Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(N2CCCC2)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(N3CCCC3)n2)ccc1-n1cnc(C)c1
Yield: 91 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 2-chloro-4-methyl-6-pyrrolidin-1-yl-pyrimidine (65 mg, 0.33 mmol) in analogous manner as described in example 90. It was obtained in 91% yield as a light brown solid. MS ISP (m/e): 365.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.21 (s, 1H), 8.10 (s, 1H), 7.62 (s, 1H), 7.27 (d, 1H), 7.15 (d, 1H), 7.00 (s, 1H), 5.86 (s, 1H), 3.79 (s, 3H), 3.45 (br m, 4H), 2.19 (s, 3H), 2.14 (s, 3H), 1.94 (br m, 4H).
Reaction SMILES: [OH-].[Na+].[C:3]1([S+:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:22][CH2:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26].CS(O[CH2:36][C:37](=[CH2:52])[C:38]([O:40][C:41]12[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH:42]1[CH3:51])[CH2:48]2)=[O:39])(=O)=O>>[C:16]1([S+:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[CH3:51][CH:42]1[CH:43]2[CH2:44][CH:45]3[CH2:46][CH:47]([CH2:48][C:41]1([O:40][C:38]([C:37](=[CH2:36])[CH2:52][O:22][CH2:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26])=[O:39])[CH2:50]3)[CH2:49]2
Reactant: C=C(COS(C)(=O)=O)C(=O)OC12CC3CC(CC(C3)C1C)C2
Reactant: O=S(=O)(O)C(F)(F)CO
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: C=C(COCC(F)(F)S(=O)(=O)O)C(=O)OC12CC3CC(CC(C3)C1C)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
In a 500-ml three-neck flask, 39.8 g (45.6 mmol) of an aqueous solution of 5% sodium hydroxide and 16.1 g (38.0 mmol) of 2-hydroxy-1,1-difluoroethanesulfonic acid triphenylsulfonium were placed. The resulting solution was stirred for 10 minutes at room temperature, thereby completely dissolving the solid substance. Subsequently, 25 g of crude 2-methyladamantyl 2-[(methanesulfonyloxy)methyl]acrylate was dropped and mixed into the solution. The mixed solution was then stirred for 1 hour at room temperature. After the completion of the reaction, the thus-obtained reaction solution was separated into an aqueous layer and a target product layer. The aqueous layer was extracted with 45 g of chloroform. The target product layer was combined with the chloroform extract. The combined product layer was washed five times with 45 g of water, washed twice with 30 g of 0.1N hydrochloric acid and further washed twice with 45 g of water. The washed product layer was concentrated under reduced pressure to distill therefrom a major part of the organic solvent. The resulting product was purified by column chromatography and dissolved in 10 g of methyl ethyl ketone at 40° C. Into the product solution, 30 g of diisopropyl ether was slowly dropped. The product solution was stirred for 1 hour at room temperature. After confirming the deposition of a crystalline substance, the crystalline substance was filtered out and dried under reduced pressure. With this, 10.5 g of the target compound (PAG-2) was obtained as a white solid substance (purity: 96%, yield: 28%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][O:13][C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[CH2:16][NH:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].[OH-].[Na+]>C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[CH2:16][NH:17][C:18]1[C:19]([CH2:20][OH:21])=[CH:23][CH:24]=[CH:25][N:26]=1
