Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][OH:17])=[NH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:18][C:19](=[O:24])[O:20][CH:21]([CH3:23])[CH3:22])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].N1C=CC=[CH:28][CH:27]=1.C(Cl)(=O)C>C1(C)C=CC=CC=1>[CH3:23][CH:21]([O:20][C:19](=[O:24])[NH:18][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[C:27]([CH3:28])[O:17][N:16]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:25])[CH2:6]1)[CH3:22]
Reactant: c1ccncc1
Reactant: CC(=O)N1c2ccc(C(=N)NO)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Product: CC(=O)N1c2ccc(-c3noc(C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 1-methylethyl {(2S,4R)-1-acetyl-6-[(hydroxyamino)(imino)methyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation, see Intermediate 56) (130 mg, 0.373 mmol) in toluene (2 mL) and pyridine (2 mL) was added acetyl chloride (a solution 0.34 mL of acetyl chloride in 5 mL of toluene was made and 0.52 mL was used, 0.485 mmol) dropwise and the resulting mixture was stirred at room temperature under nitrogen for 30 min. The mixture was then warmed to 110° C. and stirred at this temperature for 16 h then cooled to room temperature. Most of the solvents were removed in vacuo and the residue was partitioned between AcOEt and water (acidified to pH 1 with a 2N HCl aqueous solution). The two layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed with a saturated NaHCO3 aqueous solution then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient: 13 to 63% AcOEt in hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (120 mg, 0.322 mmol, 86% yield) as a white foam. LCMS (method A): Retention time 0.94 min, [M+H]+=373.05
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][CH3:21])[C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC#N>[Br:1][C:2]1[CH:3]=[C:4]([O:20][CH3:21])[C:5]([Cl:19])=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)cc(OC)c2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc(Br)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of methanone 73 (7.0 g, 18.94 mmol) in CH2Cl2/CH3CN (60 mL/60 mL) were added triethylsilane (9.1 mL, 56.81 mmol) and boron trifluoride diethyl etherate (7.0 mL, 56.81 mmol) at 0° C. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 hours. To the mixture was added aq. saturated K2CO3 solution (80 mL) slowly and extracted with EtOAc (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired product 74 (5.7 g, 87%).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[N:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]3)[N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:15][N:16]3[N:20]=[C:19]([NH2:21])[CH:18]=[N:17]3)[CH:12]=[CH:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cccc(Cn3ncc([N+](=O)[O-])n3)n2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cccc(Cn3ncc(N)n3)n2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(2-methyl-[1,3]dioxolan-2-yl)-6-(4-nitro-[1,2,3]triazol-2-ylmethyl)-pyridine (66 mg, 0.23 mmol), iron powder (38 mg, 0.68 mmol) and NH4Cl (61 mg, 1.13 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 1 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1N NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale green oil: TLC: rf (EA)=0.50. LC-MS-conditions O2: tR=0.67 min; [M+H]+=262.40.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:54])[C:26]([C:29]1[CH:34]=[CH:33][C:32](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:31][CH:30]=1)([CH3:28])[CH3:27].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25](=[O:54])[C:26]([C:29]1[CH:30]=[CH:31][C:32]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:33][CH:34]=1)([CH3:28])[CH3:27]
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.08 g, 0.27 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.082 g, 0.27 mmol), triethyl amine (2 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound was obtained as a brown oil (0.040 g, 31%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([CH3:19])[N:10]=1.[CH:20]([NH2:24])([CH2:22][CH3:23])[CH3:21]>C(O)C>[Cl:8][C:9]1[N:14]=[C:13]([NH:24][CH:20]([CH2:22][CH3:23])[CH3:21])[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([CH3:19])[N:10]=1
Reactant: CCC(C)N
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Yield: 57.2 %

