Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[F:9][C:10]([F:21])([F:20])[C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15].CCOCC.CCCCCC>CS(C)=O>[F:9][C:10]([F:20])([F:21])[C:11]1[CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CS(C)=O
Product: Nc1nc(C(F)(F)F)cc(C(F)(F)F)n1
Temperature: 110 °C
Yield: 49.8 %

Procedure:
A mixture of guanidine carbonate (180 mmol) and 1,1,1,5,5,5-hexafluoro-2,4-pentanedione (120 mmol) was dissolved in 60 ml of DMSO and warmed to 110° C. for 2 to 3 hours. Flash chromatography of the crude reaction product with ether/hexane (50:50) afforded 13.8 g of the title compound as a white crystalline solid, m.p. 94.5°-96° C. NMR (60 MHz, CDCl3): δ 6.5 (br. s, 2H); 7.2 (s, 1H). A second product isolated was the hydroxypyrimidine (A is A-3): m.p. 116°-118.5° C. NMR (90 MHz, CDCl3): δ 7.1 (br. s, 3H); 7.3 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH2:15][C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:39][O:40][C:41]([CH2:43][CH2:44][CH2:45][CH:46]=[O:47])=[O:42].C(O)(=O)C>O1CCCC1.C(OCC)C.O>[Si:1]([O:8][CH:9]([CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH:15]([CH:46]([OH:47])[CH2:45][CH2:44][CH2:43][C:41]([O:40][CH3:39])=[O:42])[C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CCCC=O
Reactant: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)COc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCC(O)C1CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
A stirred solution of (E)-2-(3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one (75 mg), prepared as described in Reference Example 46 and in the form of (±)-(E)-2β-(3β-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one, in dry tetrahydrofuran (2.55 ml) was cooled to -70° C. under an atmosphere of argon and treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M; 0.204 ml), and the mixture was stirred at -70° C. for 10 minutes. The mixture was then treated with 4-methoxycarbonylbutanal (44 mg) and stirred for a further period of 150 minutes at -70° C. The mixture was then treated with a solution of glacial acetic acid (0.019 ml) in diethyl ether (0.17 ml) and allowed to warm to the ambient temperature. The mixture was treated with water (25 ml) and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution, and with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residual oil was subjected to medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1:2 v/v), to give 6-[(E)-3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-(1-hydroxy-4-methoxycarbonylbut-1-yl)bicyclo[3,3,0]octan-2-one (47 mg), in the form of (±)-6β-[(E)-3β-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-(1-hydroxy-4-methoxycarbonylbut-1-yl)bicyclo[3,3,0]octan-2-one.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.[CH3:33][O:34][C@H:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:33][O:34][C@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36]1
Reactant: CO[C@H]1CCCNC1
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CCCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(C(F)(F)F)cc4s2)n3C)C1
Yield: 63.3 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((S)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]amide (77 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (100 mg), (S)-3-methoxy-piperidine hydrochloride (37 mg), HBTU (101 mg), and DIEA (58 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 546.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.51 (bs, 1H), 8.57-8.47 (m, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.89-7.66 (m, 3H), 7.54 (d, 1H), 4.33-4.15 (m, 1H), 4.15-4.00 (m, 1H), 3.81-3.56 (m, 4H), 3.55-3.44 (m, 1H), 3.43-3.18 (m, 6H), 2.01-1.21 (m, 4H).
Reaction SMILES: CN(C=O)C.CC(C)([O-])C.[K+].[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>O.C1COCC1>[CH3:19][Si:20]([CH3:22])([CH3:21])[CH2:23][CH2:24][O:25][CH2:26][O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Oc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCOc1cccnc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of DMF (100 mL) and THF (100 mL), was added solid potassium tert-butoxide (17.96 g, 0.16 mol). After all of the solid had dissolved, the solution was cooled to ≦5° C. and 3-hydroxypyridine (14.25 g, 0.15 mol) was added all at once. After stirring for 10 minutes, the mixture was cooled to −10° C. and SEM-Cl, 25 g, 0.15 mol) was added dropwise at such a rate that the internal temperature remained at ≦−5° C. After the addition was complete, the mixture was stirred at 0° C. for 1 hour, then at room temperature for 2 hours. The mixture was poured into water (600 mL), then extracted with ether (3×150 mL). The ether extracts were combined, washed sequentially with 2N NaOH (100 mL), water (50 mL), and saturated NaCl solution (100 mL), dried (MgSO4) and concentrated to give a brown liquid. Distillation gave the desired ether 9 as a colorless liquid (20.8 g), b.p. 95-99° C. @ 0.03 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:27])[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:5]=[CH:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[ClH:34].CCOC(C)=O>CCOC(C)=O>[ClH:34].[F:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:27])[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CCS(=O)(=O)N=C2C1(C)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(c2ccc(-c3ccccc3)c(F)c2)NCCN2CCS(=O)(=O)N=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of tert-butyl 9-(2-fluorobiphenyl-4-yl)-9-methyl-3,4,6,7-tetrahydropyrazino[2,1-c][1,2,4]thiadiazine-8(9H)-carboxylate 2,2-dioxide (150 mg) and 4 N HCl/EtOAc (5 ml) in EtOAc (5 mL) was stirred at room temperature overnight. After removing solvent, the residue was recrystallized from MeOH to give the title compound (65 mg) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH2:7][C:8]1[N:12]([CH2:13][N:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:16][C:15]2=[O:28])[CH:11]=[N:10][CH:9]=1.CCN(CC)CC>C(Cl)Cl>[O:28]=[C:15]1[CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:18][N:14]1[CH2:13][N:12]1[C:8]([CH2:7][NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[CH:9][N:10]=[CH:11]1
Reactant: NCc1cncn1CN1CC(c2cc(F)c(F)c(F)c2)CC1=O
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1cncn1CN1CC(c2cc(F)c(F)c(F)c2)CC1=O
Reaction time: 1 h

