Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.[CH2:20]([O:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34](OCC)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1)[CH3:21]>O1CCCCC1.O1CCCC1>[CH2:20]([O:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1)[CH3:21]
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: CCOCOc1ccn2c(C(=O)OCC)cnc2c1
Solvent: C1CCOCC1
Solvent: C1CCOC1
Product: CCOCOc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 0 °C
Yield: 59.5 %

Procedure:
3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (22 mg, 0.09 mmol) was dissolved in tetrahydropyran (DriSolve; 0.5 mL) and degassed before back-filling with nitrogen gas. The solution was then cooled in an ice water bath for 15 minutes before drop-wise addition of lithium bis(trimethylsilyl)amide (0.09 mL, 1 M in tetrahydrofuran). The reaction stirred for 10 minutes before drop-wise addition into a solution of ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate (11 mg, 0.04 mmol) in tetrahydrofuran (DriSolve; 0.2 mL) cooled in an ice-water bath. The reaction was then stirred while being cooled in the ice-water bath for 1.5 hours. The reaction was quenched with water and concentrated. The resulting crude material was purified by reverse phase chromatography, eluting with a gradient from 10% to 70% ACN/water over 25 column volumes, to give 7-(ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11.2 mg).
Reaction SMILES: Br[CH:2]=[C:3]1[C:16]2[CH:15]=[CH:14][C:13]([F:17])=[CH:12][C:11]=2[S:10][C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=2.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[NH:33][C:29]=3[CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:7]1[CH:6]=[CH:5][C:4]2[C:3](=[CH:2][C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[NH:33][C:29]=4[CH:28]=3)[C:16]3[C:11]([S:10][C:9]=2[CH:8]=1)=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Fc1ccc2c(c1)Sc1cc(F)ccc1C2=CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccc(F)cc4Sc4cc(F)ccc43)cc2[nH]1
Temperature: 95 °C
Yield: 17.3 %

Procedure:
Mix 9-bromomethylene-3,6-difluoro-9H-thioxanthene (104 mg, 0.32 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 1,3-dihydro-benzoimidazol-2-one (76 mg, 0.29 mmol), and Na2CO3 (2M/water, 363 μL, 0.73 mmol) in dioxane (2 mL) and sparge with nitrogen for 5 min. Add Pd(PPh3)4 (17 mg, 0.015 mmol), seal vial, and heat to 95° C. overnight. Concentrate and dilute with water (3 mL) and ethyl acetate (10 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge. Elute, collect, and concentrate 50 mL ethyl acetate. Purify on silica gel (50-60% THF/hexanes), then re-purify by semi-prep reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA added) to afford 19 mg (17%) of the title compound as a yellow foam. MS [ES] 379 (M+H), 377 (M−H); HPLC shows 100% purity;, 1H-NMR (DMSO-d6) δ 10.67 (s, 1H), 10.54 (s, 1H), 7.89 (dd, 1H, J=8.6, 5.5 Hz), 7.53 (dd, 1H, J=9.0, 2.9 Hz), 7.47 (dd, 1H, J=8.8, 2.6 Hz), 7.27 (m, 2H), 7.02 (m, 2H), 6.86 (dd, 2H, J=11.5, 8.4 Hz), 6.78 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)C2
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 56.3 %

Procedure:
By using 5-bromo-7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (542 mg, 2.0 mmol) synthesized in Reference example 83 and 1-(4-fluorophenyl)piperazine (720 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 417 mg (yield 56%). Melting point was 114 to 116° C. (ethanol-water).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.[OH-].[K+]>CO>[C:1]([C:3]1[C:4]([OH:5])=[N:6][C:7]([OH:12])=[CH:8][C:9]=1[CH3:11])#[N:2]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)nc(O)c1C#N
Temperature: 25 °C
Yield: 76.6 %