Reactant: COc1ccccc1CNc1ncccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ncccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Under a nitrogen gas stream, 2.50 g (65.8 mmol) of lithium aluminum hydride was added to tetrahydrofuran (100 mL) under ice cooling, and a tetrahydrofuran (70 mL) solution of 8.50 g (32.9 mmol) of 2-(2-methoxybenzylamino)nicotinic acid was added dropwise to the above solution. The resulting mixture was stirred for one hour at room temperature. Ethyl acetate was added to the reaction mixture, and then 26.4 mL of a 10% aqueous solution of sodium hydroxide was added thereto. Insoluble materials were filtered off. The filtrate was concentrated, and the residue thus obtained was dissolved in ethyl acetate, dried, filtered, and concentrated. Thus, 8.18 g (yield: quantitative) of the title compound was obtained as a pale yellow viscous product.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=O)[CH3:15])=[CH:4]1)[CH3:2].C(N1C2C(=CC=C(OC)C=2)C=C1)C.Cl.[OH:31][NH2:32].CC([O-])=O.[Na+]>CCO>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[N:32][OH:31])[CH3:15])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(C)=O)c2ccc(OC)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: CCn1ccc2ccc(OC)cc21
Agent: Cl
Solvent: CCO
Product: CCn1cc(C(C)=NO)c2ccc(OC)cc21
Temperature: 85 °C
Yield: 88.4 %

Procedure:
A mixture of 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone (200 mg, 0.92 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, hydroxyamine hydrochloride (128 mg, 1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH (7 mL) is heated at 85° C. for 4 h. The reaction mixture is then partitioned between H2O and EtOAc. The organic phase is dried and concentrated in vacuo. Purification by column chromatography using EtOAc/CH2Cl2 (1/9) yields 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime as a white solid (189 mg, 92%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][C:20]2=[O:23])=[CH:16][CH:15]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH:19]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:20]2=[O:23])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1Cc2ccc(Br)cc2C1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (14 mL, 2 M in pentane) was added dropwise to a solution of diisopropylamine (2.86 g, 28 mmol) in tetrahydrofuran (60 mL) cooled to −70° C. After 30 minutes of stirring at −70° C., the mixture was treated with 6-bromo-1-indanone (4.8 g, 22.7 mmol), prepared according to the procedure described in J. Org. Chem., 49:4226–423 (1984), in two portions over 5 minutes. After 10 minutes, the mixture was allowed to warm to −50° C. and was treated with ethyl bromoacetate (4.8 g, 28 mmol). The mixture was allowed to warm to −10° C. and was stirred at −10 to −15° C. for 1 hour. The reaction was quenched by careful addition of water (60 mL) followed by isopropyl acetate (60 mL). The organic layer was separated, washed with aqueous HCl (50 mL, prepared by adjusting the pH of water to 2 with conc. HCl), and then aqueous potassium carbonate (50 mL, 5%). The organic layer was concentrated under vacuum to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][CH2:20]2)=[CH:16][C:15]=1[C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][C:14]=2[O:13][CH3:12])[CH2:20][CH2:19][CH2:18]3)=[CH:28][N:27]=1)=[O:5]
Reactant: COc1cc2c(cc1-c1ccc(N)nc1)CCC2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1-c1ccc(NC(=O)c3c(F)cccc3F)nc1)CCC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (44 mg, 0.2 mmol) was added to a stirred solution of 126 (30 mg, 0.1 mmol) and Hünig's base (130 μL, 97 mg, 0.7 mmol) in dichloromethane (0.7 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (0.6 mL), methanol (0.4 mL) and 2 M sodium hydroxide solution (0.2 mL). The mixture was stirred and heated to 60° C. for 60 min then cooled to room temperature, diluted with dichloromethane (5 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 127 (14.4 mg, 30%) as a solid: LRESIMS m/z 381.1 [M+H]+, calcd. for C22H19F2N2O2 381.1.