Procedure:
In a three necked flask, under argon, propionyl chloride (0.0134 ml) is added to a solution of 1-(5-aminomethyl-imidazol-1-ylmethyl)-4-(3,4,5-trifluoro-phenyl)-pyrrolidin-2-one a34 (0.050 g, 0.15 mmol) and Et3N (0.29 ml) in CH2Cl2 (3 ml) at 0° C. After 1 h, the reaction mixture is quenched with ice-water, extracted with CH2Cl2, dried over MgSO4, filtered and evaporated in vacuo. The crude reaction mixture is purified by chromatography on reverse phase silicagel to afford N-[(1-{[2 oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide 86(37.2 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:23][C:22]=1[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:23][C:22]=1[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)CCCOc1ccc(CCC(=O)OC)c(OCCCCCOS(C)(=O)=O)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2cc(OCCCC(=O)OC)ccc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 75 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.65 g (1.41 mmol) of 2-[[5 -[(methylsulfonyl)oxy]pentyl]oxy]-4-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (from example 137), 4-(4-methoxy-4-oxobutoxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 75% yield (0.6 g) as a solid, mp 58°-59° C. This diester (1.05 mmol) was saponified with 3 mL of 3N aqueous lithium hydroxide in 30 mL of tetrahydrofuran, at room temperature, for 16 hr. Work-up as in example 4 but using dichloromethane rather than ether gave a solid acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. Recrystallization from ethyl acetate gave 0.44 g (78%) of pure 4-(3-carboxypropoxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as a colorless solid, mp 163°-164° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[N:4][C:5]([CH:9]=C)=[C:6]([Cl:8])[CH:7]=1.[O:22]1CCOCC1.O.[O-]I(=O)(=O)=O.[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:3]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[N:4][C:5]([CH:9]=[O:22])=[C:6]([Cl:8])[CH:7]=1
Reactant: C1COCCO1
Reactant: C=Cc1nc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(-c2nc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 8 h

Procedure:
13.2 g of 3-(3-fluoro-5-chloro-6-vinyl-2-pyridyl)-4-chloro-5-difluoromethoxy-1-methyl-[1 H]-pyrazole (Example H35) are initially introduced into a mixture of 120 ml of dioxane and 40 ml of water. 16.7 g of sodium (meta)periodate (NalO4) and a spatula-tip of osmium tetroxide are added, while stirring, and the mixture is subsequently stirred overnight at 22° C. The following day, the resulting mixture is taken up in ethyl acetate and washed first with dilute hydrochloric acid and then with brine. After drying over sodium sulfate, the mixture is filtered and the filtrate is concentrated in vacuo. After purification over a silica gel flash column (eluting agent: n-hexane/ethyl acetate 2/1), 9.4 g of the desired title compound are obtained as a white solid of melting point 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[N:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(O)ccc1F
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccc1F
Yield: 49.6 %