Procedure:
Cyanoacetamide (8, 34 g, 0.40 mol) and ethyl acetoacetate (9, 52 g, 0.40 mol) were dissolved in methanol (250 mL) at room temperature, a solution of potassium hydroxide (28 g, 0.42 mol) in methanol (200 mL) was slowly added, and the resulting mixture was heated to reflux for 12 h. The reaction mixture was cooled to room temperature and the white amorphous precipitate was filtered and washed with methanol (2×50 mL). The solid product was redissolved in hot water. The solution was carefully acidified and the off-white precipitate was allowed to form. The precipitate was filtered and washed with water and methanol to yield 110 (46 g, 75%): mp >300° C. (dec) [lit. (J. Org. Chem. 1960, 25, 560-564.) mp 315-320° C. (dee)]. 1H NMR (300 MHz, DMSO-d6) δ 5.58 (s, 1H), 2.22 (s, 3H).
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:17][CH2:16]1.C(Cl)Cl>C(O)(C)C>[OH:1][CH:2]([CH2:3][O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ncccc1OCC1CO1
Reactant: O=C1NCCN1C1CCNCC1
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C1NCCN1C1CCN(CC(O)COc2cccnc2[N+](=O)[O-])CC1

Procedure:
A mixture of 46.0 g of 3-(2,3-epoxy-propoxy)-2-nitropyridine and 35.0 g of 1-(4-piperidyl)-imidazolidin-2-one in 500 ml of isopropanol is refluxed for 2 hours. Working up analogously to Example 1 using methylene chloride as the extracting agent yields crude 1-{1-[2-hydroxy-3-(2-nitro-3-pyridyloxy)-propyl]-4-piperidyl}-imidazolidin-2-one, which after recrystallisation from isopropanol melts at 154°-158°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:6].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O>CN(C=O)C>[C:33]([C:30]1([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][N:7]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:5](=[O:6])[C:4]([F:20])([F:21])[F:3])=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)#[N:34]
Reactant: N#CC1(c2ccc(CBr)cc2)CC1
Reactant: O=C(NCCc1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(CN(CCc3cccc(C(F)(F)F)c3)C(=O)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
20 mg (0.51 mmol) of a sodium hydride suspension in mineral oil (60%) were suspended in 4.2 ml DMF. At 0° C. 134 mg (0.42 mmol) of 2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide dissolved in 1 ml DMF were added dropwise and the reaction mixture was stirred for 30 min at 0° C. Then 100 mg (0.42 mmol) of 1-(4-bromomethyl-phenyl)-cyclopropanecarbonitrile dissolved in 1 ml DMF were added and the reaction mixture was stirred at 0° C. for 3 h. Water was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel; heptane/diethyl ether=1:1) to yield 135 mg (72%) of N-[4-(1-cyano-cyclopropyl)-benzyl]-2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide as a yellow viscous oil. MS (ISP) 458.4 (M+NH4)+. MS (ISP). 499.1 (M+OAc)−.
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].C(N(S(F)(F)[F:28])CC)C.O>C(Cl)Cl>[F:28][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: CN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 70 %

