Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](=[S:33])[NH:24][C@H:25]([CH:30]([CH3:32])[CH3:31])[C:26]([O:28][CH3:29])=[O:27])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[CH3:32][CH:30]([CH3:31])[C@@H:25]([NH:24][C:23]([C:21]1[O:20][N:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:2]([NH:1][C:4]3[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=3)=[O:3])=[CH:13][CH:14]=2)[CH:22]=1)=[S:33])[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)[C@H](NC(=S)c1cc(-c2ccc(N)cc2)no1)C(C)C
Reactant: Cc1ccc(N=C=O)cc1
Product: COC(=O)[C@H](NC(=S)c1cc(-c2ccc(NC(=O)Nc3ccc(C)cc3)cc2)no1)C(C)C
Yield: 65 %

Procedure:
The title compound was prepared according to the procedure as set, forth in example 151, except that 1-isocyanato-4-methylbenzene was used in place of 1-fluoro-3-isocyanatobenzene and (R)-methyl 2-(3-(4-aminophenyl)isoxazole-5-carbothioamido)-3-methylbutanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 65% of the title compound. MS (ESI): m/z 467(M+H); 1HNMR (DMSO-d6, 300 MHz): δ 10.924 (d, 1H), 8.902 (s, 1H), 8.630 (s, 1H), 7.865 (d, 2H), 7.607(d, 3H), 7.351(d, 2H), 7.094(d, 2H), 4.810 (s, 1H), 3.665(s, 3H), 2.489 (m, 1H), 2.367(s, 3H), 1.033(m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([C:23](=[O:37])N2[C@H](CC3C=CC=CC=3)COC2=O)[CH2:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH:38]O.[Li+].[OH-]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([CH2:11][NH:12][C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:22])[C:23]([OH:37])=[O:38])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)OCc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of phenylmethyl {(2S)-2-[(3,4-difluorophenyl)methyl]-3-oxo-3-[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]propyl}carbamate (548 mg, 1.078 mmol) in tetrahydrofuran (16.200 ml) and Water (5.40 ml) at 0° C. was added H2O2 (0.198 ml, 1.940 mmol)[30 wt %] followed by LiOH (2.69 ml, 2.155 mmol)[0.8M solution]. After 1 h, the solution warmed to 25° C. and stirred 2 h. The reaction mixture was quenched with Na2SO3 solution and the pH was carefully adjusted to ˜3 with 2N HCl solution. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (10-60% EtOAc in hexanes) affording (2S)-3-(3,4-difluorophenyl)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]propanoic acid (260 mg, 0.700 mmol, 64.9% yield) as a clear oil: LCMS (ES) m/e 350 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. s., 1 H) 7.20-7.40 (m, 8 H) 7.03 (br. s., 1 H) 5.02 (s, 2 H) 4.52-4.75 (m, 1 H) 3.01-3.26 (m, 2 H) 2.77 (s, 2 H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][CH:12]([CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[C:22]([CH:24]=[O:25])[C:21]([O:26][CH3:27])=[CH:20][C:17]=1[CH:18]=[O:19].C(=O)[C:35]1[CH:42]=[CH:41][C:38](C=O)=[CH:37][CH:36]=1.OS(O)(=O)=O>C1COCC1.C1(C)C=CC=CC=1>[C:5]1([CH:18]([OH:19])[C:17]2[CH:20]=[C:21]([O:26][CH3:27])[C:22]([CH:24]([C:35]3[CH:42]=[CH:41][CH:38]=[CH:37][CH:36]=3)[OH:25])=[CH:23][C:16]=2[O:15][CH2:14][CH2:13][CH:12]([CH3:11])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Brc1ccccc1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: COc1cc(C=O)c(OCCC(C)CCCC(C)C)cc1C=O
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2)c(OCCC(C)CCCC(C)C)cc1C(O)c1ccccc1
Temperature: 70 °C

Procedure:
A 6 l four-neck flask with precision glass stirrer, reflux condenser and 2 dropping funnels was initially charged with 26.7 g (1.1 mol) of magnesium turnings. The apparatus was baked out under argon. At room temperature, 10 ml of absolute THF and a few crystals of iodine were added and the mixture was stirred briefly. Subsequently, a few ml of bromobenzene were added dropwise to the unstirred solution, and at the point of dropwise addition was heated briefly with a hot air blower. After the start of the reaction, a total (including the amount already added) of 215 g (1.37 mol) of bromobenzene were added dropwise