Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1[C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:20][C:21]1[C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCCCCOc1cccc2[nH]c3ccccc3c12)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.54 g, 1.6 mmol) was reacted with 4-hydroxycarbazol (0.3 g, 1.6 mmol) in the presence of potassium carbonate (0.23 g, 1.6 mmol) in dimethyl formamide to give 8-(9H-carbazol-4-yloxy)-octanoic acid benzyloxyamide as an almost colorless oil (yield 0.3 g, 42%; purified by column chromatography using silica gel and ethyl acetate: heptane 4: 6 as eluent). MS (M−H+)=429.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CO[C:13]1[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: COc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.4 %

Procedure:
A mixture of 2-fluorobenzoyl chloride (15.86 g, 0.1 mole) and 1,4-dimethoxybenzene (13.82 g, 0.1 mole) in 1,2-dichloroethane (200 ml) was cooled in an ice bath and treated cautiously with AlCl3 (13.82 g, 0.103 mole) portionwise. The temperature of the reaction mixture was kept at 0-5° during the addition, and then warmed to room temperature over 4 hrs after completion of addition. The resulting deep red reaction mixture was further refluxed for 1.5 hrs, followed by stirring at room temperature overnight. The reaction was quenched by addition of ice and 6N HCl solution in an ice bath with continued stirring at 0° for an hour. The mixture was then extracted three times with CH2Cl2. The combined organic layers were washed with 50% NaCl solution, dried over anhydrous Na2SO4 and filtered through a silica gel plug, yielding the intermediate benzophenone (24.68 g, 100%) as an orange colored oil which was used for cyclization without further purification. IR (neat): 3070, 2998, 2936, 2736, 1605, 1477, 1445, 1328, 1265, 1226, 1212, 1135, 1038, 960, 870, 792, 758 and 646 cm-1.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[CH2:26][CH3:27])([OH:3])=[O:2].[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([CH2:26][CH3:27])=[C:5]2[CH2:4][C:1]([O:3][CH3:28])=[O:2])=[O:25]
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (405 mg) in dimethylformamide were added potassium carbonate (305 mg) and methyl iodide (314 mg) and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate: n-hexane, 1:3, v/v) and crystallized from ethanol-water to give 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-(methoxycarbonylmethyl)quinoline (282 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:34](Cl)([O:36][C:37](=O)[O:38]C(Cl)(Cl)Cl)Cl.C(=O)([O-])O.[Na+]>ClCCl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:37]([O:36][CH3:34])=[O:38])[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1
Reactant: O=C(N1CCC(c2cccnc2)C1)N1CCNc2ccccc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)N2CCC(c3cccnc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
0.25 g of 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline, 8.1 ml of dichloromethane and 0.3 ml of diisopropylethylamine are placed in a 50 ml round-bottomed flask under a nitrogen atmosphere. 0.12 g of triphosgene is added at 0° C. and then the reaction mixture is left stirring at ambient temperature for three hours. 0.5 ml of diisopropylethylamine and 0.33 ml of methanol are subsequently added and the reaction mixture is stirred for twenty-four hours. A saturated aqueous sodium hydrogencarbonate solution and dichloromethane are added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, washed with water and with a saturated aqueous sodium chloride solution and dried over sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 95/5 mixture. 0.112 g of methyl 4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydroquinoxaline-1(2H)-carboxylate is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:19]=[CH:20][CH:21]=1.C(C1C=C(C=CC=1)CNC1C=CC(CCC(O)=O)=CC=1)(=O)C1C=CC=CC=1>>[C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1)(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: O=C(O)CCc1ccc(NCc2cccc(C(=O)c3ccccc3)c2)cc1
Product: O=C(c1ccccc1)c1cccc(CNc2ccc([C@@H]3C[C@H]3C(=O)O)cc2)c1
Yield: 39 %

Procedure:
It was prepared from (1R,2R)-2-(4-aminophenyl)cyclopropane carboxylic acid (0.7 g, 3.9 mmol) and [3-(bromomethyl)phenyl](phenyl)methanone (0.9 g, 3.2 mmol) by following the procedure described in Scheme 2 for Intermediate 5. (0.5 g, Yield: 39%). MS (ESI, 120 eV): m/z=372.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.O.[NH2:36][NH2:37]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:36][NH:37]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 41.1 %

