Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][S:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Reactant: OB(O)c1ccsc1
Product: COc1c(-c2ccsc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Yield: 33 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with thiophen-3-yl boronic acid (8.1 mg, 0.063 mmol) as described in Example 63, Part B to give the title compound as an off-solid (8.6 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1 H) 7.93 (d, J=2.94 Hz, 1 H) 7.87 (d, J=7.72 Hz, 1 H) 7.53-7.75 (m, 6 H) 7.49 (t, J=6.25 Hz, 1 H) 7.39 (d, J=2.57 Hz, 1 H) 6.57 (s, 1 H) 5.68 (dd, J=7.91, 2.02 Hz, 1 H) 4.19 (d, J=5.15 Hz, 2 H) 3.47 (s, 2 H) 3.21 (s, 3 H) 2.96 (s, 3 H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[Cl:28][C:29]1[S:30][C:31]([CH2:34]Cl)=[CH:32][CH:33]=1>>[Cl:28][C:29]1[S:30][C:31]([CH2:34][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:17]([CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:27])[CH2:16][CH2:15]3)=[CH:18]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc(CN2CCC(c3c[nH]c4cc(F)ccc34)CC2)c1
Reactant: ClCc1ccc(Cl)s1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4ccc(Cl)s4)c4cc(F)ccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.07 g (0.19 mmol) of 3-[4-(6-fluoro-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester and 0.05 g (0.29 mmol) of 2-chloro-5-chloromethyl-thiophene. After standard purification, 0.01 g (10% of the yield) of the expected acid were obtained.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN(CCO)CCO)cc1

Procedure:
4-{[Bis-(2-hydroxyethyl)-amino]-methyl}benzonitrile was prepared according to the general method as outlined in Example 1 (Step 4) starting from diethanolamine (10.2 g, 97 mmol) and α-bromo-p-tolunitrile (15.8 g, 81 mmol). Yield, (68%); white solid; mp 163° C. MS: 221.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)[C:20]=1[C:21]([CH3:23])([CH3:24])[CH3:22])=[O:15])[CH2:12]2
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 62.5 °C
Yield: 80 %

Procedure:
Aqueous sodium hydroxide (2M) (2.5 eq) was added portionwise over 5 minutes to a stirred suspension of methyl 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoate (Intermediate#56) (1.0 eq) in methanol (10 vol) at 20° C. (exotherm 20-27° C.). The resulting suspension was heated to 70° C. (jacket temperature), (batch refluxes approx 60-65° C.) for 1 hour (complete by LCMS). The orange reaction mixture was cooled to 20° C. (solution remained slightly cloudy) and filtered through celite to remove a small amount of solids. The filtrate was then poured into a flange flask and water (25 vol) was added. The mixture was then adjusted to pH 3 with 2M HCl (approx 800-850 ml) (turns very thick). The aqueous was then filtered and the pale yellow solid washed with water, sucked dry overnight, and washed with acetonitrile and finally 1:1 acetonotrile/diethyl ether and dried under vacuum at 50° C. for 72 hours (weekend) to give 4-[4-(2-adamantylcarbamoyl)-5-tertbutyl-pyrazol-1-yl]benzoic acid (80%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[NH2:25]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc2ccccc2c1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc2ccccc2c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-naphthaleneamine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@H:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[NH:15][C:14]1=[O:31].[CH2:36]([O:43][C:44](ON1C(=O)CCC1=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:43][C:44]([NH:10][C@H:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[NH:15][C:14]1=[O:31])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)[C@@H](N)CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.08 g (16.1 mmol) of diisopropylethylamine in 25 ml of absolute DMF are added to a solution of 3.14 g (8.48 mmol) of (34.5) and 2.11 g (8.48 mmol) of N-benzyloxycarbonyloxysuccinimide in 80 ml of absolute DMF and the mixture is left to stir at room temperature for 3 h. The solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate=6/4. (34.6) is obtained after concentrating the product fractions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.C1C=CC=CC=1>C(O)(=O)C>[CH2:19]([O:18][C:12](=[O:17])[CH:13]=[C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1)[CH3:16])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(N)cc1OC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1ccc(OC)c(OC)c1