within 45 min. At the same time, 490 ml of absolute THF were added. After the dropwise addition, the mixture was stirred under reflux for 1.5 h. Subsequently, a solution of 175.6 g (0.55 mol) of 2-(3,7-dimethyloctyloxy)-5-methoxyterephthalaldehyde in 600 ml of absolute THF were added dropwise with ice cooling. After half of the addition, the gel which had formed was admixed with 3000 ml of distilled toluene and dissolved with heating to 70° C. After cooling to room temperature, the remaining solution of terephthalaldehyde was added dropwise, and the viscous solution was stirred at 70° C. for a further 4 h. The reaction mixture was stirred into 4000 ml of ice-water with 40 ml of conc. H2SO4. The phases were separated and the aqueous phase was extracted with 1×500 ml of ethyl acetate. The combined organic phases were washed with 1×300 ml of water and dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was stirred with n-hexane twice at room temperature and once at 50° C., and filtered. Further purification was effected by melting the crude product at 65° C. in hexane. This operation was effected three times more. 157.1 g (60% of theory) of the product were obtained in 95% purity, which was used directly for the further synthesis. NMR (CDCl3): 7.38-7.44 (m, 4H), 7.24-7.35 (m, 6H), 7.09-9.12 (m, 1H), 7.04-7.07 (m, 1H), 6.54-6.57 (m, 2H, C(OH)H), 3.85-3.95 (m, 2H, OCH2), 3.76+3.77 (2×s, 3H, OCH3), 0.83-1.69 (m, 19H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][N:7]=1.S(Cl)([Cl:15])=O>>[ClH:15].[Cl:15][CH2:2][C:3]1[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCn1ccnc1CO
Product: CCCCCn1ccnc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 2-hydroxymethyl-1-pentylimidazole (3.8 g) was added thionyl chloride (38 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from methanol-ethyl acetate, to give 2-chloromethyl-1-pentylimidazole hydrochloride (3.00 g) as brown crystals.
Reaction SMILES: C(ON1C(=O)C2=CC=CC=C2C1=O)(=[O:3])C.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N1C=CC=C(C)C=1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:16]([OH:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)ON1C(=O)c2ccccc2C1=O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: Cc1cccnc1
Solvent: CC(=O)O
Product: O=C(O)c1cccnc1

Procedure:
In the presence of an oxidation catalyst (N-acetoxyphthalimide (NAPI)) and a metal catalyst (cobalt acetate and manganese acetate) with nicotinaldehyde as a co-oxidizing agent, β-picoline was oxidized in acetic acid solvent at 140° C. and 2 MPa with air to produce nicotinic acid. From the reaction mixture, acetic acid was removed and to a condensate was added 2-ethylhexanol. The mixture was cooling-crystallized to 25° C. at atmospheric pressure and filtrated, and the residue washed with methanol and filtrated to separate nicotinic acid. The filtrate and washing liquid were combined and the solvent was removed therefrom. The components in the condensed residue were analyzed, and as a result, 92 g of nicotinic acid, 160 g of 2-ethylhexanol, 1.0 g of N-acetoxyphthalimide (NAPI), 1.8 g of N-hydroxyphthalimide (NHPI), 108 g of phthalic acid (PA), 67 g of phthalimide (PI), 24 g of phthalic anhydride (APA), 11 g of total cobalt, 11.4 g of total manganese were contained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[H][H]>[Pd].C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1c(NS(C)(=O)=O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1NS(C)(=O)=O
Yield: 84 %

Procedure:
The crude product from Example 1A and 10% palladium on carbon (1.4 g) were stirred vigorously in ethyl acetate (70 mL) for 24 hours under one atmosphere of hydrogen. The reaction was placed under a nitrogen atmosphere, filtered through a 1 inch pad of 1:1 Celite:silica gel eluting with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate) to provide the title compound as a brown solid (11.06 g, 84%).
