Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(/[CH:6]=[C:7](/[C:11]([O:13][CH2:14][CH3:15])=[O:12])\[C:8]([CH3:10])=O)CC.Cl.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18]>CCO>[C:17]([N:21]1[C:8]([CH3:10])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)/C(=C/N(CC)CC)C(C)=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 25 °C
Yield: 96 %

Procedure:
A stirred solution of diethylaminomethylene ethyl acetoacetate (552 mg, 2.8 mmol, see R. A. Fecik, P. Devasthale, S. Pillai, A. Keschavarz-Shokri, L. Sehn, and L. A. Mitscher; J. Med. Chem. 2005, 48, 1229) and tert-butyl hydrazine hydrochloride (387 mg, 3.1 mmol) in EtOH (5 mL) was heated to reflux for 15 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide ethyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate (560 mg, 96%) as a yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:11]([C:12]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][N:9]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][C:7]=1[Cl:8].Cl.[CH3:28][C:29]1[CH:33]=[C:32]([NH2:34])[S:31][N:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([NH:14][C:12]([C:11]1[C:4]2[C:5](=[N:6][C:7]([Cl:8])=[C:2]([NH:34][C:32]3[S:31][N:30]=[C:29]([CH3:28])[CH:33]=3)[N:3]=2)[N:9]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(N)sn1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2nc(Cl)c(Br)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc3c(C(=O)NC(C)(C)C)cn(COCC[Si](C)(C)C)c3nc2Cl)sn1
Temperature: 150 °C
Yield: 17.9 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (125 mg, 271 μmol), 3-methylisothiazol-5-amine hydrochloride (61.2 mg, 406 μmol), Pd2(dba)3 (24.8 mg, 27.1 μmol), xantphos (47.0 mg, 81.2 μmol) and cesium carbonate (265 mg, 812 μmol) in dioxane (1.5 mL) was heated in a microwave at 150° C. for 20 min. Pd2(dba)3 (24.8 mg, 27.1 μmol) and xantphos (47.0 mg, 81.2 μmol) were added and continued to heat in a microwave at 150° C. for 30 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 10-50% ethyl acetate in hexanes) to give N-tert-butyl-3-chloro-2-(3-methylisothiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 48.5 μmol, 17.9%) as brown gum. (EI/CI) m/z: 495.1 [M+H].
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9](=[O:17])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH3:18][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9](=[O:17])[NH:8]1
Reactant: O=c1nc(-c2ccccc2)c2ccccc2[nH]1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)NC(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-Phenyl-1H-quinazolin-2-one (5.0 g, 4.5 mmol) in THF (50 ml) is added methylmagnesium bromide (15.0 ml) dropwise at −78° C. under nitrogen. The mixture is stirred overnight at room temperature. The mixture is poured into an aqueous solution of NH4Cl and then extracted with EtOAc. The organic phase is washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is purified on silica gel to give product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2cccc(Cl)c2)ccc1OCCN1CCOCC1
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.040 g, 0.12 mmol) in CH2Cl2 (1 mL) was treated with 3-chlorophenyl isocyanate (0.015 mL, 0.125 mmol). The reaction was stirred overnight, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown solid (0.016 g, 27%). LCMS m/z (%)=490 (M+H 35Cl35Cl, 100), 492 (M+H 35Cl37Cl, 76), 494 (M+H 37Cl37Cl, 15). 1H NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H), 8.79 (s, 1H), 7.74 (t, J=2.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.57 (dd, J=2.7, 6.3 Hz, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.36-7.28 (m, 2H), 7.21 (d, J=9.0 Hz, 1H), 7.04 (dt, J=1.9, 7.4 Hz, 1H), 4.22-4.15 (m, 1H), 4.11-4.05 (m, 1H), 3.70 (s, 3H), 3.56-3.51 (m, 4H), 2.66-2.48 (m, 2H), 2.42-2.30 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[S:9][CH:10]=1)C.[Li+].[OH-]>C1COCC1.O>[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[N:7]=1)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)Nc1nc(CC(=O)OCC)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCC(=O)Nc1nc(CC(=O)O)cs1

Procedure:
In a first step, (2-amino-thiazol-4-yl)-acetic acid ethyl ester is coupled to dodecanoyl chloride as described in the method of Example 334 to provide (2-Dodecanoylamino-thiazol-4-yl)-acetic acid ethyl ester as a crude solid. In a second step, the crude solid of (2-Dodecanoylamino-thiazol-4-yl)-acetic acid ethyl ester was deprotected using LiOH (2-fold excess) in THF/H2O to provide the title compound as a crude solid, which was used directly without further purification or characterization.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[N:19]1([C:6]([C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([O:11][CH3:12])[CH:4]=2)=[O:8])[CH2:22][CH2:21][CH2:20]1
Reactant: C1CNC1
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCC2)ccc1Br
Temperature: 25 °C
Reaction time: 60 h
Yield: 79.1 %

