50 ml) were added and the solution was neutralized with a strongly acidic ion exchange resin. The resin was filtered off and a aqueous solution of hydrochloric acid (2M, 20 ml) was added. The mixture was stirred at 60-70° C. for 30 min, and then evaporated to dryness, which gave a semisolid residue (13.6 g) which was used without further purification in the next steps.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[C:12]=[O:13]>>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:11][C:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[C:12]([NH:11][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[O:13])=[O:13]
Reactant: Oc1n[nH]c2ccccc12
Reactant: Cc1ccccc1CN=C=O
Product: Cc1ccccc1CNC(=O)n1c(=O)c2ccccc2n1C(=O)NCc1ccccc1C

Procedure:
In analogy to example 11, 300 mg (2.24 mmol) of 1H-indazol-3-ol were reacted with 395.5 mg (2.69 mmol) of 1-isocyanatomethyl-2-methylbenzene. Yield: 177 mg (18%), M+H+: 429.26.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:18]2[CH2:24][CH:23]3[N:25](C)[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:36]C(OCC(Cl)(Cl)Cl)=O>[Zn].C1C=CC=CC=1>[ClH:36].[CH2:28]([N:3]([CH2:1][CH3:2])[C:4](=[O:27])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:18]2[CH2:24][CH:23]3[NH:25][CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH3:29]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CC3CCC(C2)N3C)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: c1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(=C2CC3CCC(C2)N3)c2ccccc2)cc1
Product: Cl

Procedure:
A 100 mL benzene suspension of 3.1 g (5.6 mmol) N,N-diethyl-4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzamide, 3.45 g (25 mmol) K2CO3, and 1.5 mL (10 mmol) 2,2,2-trichloroethyl chloroformate was allowed to reflux for 2 h. The reaction was cooled, filtered, and the solvent evaporated. The residual oil was dissolved in MeOH then stirred at reflux with 2.6 g (40 mmol) zinc powder for 1 h. After cooling, the reaction was filtered through celite and partitioned between 3N NaOH and CH2Cl2. The organic layer was washed with brine, dried over K2CO3, filtered, and concentrated (2.1 g, 5.6 mmol). The resulting clear oil was dissolved in Et2O, filtered, and the product precipitated after the addition of ethereal HCl; mp 128-132° C. MS m/z (MH+) 375. 1H NMR 300 MHz (DMSO-d6) δ 7.15-7.4 (m, 9H), 3.9-4.0 (m, 2H), 3.15-3.3 (m, 2H), 2.55-2.65 (m, 2H), 2.25-2.35 (m, 4H), 1.9-2.0 (m, 2H), 1.75-1.85 (m, 2H), 1.0-1.2 (m, 6H). Anal calc C25H30N2O.HCl (3% H2O): C, 70.89; H, 7.71; N, 6.61. Found: C, 70.52; H, 7.41; N, 6.24.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[C:59]1[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=1>CN(C=O)C>[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[C:59]1[CH:60]=[C:61]([NH:65][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=1
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3ccccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.1 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.010 g of product in 36% yield: LCMS (ESI) m/z 408 (MH+).