Procedure:
In the same manner as in Reference Example 33 and using tert-butyl (2-fluoro-5-hydroxyphenyl)carbamate (22.4 g, 98.4 mmol), 5-bromo-2-nitropyridine (16.7 g, 82.0 mmol), cesium carbonate (40.1 g, 123 mmol) and N,N-dimethylformamide (140 mL) as starting materials, the title compound (14.2 g, 50%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)[CH3:2].Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][C:25]([CH2:26][OH:27])=[CH:28][N:14]=1)=[CH:9]2)[S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:18])[CH3:2]
Reactant: O=CC(Br)C=O
Reactant: CCN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of 7-[ethyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.10 g), bromomalonaldehyde (3.55 g) and N,N-dimethylacetamide (30 ml) was stirred at 95° C. for 1.5 hr. Water was added to the reaction mixture, and the obtained precipitate was collected by filtration and dissolved in tetrahydrofuran (30 ml) and methanol (30 ml). After cooling with an ice bath, sodium borohydride (508 mg) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and diluted with ethyl acetate-tetrahydrofuran mixture. The organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (2:1) mixture to give the title compound (800 mg, yield 17%) as a solid.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([OH:15])[CH:9]=[N+:8]2[O-].[OH-].[Na+]>[Ni]>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([OH:15])[CH:9]=[N:8]2
Reactant: [O-][n+]1cc(O)nc2ccc(Cl)cc21
Agent: [Ni]
Agent: NN
Agent: [Na+]
Solvent: O
Product: Oc1cnc2cc(Cl)ccc2n1
Reaction time: 5 h
Yield: 89.5 %

Procedure:
An aqueous Raney nickel paste (containing 0.5 g of metallic nickel) and 5.0 g of a 80% aqueous hydrazine hydrate solution were added dropwise to 200 g of an aqueous solution containing 19.7 g of 6-chloro-2-quinoxalinol-4-oxide and 8 g of sodium hydroxide at 40° to 50° C., and the resulting mixture was stirred at 40° to 70° C. for 5 hr, whereby the reducing reaction was terminated. The catalyst was then recovered by filtration, and 35% hydrochloric acid was added dropwise to the filtrate at 50° to 60° C. to adjust the pH to 4. The precipitated crystal was collected by filtration, washed with water and dried to give 16.2 g (yield 90%) of 6-chloro-2-quinoxalinol with melting point of not lower than 300° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].Cl[C:24]1C=CC(B(O)O)=C(F)[C:25]=1[O:34]C>C(C(C)=O)C(C)C>[C:25]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22])(=[O:34])[CH3:24]
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl

Procedure:
Another embodiment of the present disclosure includes a method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. The method comprises producing an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid. Methyl isobutyl ketone is added to the aqueous solution. The methyl isobutyl ketone and 4-chloro-2-fluoro-3-methoxyphenylboronic acid are separated from the water. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid is reacted with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate in methyl isobutyl ketone to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, which is deacetylated to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(OC(=O)C)C.CC([O-])=O.CC([O-])=O.[Pd+2].O.C(O)CC>[CH3:19][CH:18]([CH3:20])[CH2:17][C@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([S:22][CH3:21])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH2:15][OH:16]
Reactant: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: CSc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CSc1ccc(-c2ccc([C@H](N[C@H](CO)CC(C)C)C(F)(F)F)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A stream of nitrogen was passed through a suspension made of the bromide from Step 3 (27.7 g), 4-(methylthio)phenylboronic acid (15.7 g), 2 M Na2CO3 (100 mL) and n-propanol (500 mL) for 15 minutes. A 1:3 mixture (3.5 g) of Pd(OAc)2 and PPh3 was then added and the reaction was warmed to 70° C. and stirred under nitrogen for 8 hours. The mixture was cooled to room temperature, diluted with ethylacetate (500 mL) and poured over water (2 L) and ice (500 g). The ethyl acetate layer was separated and the aqueous further extracted with ethyl acetate (200 mL). The combined ethyl acetate extracts were washed with 0.5 N NaOH (2×200 mL), with aqueous NH4Cl, brine and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2 using a gradient of ethyl acetate and hexanes (1:4 to 1:3) and again with acetone and toluene (1:10). The residue was dissolve in hot hexanes (200 mL) and the solution was allowed to cool to 0° C. under stirring. The obtained solid was filtered and dried to yield the title compound.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O.P(Cl)(Cl)(Cl)=O>>[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=1[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1CCCCN1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)Cc1ccccc1N2C1=NCCCC1

Procedure:
Reaction of acridan, 2-piperidone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(3,4,5,6-TETRAHYDRO-2-PYRIDYL)ACRIDAN as a distillable oil, b.p. 145-150° C. at 0.15 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(3,4,5,5-TETRAHYDRO-2-PYRIDYL)ACRIDAN HYDROCHLORIDE as the hemihydrate, m.p. 190.5-192.5° C. (corr.) by trituration with hot benzene in a 19% overall yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:16]C1C=CC=CC=1CCl.[Mg].C(OCC)(=O)C(OCC)=O>>[Cl:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: ClCc1ccccc1Cl
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1ccccc1Cl
Yield: 74 %