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[N:7]1([CH2:12][C:13]23[CH2:21][CH:17]4[CH2:18][CH:19]([CH2:20]2)[C:15]([C:22](=[O:24])C)([CH2:16]4)[CH2:14]3)[CH:11]=[N:10][CH:9]=[N:8]1.CC(O)=[O:27]>O1CCOCC1.O>[N:7]1([CH2:12][C:13]23[CH2:21][CH:17]4[CH2:18][CH:19]([CH2:20]2)[C:15]([C:22]([OH:24])=[O:27])([CH2:16]4)[CH2:14]3)[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: CC(=O)C12CC3CC1CC(Cn1cncn1)(C3)C2
Reactant: CC(=O)O
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C12CC3CC1CC(Cn1cncn1)(C3)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.8 %

Procedure:
To a stirred solution of NaOH (1.75 g, 43.8 mmol), H2O (14.6 mL) and 1,4 dioxane (2 mL) at ice bath temperature was added Br2 (0.8 mL, 16.4 mmol) and the mixture was stirred for 5 minutes. The resulting hypobromite solution was added drop-wise to a stirred solution of 1-[1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]non-3-yl]ethanone (0.7 g, 2.92 mmol) in 1,4-dioxane (4 mL) at ice bath temperature. The reaction mixture was gradually warmed to room temperature and stirred for 1 h. Then it was cooled to ice bath temperature and quenched by adding AcOH (3.9 mL, 65.7 mmol). The crude reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (0.54 g) in 75% yield as an off-white solid. M.R: 230-235° C. m/z (M+1) 248. IR cm−1 3436, 3102, 2924, 2511, 1937, 1689, 1523, 1308, 1137, 979, 732. 1H NMR (CD3OD) 300 MHz δ 8.43 (s, 1H), 7.9 (s, 1H), 4.17 (s, 2H), 2.70-2.62 (m, 1H), 2.40-2.33 (m, 1H), 2.06-1.95 (m, 2H), 1.84-1.1.43 (m, 8H).
Reaction SMILES: [CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23](=[O:26])[CH2:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:10]=[C:9]([NH:25][CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Cl)CC(C1CCCCC1)C1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)CC(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 3,3-dicyclohexylpropionyl chloride (6.1 g, 0.063 mol) in 70 ml of chloroform was treated portionwise at 7°-12° C. with a solution of 8.3 g (0.063 mol) of glycine tert-butyl ester and 8.9 ml (0.064 mol) of triethylamine in 30 ml of chloroform. After the addition, the solution was stirred at room temperature for 2 hours, kept overnight, refluxed for 0.5 hours, cooled, washed with water (5×25 ml), dried (magnesium sulfate), and the solvent removed on a rotary evaporator, to give a light yellow viscous oil. The latter, which crystallized partly on standing, was dissolved in 50 ml of boiling hexane, cooled, seeded, and rubbed; a crystalline solid gradually separated. After crystallizing at room temperature and cooling overnight, the voluminous colorless solid was filtered, washed with cold hexane and air-dried (13.3 g, melting point 72°-74° C. s, 69° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](O)=[CH:5]C(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.Cl.NCCCC(O)=O.Cl[C:32]1[CH:33]=[C:34]([CH:48]=[CH:49][C:50]=1Cl)[CH2:35][N:36]([CH3:47])[C:37]([C:39]1[CH2:40][N:41]([CH3:46])[C:42](=[O:45])[C:43]=1[OH:44])=[O:38]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:46][N:41]1[CH2:40][C:39]([C:37](=[O:38])[N:36]([CH2:35][C:34]2[CH:48]=[CH:49][CH2:50][CH2:32][CH:33]=2)[CH3:47])=[C:43]([OH:44])[C:42]1=[O:45]
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: Cl
Agent: NCCCC(=O)O
Product: COC(=O)CCCN1CC(C(=O)N(C)CC2=CCCC=C2)=C(O)C1=O
Yield: 9 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-aminobutyrate hydrochloride as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (18.9 mg, 9% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (m, 2H), 7.09 (m, 1H), 4.60 (s, 2H), 4.18 (s, 2H), 3.65 (s, 3H), 3.55 (t, 2H, J=7.32), 3.03 (s, 3H), 2.36 (t, 2H, J=7.32), 1.94 (t, 2H, J=6.95). HRMS (M+H) calcd for C18H21N2Cl2O53: 415.0827. found: 415.0831.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1)[O:5][CH2:6][CH2:7][C@H:8]1[CH2:10][C@H:9]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1.C(O)(C(F)(F)F)=O.ClC1[N:46]=[CH:45][C:44]([CH3:47])=[CH:43][N:42]=1.C1CCN2C(=NCCC2)CC1>ClCCl.O.CCOC(C)=O>[CH3:47][C:44]1[CH:43]=[N:42][C:17]([N:14]2[CH2:13][CH2:12][CH:11]([C@@H:9]3[CH2:10][C@@H:8]3[CH2:7][CH2:6][O:5][C:4]3[CH:24]=[CH:25][C:26]([C:27]4[O:28][C:29]([CH3:32])=[N:30][N:31]=4)=[C:2]([F:1])[CH:3]=3)[CH2:16][CH2:15]2)=[N:46][CH:45]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: Cc1nnc(-c2ccc(OCC[C@H]3C[C@H]3C3CCN(C(=O)OC(C)(C)C)CC3)cc2F)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(N2CCC([C@@H]3C[C@@H]3CCOc3ccc(-c4nnc(C)o4)c(F)c3)CC2)nc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
