Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[S:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:3][CH:4]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Reactant: O=C(Cl)CCCCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
Thiourea 4 (200 mg, 0.61 mmol, 1 equiv.) was stirred in CH2Cl2 (10 mL) under N2 atmosphere. 6-Bromohexanoyl chloride (195.8 mg, 0.92 mmol, 1.5 equiv.) was added, followed by triethylamine (85 μL, 0.61 mmol, 1 equiv.). The beige suspension was stirred at rt for 1.5 h and diluted with CH2Cl2 (10 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×10 mL), 10% aqueous sodium hydroxide (1×50 mL), and saturated brine (1×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting brown foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 6-bromo-hexanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (166 mg, 55%) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:12]=2)=[N:8][C:7]=1[CH3:26])=[O:5])C.[OH-].[Na+]>O1CCCC1.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:13]2[C:14]([CH3:16])=[CH:15][C:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:26])[N:8]=3)=[N:12]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1sc(-c2cc(C)n(CCc3ccc(F)cc3)n2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)O
Yield: 70.7 %

Procedure:
A mixture of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester (0.32 g, 0.86 mmol), NaOH (0.17 g, 4.29 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was heated to reflux for 16 hr. The solvent was removed in vacuo and the residue was neutralized with 5% HCl to pH 5-6. The resulting solid was filtered and dried to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid as a white solid (0.21 g, 70% yield). This material was used without further purification.
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K].O>CN(C)C(=O)C>[CH3:19][C:3]1([CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CN1CCC(c3ccccc3)CC1)C2
Temperature: 180 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A suspension of 3,5,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-2H-furo[2,3-f]indole (1.11 g, 2.99 mmol), 4-phenylpiperidine (723 mg, 4.48 mmol) and potassium carboante (826 mg, 5.98 mmol) in N,N-dimethylacetamide (6 ml) was stirred for 3 hours at 180° C. under nitrogen atmosphere. To the reaction mixture was added water, and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, treated with an active charcoal, filtered and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 744 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:24][CH:25]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CN1CCC(O)CC1
Product: CN1CCC(n2ncc(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)c2-c2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared as described in Example 54 starting from {4-[3-(4-chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and 1-methyl-piperidin-4-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[CH2:10][C@@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:14][C:11]1([CH3:15])[C:12](=[O:13])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@@H]1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)-4,4-dimethyl-5-oxopyrrolidine-2-carboxylic acid (D38) (320 mg, 1.24 mmol) in acetone (10 ml), TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1.86 mmol) were added and the resulting mixture was stirred at RT for 18 hrs. TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1.86 mmol) were added and the reaction stirred for 24 hrs prior addition of further TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1.86 mmol). The final mixture was then refluxed for 18 hrs. Solvents were evaporated off and the resulting residue was re-dissolved in EtOAc, washed with water (3×10 ml), dried over Na2SO4 and evaporated in vacuo to afford a residue that was purified by Biotage SNAP-Si column (25 g) eluting with a mixture DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D39) (260 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([OH:15])[CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C=O)c(O)c2)c(OC)c(OC)c1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (743 mg, 2.14 mmol) was dissolved in acetone (50 ml) and, after addition of anhydrous sodium carbonate (593 mg, 4.30 mmol) and benzyl bromide (477 mg, 2.79 mmol), the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered and the residue obtained by concentration of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (864 mg, 1.98 mmol, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH:13]([CH2:18][CH2:19][Br:20])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:17][O:16][C:14](=[O:15])[CH:13]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH2:18][CH2:19][Br:20]
Reactant: COC(=O)C(Br)CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCBr)Oc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 3 h
Yield: 64 %

Procedure:
To the solution of 5.5 g (35.0 mmol) 3-fluoro-4-nitrophenol in 55 mL N,N-dimethylformamide, 11.8 g (45.5 mmol) methyl 2,4-dibromobutyrate and 6.3 g (45.5 mmol) potassium carbonate were added. After stirring for 3 h the reaction mixture was poured on ethyl acetate and 1 M aqueous hydrochloric acid and extracted. The organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (1:0 to 1:1 v/v) to afford the title compound as a light yellow oil (64%) which was pure enough to be used in the next step.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[C:12]([NH:15][CH2:16][CH2:17][SH:18])(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([NH:15][CH2:16][CH2:17][S:18][CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)NCCS
Reactant: O=C(O)CC(Br)C(=O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCSC(CC(=O)O)C(=O)C(=O)O
Yield: 60.7 %

