Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([F:14])=[N:12][CH:13]=1.[CH3:15][C:16]1[CH:17]=[C:18]([NH:31][C:32]2[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=2)[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:14][C:11]1[N:12]=[CH:13][C:8]([C:20]2[CH:19]=[C:18]([NH:31][C:32]3[N:37]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:35]=[CH:34][N:33]=3)[CH:17]=[C:16]([CH3:15])[CH:21]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(Br)cn1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(F)nc2)c1
Temperature: 85 °C

Procedure:
2-Methyl-THF (123 mL), sodium carbonate (2M, 18.5 mL, 36.9 mmol) and 5-bromo-2-fluoropyridine (7.15 g, 40.6 mmol) were added to N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (14 g, 36.9 mmol) and the reaction mixture was purged and flushed with Ar(g) (3×) before adding PdCl2(dppf)-dichloromethane adduct (1.51 g, 1.85 mmol). The reaction mixture was heated to 85° C. overnight. Another portion of 5-bromo-2-fluoropyridine (2.00 g) and PdCl2(dppf)-dichloromethane adduct (300 mg, 0.368 mmol) were added to the reaction mixture and heated to 85° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. A hot solution of 10% water, 20% DCM and 70% MeCN was added to the residue and the product was collected by filtration. The product was washed with cold DCM to yield N-[3-(6-fluoropyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine as a green-tinted solid. MS APC calc'd for C17H13F3N4 [M+H]+ 349. found 349. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.45 (s, 1H), 8.18 (td, J=2.4 Hz, 8.2 Hz, 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.31-7.24 (m, 2H), 7.18 (s, 1H), 3.32 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCCCO
Reactant: FC(F)(F)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Product: OCCCNc1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1

Procedure:
50 mg (0.143 mmol) of N-(3-trifluoromethyl-phenyl)-4-(2-chloro4-pyridyl)-2-pyrimidineamine are stirred for 44 h at 100° in 1 ml of 3-amino-1-propanol. Concentration by evaporation and chromatography (methylene chloride:methanol=9:1) give N-(3-trifluoromethyl-phenyl)-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine; Rf =0.1 (methylene chloride:methanol=95:5), FAB-MS: 390, m.p. 158°-163°.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:19](COCC[Si](C)(C)C)[C:20]4[C:21]([N:41]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]5[CH2:34][CH2:35][S:36](=[O:40])(=[O:39])[CH2:37][CH:38]=5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[C@H:12]2[O:11][CH2:10]1)(C(C)(C)C)(C)C.B#B.[OH-].[Na+].OO.S([O-])([O-:58])=S.[Na+].[Na+]>C1COCC1>[Cl:26][C:24]1[CH:25]=[C:20]2[NH:19][C:18]([O:17][C@@H:16]3[CH2:15][O:14][C@@H:13]4[C@H:9]([OH:8])[CH2:10][O:11][C@H:12]34)=[N:41][C:21]2=[N:22][C:23]=1[C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[CH2:38][CH2:37][S:36](=[O:39])(=[O:40])[CH2:35][CH:34]2[OH:58])=[CH:31][CH:32]=1
Reactant: [O-]S([O-])=S
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C4=CCS(=O)(=O)CC4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Agent: B#B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCC(c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(4-(2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (50 mg, 0.067 mmol) under nitrogen in anhydrous THF (0.7 ml) at room temperature was added 1M diborane in THF (0.08 ml, 0.08 mmol). The mixture was stirred at room temperature for 3 hours, then an additional aliquot of 1M diborane in THF (0.16 ml, 0.16 mmol) was added. The mixture was stirred for 17 hours, then a premixed solution of aqueous 5M NaOH (20 μl, 0.100 mmol) and 30% aqueous hydrogen peroxide (10 μl, 11 mg, 0.100 mmol) was added. After 20 hours, the mixture was poured into saturated aqueous sodium thiosulfite (20 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resultant oil was chromatographed using a 12 g silica gel cartridge eluted with 0-100% ethyl acetate in hexanes over 20 column volumes. The desired product fractions were combined and concentrated under reduced pressure. The resulant oily film was dissolved in DCM (1.0 ml) and TFA (1.0 ml). The mixture was stirred for 17 hours, then concentrated under reduced pressure. The resultant film was chromatographed using a Gilson reverse phase prep HPLC eluted with 10-90% acetonitrile in water (with 0.05% TFA). The desired product fractions were combined, frozen at −78° C., and lyophilized to dryness to provide the title compound as a white solid. LC-MS: calculated for C23H24ClN3O7S 521.10 observed m/e: 522.28 (M+H)+ (Rt 1.58/2 min).