rac-cis-tert-Butyl 4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidine-1-carboxylate from step 1 of this example (40 mg, 0.09 mmol) was dissolved in 0.5 mL dichloromethane. TFA (0.5 mL) was carefully added. The mixture was stirred at room temperature for 20 min, upon which the volatile TFA was removed in vacuo and further dried i. vac. for 2 hours. The residue was redissolved in 1 mL NMP. 2-Chloro-5-methylpyrimidine (23 mg, 0.18 mmol) and DBU (0.135 mL, 0.9 mmol) were sequentially added. The mixture was heated at 90° C. for 1.5 hours before cooled back to room temperature. The reaction was then diluted with 2 mL water and 0.5 mL EtOAc. The aqueous phase was further extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, then concentrated and purified by column chromatography through a 12 gram biotage silica gel cartridge eluting with 20% ethyl acetate/hexanes to give the product as white-solid. LRMS talc: 437.2; obs: 438.7 (M+1). Compounds Reported in Table 2 are Prepared by a General Procedure Analogous to that Described in Example 84 Above.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[C:9](=[O:20])[N:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4].CO.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:9](=[O:20])[N:8]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(=O)OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of methyl 4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate (synthesized according to the method similar to that in Example 75 (1)) (1.61 g, 3.5 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 1N sodium hydroxide (5 ml). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diethyl ether to give 4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.54 g, 98.7%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([C:19]2[C:26]([Cl:27])=[CH:25][C:22]([CH2:23]Br)=[CH:21][C:20]=2[Cl:28])=[O:18])=[CH:15][CH:14]=1.O>CN(C)C=O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:23][C:22]2[CH:21]=[C:20]([Cl:28])[C:19]([C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:30][CH:29]=3)=[C:26]([Cl:27])[CH:25]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CBr)cc1Cl
Reactant: NC(=O)c1nn[nH]c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Reaction time: 1 h
Yield: 17 %

Procedure:
A stirred ambient temperature solution of 5-amino-1,2,3-triazole-4-carboxamide (630 mg, 4.96 mmol) in dry dimethylformamide (20 ml) was treated in one portion with sodium hydride (230 mg of a 50% suspension in mineral oil, 115 mg NaH, 4.79 mmol). After 15 min. solid 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide was added in one portion. The mixture was stirred 1 hour, poured into water (20 ml), acidified to pH 6 with glacial acetic acid, and filtered. The solid was washed three times with water and dissolved in dichloromethane. The layers were separated and the organic phase was dried over anhydrous magnesium sulfate and evaporated under vacuum. The residue was chromatographed on a column of silica gel (200 g) eluted with 97:3 (v/v) dichloromethane-methanol to provide 351 mg (17%) 5-amino-1-(4-[4-chlorobenzoyl]-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH:15]=[C:14]1[C:23]([OH:25])=[O:24].[C:26](=[O:28])=[O:27]>CCCCCC.C1COCC1>[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]([C:26]([OH:28])=[O:27])=[C:14]1[C:23]([OH:25])=[O:24]