Procedure:
15 ml of triethylamine are added to a solution of 15.6 g of 2,4-dichloro-5-nitro-6-methylpyrimidine (0.075 mole) in 300 ml of absolute ethanol. With ice cooling, 6.6 g of sec. butylamine (0.09 mole) are added dropwise at 0°-5° C over the course of c. 40 minutes to the dark red solution. After the mixture has been stirred for c. 3/4 hour at this temperature, it is poured into c. 700 ml of ice water and the water is extracted 3 times with ether. The ethereal extracts are dried over magnesium sulphate and evaporated. The resultant red oily substance is crystallised from petroleum ether to yield 10.5 g of 2-chloro-4-sec. butylamino-5-nitro-6-methyl-pyrimidine of m.p. 40°-43° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 438 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.[CH:10]1([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=CC1CCCC1
Reactant: NCc1cncc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Brc1cncc(CNCC2CCCC2)c1
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A solution of (5-bromopyridin-3-yl)methanamine (LIV) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LV) (1.23 g, 4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C12H17BrN2 m/z 269 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[SH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[C:20]([O:19][C:18]([NH:17][CH2:16][CH2:15][S:14][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSc1cc(C(=O)O)c(Cl)cn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dichloroisonicotinic acid (1.82 g) in anhydrous N,N-dimethylformamide (10 ml) was added 60% sodium hydride (0.455 g) in small portions. After gas evolution had ceased tert-butyl 2-mercaptoethylcarbamate (1.60 ml) was added. The reaction mixture was then heated at 60° C. under nitrogen for 10 hours. Further amounts of 60% sodium hydride (0.225 g) and tert-butyl 2-mercaptoethylcarbamate (1.60 ml) were then added and heating was continued for 2 hours. The reaction mixture was concentrated and the residue suspended in 2M aqueous hydrochloric acid (25 ml) and extracted into ethyl acetate (3×25 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate:acetic acid (6:4:0.1) to afford the sub-titled compound (1.0 g) as a colourless powder.
Reaction SMILES: ClC1C=CC(CP(=O)(OCC)OCC)=CC=1.[CH2:17]([O:20][C:21]1[CH:28]=[CH:27][C:24](C=O)=[CH:23][C:22]=1[O:29][CH3:30])C=C.CC([O-])(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[K+]>C1(OC)C=CC=CC=1>[C:22]1([O:29][CH3:30])[C:21](=[CH:28][CH:27]=[CH:24][CH:23]=1)[O:20][CH3:17]
Reactant: C=CCOc1ccc(C=O)cc1OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Solvent: COc1ccccc1
Product: COc1ccccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution containing 147.0 g (306 mmol) of the tetraethyl stilbene-4,4'-bis(methylenephosphonate) described in (c) above and 129.4 g (673 mmol) of the 4-allyloxy-3-methoxybenzaldehyde described in Example 2 (b) above in 900 ml of anisole, is added dropwise with stirring and at a temperature of 0° to 10° C. to a suspension containing 94.4 g (841 mmol) of potassium tert-butylate, 6.1 g (23 mmol) of 18-crown-6 and 1.75 g (10 mmol) of potassium iodide in 1300 ml of anisole. The mixture is then stirred at room temperature for an additional 1 hour and then at 110° C. for an additional 3 hours. The mixture is cooled to room temperature and the resultant solid is filtered off with suction and recrystallized first from dimethyl sulfoxide and then from veratrol (1,2-dimethoxybenzene), giving 119.5 g of yellow crystals, which corresponds to a yield of 73%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12]1(O)[CH2:16]CC[CH2:13]1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:12]([CH3:16])[CH3:13])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: OC1CCCC1
Solvent: CC(C)O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21

Procedure:
2,6-Dichloro-9-(2-propyl)purine is prepared from 2,6-dichloropurine and isopropanol essentially as described in Example 1, Scheme A, step a, but substituting isopropanol for cyclopentanol.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[N:13][N:14]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH3:20][C:19]1[O:18][N:17]=[C:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]=1[C:12]1[O:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=2)=[N:14][N:13]=1
Reactant: COC(=O)c1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)O)cc2)o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzoic acid methyl ester (1.95 g, 5.47 mmol) in methanol (10 mL) was added aqueous sodium hydroxide (1 M, 11 mL, 11 mmol) and the mixture was stirred for 3 h at 70° C. After concentration the residue was diluted with water (20 mL) and the resulting suspension was acidified with aqueous HCl (1 N) to pH=1. filtration and washing with water afforded the title compound (1.90 g, 99%) which was obtained as a white solid. MS: m/e=348.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:23]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([CH3:1])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(C)cc2N)sc2ccccc12
Yield: 62.2 %

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (6.5 g), ethyl acetate (140 ml), 10% palladium-carbon and hydrogen (500 mg, 60 atm kg/cm2), ethyl 2-(2-amino-4-methylanilino)benzo[b]thiophene-3-carboxylate (3.7 g) was obtained.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:2]1([CH2:1][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(Cn2cnc3ccccc32)cc1

Procedure:
To benzyl chloride (13 g, 0.103 mol), 1h-benzimidazole (11.81 g, 0.10 mol), K2CO3 (60 g, 0.434 mol) was added acetonitrile (200 mL) and the mixture was stirred and heated under reflux for 3 h, filtered hot, and washed with hot CH3CN (100 mL). The solvent of the filtrate was evaporated and the residual mass recrystallized as needles (16.5 g, 79%): mp 119°-120° C. (benzene)(lit1 mp 105° C.); 1H NMR (270 MHz, CDCl3) δ 5.40 (s, 2H, CH2), 7.20-7.41 (m, 8H), 7.85-7.89 (m, 1H), 8.02 (s, 1H, NCHN); IR (CDCl3) 3093 (w), 3065 (w), 3037 (w), 2929 (w), 1615 (w), 1496 (s), 1456, 1385 (w), 1361, 1331, 1285, 1261, 1204, 1181, 1007 (w), 963 (w), 947 (w) cm-1. MS (EI) m/e 208 (M+, 57.8), 91 (100); Anal. Calcd for C14H22N2 (208.26): C, 80.74; H, 5.81; N, 13.45; Found: C, 80.70; H, 6.02; N, 13.31.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>C1COCC1>[Cl:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH:1]=[CH2:2]
Reactant: O=C(CCCl)c1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)(CCCl)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 270 %