Procedure:
4-Aminoveratrole (62.0 g.), ethyl acetoacetate (63.0 g.), benzene (375 ml.), and acetic acid (2.1 ml.) are combined and refluxed in a flask equipped with a Dean-Stark trap to remove water until thin layer chromatography indicated the reaction is complete. The solvent is removed under reduced pressure to give a dark oil which crystallized upon standing. Recrystallization from hexane gives 79.0 g. of a tan powder, m.p. 59°-60°; a second crop afforded 6.7 g., m.p. 54°-56°. A sample is recrystallized from ethanol/water to give an analytical sample, m.p. 57°-58°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH3:25][CH:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH:13][S:28]([CH:26]([CH3:27])[CH3:25])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: Nc1ccsc1-c1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 22 h
Yield: 43985.1 %

Procedure:
Charge a double jacketed 20 L reactor equipped with mechanical stirrer and set under inert atmosphere of argon with 2-(4-Bromo-phenyl)-thiophene-3-ylamine (562 g, 2.21 mol) and CH2Cl2 (9.435 L). Obtain a clear solution. Add DBU (1.999 L) and cool the mixture to 9.4° C. Add propane-2-sulfonyl chloride (0.616 g) in 20 minutes maintaining the temperature below 25° C. Stir the reaction mixture 22 h at 20° C. After completion of reaction, cool the reaction mixture to 11° C. and add an aqueous solution of satd. aq. NH4Cl (7.65 L) cooled at 10° C. in 5 minutes. Heat the mixture to 20° C. and separate the aqueous phase. Wash the organic layer with 2N HCl (5.12 L), evaporate to dryness and take the residue into ethyl alcohol (800 g) . Heat the mixture until complete dissolution at 70° C. Cool the solution to 41° C. and add water (1384 mL). Stir the suspension overnight at 22° C., filter and wash two times with 254 mL of a 1/1 EtOH/H2O mixture. Dry the resulting beige solid under vacuum at 26° C. for 4 days to give propane-2-sulfonic acid[2-(4-bromo-phenyl)-thiophene-3-yl]-amide (688 g, 1.9 mol). 1H NMR (250 MHz, CDCl3): 1.25(d,6 H, J=6.9 H), 3.16 (hept, 1 H, J=6.9 Hz), 7.28(pseudo s, 2 H), 7.33(d, 2 H, J=8.5 Hz), 7.6(d, 2 H, J=8.5 Hz)
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:26])=[CH:11][CH:10]=1)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:26])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
To a chilled suspension of (tert-butoxy)-N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl]carboxamide (0.35 g, 1 mmol) in CH2Cl2 (2 mL) was added neat TFA (2 mL). The resulting solution was stirred cold for 1 hr, concentrated in vacuo, azeotroped with heptane and dried to give desired compound (0.376 g, 99%) as the mono TFA salt. ES-MS (M+H)+=254.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].C([Li])(C)(C)C.[CH3:11][O:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19]>C1COCC1>[CH2:1]([O:3][C:4]([C:18]([OH:20])([CH3:19])[CH2:17][CH2:16][CH2:15][O:14][CH2:13][O:12][CH3:11])=[CH2:5])[CH3:2]
Reactant: C=COCC
Reactant: COCOCCCC(C)=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(OCC)C(C)(O)CCCOCOC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl vinyl ether (19.47 g, 270 mmol) in THF was added 106 mL of tert-butyl lithium (1.7 M, 180 mmol) dropwise at −78° C. The solution was warmed to 0° C. with an ice bath, stirred for another one hour and then re-cooled to −78° C. To this lithiated enol ether was added dropwise a solution of 5-methoxymethoxy-2-pentanone (13.16 g 90 mmol) in 10 mL of THF. The resulting mixture was stirred for one hour at −78° C. and one and a half hour at 0° C., and then slowly warmed up to room temperature. The reaction mixture was quenched with 70 mL of saturated NH4Cl aq. The organic layer was separated and the aqueous layer was extracted with 3×100 mL of diethyl ether. The combined organic layer was dried over Na2SO4 and concentrated via rotary evaporation to afford 2-ethoxy-3-hydroxy-6-methoxymethoxy-3-methyl-1-hexene in quantitative yield (19.4 g). The crude product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13].Cl.[NH2:18][OH:19].C(N(CC)CC)C>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:18][OH:19])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13]