Reactant: O=C(O)C1=COc2ccccc2O1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)C1=C(C(=O)O)Oc2ccccc2O1
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (185 ml, of a 1.42M solution in hexane) was added to a solution of diisopropylamine (37.0 ml), in dry THF (300 ml) at -78° and the the solution was stirred for 0.25 h. A solution of 1,4-benzodioxin-2-carboxylic acid (23.40 g) in dry THF (400 ml) was then added over 0.5 h and the resulting solution was stirred at -78° for 1 h. The solution was then poured onto finely crushed CO2 and the mixture left to stand overnight. The mixture was evaporated and 2N-hydrochloric acid (250 ml) was added cautiously, followed by concentrated hydrochloric acid (40 ml). EA (500 ml) and THF (100 ml) were added to the mixture, which was shaken and the organic layer separated. The aqueous phase was further extracted with EA and the combined extracts were dried. Evaporation of the solvent gave an orange solid which was triturated under ER for 0.5 h. The solid was collected, washed with ER and dried in vacuo to afford the title compound (25.0 g) m.p. 215°-218°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.[OH-].[NH4+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:19])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
3-Bromo-5-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (50 mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 μL), and the mixture stirred overnight. The solvents were pumped off. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for thirty mins. The phases were separated and the organic phase washed 1× with brine, dried over anhydrous Na2SO4, filtered, and evaporated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.57 min (ret time); analytical HPLC shows 96.5% purity, (ret time: 12.131 min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].Cl.O1CCOCC1.CO[C:19](OC)([CH3:21])[CH3:20]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.CC(N(C)C)=O>[CH3:20][C:19]1([CH3:21])[O:9][CH:6]([CH2:5][NH:4][CH2:3][CH2:2][OH:1])[CH2:7][O:8]1
Reactant: OCCNCC(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC1(C)OCC(CNCCO)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
The N-(hydroxyethyl)-amino-2,3-propanediol (16.5 g, 122 mmol) was treated with a solution of HCl in dioxane (33.5 ml, 134 mmol). To this solution were added 2,2-dimethoxypropane (15.3 g, 147 mmol), DMAC (50 mL), and a catalytic amount of para-toluene sulphonic acid (0.006 mol, 1.16 g). The mixture stirred at room temperature for 24 hours. Triethylamine (1 mL) was then added, and the solvents removed by rotary evaporation. The viscous crude mixture was dissolved into triethylamine (30 mL) and ethyl acetate (500 mL) and stirred at RT for 30 min. The mixture was filtered and the collected solid washed several times with ethyl acetate. The filtrate was then evaporated on a high vacuum rotary evaporator at 40° C. to give a yellow liquid (0.122 mol, 99% yield).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][OH:9])[C:5]2[CH:10]=[CH:11][C:12]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:13][C:4]=2[S:3]1.NC1SC2C=C(OC(F)(F)F)C=CC=2N=1.[Br:34]CCO>C(O)C>[BrH:34].[NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][OH:9])[C:5]2[CH:10]=[CH:11][C:12]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:13][C:4]=2[S:3]1
Reactant: OCCBr
Agent: N=c1sc2cc(OC(F)(F)F)ccc2n1CCO
Agent: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: CCO
Product: Br
Temperature: 20 °C
Reaction time: 95 h

Procedure:
2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol may be prepared according to the following process: 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 2-bromoethanol (10 g) in absolute ethanol (30 cc) are heated to boiling for 95 hours. The mixture is then cooled to a temperature in the region of 20° C. The precipitate formed is filtered off and washed with ethyl ether (100 cc). 2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol hydrobromide (6.4 g), m.p. 219° C., is obtained.