Procedure:
Anhydrous CeCl3 (16 g, 64.9 mmol) was stirred vigorously in 100 mL THF for 2 h 15 min. The suspension was then cooled to −78° C. and a 1 M solution of vinylmagnesiumbromide (62 mL, 62.3 mmol) was added. After 1.5 h at −78° C., a solution of 3-chloropropiophenone (7 g, 14.5 mmol) in 20 mL THF was added dropwise via cannula. The reaction mixture was stirred for 1 h, then gradually warmed to room temperature and quenched by the addition of saturated aqueous NaHCO3. Extraction into EtOAc (3×) followed by purification by silica gel chromatography (4:1 hexanes:EtOAc) afforded the 5-chloro-3-phenylpent-1-en-3-ol (7.7 g, 94%) as a yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.45-7.34 (m, 4H), 7.28 (m, 1H), 6.18 (dd, 1H, J=17.2, 10.6 Hz), 5.34 (d, 1H, J=17.2 Hz), 5.23 (d, 1H, J=10.8 Hz), 3.59 (td, 1H, J=10.6, 5.5 Hz), 3.41 (td, 1H, J=10.5, 5.5 Hz), 2.40 (m, 2H), 2.0 (br. s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8]O)[CH:2]=1.C(Br)(Br)(Br)[Br:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:11][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1cccnc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(3-pyridyl)ethan-1-ol (100 mg, 0.79 mmol) and CBr4 (314 mg, 0.95 mmol) in THF (2 mL) was cooled to 0° C. and PPh3 (313 mg, 1.18 mmol) was added portionwise. The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and diluted with CH2Cl2. The mixture was basified using saturated NaHCO3 and the organic phase was separated. The aqueous phase was re-extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4 and concentrated. Silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent afforded 3-(2-bromo-ethyl)-pyridine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:18]=[C:17]([CH3:19])[C:9]([C:10]([O:12]CC3CC3)=[O:11])=[C:8]([CH3:20])[CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[OH-].[Li+].C(OCCO)C.Cl>CO.C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:18]=[C:17]([CH3:19])[C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:20])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(OCC2CC2)cc(C)c1C(=O)OCC1CC1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCCO
Product: Cc1cc(OCC2CC2)cc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A mixture of cyclopropylmethyl 4-(cyclopropylmethoxy)-2,6-dimethylbenzoate (1.35 g), THF (15 mL), methanol (15 mL) and 1M sodium hydroxide (15 mL) was stirred at room temperature for 2 hr, and then at 70° C. for 2 hr. To the reaction mixture was added 4M lithium hydroxide (10 mL), and the obtained mixture was stirred overnight at 70° C., and then at 100° C. for 2 hr. To the reaction mixture was added 2-ethoxyethanol (10 mL), and the obtained mixture was stirred at 120° C. for 2 days. The reaction mixture was cooled to 0° C., and acidified with 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (960 mg).
Reaction SMILES: [CH:1]([S:4][C:5]1[N:6]([CH3:11])[C:7]([SH:10])=[N:8][N:9]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:15]1[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][N:20]=1>CN(C=O)C.C1C=CC=CC=1>[CH:1]([S:4][C:5]1[N:6]([CH3:11])[C:7]([S:10][C:15]2[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][N:20]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Sc1nnc(S)n1C
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)Sc1nnc(Sc2nccnc2C#N)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(isopropylthio)-4-methyl-4H-1,2,4-triazole-3-thiol (379 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 2 hr.
Reaction SMILES: [Cl: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]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][CH:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=1)=[O:23])[CH2:36][OH:37]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: NC(CO)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(CO)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.44 mmol), 2-aminopropane-1,3-diol (119 mg, 1.31 mmol), HBTU (331 mg, 0.87 mmol), and HOBT (134 mg, 0.87 mmol). Then added DMF (1 mL) followed by N,N-diisopropylethylamine (0.31 mL, 1.75 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 157 mg (68%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide as a white solid. MS: [M+Na]+=552.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.[CH3:27][N:28]([CH2:30][CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36](O)[CH:37]=2)[CH2:32]1)[CH3:29].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.N1C=CC=CC=1>[C:1]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][C:4]([C:7]([O:9][C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH:31]([CH2:30][N:28]([CH3:29])[CH3:27])[CH2:40][CH2:39]3)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CC1CCc2cc(OC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 53.3 %

Procedure:
4-Biphenylylcarboxylic acid (580 mg) and WSC (560 mg) were added to pyridine solution (6 ml) of 2-[(N,N-dimethylamino)methyl]-6-hydroxytetralin (300 mg), which was stirred at room temperature for 36 hours. Saturated sodium bicarbonate solution and water were added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=10:1), and recrystallized (hexane) to give the titled compound (300 mg).