Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:47]([CH:50]1[CH2:54][CH2:53][CH2:52][NH:51]1)([CH3:49])[CH3:48].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:51]2[CH2:52][CH2:53][CH2:54][CH:50]2[CH:47]([CH3:49])[CH3:48])=[O:22])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCCN1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C1CCCN1C(=O)c1cc2cc(C(=O)N3CCN(C(C)C)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-isopropylpyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])(=[O:3])[CH3:2]>CO.[Pd]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:10][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[C:17]1=[O:32]
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 2 h

Procedure:
To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)-cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (˜0.115 mol) in methanol (600 mL) was added 10% Pd/C (6 g of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen. The mixture was stirred under 1 atm H2 for 2 h and the catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo to provide N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide as an oil, which was taken on to the next step without further purification. LC/MS found [M+H]+=311.47. 1H-NMR (400 MHz, d4-MeOH): δ 4.39 (br s, 1H), 4.00 (m, 1H), 3.3-3.5 (m, 4H), 2.73 (m, 1H), 2.38 (m, 1H), 2.25 (s, 3H), 2.0-2.2 (m, 3H), 1.94 (s, 3H), 1.6-1.75 (m, 4H), 1.07 (app. dd, J=21, 6.4 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[Si]([C:29]#[N:30])(C)(C)C.[OH-].[Na+]>C(#N)C>[C:29]([CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:4]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1nc(CC#N)c2cccnc21
Temperature: 60 °C
Yield: 79.5 %

