Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1COCC1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 1-benzyl-4-piperidone (5.6 mL, 30.0 mmol) in 50 mL THF was added a solution of methyl]ithium in THF (24.0 mL, 36 mmol) dropwise at 0° C. over 15 min. The reaction mixture was allowed to warm to room temperature over 3 h and then quenched with 30 mL of sat. NH4Cl solution. The organic layer was extracted with diethyl ether (2×100 mL) and the combined organic layer was washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain yellow gum. It was purified by column chromatography over silica gel with 9:1 EtOAc-MeOH as the eluting system to obtain 1-benzyl-4-methyl-4-piperidinol as a yellow thick oil (3.6 g, 59% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:12][CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31]([C:37]3[N:38]=[C:39]4[C:45]([C:46](O)=[O:47])=[CH:44][N:43]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:40]4=[N:41][CH:42]=3)=[N:32][N:33]2[CH3:36])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:16][C:13]([C:9]1([NH:8][C:46]([C:45]2[C:39]3[C:40](=[N:41][CH:42]=[C:37]([C:31]4[C:30]5[C:34](=[CH:35][C:27]([F:26])=[CH:28][CH:29]=5)[N:33]([CH3:36])[N:32]=4)[N:38]=3)[N:43]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:44]=2)=[O:47])[CH2:12][CH2:11][CH2:10]1)([CH3:15])[CH3:14]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(C)(O)C1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(C(C)(C)O)CCC2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
In a round-bottomed flask, 2-(1-amino-cyclobutyl)-propan-2-ol trifluoroacetate (214 mg, 0.62 mmol) was dissolved in DMF (1.2 ml) and N,N-diisopropylethylamine (0.44 ml, 2.52 mmol). Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.25 mmol) and HATU (104 mg, 0.27 mmol) were added. The yellow reaction mixture was stirred at room temperature overnight then water and petroleum ether were added. The resulting precipitate was collected by filtration. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 142 mg (98%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-hydroxy-1-methyl-ethyl)-cyclobutyl]-amide as an off-white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[CH:7]=[C:6]2[C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1
Reactant: COc1ccc2[nH]cc(-c3cc4nccnc4[nH]3)c2c1
Reactant: O=C(CCl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2CC(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A stirred solution of 6-(5-methoxy-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [70 mg, Example 11] in dry dimethylformamide (10 mL) was treated with sodium hydride (21.6 mg, 60% dispersion in mineral oil). After stirring for 30 minutes this mixture was treated with a solution of 4-(2-chloroacetyl)morpholine (44.1 mg) in dimethylformamide (1 mL) and stirring was continued for a further 3 hours. The reaction mixture was poured into water (20 mL) and then extracted three times with ethyl acetate (30 mL). The combined extracts were dried over sodium sulfate and then evaporated. The residue was triturated with diethyl ether to give the title compound (55 mg) as a yellow solid, m.p. 263-267° C. MS: 392.21 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:29]([N:25]1[CH2:26][CH2:27][CH:22]([C:20]2[CH:19]=[CH:18][N:17]3[C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:12]=4)=[CH:14][N:15]=[C:16]3[CH:21]=2)[CH2:23][CH2:24]1)([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: c1ccc(-c2cc(-c3cnc4cc(C5CCNCC5)ccn34)ccn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-phenyl-pyridin-4-yl)-7-piperidin-4-yl-imidazo[1,2-a]pyridine (Ex. 1.198) (1.0 eq, 0.16 mmol, 80 mg) in MeOH (2 ml) is added acetone (10 eq, 1.6 mmol, 0.12 ml) and acetic acid (2 eq, 0.33 mmol, 0.19 ml) and the reaction mixture is stirred at room temperature for 30min. After this time sodium triacetoxyborohydride (5 eq, 0.82 mmol, 183 mg) is added to the reaction mixture and is stirred for a further 2 h. The reaction is diluted with CH2C12 and the organic phase is washed with NaHCO3. The aqueous layer is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-(1-Isopropyl-piperidin-4-yl)-3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridine as a light yellow solid; [M+H]+=397
Reaction SMILES: [C:1]1([S:11]([NH:14][C@@H:15]([CH2:19][NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>C(O)C(C)C>[CH2:4]([O:17][C:16](=[O:18])[C@@H:15]([NH:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH2:19][NH:20][C:21](=[O:39])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:37][CH2:36][CH2:35][CH2:34][N:33]=2)=[CH:24][CH:23]=1)[CH:5]([CH3:10])[CH3:6]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Agent: O=S(=O)(O)O
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Reaction time: 24 h

