Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][C@@H:36]([C:38]([OH:40])=O)[CH3:37])[C:32]3[C:27](=[CH:28][C:29]([CH3:41])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.FC(F)(F)C(O)=O.[CH:66]1([NH:70][C:71]([C@@H:73]2[CH2:77][CH2:76][CH2:75][NH:74]2)=[O:72])[CH2:69][CH2:68][CH2:67]1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][C@H:36]([CH3:37])[C:38]([N:74]3[CH2:75][CH2:76][CH2:77][C@H:73]3[C:71](=[O:72])[NH:70][CH:66]3[CH2:67][CH2:68][CH2:69]3)=[O:40])[C:32]3[C:27](=[CH:28][C:29]([CH3:41])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)O)c3ccc(C)cc3n2)CC1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 121 mg of 4-((S)-3-tert-Butoxycarbonyl-2-{[4-((R)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester in 1 ml of DCM, 43 mg of EDC, 43 mg of pentafluorophenol and 27 mg of NEM was added and the reaction mixture was stirred for 2 h. Then, 67 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 20 mg of NEM in 2 ml of DCM was added. After 1 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.
Reaction SMILES: [CH2:1]([C:9]1[S:13][C:12]2[S:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([CH:24]([CH2:27]O)[CH2:25][OH:26])[CH2:20][CH2:21][CH2:22][CH3:23].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C:9]1[S:13][C:12]2[S:14][C:15]([C@H:17]3[O:26][CH2:25][C@H:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:27][O:18]3)=[CH:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(CO)CO
Reactant: CCCCCCCCc1cc2cc(C=O)sc2s1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCc1cc2cc([C@H]3OC[C@H](CCCCC)CO3)sc2s1

Procedure:
20.4 g of 5-n-octylthieno[2,3-b]thiophene-2-carbaldehyde (obtainable from 2-n-octylthieno[2,3-b]thiophene by Vilsmeyer formylation with phosphorus oxychloride/dimethylformamide) and 9.5 g of 2-n-pentylpropane-1,3-diol are dissolved in 150 ml of toluene, a pinch of toluenesulfonic acid is added, and the mixture is heated under a water separator until water is no longer separated off. The acid is washed out with sodium bicarbonate solution, the organic phase is dried over sodium sulfate, and the toluene is distilled off. The pure trans-2-(5-n-octylthieno[2,3-b]thien-2-yl)-5-n-pentyl-1,3-dioxane is obtained by repeated recrystallization from ethanol (17.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.ClC(OC)=O.O.[NH2:37][NH2:38]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:37][NH2:38])=[O:28])=[C:22]([F:30])[CH:21]=3)[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NNC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of [4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetic acid (500 mg, 1.152 mmol) in 5 mL of THF cooled to −10° C. and TEA (0.177 mL, 1.268 mmol) was added. Methyl chloroformate (0.098 mL, 1.268 mmol) was added and the mixture stirred for 30 minutes at −10° C. The mixture was filtered and the filtercake washed with 10 mL THF. The filtrate was collected and concentrated under reduced pressure. The residue (265 mg, 0.539 mmol) was dissolved in 1 mL of DMF and hydrazine monohydrate (0.052 mL, 1.077 mmol) added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (3 mL) and washed with water (2 mL) and brine (2 mL). The organics fractions were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using preparative TLC (1000 μM, silica gel) developing with 5% methanol in DCM. The band containing the product was collected and the silica washed with 10% methanol in DCM to elute the product. The solution was concentrated under reduced pressure to afford the title compound. HPLC/MS; 1.22 min(2 minute run), 448 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([CH:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C[Si]([C:25]#[N:26])(C)C>>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:19]=[CH:18][C:7]([CH:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[C:25]#[N:26])=[CH:6][CH:5]=1
Reactant: CSc1ccc(N=Cc2ccc(OC(F)F)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CSc1ccc(NC(C#N)c2ccc(OC(F)F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-difluoromethoxybenzaldehyde and 4-methylthioaniline as starting materials, N-(4-difluoromethoxybenzylidene)-4-methylthioaniline was obtained in a yield of 91%. This aniline compound and trimethylsilyl cyanide were then reacted together in a similar manner to that described in Example 1(ii), to give the title compound as a slightly yellow powder (yield 80%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].CN=[C:9]1[S:12][CH2:11][S:10]1.C(N=C1SCS1)(C)C.C(N=C1SCS1)(C)(C)C.C(N=C1SCS1)CCCCCCC>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]=[C:9]1[S:12][CH2:11][S:10]1)[CH3:2]
Reactant: CN=C1SCS1
Reactant: CCOCCN
Agent: CC(C)(C)N=C1SCS1
Agent: CC(C)N=C1SCS1
Agent: CCCCCCCCN=C1SCS1
Product: CCOCCN=C1SCS1