Procedure:
tert-Butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridin-1-carboxylate (700 mg, 2.24 mmol), potassium carbonate (370 mg, 2.68 mmol) and TMSCN (265 mg, 2.67 mmol) were added into 10 mL acetonitrile, and heated to 60° C. and reacted for 9 hours. After completion of the reaction, it was cooled. 1 M sodium hydroxide solution 100 mL was added, and extracted with ethyl acetate 150 mL. The organic phase was washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, rotate evaporated to dryness, and chromatographed on a column (PE:EA=20:1) to obtain a white solid 460 mg, at a yield of 79.5%
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])=[O:4].[NH2:20][CH2:21][C:22]([OH:24])=[O:23].Cl>[OH-].[Na+]>[C:22]([CH2:21][NH:20][CH2:2][C:3]([N:5]1[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])=[O:4])([OH:24])=[O:23]
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCl
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4R)-3-Chloroacetyl-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (6 g) was added to a stirred solution of glycine (1.5 g) in N sodium hydroxide (80 ml), and stirred overnight at room temperature. The solution was adjusted to pH 1.5 by 20% hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 3.2, and the separated crystals were collected by filtration to 3.28 g (48.2%) of the titled compound: mp 181°-182° C. (dec.) (water); [α]D24 +271.2° (c=0.5, N--NaOH). IR (KBr, cm-1): 3400, 3200, 1740, 1672, 1560, 1440, 1380, 1335, 1212, 752, 648, NMR (K2CO3 in D2O, δ): 3.0-4.3 (6H, m, C5 --H, COCH2NHCH2CO2H), 6.33 and 6.43 (1H, each s, C2 --H), 6.6-7.3 (3H, m, arom. H), 7.82 (1H, br. d, J=8 Hz, arom. H), 9.0-10.3 (2H, br. s, --OH, --CO2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH2:20][O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1.C(OC(C)C)(C)C>ClCCl>[ClH:23].[O:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[C:22]=2[O:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc3c2OCO3)CC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: C1=C(c2cccc3c2OCO3)CCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
In a 50 mL flask, 4-Benzo[1,3]dioxol-4-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.22 g, 4.02 mmol was combined with dichloromethane (20 ml) to give a colorless solution. Hydrochloric acid solution, 4M in dioxane (10.1 ml, 40.2 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. 15 ml of diisoproylether were added and the mixture was stirred for 5 min at 0° C. The precipitate was collected by filtration, washed with 2 ml of diisopropylether and dried to yield the title compound as a white solid (0.820 grs, 85%). MS (ISP) m/z=204.2[(M+H)+].
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]([C:35](=[O:37])[CH3:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:17][CH2:16]1)=O)(C)(C)C>>[C:35]([N:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:37])[CH3:36]
Reactant: CCCCCCN(C(C)=O)c1ccccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCN(C(C)=O)c1ccccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
Trifluoroacetic acid (25 ml) was added to 1-tert-butyloxycarbonyl-4-(N-acetyl-N-hexylaminophenyloxy)piperidine (12.5 g) with ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and methylene chloride (50 ml) was added to the residue and the mixture was washed with aqueous saturated solution of sodium bicarbonate. The aqueous layer was extracted with methylene chloride (50 ml×3), the combined organic layer were dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 4-(N-acetyl-N-hexylaminophenyloxy)piperidine (9.7 g) as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].B.C1COCC1>O1CCCC1.C1(C)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C@@H:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc([C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
Solutions of 4.006 g (15 mmol) of 2-bromo-1-(3-trifluoromethylphenyl)-ethanone, 15 mL of anhydrous tetrahydrofuran and 15 mL of 1M borane-THF in tetrahydrofuran were added simultaneously to a stirring solution of 1.5 mL of 1M (R)-(3aR)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole in toluene and 15 mL of anhydrous tetrahydrofuran, cooled in an ice water bath at ca. 15 degrees, over 12.5 minutes. The cooling bath was removed and the mixture stirred at room temperature. After 1.5 h, ca. 0.48 g of methanol was added dropwise (gas evolution) and the mixture stirred for 5 minutes, then 15 mL of 2 M sodium hydroxide was added over 3 minutes. The mixture was stirred at room temperature. After 1.5 h, the mixture was concentrated under reduced pressure to remove the tetrahydrofuran, and the remaining aqueous phase was extracted twice with diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2.553 g (90%) of (R)-2-(3-trifluoromethyl-phenyl)oxirane as a light amber liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.87 (dd, J=5.27, 2.51 Hz, 1H) 3.12 (dd, J=5.27, 4.02 Hz, 1H) 4.04 (dd, J=4.27, 2.51 Hz, 1H) 7.54-7.58 (m, 2H) 7.60 (s, 1H) 7.62-7.67 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([C:26]1[C:27]([N:38]=[CH:39][N:40]([CH3:42])C)=[N:28][C:29]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:31]=1)#N.NC1C=C(OCC2C=CC(OC)=CC=2)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([S:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:2]([NH:1][C:42]2[C:26]3[CH:31]=[CH:30][C:29]([CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[N:28][C:27]=3[N:38]=[CH:39][N:40]=2)[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C=Nc1nc(C2CCCCC2)ccc1C#N
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Agent: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ncnc3nc(C4CCCCC4)ccc23)cc1

Procedure:
The product from Example 27A was reacted with the product from Example 135A using the procedure from Example 10F substituting the product from Example 27A for the product from Example 10E and substituting the product from Example 135A for the product from Example 10B to provide the title product. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.23-1.51 (m, 4H), 1.53-1.79 (m, 4H), 1.80-2.00 (m, 2H), 2.77-3.02 (m, 1H), 5.10 (s, 2H), 6.67 (d, J=8.46 Hz, 2H), 6.88-7.01 (m, 1H), 7.11 (d, J=8.82 Hz, 2H), 7.22-7.31 (m, 1H), 7.32-7.49 (m, 6H), 7.56 (d, J=7.72 Hz, 1H), 8.55 (s, 1H), 8.73 (d, J=8.09 Hz, 1H), 9.94 (s, 1H); MS (APCI) m/z 535 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH:32]([C:34]1[S:35][CH:36]=[C:37](B(O)O)[CH:38]=1)=[O:33].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:38]=[C:34]([CH:32]=[O:33])[S:35][CH:36]=3)[C:3]=12
Reactant: O=Cc1cc(B(O)O)cs1
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2csc(C=O)c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.2 %