Procedure:
A solution of 12.1 g (0.04 mol) of 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one in 25 ml of anhydrous methylene chloride was added dropwise over a period of 15 min. to a stirred solution of 12.6 ml (0.1 mol) of diethylaminosulfur trifluoride in 300 ml of anhydrous methylene chloride cooled to -70°. The reaction mixture was allowed to warm slowly over a period of 45 min. to 5° and then poured into 500 ml of ice and water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 10.9 g (90% yield) of crude product as a light yellow solid residue. Recrystallization from heptane gave 8.48 g (70% yield) of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 138°-140°; 19F nmr (CCl3D) δ -161.7 ppm (d, J = 57 Hz); 1H nmr (CCl3D) δ 3.43 ppm (s, 3H), 5.54 ppm (d, J = 57 Hz, 1H), 7.5 ppm (m, 8H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21]([OH:23])=O)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[F:30][C@H:31]1[CH2:33][C@H:32]1[NH2:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[F:30][C@H:31]1[CH2:33][C@H:32]1[NH:34][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:23]
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Reactant: N[C@@H]1C[C@@H]1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)N[C@@H]4C[C@@H]4F)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (20 mg) was treated with cis-2-fluorocyclopropylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (9 mg) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
688 mg of the compound of Example 51A with 76% purity (1.23 mmol) are provided in 29 ml of tetrahydrofuran and, at room temperature, 389 mg (16.2 mmol) of lithium hydroxide and 10 ml of water are added. The mixture is stirred at room temperature for 5 h, a 1N aqueous hydrogen chloride solution is subsequently added until the pH is acidic, and the mixture is extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue is stirred in a little cyclohexane and the precipitate is collected by suction filtration. 413 mg (83% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C([S:13]P([O-])(OCC)=S)C.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]([NH2:6])=[S:13]
Reactant: COc1ccccc1C#N
Reactant: CCOP([O-])(=S)SCC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1C(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.5 g of o-methyoxybenzonitrile and 8.22 ml of diethyldithiophosphate in 200 ml of ethyl aceate was saturated with hydrogen chloride gas, and the resulting reaction mixture allowed to stir overnight at room temperature. The solvent was removed in vacuo and the oily residue triturated with hexane. The resulting solid was filtered and dried, 3.6 g.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CS(C)=O>O>[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:19][CH2:18]1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: COCCN1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: COCCN1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
4-Fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol), 1-(2-methoxyethyl)piperazine (0.94 mL, 6.5 mmol) and DMSO (3.5 mL) were added and stirred at 100° C. for 1.0 hour. The reaction mixture was added with water and was washed with hexane/ethyl acetate (4/1) to remove impurities. After removing impurities, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4-[4-(2-methoxyethyl) piperazin-1-yl]-2-nitrobenzaldehyde (0.23 g, 68%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20](Cl)=[O:21]>O1CCCC1.CCCCCC>[C:12]([C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:16][C:17](=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([O:16][C:6]1[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)c(OC(=O)c2ccccc2C(=O)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred, ice-cold solution of 11.6 g (0.05 mol) 2,6-di-tert-butyl-4-methylphenol in 100 mL dry tetrahydrofuran was added dropwise under argon 25 mL 23M n-butyllithium in hexane. After 2.5 hours, 5.3 g (0.026 mol) fresh phthaloyl chloride was added dropwise and the mixture stirred overnight at room temperature. Product was isolated by extraction, washed with ligroin and recrystallized from acetonitrile to give 4 g nearly pure Compound 6, as white crystals, m.p. 262°-5° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1)(C)(C)C.Cl>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1

Procedure:
A suspension of trans-{4-[(naphthalene-1-sulfonylamino)methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (25 g) in chloroform (300 ml) is treated with a 4 N HCl solution in dioxane (300 ml) at 0° C. After completion, the reaction mixture is concentrated in vacuo, the residue is taken up in a 1 N sodium hydroxide solution and dichloromethane. After extraction with dichloromethane, the organics are dried over sodium sulfate and concentrated to 18.5 g of trans-naphthalene-1-sulfonic acid (4-aminomethyl-cyclohexylmethyl)-amide as a white powder melting at 157-162° C. Rf(C3) 0.36.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39]>CN(C=O)C.O>[F:31][C:29]1[CH:28]=[C:27]([F:32])[CH:26]=[C:25]2[C:30]=1[C:21]([O:13][C:9]1[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=[N:11][CH:10]=1)=[C:22]([CH3:39])[C:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[N:24]2
Reactant: Oc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Oc1cncc(N2CCOCC2)c1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a vial containing 5-morpholinopyridin-3-ol (67.3 mg, 0.37 mmol) in DMF (3 mL) was added cesium carbonate (0.26 g, 0.8 mmol) in portions. The mixture was stirred at 23° C. for 15 minutes, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (90.7 mg, 0.31 mmol) was added in portions. Upon complete addition, the mixture was warmed to 100° C. After 18 h, the reaction mixture was diluted with water then subsequently extracted five times with EtOAc. The organic extractions were then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM) to afford light yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 4-(5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yloxy)pyridin-3-yl)morpholine. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.6 Hz), 8.12 (1H, d, J=2.4 Hz), 7.98 (2H, m), 7.68 (1H, dd, J=9.4, 1.3 Hz), 7.59 (1H, d, J=2.2 Hz), 7.43 (1H, sxt, J=4.4 Hz), 7.02 (1H, ddd, J=11.4, 8.9, 2.4 Hz), 6.87 (1H, s), 3.93 (4H, m), 3.29 (4H, m), 2.41 (3H, s). Mass Spectrum (pos.) m/e: 435.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
To a solution of 4-amino-2,6-dichloropyridine (1.07 g, 6.56 mmol) in conc H2SO4 (3.5 mL) was added 0.50 mL of 70% HNO3 (7.94 mmol) at room temperature. The mixture was stirred at 55° C. for 15 h, then poured into ice-H2O (70 mL). To this mixture was added 40% aq. NaOH slowly to adjust the pH to 10. The precipitate was filtered, washed with water and dried to give 1.052 g (77%) of 23 as a pale yellow powder, mp 136°-8° C. 1H NMR (CDCl3) δ 6.116 (bs, 2H), 6.750 (s, 1H). It was used for the next reaction without further purification.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[C:32]1([C@H:38]([CH3:42])[C:39]([O-:41])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cs+].[I-].[Na+].O>C(#N)C>[C:28]([N:5]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)[C:4]([O:3][CH2:2][O:41][C:39](=[O:40])[C@H:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42])=[O:31])(=[O:30])[CH3:29]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Reactant: C[C@H](C(=O)[O-])c1ccccc1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H](C)c1ccccc1
Temperature: 25 °C
Yield: 75 %