Procedure:
In 20 ml of dichloromethane was suspended 1.0 g of 3-bromo-2-oxoglutaric acid. To the suspension was added, while stirring under ice-cooling, 0.5 g of 2-acetamidoethanethiol, followed by addition of 1.83 ml of triethylamine. The reaction solution was stirred at room temperature for one hour, then the solvent was evaporated off. To the residue were added ethyl acetate and water. The aqueous layer was taken, which was adjusted to pH 1~2 with 1N-HCl, followed by extraction with ethyl acetate. The extract solution was washed with water and dried (MgSO4), followed by evaporating off the solvent to give 0.67 g of 3-(2-acetamidoethylthio)-2-oxoglutaric acid as a pale yellow oily product. To this product were added, while stirring under ice-cooling, 0.32 ml of dicyclohexylamine and 0.34 g of 4-nitrobenzyl bromide. The reaction solution was stirred for 15 hours at room temperature, followed by dilution with ethyl acetate. The crystals which separated out were filtered off, and the filtrate was washed with water and dried (MgSO4), followed by evaporating off the solvent. The residue was subjected to a silica gel column chromatography, followed by elution with ethyl acetate then with ethyl acetate--acetic acid (100:3) to give 0.4 g of the subject Compound (70) as a pale yellow oily product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCOCC1.O>[CH2:18]([O:25][C:26]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H](CO)Cc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a mixture of L-phenylalaninol (20.2 g, 0.134 mol), sodium carbonate (21.1 g, 0.200 mol) and 1,4-dioxane (150 mL) was added a solution of benzyloxycarbonyl chloride (19.1 mL, 0.134 mol) in 1,4-dioxane (50 mL) and the mixture was stirred at room temperature for 3 hours. Water (300 mL) was added to the reaction mixture and the obtained mixture was added to ice-cooled 0.5 N hydrochloric acid (500 mL). The precipitated crystals were collected by filtration and washed with hexane and dried to give N-benzyloxycarbonyl-L-phenylalaninol as white crystals (28.8 g, 76%).
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[CH3:13][S:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.CON(C)[C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1>C1COCC1>[CH3:13][S:14][C:15]1[N:20]=[C:19]([CH2:21][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:36])[CH:18]=[CH:17][N:16]=1
Reactant: CSc1nccc(C)n1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2cccc(C(F)(F)F)c2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of diisopropylamine (7.9 mL, 0.056 mole) in THF (100 mL) at -78° C. under argon was added 2.5M N-butyllithium (22.5 mL, 0.056 mole), followed after 5 minutes by a solution of 2-methylthio-4-methylpyrimidine (5.27 g, 0.0376 mole) in THF (20 mL). Upon stirring for 15 min. at -78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (9.63 g, 0.041 mole) in THF (90 mL) was added. The reaction was allowed to warm to 0° C. and then quenched by pouring into water (400 mL) and ethyl acetate (400 mL). The layers were separated and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid (11.9 g). Trituration with 10% ether/hexane (100 mL) gave 9.5 g of the title compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].C(Cl)(Cl)[Cl:50].CO>Cl.C(OCC)(=O)C>[NH:1]([Cl:50])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NCl)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1

Procedure:
The solution of 137 mg (0.2 mmol) of Boc-Ala-Arg(Tos)-Pro-OBzl in 3 ml of hydrogen chloride in ethyl acetate (4 mol/L) was stirred at room temperature for 2 h and TLC (chloroform/methanol, 20:1) indicated complete disappearance of Boc-Ala-Arg(Tos)-Pro-OBzl. The reaction mixture was evaporated under reduced pressure with ethyl acetate, repeatedly, to remove hydrogen chloride. The residue was triturated with ether to provide the title compound as a colorless powder, which was used for the next reaction directly.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].[OH-].[Na+]>O1CCCC1>[C:11]([C:8]1[CH:9]=[C:10]2[C:2]([NH:1][C:26](=[O:28])[CH3:27])=[N:3][NH:4][C:5]2=[N:6][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1cc2c(N)n[nH]c2nc1-c1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1n[nH]c2nc(-c3ccc(O)cc3)c(C#N)cc12
Yield: 36.2 %