Procedure:
A mixture of crude N-({(2S,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)benzenesulfonamide (0.29 mmol theoretical) and hydrazine monohydrate (0.28 mL, 5.78 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 17 hours. The mixture was concentrated in vacuo and the residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were combined and concentrated in vacuo, taken up in EtOAc (15 mL) and a little CH3OH, washed with saturated aqueous NaHCO3 (2×10 mL) and brine (10 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (59 mg) as a pale yellow solid. LC-MS (ES) m/z=495 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.3 Hz, 3H), 2.65-2.80 (m, 1H), 2.86-3.04 (m, 2H), 3.34-3.43 (m, 1H), 3.47-3.59 (m, 1H), 3.65-3.75 (m, 1H), 3.85-4.75 (bs, 2H), 5.39 (s, 2H), 6.13 (s, 2H), 6.52 (s, 1H), 7.56 (dd, J=8.6, 1.0 Hz, 1H), 7.58-7.68 (m, 3H), 7.69-7.74 (m, 1H), 7.85 (dd, J=7.6, 1.7 Hz, 2H), 7.88-7.97 (m, 2H), 11.53 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[S:31]1[C:35]([C:36]([NH:38][NH2:39])=O)=[N:34][CH:33]=[N:32]1.ClCCl.CO>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:36]([C:35]3[S:31][N:32]=[CH:33][N:34]=3)=[N:38][N:39]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Reactant: NNC(=O)c1ncns1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc(F)c(Cl)c1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 120 °C

Procedure:
4-[(2,3-Dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (0.25 g, 0.859 mmol) was dissolved in dichloromethane (DCM) (2.147 ml) and stirred under an argon atmosphere. Triethyloxonium tetrafluoroborate (0.196 g, 1.031 mmol) was added and the solution was left to stir for 40 minutes. A clear solution formed. 1,2,4-Thiadiazole-5-carbohydrazide (I80) (0.149 g, 1.031 mmol) was added and the solution was left to stir under argon for 60 minutes and then the solvent was removed under reduced pressure. 1-Butanol (2.147 ml) was added and the solution was left to reflux at 120° C. under an argon atmosphere for 5 hours. The solvent was removed under reduced pressure to afford a crude light orange solid of 0.56 g. TLC (DCM/MeOH 90:10): showed amide remained but some product had been formed. The crude material was purified by flash chromatography (Biotage SP4, 50 g cartridge) with a gradient of MeOH 0-10% in DCM. The solvent was removed under reduced pressure to afford desired product but still containing some impurities. The isolated material was then purified by MDAP and the solvent was removed under reduced pressure and transferred to a vial. The material was triturated with ether to afford desired product in 5.7 mg.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](F)=[C:9]([F:14])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN(C)C(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[C:9]([F:14])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1ccc(F)c(F)c1)C1CC1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccc(N2CCNCC2)c(F)c1)C1CC1
Temperature: 80 °C

Procedure:
To 0.2 mmol 4-cyclopropanesulfonyl-1,2-difluoro-benzene in 5 ml N,N-dimethylacetamide was added 0.5 mmol piperazine and the mixture was heated at 80° C. for 90 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 285.0 (M+H+, 100%)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH:18]=CC2=NC=C[CH:16]=[C:11]2[CH2:10]1.C[N+:21]1([O-])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.S(=O)(=O)(O)[O-:29].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][C@@H:18]([OH:29])[C@@H:25]([OH:24])[C:26]2=[N:21][CH:22]=[CH:23][CH:16]=[C:11]2[CH2:10]1
Reactant: O=S(=O)([O-])O
Reactant: Fc1cccc([C@@H]2CC=Cc3ncccc3C2)c1F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O[C@@H]1C[C@@H](c2cccc(F)c2F)Cc2cccnc2[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round-bottom flask was dissolved (R,Z)-6-(2,3-difluorophenyl)-6,7-dihydro-5H-cyclohepta[b]pyridine (110 mg, 0.428 mmol) and NMO (110 mg, 0.941 mmol) in acetone (2 mL) and water (0.04 mL) to give a tan solution. Osmium tetroxide (0.021 mL, 1.710 μmol) (2.5 wt-% solution in 2-methyl-2-propanol) was added (the tan color instantly changed to very light yellow). The mixture was stirred at room temperature. 1 h: <5% conversion. 0.021 mL OsO4 was added. 22 h: ⅓ conversion. Another 0.021 mL OsO4 solution was added. 28 h (50 h total). Sodium bisulfate (1.2 g) was added and stirring continued for 30 min. Acetone was removed in vacuo and the residue was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried and concentrated to an off-white solid. FCC (a few drops of methanol helped to completely dissolve the solids in methylene chloride) up to 10% methanol/methylene chloride afforded two products: a less polar, likely the desired trans product (61 mg, 49%) and a more polar cis product (47.1 mg, 38%) as white solids. MS(ESI)[M+H+]=258.16, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (d, J=5.04 Hz, 1H) 7.50 (dd, J=7.55, 1.26 Hz, 1H) 7.22 (dd, J=7.43, 4.91 Hz, 1H) 7.01-7.10 (m, 3H) 5.04 (s, 1H) 4.43 (br. s., 1H) 3.35 (dd, J=11.33, 3.53 Hz, 1H) 3.24 (t, J=12.97 Hz, 1H) 2.86 (d, J=14.35 Hz, 1H) 2.30-2.44 (m, 2H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −138.07-−137.86 (m, 1F) −142.98-−142.63 (m, 1F).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=1.BrC1C=CC2N(C(CNC(=O)OC(C)(C)C)=NN=2)C=1.[C:44](O)([C:46]([F:49])(F)F)=O.[Cl:51][C:52]1C=CN=[C:56]2[C:61]=1N=CC(OC)=[CH:57]2>C(Cl)Cl>[Cl:51][C:52]1[CH:61]=[C:56]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[CH:7]=2)[CH:57]=[CH:44][C:46]=1[F:49]
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cnc2c(NCc3nnc4ccc(Br)cn34)ccnc2c1
Agent: CC(C)(C)OC(=O)NCc1nnc2ccc(Br)cn12
Solvent: ClCCl
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(F)c(Cl)c5)cn34)ccnc2c1
Temperature: 25 °C