Reaction SMILES: Cl.N[C:3]1[CH:8]=[N:7][C:6]([Br:9])=[CH:5][N:4]=1.N([O:12][CH2:13]CC(C)C)=O>CO>[Br:9][C:6]1[CH:5]=[N:4][C:3]([O:12][CH3:13])=[CH:8][N:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CO
Product: COc1cnc(Br)cn1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
Methanolic hydrogen chloride (0.8 mL of a 10M methanolic solution) was added to a stirred solution of 2-amino-5-bromopyrazine (6.96 g, 0.04 mol) in anhydrous methanol (125 mL). To this cooled (-10° C.) solution was added isoamyl nitrite (16.1 mL, 0.12 mol) and the reaction mixture was stirred at -10° C. for 1.5 hours then at room temperature for 2 hours. The solvent was evaporated and the residue partitioned between aqueous saturated sodium carbonate (50 mL) and dichloromethane (4×50 mL). The combined organics were dried (sodium carbonate) and evaporated to give a brown oil which was purified by column chromatography on silica using 5% ethyl acetate in petroleum ether (60-80) to afford 2-bromo-5-methoxypyrazine as a pale yellow solid (6.45 g, 85%).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[C:1]1([C@H:7]([CH3:11])[C:8]([NH:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)NNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
EDC (734 mg) was added to a solution of (S)-(+)-2-phenylpropionic acid (CAS #7782-24-3, 500 mg), tert-butyl carbazate (CAS #870-46-2, 440 mg) and HOBT (517 mg) in DMF (7.5 ml), and the reaction solution was stirred at room temperature for eight hours. Ethyl acetate and a sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Ethyl acetate and heptane were added to the resulting residue, and the precipitated solid was collected by filtration to obtain 482 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=S)[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].[CH2:23]([O:25][CH2:26][C:27]([NH:29][NH2:30])=O)[CH3:24]>C(O)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:27]([CH2:26][O:25][CH2:23][CH3:24])=[N:29][N:30]=[C:12]3[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: CCOCC(=O)NN
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Solvent: CCCCO
Product: CCOCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-7-nitro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with ethoxyacetic acid hydrazide to give 8-nitro-1-(ethoxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.C(OCC)(=O)C.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:9][N:10]=[CH:11]3)(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc2[nH]ncc2c1
Reactant: Nc1cccc(F)c1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccc(F)c1)c1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
N-(3-Fluorophenyl)-(1H-indazol-5-yl)sulfonamide can be obtained in the following way: 0.98 ml of 3-fluoroaniline is added dropwise to a solution, cooled to a temperature in the region of 0° C., of 2.57 g of (1H-indazol-5-yl)sulfonyl chloride in 40 ml of pyridine. Stirring is maintained for 2 hours at a temperature in the region of 0° C. and then for 18 hours at a temperature in the region of 20° C. The medium is concentrated by evaporation under reduced pressure, and the residue obtained is taken up with 50 ml of ethyl acetate and 40 ml of water. The organic phase is washed with 2 times 20 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue obtained is purified by chromatography on a silica column with an ethyl acetate/cyclohexane (1/3 by volume) mixture as eluent. 8 mg of N-(3-fluorophenyl)-(1H-indazol-5-yl)sulfonamide are thus obtained in the form of an orange solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][CH:28]([CH2:32][CH3:33])[C:29](O)=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[CH:28]([CH3:27])[CH2:32][CH3:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CCC(C)C(=O)O
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (84 mg, 82%), MS (ISP) m/z=413.5 [(M+H)+], mp 210° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-2-methyl-butyric acid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.5 g (50 mmol) 4-bromobenzylbromide is slowly added dropwise to a solution of 4.52 mL (55 mmol) pyrrolidine and 10.3 mL (60 mmol) ethyldiisopropylamine in 100 mL THF and stirred overnight at RT. The precipitate is filtered off and the solvent is eliminated i.vac. The product is obtained as a light-brown liquid which is further reacted without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1.CC1C(C2C=CC=CN=2)=NC(C)=CC=1.CC1C(C2C=CC=CN=2)=NC=C(C)C=1.C([N-]C(C)C)(C)C.[Li+].O1CCCC1.CCCCCC.C(NC(C)C)(C)C.Cl[CH2:70][O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.Cl>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:72]([O:71][CH2:70][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1cc(C)nc(-c2ccccn2)c1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(C)c(-c2ccccn2)n1
Agent: Cc1cnc(-c2ccccn2)c(C)c1