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C=NO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a suspension of 4-formyl-2-trifluoromethyl-benzoic acid methyl ester (Example I10) (5.98 g) and hydroxylamine hydrochloride (1.79 g) in methanol (80 ml) was added triethylamine (5.4 ml). The reaction mixture was stirred at ambient temperature for 1 hour. More hydroxylamine hydrochloride (5.4 g) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed and the residue diluted with ethyl acetate (200 ml) and water (150 ml). The phases were separated and the organic layer was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was dissolved in a mixture of dichloromethane and heptane and crystallized by slowly evaporating the dichloromethane to give 4-(hydroxyimino-methyl)-2-trifluoromethyl-benzoic acid methyl ester (3.90 g) as a white crystalline powder. 1H-NMR (CDCl3, 400 MHz): 8.18 (s, 1H), 7.97-7.64 (m, 4H), 3.95 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:20](=[O:30])[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH3:23].O>C1COCC1>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:30])[CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH3:23])=[CH:3][CH:4]=1
Reactant: CCC(C(=O)N(C)OC)c1ccccc1
Reactant: COCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(=O)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a stirred solution of 13 (99.0 g, 0.46 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 310 mL, 0.50 mol) dropwise at −78° C. The reaction mixture was stirred for 30 min and 14 (90.1 g, 0.43 mol) dissolved in THF (500 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h and then slowly warmed to 0° C. H2O (500 mL) was added and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts were washed with water (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated. The residue was recrystallized from hexanes to afford 97.6 g (80%) of 15 as white needles. 1HNMR (400 MHz, DMSO-d6): δ 0.79 (t, J=7.3 Hz, 3H), 1.68 (h, J=7.0 Hz, 1H), 2.03 (h, J=7.0 Hz, 1H), 3.32 (s, 3H), 4.65 (t, J=7.3 Hz, 1H), 5.21 (s, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.15 (t, J=7.1 Hz, 1H), 7.23-7.30 (m, 4H), 7.98 (d, J=8.8 Hz, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C:14]([NH2:15])=[CH:13][C:12]([CH:16]([CH3:18])[CH3:17])=[N:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C=CC=CC=1.[C:25](Cl)([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C:14]([NH:15][C:25](=[O:26])[O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[CH:13][C:12]([CH:16]([CH3:18])[CH3:17])=[N:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)c1cc(N)n(-c2ccc3ncsc3c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3ncsc3c2)n1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
To a stirring solution of 1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-amine (0.80 g, 3.1 mmol) and pyridine (0.51 ml, 6.2 mmol) in CH2Cl2 (30 ml) at RT was added Troc-Cl (0.51 ml, 3.7 mmol). After 2 h, the completed reaction was washed with 10% CuSO4 (2×), H2O (1×), brine (1×), dried (MgSO4), evaporated and purified by flash column chromatography (EtOAc/hexanes) to afford 2,2,2-trichloroethyl 1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (0.31 g, 23% yield) as an oil. MS (ESI) m/z: 433.0 (M+H+), 435.0 (M+2+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([Cl:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=S(Cl)Cl
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O