Procedure:
N-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine. To a suspension of tert-butyl (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methylcarbamate (0.900 g, 2.75 mmol) in CH2Cl2 (10 mL) was added TFA (0.848 ml, 11.0 mmol) and the mixture stirred at rt. After 30 minutes additional TFA (0.848 ml, 11.0 mmol) was added, and the mixture stirred at rt 2 h more then concentrated. The residue was taken up into 2-butanol (5 mL) and combined with 8-chloro-3-methoxy-1,5-naphthyridine (0.535 g, 2.75 mmol) in a 5 mL microwave vessel. The vessel was sealed and the mixture heated in the microwave for 10 min at 120 C with a 60 sec prestir. The mixture was concentrated, diluted with DCM and stirred with 2N NaOH (pH 14) for 30 minutes. The solid was filtered to afford the title compound as a beige solid.
Reaction SMILES: C(O[C:6](=[O:18])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)=O)(C)(C)C.Cl.Cl.[NH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:17][S:16][C:12]1[N:11]=[C:10]([C:8]2[N:22]3[CH2:23][CH2:24][CH2:25][N:21]3[C:6](=[O:18])[CH:7]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CSc1nccc(C(=O)CC(=O)OC(C)(C)C)n1
Reactant: C1CNNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2cc(=O)n3n2CCC3)n1
Reaction time: 4 h

Procedure:
To a solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid tert-butyl ester, 19, (6.8 g, 25.4 mmol), pyrazolidine-bishydrochloride (5.5 g, 38.1 mmol) and 4-angstrom molecular sieves (8.5 g) in toluene is added triethylamine (10.6 mL, 76.1 mmol). The reaction mixture is stirred for 4 hours at reflux. The solution is filtered through celite and washed with ether. The resulting yellow solid is purified over silica (10% MeOH/chloroform) to afford 5 g of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=5.1 Hz, 1H), 7.62 (d, J=5.1 Hz, 1H), 6.08 (s, 1H), 4.26 (t, J=7.5 Hz, 2H), 3.80 (t, J=7.8 Hz, 2H), 2.62 (dddd, J=7.5, 7.5, 7.5, 7.5 Hz, 2H), 2.60 (s, 3H); ESI+ MS: m/z (rel intensity) 249.1 (70, M++H).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:28])[NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH:13]=[CH:12][C:11]=12.[N+]([C:32]1[CH:40]=CC(C(O)=O)=C[CH:33]=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[C:14]([NH:16][C:17]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:5][CH2:4][CH2:3][C:2]4[CH:6]=[CH:40][CH:32]=[CH:33][CH:1]=4)=[O:25])=[CH:26][CH:27]=3)=[O:28])[CH:13]=[CH:12][C:11]=12
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc2nccn2c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CCN
Product: O=C(Nc1ccc(C(=O)NCCc2ccccc2)cc1)Nc1ccc2nccn2c1