Procedure:
Following this procedure, but substituting the appropriate amine for 2-ethoxyethylamine, yields the compounds listed as follows:Example No. Compound m.p. °C.__________________________________________________________________________67 2-(Methylimino)-1,3-dithietane --68 2-(Isopropylimino)-1,3-dithietane --69 2-(tert-Butylimino)-1,3-dithietane oil70 2-(Heptylimino)-1,3-dithietane oil71 2-(Dodecylimino)-1,3-dithietane 40.5-4272 2-(Cyclohexylimino)-1,3-dithietane 78-8073 2-(Methylallylimino)-1,3-dithietane oil74 2-(Isobutylimino)-1,3-dithietane oil75 2-(1,4-Dimethylpentylimino)-1,3- oil dithietane76 2-(n-Octylimino)-1,3-dithietane oil77 2-(n-Hexylimino)-1,3-dithietane oil__________________________________________________________________________
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C([O-])(O)=[O:15].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: O=C([O-])O
Reactant: Fc1ccccc1C1=CCCCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccccc1C12CCCCC1O2
Reaction time: 2 h

Procedure:
1-(2-Fluorophenyl)cyclohexene of Example 1(a) [6.76 g; 0.038 mole] was dissolved in a two-phase system consisting of 350 ml of CH2Cl2 and 110 ml of 0.5M NaHCO3. m-Chloroperbenzoic acid (7.80 g of 85%; 0.38 mole) was then added portionwise with vigorous mechanical stirring. After 2 hours TLC indicated that the reaction was complete. The organic layer was separated and washed with 100 ml of N NaOH and 100 ml of water. Drying and concentration under reduced pressure gave an oil which amounted to 6.34 g (86%) after distillation, b.p. 113°/0.075 mm (Kugelrohr). A small portion was chromatographed over silica gel (CHCl3) to remove traces of polar impurities and distilled again to provide the sample of 1-(2-fluorophenyl)cyclohexene oxide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[NH:18][CH2:17][CH2:16][S:15]1)=[O:13].[OH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[N:18]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[C:37]([OH:36])[CH:38]=2)[CH2:17][CH2:16][S:15]1)=[O:13]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@@H]1SCCN1Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (I5, 300 mg, 0.52 mmol) in DCM (2 mL) was added 3-hydroxybenzaldehyde (172 mg, 1.2 mmol) followed by glacial AcOH (0.11 mL, 2.08 mmol). The reaction was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (500 mg, 2.26 mmol) was added and the reaction was stirred at room temperature for 4 h. DCM (50 mL) and 1 N HCl (20 mL) were added to quench the reaction. The layers were separated and the organic layer washed with 1 N HCl (2×20 mL), passed through a hydrophobic fit and the solvent was removed in vacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1C=C(O)[CH:5]=[CH:4][C:3]=1[CH3:9].OS(O)(=O)=O.[CH2:15]([O:17][C:18](=[O:23])[CH2:19][C:20]([CH3:22])=O)[CH3:16]>>[CH3:22][C:20]1[C:5]2[C:15](=[CH:16][C:2]([OH:1])=[C:3]([CH3:9])[CH:4]=2)[O:17][C:18](=[O:23])[CH:19]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(O)cc1O
Agent: O=S(=O)(O)O
Product: Cc1cc2c(C)cc(=O)oc2cc1O