Reaction SMILES: C([C@:5]1([C:23]2[NH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[NH:44][C:43]([C@@H:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[C@@H:51]([NH:55][C:56](=[O:59])[O:57][CH3:58])[CH:52]([CH3:54])[CH3:53])=[N:42][CH:41]=5)=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[CH2:9][C@H:8]([CH2:10][O:11][CH3:12])[CH2:7][N:6]1[C:13](=[O:22])[C@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.Cl.[CH:62]1([C:65]([OH:67])=O)[CH2:64][CH2:63]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH:62]1([C:65]([NH:21][C@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:13]([N:6]2[CH2:7][C@@H:8]([CH2:10][O:11][CH3:12])[CH2:9][C@H:5]2[C:23]2[NH:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:35]=[CH:36][C:37]([C:40]5[NH:44][C:43]([C@@H:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[C@@H:51]([NH:55][C:56](=[O:59])[O:57][CH3:58])[CH:52]([CH3:54])[CH3:53])=[N:42][CH:41]=5)=[CH:38][CH:39]=4)=[CH:32][CH:33]=3)=[CH:26][N:27]=2)=[O:22])=[O:67])[CH2:64][CH2:63]1
Reactant: COC[C@@H]1CN(C(=O)[C@H](N)c2ccccc2)[C@](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)(C(C)(C)C)C1
Reactant: O=C(O)C1CC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@H](NC(=O)C2CC2)c2ccccc2)C1
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To methyl (S)-1-((S)-2-(5-(4′-(2-((2S,4S)-(tert-butyl)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (187 mg, 0.22 mmol) in DCM (5 mL) and MeOH (1 mL) was added HCl (4M in dioxane, 1.0 mL). The solution was stirred for 16 h, and the solvent was removed. The intermediate was dissolved in DMF (5 mL). Cyclopropanecarboxylic acid (34 μL, 0.44 mmol), COMU (104 mg, 0.22 mmol), and DIPEA (0.19 mL, 1.09 mmol) were added sequentially. The solution stirred for 30 min. It was purified by HPLC to yield product (66.5 mg). LCMS-ESI+: calc'd for C47H50N8O7: 826.98 (M+); Found: 827.37 (M+H+).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([NH:31]N)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:21]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: NNc1cccc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=365.1 (M+H)+
Reaction SMILES: [F:1][C:2]([S:5]([O:8]S(C(F)(F)F)(=O)=O)(=[O:7])=[O:6])([F:4])[F:3].[CH3:16][C:17]1([CH3:24])[O:21][CH:20]([CH2:22]O)[CH2:19][O:18]1.N1C(C)=CC=CC=1C>C(Cl)Cl.O>[F:1][C:2]([F:4])([F:3])[S:5]([O:8][CH2:22][CH:20]1[CH2:19][O:18][C:17]([CH3:24])([CH3:16])[O:21]1)(=[O:7])=[O:6]
Reactant: CC1(C)OCC(CO)O1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC1(C)OCC(COS(=O)(=O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trifluoromethylsulfonic anhydride (7.03 ml, 41.6 mmol) was added dropwise over 15 mins to a solution of solketal (4.70 ml, 37.8 mmol) and 2,6-lutidine (5.73 ml, 49.2 mmol) in DCM (126 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. The mixture was diluted with DCM (100 mL) and water (100 mL), the phases were separated and the aqueous phase extracted with DCM (3×50 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum to afford the title compound as a crude material which was used directly.
Reaction SMILES: N[C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:17]=O.[C:19]([BH3-])#[N:20].[Na+]>C(O)(=O)C>[CH3:17][N:20]([CH3:19])[C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)c1cccn1CC2
Reactant: [BH3-]C#N
Reactant: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1ccc2c(c1)C(=O)c1cccn1CC2
Reaction time: 0.25 h

Procedure:
To a solution of 9-amino-6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-one (2.1 g., 10 mmoles) and 4 ml. (50 mmoles) of 37% aqueous formaldehyde in 15 ml. of acetonitrite is added 1 g. (16 mmoles) of sodium cyano borohydride. A vigorous and exothermic reaction takes place and a dark residue separates. The mixture is stirred for 15 minutes and then glacial acetic acid is added dropwise until the solution tests neutral on wet pH paper. Stirring is maintained for an additional 2 hours. The volatiles are removed under vacuum, and the residue is dissolved in chloroform. The solution is washed with base and with water, dried over sodium sulfate, and concentrated to leave a residue that is purified by chromatography on silica gel. Elution with chloroform yields 9-dimethylamino-6,11-dihydro-5H-pyrrolo [2,1-b][3]benzazepin-11one as a dark brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C1C=CC=CC=1>[CH3:19][O:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of N-t-butoxycarbonyl isonipecotic acid (8.8 g, 34.9 mmol), in a 10% mixture of methanol in benzene (250 ml), was added a 2.0 M solution of trimethylsilyldiazomethane in hexanes, dropwise, until a consistent yellow color was obtained (˜30 ml). After vigorous gas evolution had ceased, the reaction mixture was stirred for 1 hr at room temperature. The mixture was then treated dropwise with glacial acetic acid until the yellow color had dissipated. The reaction was stirred 15 min. and concentrated in vacuo to a pale yellow oil. The residue was purified by chromatography (SiO2,eluting with 20% EtOAc in hexanes). Evaporation of the solvent in vacuo afforded the product as a colorless oil.