Procedure:
To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (5 ml), ethanol (2.5 ml) and water (2.5 ml), 2-formyl-4-thiopheneboronic acid (0.155 g, 0.995 mmoles) and sodium carbonate (0.210 g, 1.98 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.038 g, 0.033 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as light brown solid (0.065 g, 19% yield). MP: 192-195° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 10.01(s,1H), 8.30(s,1H), 8.24(s,1H), 8.07(s,1H), 8.05(dd, J=7.9,1.4Hz, 1H), 7.85(m,1H),7.69(d, J=8.4Hz, 1H),7.53(t, J=7.8Hz, 1H),7.28(br s,1H), 7.06(t, J=8.8Hz, 1H),6.93(br s, 2H), 6.04(q, J=7.0 Hz, 1H),1.89(d, J=7.0 Hz, 3H). Mass: 511.95(M+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[F:12].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:21])=[CH:9]2)=[CH:4][C:3]=1[F:12]
Reactant: Fc1cc2ccncc2cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
25 g (137.7 mmol) of 7-chloro-6-fluoro-isoquinoline (4) were in dissolved in 500 mL of dichloromethane. At room temperature 50.9 g (206.5 mmol) of m-chloro perbenzoic acid (70%) were added and the mixture was stirred at room temperature until complete conversion iwas achieved. For workup, the precipitate was filtered off and washed with dichloromethane. The filtrate was washed twice with sodium bicarbonate-solution. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried with MgSO4 and evaporated. The so obtained solid material (18.4 g) was used without further purification. Rt=0.87 min (Method C). Detected mass: 198.1/200.1 (M+H+).
Reaction SMILES: [C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2].[CH3:13]O>>[C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([O:3][CH3:13])=[O:2]
Reactant: CO
Reactant: O=C(O)C1Cc2ccccc2C1
Product: COC(=O)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 2-carboxy-indan (2.5 g, 15.4 mmol) in methanol and cool to 0° C. Saturate with hydrochloride gas then add 2,2-dimethoxypropane (2-3 mL). Stir overnight then evaporate the solvent in vacuo. Purify by silica gel chromatography (2:1 methylene chloride/hexane) to give 2-carbomethoxy-indan as a water white oil. (2.04 g, 75%).
Reaction SMILES: [SH-:1].[Na+].[CH2:3]([S:5]([C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([Cl:15])[CH:9]=1)(=[O:7])=[O:6])[CH3:4]>CN(C=O)C.[OH-].[Na+]>[Cl:15][C:10]1[CH:9]=[C:8]([S:5]([CH2:3][CH3:4])(=[O:7])=[O:6])[CH:13]=[CH:12][C:11]=1[SH:1]
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: [SH-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(S)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydrosulphide (0.252 g) was added to the product from example 4 step (i) (11.0 g) in dry DMF (10 ml) and stirred at RT for 2 h. The mixture was diluted with 2M sodium hydroxide solution and extracted with diethylether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried and evaporated under reduced pressure, crude yield 1.60 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(OC(C)C)c(-n3ccnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(OC(C)C)c(-n3ccnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A reaction mixture solution prepared by dissolving 501 mg of ethyl 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylate in 10 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 1.35 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 1.35 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 8 mL of water was added and extraction was performed using 20 mL of ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 415 mg of 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][OH:9])=[CH:5][N:4]=[C:3]1[CH3:16].Br[CH2:18][C:19]1[N:24]=[C:23]([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:1][N:2]1[C:6]([C:7](=[N:8][O:9][CH2:18][C:19]2[N:24]=[C:23]([N:25]3[C:26](=[O:35])[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:33]3=[O:34])[CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=[C:3]1[CH3:16]
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: Cc1ncc(C(=NO)c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: Cc1ncc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 31.5 h
Yield: 17.7 %