Procedure:
A solution of 2,4-dihydroxytoluene (10.0 g) in ethylacetoacetate (12 ml) was poured in small portion into conc. H2SO4 (26 ml), chilling in an ice bath. After the addition was completed the solid obtained was separated by filtration, washed several times with water up to neutrality of the washings, dried and crystallized from MeOH, yielding 4,6-dimethyl-7-hydroxycoumarin (III) (10.64 g; m.p. 273° C.). ##STR9##
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.[NH2:17][C:18]1[C:23]([F:24])=[C:22](Cl)[N:21]=[C:20]([C:26]([O:28][CH3:29])=[O:27])[C:19]=1[CH:30]=[CH2:31].[F-].[K+].C(#N)C>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:17][C:18]1[C:23]([F:24])=[C:22]([C:9]2[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=2)[N:21]=[C:20]([C:26]([O:28][CH3:29])=[O:27])[C:19]=1[CH:30]=[CH2:31]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(N)cc2)c(F)c1N
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
In a microwave vessel, a suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (commercially available) (0.617 g, 2.82 mmol), methyl 4-amino-6-chloro-5-fluoro-3-vinylpicolinate (Head G) (0.5 g, 2.168 mmol), bis(triphenyl phosphine)palladium(II) chloride (0.152 g, 0.217 mmol) and potassium fluoride (0.327 g, 5.64 mmol) in a 1:1 mixture of acetonitrile (3.61 mL) and water (3.61 mL) was stirred under microwave irradiation (120° C., 20 min). The reaction mixture was poured into a half saturated brine solution and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2 24 g, hexanes/EtOAc gradient) to afford the title compound as a yellow solid (0.552 g, 89%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.58 (m, 2H), 6.72 (dd, J=17.7, 11.5 Hz, 1H), 6.65-6.58 (m, 2H), 6.24 (s, 2H), 5.47 (s, 2H), 5.45 (dd, J=11.5, 1.2 Hz, 1H), 5.38 (dd, J=17.7, 1.2 Hz, 1H), 3.77 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −146.62; ESIMS m/z 286 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([Br:7])=[N:4][N:3]=1.[H-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH2:10]([N:6]1[C:5]([Br:7])=[N:4][N:3]=[C:2]1[Br:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Brc1nnc(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1nnc(Br)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 3,5-dibromo-4H-1,2,4-triazole (3.0 g, 13.3 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil, 0.58 g, 14.5 mmol) (CAUTION: NaH and DMF can become a runaway reaction. All necessary safety precautions were performed). After the mixture was stirred at 0° C. for 30 minutes, benzyl bromide (1.57 mL, 13.2 mmol) was added. The mixture was stirred at 0° C. for 2 hours, then the mixture was partitioned between EtOAc (150 mL) and water (30 mL). The organic layer was washed with brine (2×30 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 50:1 to 10:1) to yield 3.71 g (89%) of the title compound as a white solid. m/z (ES+) 316, 318, 320 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH3:24][S:25][C:26]1[N:27]2[CH:37]=[N:36][CH:35]=[C:28]2[S:29][C:30]=1[Si](C)(C)C.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[CH3:24][S:25][C:26]1[N:27]2[CH:37]=[N:36][CH:35]=[C:28]2[S:29][CH:30]=1
Reactant: CSc1c([Si](C)(C)C)sc2cncn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1csc2cncn12
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
A 1 M Tetra-n-butylammonium fluoride/THF solution (20.0 ml) was added in an argon atmosphere at room temperature to a solution of 3.87 g of 3-methylthio-2-(trimethylsilyl)imidazo[5,1-b]-thiazole in 70 ml of dry THF. The mixture was stirred at the same temperature for 15 min. Semi-saturated brine was added to the reaction mixture. Ethyl acetate was then added thereto, followed by washing with semi-saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 2.62 g of 3-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[C:13]([CH2:16][N:17]([CH3:19])[CH3:18])[S:14][CH:15]=1)SC.[N+:20]([CH3:23])([O-:22])=[O:21]>CC(O)CC>[CH3:1][NH:2][C:3]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[C:13]([CH2:16][N:17]([CH3:18])[CH3:19])[S:14][CH:15]=1)=[CH:23][N+:20]([O-:22])=[O:21]
Reactant: CNC(=NCCSCc1csc(CN(C)C)n1)SC
Reactant: C[N+](=O)[O-]
Solvent: CCC(C)O
Product: CNC(=C[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Temperature: 25 °C

Procedure:
Nine g. of N-methyl-S-methyl-N'-[2-(2-dimethylaminomethylthiazol-4-ylmethylthio)ethyl]isothiourea was stirred in 45 ml. of nitromethane and 45 ml. of 2-butanol in a 95° bath for 20 hours. The reaction mixture was then evaporated to dryness on a warm water bath under vacuum, and the residue was dissolved in 50 ml. of ethyl acetate and stirred at ambient temperature. A solid crystallized out, and the solution was cooled in an ice bath for 30 minutes. The mixture was then filtered and the solids were washed with cold ethyl acetate and dried in air to obtain 6.5 g. of the desired product in crude form, which was found to be 88.6% pure, with 6 impurities, by high performance liquid chromatography analysis (HPLC). Six g. of the crude product was dissolved in 50 ml. of warm denatured ethanol, and the solution was stirred while it cooled to ambient temperature. The crystals were collected by filtration, washed with denatured ethanol and air dried overnight to obtain 4.61 g. of purified nizatidine, m.p. 134-136°, found to be 96.7% pure by HPLC.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[O:8])[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:15][C:11]1[CH:10]=[C:9]([C:7]([N:4]2[CH2:5][CH2:6][C:2]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)=[N:3]2)=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(c1cccc(F)c1)N1CCC(Cl)=N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C2=NN(C(=O)c3cccc(F)c3)CC2)cc1
Temperature: 110 °C