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: Cc1cc(CCOCc2ccccc2)cc(-c2ccccn2)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
36.4 g (0.2 mol) of a mixture of isomers, consisting of 4,6-dimethyl-2,2'-bipyridine (45% by weight), 3,6-dimethyl-2,2'-bipyridine (45% by weight) and 3,5-dimethyl-2,2'-bipyridine (10% by weight) are dissolved in 150 ml of anhydrous tetrahydrofuran (THF). At 0° C., a solution of lithium diisopropylamide and hexamethylphosphoric acid triamide in THF/n-hexane [ratio about 1:1 by volume; prepared from 12.2 g (0.12 mol) of diisopropylamine in 50 ml of anhydrous THF, 60 ml of 2-molar n-butyllithium solution in n-hexane and 25.9 g (0.12 mol) of anhydrous hexamethylphosphoric acid triamide] is added dropwise in the course of 2 hours. Subsequently, the mixture is stirred for 30 minutes at 0° C. and for 15 minutes at 23° C. At -75° C., 20.3 g (0.13 mol) of benzyl chloromethyl ether are added dropwise in the course of 30 minutes. The reaction mixture is warmed slowly to 23° C., stirred for 1 hour at this temperature and then added to 200 ml of 10% hydrochloric acid. The solution is washed with three times 250 ml of ethyl acetate. The aqueous phase is rendered alkaline with potassium carbonate and the product obtained is extracted with four times 250 ml of ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and the solvent is removed in vacuo. The residue is distilled in a high vacuum. The initial fraction (16.8 g; boiling point 75°-83° C./0.27 Pa) contains 78% by weight of 3,6-dimethyl-2,2'-bipyridine, 14% by weight of 3,5-dimethyl-2,2'-bipyridine and 3% by weight of unconverted 4,6-dimethyl-2,2'-bipyridine. At 174°-176° C./0.09 Pa, 20.3 g of 4-[2-(benzyloxy)-ethyl]-6-methyl-2,2'-bipyridine distil over; yield 78% of theory, calculated on the 4,6-dimethyl-2,2'-bipyridine present in the mixture of isomers employed. nD20 =1.6007.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)ccc2c1CCC(N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 179 heating at 140° C. Product was isolated as a white foam (33 mg, 30%). LCMS (m/e) 586 (M+H); 1H NMR (400 MHz, CDCl3) δ12.93 (broad s, 1H), 10.32 (broad s, 1H), 8.35 (d, 1H, J=8.34 Hz), 8.00 (s, 1H), 7.91 (d, 1H, J=8.08 Hz), 7.52 (d, 1H, J=8.08 Hz), 7.41 (t, 1H, J=7.58 Hz), 7.33 (t, 1H, J=7.58 Hz), 6.90 (d, 1H, J=8.09 Hz), 4.02 (m, 4H), 3.74 (s, 3H), 3.57 (m, 2H), 3.34 (d, 2H, J=10.9 Hz), 3.20 (m, 2H), 2.94-3.08 (m, 3H), 2.82 (m, 1H), 2.40-2.50 (m, 2H), 1.50 (m, 2H), 1.31 (t, 6H, J=6.31).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:18]2=[CH:19][CH:20]=[N:21][CH:22]=[C:17]2[C:5]2[C:6]([OH:16])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH3:15])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:16][C:6]1[C:5]2[C:17]3[C:18]([C:2]([CH3:1])([CH3:23])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH3:15])[CH3:11])[CH:7]=1)=[CH:19][CH:20]=[N:21][CH:22]=3)(=[O:26])[CH3:25]
Reactant: CCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCC(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(2-hexyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(2-hexyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: NCC1C=NC=CC=1.[O:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][NH2:15].[F:16][C:17]1([F:36])[CH2:19][CH:18]1[CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35]>>[F:36][C:17]1([F:16])[CH2:19][CH:18]1[CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32]([NH:15][CH2:14][C:10]3[O:9][CH:13]=[CH:12][N:11]=3)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35]
Reactant: NCc1ncco1
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)NCc1ncco1
Yield: 69 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 3-(aminomethyl)pyridine with (oxazol-2-yl)methylamine to react with 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colourless solid in 69% yield: mp 156-158° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=5.7 Hz, 1H), 8.09 (s, 1H), 7.12 (s, 1H), 4.44 (d, J=5.7 Hz, 2H), 3.99 (t, J=8.4 Hz, 2H), 3.64-3.47 (m, 3H), 3.19-3.12 (m, 1H), 2.44 (s, 3H), 2.05-1.89 (m, 1H), 1.68-1.55 (m, 1H), 1.37-1.36 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 163.8, 163.1, 159.5, 156.8, 153.4, 141.5, 128.9, 119.2, 43.9, 43.6, 42.6, 42.6, 38.4, 21.8 5 (t, 1JC-F=42 Hz), 19.0, 16.4 5 (t, 1JC-F=42 Hz); MS (ES+) m/z 399.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH3:18])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: CCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid 2,47 g) and 4-nitrophenol (1.5 g) in 15 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (1.86 g). The mixture was stirred at room temperature for 3 days. Crystallization of the crude product from 2-propanol furnished 2,5 g of (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid 4-nitrophenyl ester, mp 90°-92° C.