Procedure:
600 mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was dissolved in 12 ml of isobutanol and 0.1 ml of concentrated sulfuric acid was added. The reaction solution was boiled for 24 hours. The solvent was removed in vacuo, and the residue was chromatographed on silica gel eluting with dichloromethane/methanol/acetic acid/water (9/1/0.1/0.1). The product was dissolved in acetic acid/water and lyophilized. Yield 250 mg. MS (ES+): m/e=608.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[K+].[CH3:14][C:15]([CH:17]=O)=O.O>C(O)C>[CH3:17][C:15]1[CH:14]=[N:11][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:10]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CC(=O)C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cnc2c([N+](=O)[O-])cccc2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 3-nitro-1,2-phenylenediamine (2.67 g) and a 2N KOH (8.7 mL) in ethanol (250 mL) was added a 40% aqueous solution of pyruvic aldehyde (17.72 g) at 60° C. The mixture was heated under reflux for 10 minutes, and thereto was added water (150 mL). The mixture was cooled to room temperature, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with cold water, and dried under reduced pressure to give 2-methyl-5-nitroquinoxaline (2.21 g, 67%) as pale brown solid.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][C@@H:24]([O:27][CH2:28][CH2:29][CH2:30]O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>ClCCl>[C:14]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][C@@H:24]([O:27][CH2:28][CH2:29][CH2:30][F:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](OCCCO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](OCCCF)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Deoxo-Fluor (5 mg, 0.02 mmol) was added to a solution of cis-4-(3-hydroxy-propoxy)-cyclohexanecarboxylic acid tert-butyl ester (3.9 mg, 0.015 mmol) in dichloromethane (0.1 ml), and the mixture was stirred at room temperature for two hours. An aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give cis-4-(3-fluoro-propoxy)-cyclohexanecarboxylic acid tert-butyl ester (3.1 mg, 79%).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[CH2:13]=[O:14]>C(O)C>[OH:14][CH2:13][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: C=O
Solvent: CCO
Product: O=C1c2ccccc2S(=O)(=O)N1CO
Yield: 70 %

Procedure:
Following a procedure similar to that described in Preparation 2, reaction of 18.3 g (0.1 mol) of saccharin with 70 ml of 37% formalin in ethanol afforded 3.58 g (70%) of 2-hydroxymethylsaccharin. The latter (25 g, 0.117 mol) was reacted with 63.3 g (0.234 mol) of phosphorus tribromide in diethyl ether to give 29.8 g (92%) of 2-bromomethylsaccharin, mp 155°-157° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:36])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.O>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:4][C:3]([OH:37])=[O:2])[CH2:10][CH2:9]3)=[CH:12][CH:13]=2)=[O:36])=[O:23])=[CH:29][CH:28]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3ccc(-c4ccccc4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3ccc(-c4ccccc4)cc3)cc2)CC1
Reaction time: 24 h

Procedure:
Trans-[4-(4-{3-[(biphenyl-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (60 mg, 0.120 mmol) was put into THF/water (20 mL, 3:1) solvent, and NaOH (38.51 mg, 0.963 mmol) was added thereto. The mixture was stirred for 24 hours, THF was removed, and pH of the mixture was adjusted to be 2-3 with 1N hydrochloric acid. The reaction mixture was extracted with EtOAC (3×100 mL), washed with brine and dried with anhydrous sodium sulfate, and the solvent was removed. The obtained crude material was crystallized with acetonitrile to obtain the desired compound (56 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH2:5][O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Br:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.CO>[Br:14][CH2:2][C:1]([C:4]1[CH2:5][O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:3]
Reactant: BrBr
Reactant: CC(=O)C1=Cc2ccccc2OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: O=C(CBr)C1=Cc2ccccc2OC1
Reaction time: 2 h