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[OH-].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C1(C)C=CC=CC=1>[CH2:21]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A reactor was charged with DMSO (6 L), followed by 4-tert-butyl-2-nitrophenylamine (Preparation 108, 3.0 kg, 15.4 mol) and potassium hydroxide (1.32 kg, 23.5 mol). The mixture was stirred at room temperature for twenty minutes. Toluene (12 L) was added and the mixture stirred for another twenty minutes. After cooling to 10° C., benzyl bromide (3.16 kg, 18.5 mol) was added slowly and the reaction mixture was stirred for 4 hours. Water (30 L) was added, the mixture stirred for 30 minutes and the layers allowed to settle. The aqueous layer was extracted with toluene (2×10 L), followed by ethyl acetate (10 L), and the combined organic extracts concentrated under vacuum at <50° C. Isopropanol (4 L) was added and the mixture cooled to −5° C. The slurry was stirred for 1 hour before collecting the solids by filtration, washing with isopropanol (2×1.5 L) and drying at 55-60° C. to provide 2.8 kg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[S:5][C:6]=1[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1.[ClH:18].[C:19](OCC)(=O)[CH3:20]>CN(C)C=O.O1CCOCC1.ICC>[ClH:18].[ClH:18].[CH3:1][C:2]1[N:3]=[C:4]([NH:14][C:15](=[NH:17])[S:16][CH2:19][CH3:20])[S:5][C:6]=1[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1ccnc(-c2sc(NC(N)=S)nc2C)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCI
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a suspension of N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)thiourea (529 mg) in N,N-dimethylformamide (10 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) and iodoethane (0.8 ml), and the mixture was stirred at 70° C. for 4 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration and purified by column chromatography (silica gel, triethylamine:methanol:dichloromethane=1:2:100). The combined fractions were evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (5 ml). To the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 1.25 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea dihydrochloride (0.69 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])[CH:11]=[CH:10][C:8]=2[CH:9]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:8]2[CH:9]=[C:5]([CH2:4][CH2:3][C:1]3[NH:30][N:29]=[N:28][N:2]=3)[O:6][C:7]=2[CH:13]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCC#N)oc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCc3nnn[nH]3)oc2c1
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A mixture of 2-(2-cyanoethyl)-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (1.20 g), sodium azide (1.09 g), ammonium chloride (0.90 g) and N,N-dimethylformamide (30 ml) was stirred at 130° to 140° C. for 16 hours. The reaction mixture was poured over water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; the residue was subjected to silica gel column chromatography. From the fraction eluted with methanol-chloroform (5:95, v/v), 5-[2-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]ethyl ]-1H-tetrazole (1.05 g, 78%) was obtained, which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 177° to 178° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]1[CH:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:12]1>C1COCC1>[C:4]1([CH2:3][O:10][CH2:12][CH:13]([OH:11])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: FC(F)(F)c1cccc(OCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)COc1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Sodium hydride (80% dispersion in oil, 0.045 g) was added to a mixture of benzyl alcohol (4 ml) and THF (3 ml) and warmed gently until effervescence ceased. To the cooled solution was added 1,2-epoxy-3-[3-(trifluoromethyl)phenoxy]propane (2.12 g). After stirring for 3 h the mixture was poured into ER (50 ml) and washed with brine. The dried extracts were evaporated and the residue distilled (b.p. 140°-144°/0.03 mm) to yield the title compound as an oil (2.25 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4)c3O2)cc1
Yield: 67.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.367 g (68%) of (±)-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as an orange solid. mp 130-133° C.; Anal. calcd. for C22H19ClO4S: C, 63.69; H, 4.62. Found: C, 62.82; H, 4.56.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[NH2:2].O=[C:16]([CH3:29])[CH:17]([CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C:18](OC)=[O:19]>CCO.CC(O)=O.CCOC(C)=O>[CH3:13][N:12]([CH3:14])[S:9]([C:6]1[CH:7]=[N:8][C:3]([N:1]2[C:18](=[O:19])[C:17]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[C:16]([CH3:29])[NH:2]2)=[CH:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: CN(C)S(=O)(=O)c1ccc(NN)nc1
Reactant: COC(=O)C(Cc1cccnc1)C(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]n(-c2ccc(S(=O)(=O)N(C)C)cn2)c(=O)c1Cc1cccnc1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
A mixture of 400 mg (1.85 mmol) of 6-hydrazino-N,N-dimethylpyridine-3-sulfonamide and 383 mg (1.85 mmol) of methyl 3-oxo-2-(pyridin-3-ylmethyl)butanoate in 4 mL of EtOH/AcOH mixture (1:1) is heated for 4 hours at 80° C. and then concentrated under reduced pressure. The residue obtained is taken up in 20 mL of EtOAc, washed successively with water (2×20 mL), saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is then solidified in 20 mL of an Et2O/pentane mixture (1/1), filtered and recrystallized from a cyclohexane/EtOH mixture. 188 mg of N,N-dimethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-sulfonamide are obtained in the form of white crystals.