Procedure:
3,5-Di-t-butyl-4-hydroxybenzoic acid is refluxed with thionyl chloride as described in the procedure of Example 27 to give 3,5-di-t-butyl-4-hydroxybenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH2:9]([S-:11])[CH3:10].[Na+]>CN(C=O)C>[CH2:9]([S:11][C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)[CH3:10]
Reactant: Nc1cccc(Br)n1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1cccc(N)n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 204 %

Procedure:
2-Amino-6-bromopyridine (0.88 g) and sodium ethanethiolate (0.46 g) were dissolved in DMF (10 mL) stirred at RT for 20 h and subsequently at 60° C. for further 20 h to complete the reaction according to HPLC analysis. The mixture was concentrated in vacuo, partitioned between AcOEt and water, the layers were separated and the organic layer dried over Na2SO4, filtered and evaporated to give to give 6-ethylsulfanyl-pyridin-2-ylamine as brown oil (1.6 g) that was used directly in the next reaction step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+]>>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([F:15])[C:12]([N+:21]([O-:23])=[O:22])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1OCC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1OCC
Temperature: 0 °C
Reaction time: 3.4 h

Procedure:
In nitrogen atmosphere, to ethyl 2-ethoxy-4-fluorobenzoate as synthesized in above Production Example 31, 6.51 g, conc. sulfuric acid 34 mL was added under cooling with ice. Potassium nitrate 3.26 g was further added little by little, under cooling with salt-ice, followed by stirring for 3.4 hours under cooling with ice. The reaction liquid was poured in ice water, and the precipitated crystals were recovered by filtration and washed with water. Recrystallizing the crystals from tert-butyl methyl ether-hexane mixed solvent, 4.49 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH:10](Br)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CN(C)C=O>C(N(CC)CC)C>[CH2:1]([O:8][C:9](=[O:16])[CH:10]([O:25][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(Br)C(=O)OCc1ccccc1
Reactant: O=C(O)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(OC(=O)c1ccncc1)C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A total of 29.5 g of benzyl-(RS)-α-bromo-isocaproate was added dropwise at 60° with stirring over a period of 15 minutes to a solution of 12.8 g of isonicotinic acid in a mixture of 60 ml. of dimethylformamide and 14.8 ml of triethylamine. The reaction mixture was stirred for 5 hours at 90°. The triethylamine hydrobromide was then filtered off by suction and the filtrate evaporated under reduced pressure at 60°. The residue was dissolved in 100 ml of ethyl acetate and filtered and the filtrate washed three times with 15 ml portions of 1-N potassium bicarbonate solution and twice with 20 ml portions of water. The ethyl acetate solution was dried with magnesium sulphate and evaporated under reduced pressure at 45°. Benzyl-(RS)-2-(isonicotinoyloxy)-isocaproate was obtained as an oil.
Reaction SMILES: II.[C:3]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([CH:19]=[C:20]2[NH:24][C:23](=[O:25])[NH:22][C:21]2=O)[CH:11]=1)(=[O:5])[CH3:4]>C(#N)C>[C:3]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:21]3[NH:22][C:23](=[O:25])[NH:24][C:20]3=[CH:19][C:12]=2[CH:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCOc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Agent: II
Solvent: CC#N
Product: CC(=O)OCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1

Procedure:
This compound, m.p. 299°-302° C. (dec.), was prepared analogous to Example 10 (using acetonitrile in place of methanol for the iodine treatment) from 2-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1.[ClH:20]>CO.O1CCOCC1>[ClH:20].[ClH:20].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
tert-Butyl (1-pyridin-2-ylpyrrolidin-3-yl)carbamate (2.5 g) was dissolved in methanol (4 mL) and was treated with 4M hydrogen chloride in 1,4-dioxane (8 mL). The mixture was stirred overnight at RT. The solvents were evaporated under reduced pressure. The residue was washed with ether and dried to give the desired product (2.1 g, 92%). LCMS: (M+H)=164.1.
Reaction SMILES: [NH2:1][C@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[O:26][CH2:25]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:41]([O:43][CH3:44])=[O:42]>ClCCl>[CH3:32][C:23]1[C:24]2[CH2:25][O:26][C:27](=[O:31])[C:28]=2[CH:29]=[CH:30][C:22]=1[C@@H:2]([NH:1][C:41](=[O:42])[O:43][CH3:44])[CH2:3][N:4]1[CH2:5][CH2:6][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:20][CH2:21]1
Reactant: CC1=C(N2CCC3(CCN(C[C@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@H](CN1CCC2(CC1)CCN(C1=C(C)C(=O)OC1)C2=O)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-8-(2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 62) (35 mg, 0.08 mmol) and triethylamine (17 μL, 0.12 mmol) in dichloromethane (2 mL) was added methyl chloroformate (11 mg, 0.12 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stir for 2 h. TLC indicated half of starting material remained. The reaction mixture was re-cooled to 0° C. and triethylamine (17 μL, 0.12 mmol) was added thereto, followed by methyl chloroformate (11 mg, 0.12 mmol). The reaction mixture was allowed to warm to room temperature and stirred for another 2 h. TLC showed the reaction was complete. The resulting mixture was concentrated in vacuo. The residue was taken up into small amount of DCM and purified by preparative TLC (dichloromethane: methanol=15:1) to afford the title compound. MS-ESI (m/z): 498 (M+1)+.