Procedure:
3-Acetyl-2H-chromene (0.2 mole) is dissolved in diethyl ether (250 ml) and methanol (10 ml). The solution is cooled to 0°-5° C. Bromine (0.21 mole) is added dropwise thereto, with stirring. The resulting material is left aside 2 hours at room temperature. Anhydrous potassium carbonate (25 g) is then added and the material is evaporated to dryness. The pasty residue is placed in a flask with 600 ml hexane, and is refluxed for 1 hour. The reaction mixture is decanted hot, allowed to cool, and the organic solution is placed in the freezer. Brown-yellow crystals having a sufficient purity for the next step separate out. After two recrystallizations from hexane, a sample gives long pale yellow needles, M.p.=87° C.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1)/[CH:11]=[C:12]1/[C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH2:17]/1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:38]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48]Cl)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>C(OCC)(=O)C.O>[C:38]([C:42]1[CH:43]=[CH:44][C:45]([CH2:48][N:14]2[CH2:15][CH2:16][CH2:17]/[C:12](=[CH:11]\[C:10]3[CH:19]=[CH:20][C:21]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:8]([O:7][CH3:6])[CH:9]=3)/[C:13]2=[O:18])=[CH:46][CH:47]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: COc1cc(/C=C2\CCCNC2=O)ccc1-n1cnc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN(Cc3ccc(C(C)(C)C)cc3)C2=O)ccc1-n1cnc(C)c1
Reaction time: 0.5 h

Procedure:
To a DMF (2 mL) solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one (70 mg) obtained in Example 416, lithium bis(trimethylsilyl)amide (1M THF solution, 0.47 mL) was added dropwise under ice-cooling, and the reaction solution was agitated for 30 minutes under ice-cooling. Subsequently, 1-tert-butyl-4-chloromethylbenzene (0.073 mL) was added to the reaction solution, and the reaction solution was agitated for 30 minutes under ice-cooling. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), and 37.8 mg of the title compound was obtained. The physical properties are as follows.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.[BH4-].[Na+]>CO>[OH:9][CH2:8][C:6]1[CH:7]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:4][CH:5]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)c1cc(CO)co1
Reaction time: 0.75 h

Procedure:
2-Trimethylsilyl-4-furaldehyde (1.57 g, 9.35 mmol) was added to a suspension of sodium borohydride (424 mg, 11.2 mmol) in methanol (10 ml) at 0° C. After 45 minutes, most of the methanol was evaporated and the residue taken up in ethyl ether. The ethyl ether extracts were combined, washed (water), dried (magnesium sulfate) and evaporated to dryness to give an oil, which was purified by flash chromatography on silica using 30% ethyl ether/hexane to give the title alcohol as a pale yellow oil.
Reaction SMILES: C([NH:4][C@@:5]1([C:22](NC(C)(C)C)=[O:23])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:13]1[O:17]C(C)(C)C(C)(C)[O:14]1)(=O)C.[OH2:29]>Cl>[NH2:4][C@@:5]1([C:22]([OH:23])=[O:29])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17]
Reactant: O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCO[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Product: N[C@@]1(C(=O)O)CCO[C@@H]1CCCB(O)O
Temperature: 25 °C

Procedure:
A solution of (2R,3S)-3-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)tetrahydrofuran-3-carboxamide (860 mg) in 6 N HCl (15 mL) was stirred at 90° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a separator funnel, diluted with deionized water (10 mL) and washed with dichloromethane (3×). The aqueous solution was concentrated. Purification by RP-HPLC (10-100% acetonitrile in water) gave (2R,3S)-3-amino-2-(3-boronopropyl)tetrahydrofuran-3-carboxylic acid, as a white solid (269 mg). 1H NMR (D2O, 300 MHz) δ 3.97 (m, 2 H), 3.82 (m, 1 H), 2.66 (ddd, J1=15 Hz, J2=9.5 Hz, J3=5.5 Hz, 1 H), 2.14 (ddd, J1=15 Hz, J2=9 Hz, J3=6.5 Hz, 1 H), 1.22-1.49 (m, 4 H), 0.67 (m, 2 H); MS (+CI): m/z for C8H16BlNO5: expected 217.1; found 435.3 (2M+H)+, 417.2 (2M+H−H2O)+, 217.7 (M+H)+, 200.0 (M+H−2H2O)+.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1.[BrH:16]>>[BrH:16].[Br:16][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:15])=[N:12][CH:11]=1
Reactant: Cc1ccccc1-c1ccc(CO)cn1
Agent: Br
Product: Cc1ccccc1-c1ccc(CBr)cn1
Yield: 95 %