Procedure:
To a solution of 1-(1,2-dimethyl-1H-imidazol-5-yl)-N-hydroxy-1-phenylmethanimine (2.29 g, 10.6 mmol) and 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (3.71 g, 11.7 mmol) in acetonitrile (100 mL) were added cesium carbonate (7.27 g, 22.3 mmol) and potassium iodide (176 mg, 1.06 mmol). After stirring at room temperature for 31.5 h, the reaction mixture was filtered, the insolubles washed with dichloromethane, and the filtrate concentrated in vacuo. Purification on silica gel afforded 2-{6-[({[(1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione [848 mg, yield 16%; HPLC/MS: m/z=452 (M+H); log P(HCOOH)=1.84].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]([CH3:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:4]([CH3:13])[C:3]([O:2][CH3:1])=[O:14])(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: COC(=O)[C@@H](C)NCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyl-D-alanine methyl ester (~2 g) in methylene chloride (40 mL) containing triethylamine (2.47 mL, 17.7 mmol) is added 4-methoxybenzenesulfonyl chloride (2.44 g, 11.8 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is acidified with 1N HCl and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (10%-→20% ethyl acetate/hexanes) to provide methyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH2:18]>N1C=CC=CC=1>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:18][C:1](=[O:5])[CH:2]=[CH:3][CH3:4]
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: C/C=C/C(=O)Cl
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 19 °C
Reaction time: 12 h

Procedure:
0.24 cm3 of crotonyl chloride is added to 500 mg of 5-(trifluoromethyl)-1H-indazole-3-amine, prepared according to patent U.S. Pat. No. 3,133,081, in 15 cm3 of pyridine. The reaction medium is stirred at about 19° C. for 12 hours and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 25 cm3 of tetrahydrofuran, 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed again with 25 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (40/60 by volume) and collecting 25 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 63 mg of N-[5-(trifluoromethyl)-1H-indazol-3-yl]-2-butenamide (E form) are obtained in the form of an off-white solid melting at about 242° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:24])[CH3:23])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[OH:8].Cl[CH2:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:23])[CH3:24])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[O:8][CH2:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][N:31]=1
Reactant: Fc1cnc(CCl)c(F)c1
Reactant: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ncc(F)cc2F)c(Cl)c1=O
Temperature: 60 °C
Yield: 37.1 %

Procedure:
To a solution of Intermediate 1 (505 mg, 1.31 mmol) in N,N-dimethylformamide (3 mL) was added 2-chloromethyl-3,5-difluoro-pyridine from Step C (214 mg, 1.31 mmol), potassium carbonate (452 mg, 3.27 mmol) and 18-crown-6 (40 mg). The slurry was heated at 60° C. for eighteen hours. After cooling the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a colorless oil (250 mg, 37% yield). MS (M+H): 514; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.16 (s, 3H), 2.21 (s, 3H), 5.62-5.72 (m, 2H), 7.28-7.30 (m, 1H), 7.54-7.58 (m, 2H), 7.92 (s, 1H), 8.14 (d, J=8.21 Hz, 1H), 8.40 (s, 1H), 8.78 (d, J=5.47, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:11]=[C:10]([OH:12])[C:8](=[O:9])[CH:7]=[CH:6][CH:5]=1)[CH3:3].O.O.O.O.O.O.[Cl-].[Al+3:20].[Cl-].[Cl-]>C(O)C>[CH3:3][CH:2]([C:4]1[CH:11]=[C:10]([OH:12])[C:8](=[O:9])[CH:7]=[CH:6][CH:5]=1)[CH3:1].[Al:20]
Reactant: [Al+3]
Agent: CC(C)c1cccc(=O)c(O)c1
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: [Al]

Procedure:
Subsequently, hinokitiol and aluminum chloride hexa-hydrate salt were mixed in aqueous ethanol solution at a molar ratio and the compounding amount shown in the following Table 27, and the complex compound of hinokitiol with an aluminum compound was respectively formed in the solution.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17]C(C)(C)C)=[S:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:22].C(OCC)C>C(O)(=O)C>[BrH:22].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=S)NC1CCN(Cc2ccccc2)CC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC(=S)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17 g of N-(1-benzylpiperid-4-yl)-N'-tert-butylthiourea are added to 170 ml of 33% hydrobromic acid in acetic acid; the reaction mixture is stirred at room temperature for 4 hours, then it is poured over diethylether. The crystals obtained are filtered and they are thoroughly washed with diethylether in order to obtain white crystals which melt at 120° C.; yield: quantitative.