Procedure:
To a degassed solution of (3-Chloro-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone (0.19 g, 0.0008 moles, 1 equiv) in dry 1,2-DME-water, 5 mL, (4:1) was added 4-Methoxyphenylboronic acid (0.17 g, 0.0112 moles, 1.4 equiv), anhydrous sodium carbonate (0.17 g, 0.0016 moles, 2 equiv) and Tetrakis-(triphenylphosphine)-palladium (0) (0.092 g, 0.00008 moles, 0.1 equiv). The reaction mixture was heated at 110° C. for 0.5 h under nitrogen atmosphere in microwave conditions or 6-8 h in thermal conditions. Consumption of starting material was confirmed by TLC and LC-MS. 1,2-DME was distilled under reduced pressure, the crude residue was dissolved in dichloromethane (25 mL), washed with water, saturated brine, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to get the pure compound (3-Fluorophenyl)-[3-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl]-methanone in 0.100 g. P.S.: (a) In case of Carboxy boronic acid, LiCl (3 eq) was added to the reaction mixture as an additive. (b) In Case of Cyano boronic acid, K3PO4 (2 eq) was used as base.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[C:25](O)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:27].CC1C=CC=C(C)N=1>ClCCl>[Br:16][C:17]1[C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:27]
Reactant: O=C1CCc2c1ccc(O)c2Br
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (4.0 mL) is added dropwise to a solution of 4-bromo-5-hydroxy-indan-1-one (5.0 g) and 2,6-dimethylpyridine (5.1 mL) in dichloromethane (50 mL) cooled to 0° C. The cooling bath is removed and the mixture is stirred for 2 h at room temperature. The solution is partitioned between saturated aqueous NH4Cl solution and dichloromethane. The organic phase is separated, washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. LC (method 2): tR=1.08 min; Mass spectrum (ESI+): m/z=359/361 (Br) [M+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:21]>O>[Br:21][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-(4-aminophenyl)piperidin-4-ol (600 mg, 3.12 mmol), HBr (14 mL, 48%), was mixed and cooled to 0° C., the solution of NaNO2 (215 mg, 3.12 mmol) in 2.3 mL water was added in. the mixture was stirred for 15 minutes, the solution of CuBr (246 mg, 1.72 mmol) in HBr (4.4 mL 4.8%) was added and reacted at 100° C. for 3 hours. 2M NaOH solution was added, extracted by EA, washed by 2M NaOH, dried over Na2SO4, concentrated and purified by flash chromatography. (PE:EA=3:1) to give 520 mg pale brown solid.
Reaction SMILES: CS(O)(=O)=O.[C:6]([CH2:8][NH:9][C:10](=[O:41])[C@H:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:12][C:13]1[S:17][N:16]=[CH:15][C:14]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1N1CCN(C(OC(C)(C)C)=O)CC1)#[N:7].[CH2:42]1[CH2:46]OCC1>>[C:6]([CH2:8][NH:9][C:10](=[O:41])[C@H:11]([CH2:37][CH:38]([CH3:39])[CH3:40])[NH:12][C:13]1[S:17][N:16]=[CH:15][C:14]=1[C:18]1[CH:19]=[CH:20][C:21]([N:7]2[CH2:42][CH2:46][NH:9][CH2:8][CH2:6]2)=[CH:22][CH:23]=1)#[N:7]
Reactant: CC(C)C[C@H](Nc1sncc1-c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)NCC#N
Reactant: C1CCOC1
Agent: CS(=O)(=O)O
Product: CC(C)C[C@H](Nc1sncc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N

Procedure:
Methanesulfonic acid (16 μL, 0.24 mmol) was added dropwise over 5 min to a stirred solution of N1-(cyanomethyl)-N2-[4-(4-(tert-butoxycarbonyl)piperazin-1-ylphenyl)isothiazol-5-yl]leucinamide (63 mg, 0.12 mmol) in THF (0.21 mL) at rt. Stirring was continued for 1 h before additional methanesulfonic acid (16 μL, 0.24 mmol) was introduced in the same manner with stirring for 1 h. A final portion of methanesulfonic acid (8 μL, 0.12 mmol) was added dropwise over 3 min and the mixture was stirred at rt for 8 h. The reaction was quenched by the careful addition of an excess of saturated sodium bicarbonate solution. Extraction with ethyl acetate (3×), drying of the combined organics (Na2SO4) and concentration in vacuo gave 48 mg of N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)isothiazol-5-yl]leucinamide as a tan foam. MS (+ESI): 413.2 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[CH:5]([CH3:28])[N:6]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=12.B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:6]2[CH:5]([CH3:28])[C:4]3[C:3]([OH:2])=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3cccc(OC)c3C2C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CC1c2c(O)cccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 60.8 %

Procedure:
The title compound was prepared from 7-methoxy-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.17 g, 0.43 mmol), tetrabutylammonium iodide (0.39 g, 1.1 mmol), and 1 M boron trichloride in dichloromethane (2.6 mL, 2.6 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:1), followed by trituration from dichloromethane, to yield 5-[(4-hydroxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridin-7-ol as a homogenous solid (0.096 g, 61%);