Procedure:
The title compound was prepared as described for B4 using 2-chlorobenzyl chloride (1.250 g, 7.76 mmol), magnesium (0.208 g, 8.54 mmol), diethyl oxalate (2.269 g, 15.53 mmol). The product was isolated in the form of colorless oil in 74% yield and use instantly in next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][NH:15][C:4]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NCC(O)CO
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1NCC(O)CO

Procedure:
23 g (0.10 moles) 4-chloro-3-nitro-1-trifluoromethyl-benzene are heated with 30 g 1-amino-2,3-propandiol for 3 hours to 100° C. After cooling, the product is precipitated with water, vacuumed off and dried. One obtains 26.7 g (93% of the theoretical yield) of a yellow product with a melting range of 117°-118 C.
Reaction SMILES: CC(C)(OC(N[C@H](C(O)=O)CC1N(COCC2C=CC=CC=2)C=NC=1)=O)C.[ClH:28].NC(C(O)CC1CCCCC1)C(O)CS(NCCCC)(=O)=O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:68][C:69]([CH3:115])([O:71][C:72]([NH:74][C@H:75]([C:91]([NH:93][CH:94]([CH2:108][CH:109]1[CH2:114][CH2:113][CH2:112][CH2:111][CH2:110]1)[CH:95]([OH:107])[CH:96]([OH:106])[CH2:97][S:98]([NH:101][CH2:102][CH2:103][CH2:104][CH3:105])(=[O:100])=[O:99])=[O:92])[CH2:76][C:77]1[N:81](COCC2C=CC=CC=2)[CH:80]=[N:79][CH:78]=1)=[O:73])[CH3:70]>CN(C)C=O.ClCCl.CO>[ClH:28].[CH3:115][C:69]([CH3:68])([O:71][C:72]([NH:74][C@H:75]([C:91]([NH:93][CH:94]([CH2:108][CH:109]1[CH2:114][CH2:113][CH2:112][CH2:111][CH2:110]1)[CH:95]([OH:107])[CH:96]([OH:106])[CH2:97][S:98]([NH:101][CH2:102][CH2:103][CH2:104][CH3:105])(=[O:99])=[O:100])=[O:92])[CH2:76][C:77]1[N:81]=[CH:80][NH:79][CH:78]=1)=[O:73])[CH3:70]
Reactant: CCCCNS(=O)(=O)CC(O)C(O)C(CC1CCCCC1)NC(=O)[C@H](Cc1cncn1COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cncn1COCc1ccccc1)C(=O)O
Agent: CCCCNS(=O)(=O)CC(O)C(N)C(O)CC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCCNS(=O)(=O)CC(O)C(O)C(CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(1,1-Dimethylethoxy)carbonyl]-3-[(phenylmethoxy)methyl]-L-histidine (101 mg., 0.268 mmole, 1 eq.) and [βR-(βR*,δR*,γS*)-γ-amino-N-butyl-β,δ-dihydroxycyclohexanepentanesulfonamide, monohydrochloride (100 mg., 0.268 mmole, 1 eq., product of Example 1) were dissolved in dimethylformamide under an argon atmosphere. The solution was cooled to 0° and treated with 1-hydroxybenzotriazole (36 mg., 0.268 mmole, 1 eq.), triethylamine (56 μl, 0.402 mmole, 1.5 eq.) and ethyl-3-(3-dimethylamino)-propyl carbodiimide (51 mg., 0.268 mmole, 1 eq.). The mixture was allowed to warm slowly to room temperature and stirred overnight. Aqueous buffer (pH 4, 7 ml., Mallinckrodt) was added and the mixture was stirred for 30 minutes. The product was extracted into ethyl acetate (2×10 ml.), dried MgSO4), and freed of solvent in vacuo. The remaining material was chromatographed on silica gel (Merck, 15 g.) eluting with 3% methanol in dichloromethane containing 0.2% NH4OH to give 176 mg. of [1S-(1R*,2S*,3S*)]-[(1,1-dimethylethoxy)carbonyl]-N-[4-[(butylamino)-sulfonyl]-1-(cyclohexylmethyl)-2,3-dihydroxybutyl]-3-[(phenylmethoxy)methyl]-L-histidinamide. TLC (silica gel; 10% methanol in dichloromethane containing 0.2% NH4OH) Rf =0.59.