Procedure:
The title compound was prepared as described in Example 1A, substituting 2-phenylethanamine for 3-methylbutan-1-amine and 4-(3-imidazo[1,2-a]pyridin-6-ylureido)benzoic acid for 4-nitrobenzoic acid. 1H NMR (500 MHz, DMSO-d6/D2O, Temp=90° C.) δ ppm 9.33 (dd, J=1.9, 0.8 Hz, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.90 (d, J=9.7 Hz, 1H), 7.85-7.74 (m, 3H), 7.61-7.51 (m, 2H), 7.35-7.20 (m, 5H), 3.49 (dd, J=8.1, 6.9 Hz, 2H), 2.94-2.79 (m, 2H); MS (ESI(+)) m/e 400 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([CH2:26][O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[CH2:25][CH2:24]1.[O-]CC.[Na+]>C(O)C>[CH:23]1([CH2:26][O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2/[CH:30]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH2:24][CH2:25]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 47.4 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (370 mg, 1.132 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (327 mg, 1.583 mmol) and sodium ethoxide (154 mg, 2.264 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to afford 276 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 0.30-0.34 (m, 2H), 0.54-0.60 (m, 2H), 1.17-1.24 (m, 1H), 3.79 (d, J=7.2 Hz, 2H), 3.84 (s, 3H), 6.84-6.87 (m, 1H) 6.96-7.00 (m, 4H) 7.31 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.96 (d, J=4.8 Hz), 8.33 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 515.18 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[CH2:8]1[C:11]2([O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]2)[CH2:10][CH2:9]1
Reactant: O=C1CCC1
Reactant: OCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: OCC1COC2(CCC2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (5.58 g, 52.6 mmol), cyclobutanone (3.69 g, 52.6 mmol), p-toluenesulfonic acid monohydrate (550 mg, 2.89 mmol) and benzene (92.9 ml) was refluxed in a round-bottom flask equipped with a cooling tube and Dean-Stark for 8 hours and 35 minutes. After the reaction mixture was cooled to room temperature, triethylamine (1 ml) was added to the reaction mixture and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel: 300 g, elution solvent: heptane, heptane/ethyl acetate=1/1). The fractions containing the title compound were collected with ethyl acetate and concentrated. The residue was dissolved in diethyl ether and then the mixture was concentrated to obtain the title compound (6.08 g, yield: 73.1%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-:27]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:27])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:27])(=[O:24])=[O:23])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)CCCCCCCc1ccccc1OCc1ccccc1
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=S(=O)(F)CCCCCCCc1ccc(OCc2ccccc2)cc1
Product: O=S(=O)(F)CCCCCCCc1ccccc1OCc1ccccc1
Yield: 183.7 %

Procedure:
7-(2-Benzyloxy-phenyl)-heptanesulfonyl fluoride (13.3) was prepared as in 13.1 using 12.3 (0.09 g, 0.236 mmol) and NH4F (0.018 g, 0.486 mmol) in dry acetone (10 mL). Purification by flash column chromatography gave the title compound (0.079 g, 92% yield) as a viscous liquid.
Reaction SMILES: C([O:5][C:6]([CH:8](C(OC(C)(C)C)=O)[C:9]1[C:18]2[C:13](=[C:14]([NH:19][C:20](=[O:29])[C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][C:9]1[C:18]2[C:13](=[C:14]([NH:19][C:20](=[O:29])[C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])([OH:7])=[O:5]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 4-[bis(tert-butoxycarbonyl)methyl]-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (5.8 g) in dichloromethane (15 ml) was dropwise added trifluoroacetic acid (45 ml) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was pulverized with diethyl ether to give 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (4.08 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1.[OH-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 0.17 h

Procedure:
To a 50 mL beaker was added about 1 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole to 30 mL of dimethylformamide (DMF) containing 1 mL of ammonium hydroxide. Additional (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole was added to the resulting solution until a suspension of the material was formed. The solution was stirred for approximately 10 minutes, and then filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) or Nylon filter. The resulting saturated solution was placed in a shallow petri dish, covered and stored under ambient conditions (approximately 25° C.) and a humidity range of 0 to 50 percent until crystals formed (between 1-4 days). The identity of the title compound is confirmed by single crystal x-ray diffraction and/or Raman spectroscopy. The resulting material was shown to contain between about 96 and 98 percent (w/w) of the 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and between about 2 and 4 percent (w/w) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.