Procedure:
To a mixture of 165 mg (0.66 mmol) of 3-amino-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile obtained following general procedure D1 and of 180 μL (2.16 mmol) of pyridine diluted in 1.6 ml of anhydrous tetrahydrofuran, are added dropwise at 0° C. 168 mg (2.16 mmol) of acetyl chloride. The solution is stirred under reflux for 4 h, then 655 μL (5M, 3.28 mmol) of sodium hydroxide solution are added, and the mixture is stirred for 1 h30 at 40° C. The tetrahydrofuran is concentrated and the solution is brought to acid pH (in the order of 3/4). The solid is filtered, washed with water, dried, and triturated in ethanol to yield 70 mg of N-(5-cyano-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)acetamide in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([CH:22]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1c(Nc2cc(Br)ccc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(Br)ccc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(5-bromo-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-5-bromoanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][C:13]1([CH3:20])[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[O:14]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[S:1]1[C:2]([CH:10]=[CH:19][C:15]2[O:14][C:13]([CH3:20])([CH3:12])[C:17](=[O:18])[CH:16]=2)=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cc3ccccc3s2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a solution of 2-benzothiophenecarboxaldehyde (1.5 g, 9.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.6 g, 9.2 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM). After the reaction solution was stirred at room temperature for one day, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The residue was purified by chromatography (silica gel, hexane-ethyl acetate) to afford a yellow solid (2.2 g, 58% yield), m.p. 103.5°-104° C.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[OH-].[Li+]>C1COCC1.O>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of methyl 5-(difluoromethoxy)picolinate from step K2 (730 mg, 3.59 mmol) in THF (8 mL), was added a solution of lithium hydroxide (430 mg, 18.0 mmol) in water (5 mL). The mixture was stirred at rt for 3 h, then concentrated in vacuo. After the addition of 10 mL of 1 N HCl, 150 mL of EtOAc was added. The resulting mixture was washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(difluoromethoxy)picolinic acid (610 mg, 3.23 mmol, 90% yield). LCMS (M+H)+=190.1. 1H NMR (500 HMz, chloroform-d) δ 8.52 (d, J=2.0 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 2.6 Hz, 1H), 6.84-6.53 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17].C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[NH:16][NH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)NN
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of carbamoyl chloride 1 (1.00 g; from above) in dry THF (3.5 ml) was added over 10 minutes to an ice-cold solution of anhydrous hydrazine (0.269 g; 0.310 ml; 8.40 mmol) and triethylamine (0.708 g; 0.975 ml; 7.00 mmol) in dry THF (4 ml). Stirring was continued overnight at room temperature. The mixture was filtered and evaporated to a light yellow solid. Recrystallization from hexanes-ethyl/acetate gave pure carbazide 3 (0.533 g; 2.33 mmol; 52%) as a white solid, mp 83°-84° C. TLC (silica gel; CH2Cl2 --CH3OH, 10:1)Rf=0.25-0.35. MS m/e 173 (M+ -56). Analysis: Calculated for C10H19N3O3 : C, 52.39; H, 8.35; N, 18.33. Found: C, 52.08; H, 8.58; N, 18.01; NMR (CDCl3); δ1.43 (9H.S); 2.0-2.3 (4H,m); 3.1-3.4(2H,m); 3.8(2H,bs): 4.3-4.6(1H,m); 6.2(1H,bs); IR(CHCl3 ): 3500-3300, 1730, 1660, 1640 cm-1. [α]D =-46.5±0.5°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([O:27][CH2:28][C@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][N:30]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(N(CC)CC)C>[CH2:20]([O:27][CH2:28][C@H:29]1[CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:32][CH2:31][N:30]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1COCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 85 °C
Yield: 84.7 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (450 mg, 1.66 mmol) in 10 mL DMF was added a solution of (R)-tert-butyl 2-((benzyloxy)methyl)piperazine-1-carboxylate (610 mg, 1.99 mmol) in DMF and triethylamine (0.46 mL). The reaction mixture was then refluxed at 85° C. for 30 minutes, quenched with water, extracted twice with CH2Cl2, dried over Na2SO4, and concentrated to give (R)-tert-butyl 2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate (760 mg, 85%). This material was used in the next step without further purification. LC/MS: m/z 541.5 (M+H)+ at 3.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([C@@H:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]([O:32]C)=[O:31])=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[F:34].[OH-].[Na+]>CO.C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([C@@H:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]([OH:32])=[O:31])=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[F:34]
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccccc4[nH]3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccccc4[nH]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
Methyl (1R,2R)-2-{[4′-(1H-benzimidazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]-carbonyl}cyclopentanecarboxylate (100 mg, 0.22 mmol) was dissolved in methanol and treated with an excess of 1 N aqueous sodium hydroxide solution (2.19 mL, 2.19 mmol). The solution was stirred at rt for 1 h, and then was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the aqueous layer was adjusted to pH 2 by the addition of 1 N aqueous HCl. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated under reduced pressure to provide an orange oil. The oil was suspended in THF and stirred until a precipitate formed. The precipitate was collected by filtration and washed with additional THF to provide the title compound as a yellow solid (30 mg, 31%, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 13.12 (br s, 1H), 11.30 (br s, 1H), 8.12 (d, 2H), 7.96-7.76 (m, 5H), 7.46-7.42 (m, 2H), 7.30-7.26 (m, 2H), 4.15-4.07 (m, 1H), 3.27-3.19 (m, 1H), 2.21-2.12 (m, 1H), 2.05-1.96 (m, 1H), 1.86-1.55 (m, 4H); LC-MS m/z 444.4 (MH+), retention time 2.79 minutes.