Reaction SMILES: [Cl-:1].C([O:6][C:7]([C@@H:9]([NH:17][C:18]([CH2:20][N+:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@H:23]([NH:29][C:30]([NH2:43])=[N:31][C:32]([C:34]1[C:39]([NH2:40])=[N:38][C:37]([NH2:41])=[C:36]([Cl:42])[N:35]=1)=[O:33])[CH2:22]2)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(C)(C)C.Cl>C(OCC)C>[ClH:42].[Cl-:1].[C:7]([C@@H:9]([NH:17][C:18]([CH2:20][N+:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@H:23]([NH:29][C:30]([NH2:43])=[N:31][C:32]([C:34]1[C:39]([NH2:40])=[N:38][C:37]([NH2:41])=[C:36]([Cl:42])[N:35]=1)=[O:33])[CH2:22]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)C[N+]12CCC(CC1)[C@H](NC(N)=NC(=O)c1nc(Cl)c(N)nc1N)C2
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)N[C@@H]1C[N+]2(CC(=O)N[C@@H](Cc3ccccc3)C(=O)O)CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.9 %

Procedure:
A mixture of 140 mg (0.22 mmol) (S)-1-[((S)-1-tert-butoxycarbonyl-2-phenyl-ethylcarbamoyl)-methyl]-3-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-1-azonia-bicyclo-[2.2.2]-octane chloride (Intermediate 59) and 6.2 mL (12.4 mmol) HCl (2 M) in diethyl ether is stirred overnight at room temperature. The resulting solid is collected by filtration and washed with diethyl ether. Recrystallization from acetone yields the title compound (78 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.[CH3:24]O>>[CH3:24][O:16][C:15](=[O:17])[CH2:14][CH2:13][C:12](=[O:18])[C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1
Reactant: CO
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
4-[(methylsulfonyl)amino]γ-oxobenzenebutanoic acid IIe, (125 g, 0.46 mol) was placed in a flask with 2.5 L of methanol, and 4.6 g of concentrated sulfuric acid (0.047 mol) was added. The slurry was heated to 60° C. for 4 hr, during this period the solids went into solution. After 4 hrs, an aliquot was removed to monitor completion by HPLC. The reaction was determined complete when NMT 2% of the starting material remained. The solution was cooled to 21° C., allowing the product to crystallize. The slurry was cooled to 0° C., and the product was collected by filtration. The filter cake was washed with a mixture of 375 ml of methanol and 12.5 ml of triethylamine (×2), followed by 375 mL of methanol. The title product was obtained in 92% yield (99 area %). Melting point 181-183° C. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 3.58 (s, 3H), 3.2(s, 1H), 3.24 (t, J=6.4 Hz, 2H), 3.1 (s, 3H), 2.63 (t, J=6.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ C 196.8, 172.8, 143.0, 131.0; CH 129.6, 117.5; CH2 32.7, 27.6; CH3 51.3, 39.8; MS m/z calcd for C12H14NO5S 284.31 (M−H)+; found 284.00 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)[CH:5]=1)[CH3:29]
Reactant: CC(N)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NC(C)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and (±)-2-amino-1-propanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.