Procedure:
(R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (0.40 g, 0.84 mmol), cesium 2(S)-phenyl-propionate (0.37 g, 1.31 mmol) and sodium iodide (0.13 g, 0.86 mmol) in acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 75%. 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.39 (m, 1H), 7.33 (t, 1H), 7.27-7.15 (m, 6H), 5.78-5.72 (m, 2H), 4.63-4.57 (m, 1H0, 4.02-3.95 (m, 2H), 3.84 (q, 1H), 3.76-3.69 (m, 2H), 3.36-3.26 (m, partially obscured by water, 2H), 3.18-3.12 (m, 1H), 3.07-3.04 (m, 2H), 2.30 (d, 3H), 2.11 (q, 2H), 2.01-1.97 (m, 2H), 1.35 (d, 3H); MS-APCI (m/z+): 341, 385, 517, 591.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][C:14]([C:28]3[CH:33]=[CH:32][C:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[CH:30][CH:29]=3)=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=3)[N:16]=2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH2:39]([O:41][C:42]([N:44]=[C:45]=[O:46])=[O:43])[CH3:40].CO>C(Cl)(Cl)Cl>[CH2:39]([O:41][C:42]([NH:44][C:45]([N:13]1[C:14]([C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[CH:30][CH:29]=2)=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:21][CH:22]=2)[N:16]=[C:12]1[C:5]1[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:46])=[O:43])[CH3:40]
Reactant: CCN(CC)c1ccc(-c2nc(-c3cc(OC)c(O)c(OC)c3)[nH]c2-c2ccc(N(CC)CC)cc2)cc1
Reactant: CCOC(=O)N=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=O)n1c(-c2cc(OC)c(O)c(OC)c2)nc(-c2ccc(N(CC)CC)cc2)c1-c1ccc(N(CC)CC)cc1
Reaction time: 5 h
Yield: 61.3 %

Procedure:
In 20 ml of chloroform, 0.8 g of 2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis(4-diethylaminophenyl)imidazole obtained in Example 1 (2) was dissolved. Then, 0.7 g of ethoxycarbonyl isocyanate (mfd. by Aldrich Chemical Co. Inc.) was added to the resulting solution and the reaction was carried out at room temperature for 5 hours with stirring. After the reaction, 5 ml of methanol was added to the reaction solution to decompose excess ethoxycarbonyl isocyanate, followed by removal of the solvent by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: a mixed solvent of ethyl acetate and n-hexane) to give 0.6 g of green crystals of 1-(ethoxycarbonylaminocarbonyl)-2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis(4-diethylaminophenyl)imidazol having a m.p. of 60° C.