Procedure:
To a stirred solution of 4-bromo-3-methoxybenzoic acid (400 mg) in DMF (4.0 mL) was added potassium carbonate (720 mg), azetidine (148 mg) and TBTU (890 mg). The mixture was stirred at room temperature for 60 h. Water was added, the mixture was stirred for 15 minutes and the solvent was removed in vacuum. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 370 mg of the title compound.
Reaction SMILES: O[C:2]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][CH:2]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[CH2:3][CH2:4][CH:5]([CH3:6])[CH3:7]
Reactant: CC(C)CCC(C)(O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CCC(C)c1ccccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.1 %

Procedure:
After 2.7 g (13.1 mols) of the 2-(1-hydroxy-1,4-dimethylpentyl)aniline obtained in Example 3-1 was diluted with toluene, p-toluenesulfonic acid monohydrate (225 mg) was added thereto, and the resulting mixture was dehydrated with refluxing over a period of 3 hours by the use of a Dean-Stark trap. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in ethanol, followed by adding thereto 5% palladium-carbon (100 mg), and the resulting mixture was stirred under a hydrogen atmosphere at room temperature for 12 hours. The reaction mixture was filtered through Celite and the residue was concentrated under reduced pressure to obtain 2.2 g of 2-(1,4-dimethylpentyl)aniline.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][CH:24]([C@@H:26]5[CH2:29][C@H:28](OS(C)(=O)=O)[CH2:27]5)[CH3:25])=[O:22])=[CH:19][N:18]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C-:43]#[N:44].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[C:43]([C@H:28]1[CH2:29][C@H:26]([CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])[CH:19]=2)=[O:22])[CH3:25])[CH2:27]1)#[N:44]
Reactant: [C-]#N
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](OS(C)(=O)=O)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](C#N)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a solution of methanesulfonic acid cis-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester (crude from step 1, 114 mg, 0.19 mmol) in DMSO (1.5 mL) at room temperature was added potassium cyanide (48 mg, 0.74 mmol). The reaction mixture was heated at 60° C. for 2.5 h. 18-Crown-6 (10 mg, 0.04 mmol) was added and heated was continued at 80° C. for 2 h then at 100° C. overnight. The reaction was cooled to room temperature, quenched with water, and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified via chromatography with 30% to 50% EtOAc/hexanes to isolate 46 mg (45%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-cyano-cyclobutyl)-ethyl]-amide as a yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH:32]=O)=[N:24]1.N1CCCCC1>CO>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](/[CH:32]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:24]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CS(=O)(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CS(=O)(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 6-hydroxy-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}benzofuran-3(2H)-one (0.0681 g, 0.209 mmol) in methanol (0.8 mL) was added with 1H-indazole-3-carboxaldehyde (0.0305 g, 0.209 mmol) and piperidine (0.00178 g, 0.0209 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then added with methanol (2 mL), and the precipitated solid was suspended in methanol and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}benzofuran-3(2H)-one (0.0503 g, 53%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][N:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCSc1cnc(Cl)cc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCSc1cnc(Oc2ccc(Cl)c(Cl)c2)cc1C#N

Procedure:
2-Chloro-5-ethylthio-4-pyridinecarbonitrile (4.0 g) was reacted with 3.6 g of 3,4-dichlorophenol in the presence of 2.6 g of t-BuOK in 40 ml of THF and 4 ml of DMSO. 5.5 g (84.6%) of the desired, 2-(3,4-dichlorophenoxy)-5-ethylthio-4-pyridinecarbonitrile was recovered, m.p. 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)c1cc(Br)ccc1N
Product: CC(O)(c1ccccc1)c1cc(Br)ccc1N

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl)-ethanone and phenyl magnesium bromide generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 7.32-7.16 (m, 6H), 7.11 (dd, J=2.03, 8.48 Hz, 1H), 6.49 (d, J=8.55 Hz, 1H), 6.02 (s, 1H), 5.16 (s, 2H), 1.74 (s, 3H); MS (ES) m/z 274/276 ([M+H]+, 100%); Anal. Calc. For C14H14BrNO: C, 57.55; H, 4.83; N, 4.79. Found: C, 57.67; H, 4.83; N, 4.79.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[CH2:19]([NH2:21])[CH3:20].C(OCC)C>C(O)C>[CH2:19]([NH:21][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1)[CH3:20]
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Reactant: CCN
Solvent: CCO
Solvent: CCOCC
Product: CCCOc1ccccc1-c1nc(NCC)cc(=O)[nH]1