Procedure:
A solution of 4.49 g (22.5 mmol) of (6-o-tolylpyridin-3-yl)methanol in 75 mL of 48% hydrobromic acid was heated to reflux for 64 h. The reaction mixture was partially cooled and excess hydrobromic acid was removed by vacuum distillation (110° C.@2 Torr) until a tan solid residue remained in the flask. Distillation was carried out using a large KOH pellet trap placed between the distillation apparatus and the vacuum pump. The solid residue was slurried in diethyl ether, filtered and dried under a nitrogen stream to give 7.38 g of product, 95% yield.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1I.[OH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][OH:16])=[CH:19][CH:20]=1
Reactant: CC(C)Cn1nnc2c(Br)c(I)ccc21
Reactant: CC1(C)OB(c2ccc(CO)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Cn1nnc2c(Br)c(-c3ccc(CO)cc3)ccc21
Temperature: 40 °C

Procedure:
4-Bromo-5-iodo-1-(2-methylpropyl)-1H-benzotriazole (554 mg, 1.458 mmol), 4-(hydroxymethyl)benzeneboronic acid pinacol ester (325 mg, 1.388 mmol), PdCl2(dppf)-dichloromethane adduct (56.7 mg, 0.069 mmol) and cesium carbonate (1357 mg, 4.16 mmol) were combined in tetrahydrofuran (7 ml) and water (0.700 ml). The vessel was sealed and heated at 40° C. for 48 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The residue was purified via silica gel chromatography (ethyl acetate/hexane gradient), providing the titled compound as white foam. LRMS m/z (M+H) 359.9 and 361.9 found, 360.06 and 362.06 required.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN(C3SC=CN=3)C2)=NC=1CC.Br[C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1.[Cl:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1[C:49]1[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]2[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][NH:60][CH2:59]2)=[N:53][C:54]=1[CH2:55][CH3:56]>>[Cl:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1[C:49]1[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]2[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][N:60]([C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:59]2)=[N:53][C:54]=1[CH2:55][CH3:56]
Reactant: Brc1ncccn1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Agent: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 2-bromopyrimidine and starting with 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.17, 1.26–1.34, 2.51, 2.76, 3.54, 3.78, 3.86, 3.97, 4.27, 4.91, 5.25, 6.61, 6.90, 7.02, 7.25, 8.40; IR (diffuse reflectance) 2971, 2392 (w), 2352 (w), 2307 (w), 2265 (w), 2170 (w), 1583 (s), 1569, 1549 (s), 1508 (s), 1481 (s), 1475 (s), 1397, 1392, 1384 cm−1 HRMS (EI) calcd for C25H31ClN6O2 482.2197. found 482.2192.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=2)[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=1.O.Cl>C(O)C.[Fe]>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc(N)ccc21
Yield: 40.1 %

Procedure:
3-(1H-Benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl-amine can be obtained in the following way: 485 mg of powdered iron are added, in small fractions, to a solution, brought to reflux, of 350 mg of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole, of 15 ml of ethanol, of 200 μl of distilled water and of 320 μl 12N hydrochloric acid and the mixture is maintained at reflux for 16 hours. After returning to a temperature in the region of 20° C., the medium is diluted with 60 ml of ethanol, stirred, and then filtered through a bed of Celite® 535, which is then washed with ethanol. The filtrate is basified to a pH in the region of 9 with a saturated aqueous sodium hydrogencarbonate solution. The precipitate thus formed is removed by filtration, and washed with ethanol, and the filtrate is then concentrated to dryness under reduced pressure. The evaporation residue is dissolved in distilled water and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 130 mg of 3-(1H-benzimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-ylamine are thus obtained in the form of an orange lac (Rf=0.34, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (50/50 by volume); mass analysis: EI: m/z 379 (M+.) (base peak), m/z 306).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:8]=1)(=[O:3])[NH2:2].[ClH:23]>C(O)(C)C>[ClH:23].[NH:13]1[CH2:14][CH2:15][CH:10]([CH2:9][N:7]2[CH:8]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=[N:6]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(C(N)=O)cn2)CC1
Agent: Cl
Solvent: CC(C)O
Product: NC(=O)c1cnn(CC2CCNCC2)c1
Yield: 103.9 %

Procedure:
A suspension of 0.96 g (3.11 mmol) of tert-butyl 4-(4-carbamoylpyrazol-1-ylmethyl)piperidine-1-carboxylate, obtained in stage 13.1., in 25 ml of a 5N solution of hydrochloric acid (124 mmol) in isopropanol is stirred overnight. It is evaporated to dryness and then coevaporated twice with 25 ml of ethyl acetate. The product is resuspended in 25 ml of ethyl acetate. It is filtered, washed twice with 10 ml of ethyl acetate and dried under vacuum in order to obtain 0.91 g (3.23 mmol) of product in the form of a white powder.