Procedure:
4-Chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.66 g) and ethylamine in ethanol (33%, 20 ml) was heated at 90° C. in a pressure vessel for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which solidified on trituration with diethyl ether. The residue was recrystallised from isopropanol: diethyl ether, washed with water and recrystallised from isopropanol:water to yield the title compound, 0.47 g, m.p. 187°-8° C.
Reaction SMILES: [N:1]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:10]([O:12]C(C)(C)C)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]>FC(F)(F)C(O)=O>[N:1]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
2.63 g of Z-Pro-Val-OtBu are dissolved in 20 ml of 90% trifluoroacetic acid. The mixture is left to stand at room temperature for one hour, and is concentrated. The residue is triturated with water. The precipitate is filtered off with suction and dried over P2O5. For further purification, the product is chromatographed on silica gel in CH2Cl2 /CH30H/petroleum ether/acetic acid/water 18:1:2:0.1:0.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:20])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](OC)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of (2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-hydroxy pyrrolidine (10 g, 40.81 mmol) in DMF (60 mL) at 0° C. was added NaH (2.9 g, 122.4 mmol) and the resultant mixture was allowed to stir at the same temperature for 30 min. To this mixture was added MeI (5.08 mL, 81.63 mmol) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was poured onto ice-cold water (200 mL) and extracted with EtOAc (250 mL). The organic layer was washed with water (8×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded (2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-methoxy pyrrolidine (9 g) which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.C(OCC)(=O)C>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][CH:27]=[C:19]2[N:18]1[C@H:28]1[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH3:43])[CH2:30][CH2:29]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1.3 g) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 1.3 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.12 g, 94%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2I)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C([Mg]Cl)(C)C.[CH2:27]([Sn:31]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])Cl)[CH2:28][CH2:29][CH3:30]>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[Sn:31]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:27][CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc2c(I)n[nH]c12
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2c(C(C)(C)O[SiH2]C(C)(C)C)cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, 7-(tert-butyl-dimethyl-silanyloxymethyl)-3-iodo-1H-indazole (200 mg, 0.52 mmol) was dissolved in THF (2.8 ml) and sodium hydride (60% in mineral oil, 25 mg, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 10 min then cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.36 ml, 0.72 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 30 min then tributylchlorostannane (0.16 ml, 0.59 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 7-(tert-butyl-dimethyl-silanyloxymethyl)-3-tributylstannanyl-1H-indazole as a yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([NH:7][C:8]([CH2:13][OH:14])([CH2:11][OH:12])CO)[CH2:2]S(O)(=O)=O.N1CCC[C@H]1C(O)=[O:18].O=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:14][C@@H:13]1[CH2:2][CH2:1][NH:7][C@@H:8]1[C:11]([OH:12])=[O:18]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=S(=O)(O)CCNC(CO)(CO)CO
Agent: O=C(O)CCC(=O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@H]1NCC[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The cells, the treated cells or the enzyme preparation are added to 240 mM TES [N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid] buffer containing 12 mM L-proline, 24 mM 2-ketoglutaric acid, 4 mM ferrous sulfate and 8 mM L-ascorbic acid to make 250 μl in total. The mixture is kept at 35° C. for 10 minutes. The reaction mixture is heated at 100° C. for 2 minutes to stop the reaction, and the amount of cis-3-hydroxy-L-proline produced in the reaction mixture is determined by HPLC.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH:26]([NH2:28])[CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][NH:34]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[C:8]=2[CH:26]([NH:28][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][NH:34]3)[CH3:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(C)N)c(-c3ccccc3)c3ccccc32)cc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2c(C(C)Nc3ncnc4[nH]cnc34)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 120 °C
Reaction time: 56 h
Yield: 91.4 %

Procedure:
A mixture of 1-[3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]ethylamine (294 mg, 0.753 mmol), 6-chloro-9H-purine (140 mg, 0.903 mmol) and DIPEA (0.20 mL, 1.13 mmol) in n-butanol (1.5 mL) was stirred in a sealed tube for 56 h at 120° C. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-7% 2M NH3/MeOH in DCM) affording N-(1-(3-phenyl-1-tosyl-1H-indol-2-yl)ethyl)-9H-purin-6-amine as a yellow solid (350 mg, 91%). LCMS: RT 3.31 min [M+H]+ 509.1