Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)Cl.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:26][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: BrBr
Reactant: c1cncc(-c2c3ccccc3cc3ccccc23)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Brc1c2ccccc2c(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 26 h
Yield: 55.4 %

Procedure:
In a 200 mL three-necked flask were placed 1.0 g (4.0 mmol) of 3-(9-anthryl)pyridine and 25 mL of carbon tetrachloride. Under a nitrogen stream, 10 mL of a carbon tetrachloride solution containing 0.83 g (5.1 mmol) of bromine was dripped into this solution, followed by stirring at room temperature for 26 hours. After a predetermined time has passed, 100 mL of a 1.0 M sodium thiosulfate solution was added to this mixture. The aqueous layer of this mixture was extracted with chloroform. The obtained extract and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and with saturated brine, and dried with magnesium sulfate. This mixture was subjected to gravity filtration, and the filtrate was concentrated to give a solid. A chloroform solution of the obtained solid was suction filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to give a solid. Recrystallization of this solid from a mixed solvent of ethyl acetate and hexane gave 0.74 g of a pale yellow powder in 53% yield, which was the desired substance.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]#[N:20])[CH:12]=2)[C@H:6]([C:8]([OH:10])=O)[CH3:7])[CH2:3][CH2:2]1.[CH2:21]([NH2:23])[CH3:22]>>[CH:1]1([CH2:4][N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]#[N:20])[CH:12]=2)[C@H:6]([C:8]([NH:23][CH2:21][CH3:22])=[O:10])[CH3:7])[CH2:2][CH2:3]1
Reactant: CCN
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C#N)c1
Product: CCNC(=O)[C@H](C)N(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(cyclopropylmethyl)-N-(3,4-dicyanophenyl)alanine and ethylamine: MS (ES) m/z 297 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH:26]([CH3:28])[CH3:27])[CH:17]=1.C(OCC)(=O)C>CS(C)=O>[CH:26]([O:25][C:18]1[CH:17]=[C:16]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])([CH3:28])[CH3:27]
Reactant: CN1CCC(N)CC1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(NC2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 63.7 %

Procedure:
1.7 g of potassium carbonate and 1.0 g of 4-amino-1-methylpiperidine are successively added to a solution of 1.6 g of 4-fluoro-2-isopropoxy-1-nitrobenzene in 13.5 ml of dimethyl sulfoxide. The reaction mixture is heated at 120° C. for 3 h and is then cooled to ambient temperature and poured into a mixture of 150 ml of ice-cold water and 100 ml of ethyl acetate. After settling out, the organic phase is separated and the aqueous phase is extracted twice with 70 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 90 g silica cartridge, elution being carried out with a 97.5/2/0.5 v/v/v dichloromethane/methanol/20% aqueous ammonia mixture at a flow rate of 50 ml/min, so as to obtain 1.5 g of (3-isopropoxy-4-nitrophenyl)(1-methylpiperidin-4-yl)amine in the form of a bright yellow oil.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[N:22]=[C:21]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:40]1[N:45]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH:43]=[CH:42][CH:41]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[C:27]1([CH3:31])[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[N:22]=[C:21]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:40]4[N:45]=[C:44]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=5)[CH:43]=[CH:42][CH:41]=4)=[CH:18][CH:17]=3)[N:24]=2)[CH:26]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: Cc1cccc(-c2nc(-c3ccc(Br)cc3)nc(-c3cccc(C)c3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(-c2nc(-c3ccc(-c4cccc(-c5ccccn5)n4)cc3)nc(-c3cccc(C)c3)n2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 60 ml of tetrahydrofuran cooled to −78° C. in which 1.25 g of 2-(4-bromophenyl)-4,6-di-m-tolyl-1,3,5-triazine obtained in Reference Example 2 had been dissolved. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 20 ml portion of tetrahydrofuran prepared by dissolving 0.85 g of 6-bromo-2,2′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (developing solvent hexane:chloroform=1:1 to 1:2) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 6-[4-(4,6-di-m-tolyl-1,3,5-triazin-2-yl)phenyl]-2,2′-bipyridyl (0.89 g, yield 61%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH3:25][O:26][CH2:27]Cl.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][O:26][CH3:27])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: COCCl
Reactant: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2n1COC
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a solution of 6-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (3.00 g, 10 mmol) in DMF (30 ml) was added 60% sodium hydride in oil (0.49 g, 12 mmol) under ice cooling and the mixture was stirred for 15 minutes. Then to the mixture was added chloromethyl methyl ether (1.0 ml, 13 mmol) under ice cooling and stirred for 0.5 hour. Water (60 ml) was added to the reaction mixture and extracted with AcOEt, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate and evaporated to give the title compound (3.45 g) as a pale brown oil.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][CH2:10][N:11]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:12][CH2:13][C:14](OCC)=[O:15])=[CH:7][CH:6]=1.Cl>C(OCC)C>[OH:2][NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]1[CH:30]=[CH:31][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: CCOC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(CCN(CCC(=O)NO)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Freshly prepared hydroxylamine reagent (6 mL; 6 mmol) was added to ethyl 3-[(4-methoxyphenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (587 mg; 1.40 mmol) and the resulting mixture stirred overnight at room temperature. The mixture was poured into 1 N HCl (40 mL) and extracted with CH2Cl2 (2×40 mL). The combined extracts were washed with saturated aqueous NaCl (40 mL), dried over MgSO4, and evaporated under reduced pressure to give crude product. Trituration with diethyl ether afforded 408 mg (71%) of the title compound as a white solid. 300 MHz 1H-NMR (DMSO-d6): δ 2.24 (t, 2H), 2.68 (t, 2H), 3.21 (t, 2H), 3.31 (m, 2H), 3.72 (s, 3H), 3.84 (s, 3H), 6.84 (d, 2H), 7.11 (d, 4H), 7.71 (d, 2H), 8.78 (s, 1H), 10.49 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14](F)[CH:13]=1>CN(C=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[C:16]([CH:17]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: CN1CCC(O)CC1
Reactant: Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1OC1CCN(C)CC1
Reaction time: 0.5 h

Procedure:
Add sodium hydride (60% dispersion in oil, 880 mg, 22 mmol) to a solution of 4-hydroxy-1-methyl-piperidine (2.304 g, 20 mmol) in DMF (12 mL), stir. After 30 min., add 4-bromo-2-fluorotoluene (4.159 g, 22 mmol) and beat at 70° C. After 21 hr., quench the reaction with saturated NaHCO3 solution, extract with ether three times, combine the organic layers, wash with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a residue. Purify by chromatography (silica gel, eluting with 6% 2M NH3-methanol in CH2Cl2) provides of the title compound as a slightly yellow oil (3.90 g, 69%). Mass spectrum (ion spray): m/z=284.0 (M+1); 1H NMR (CDCl3, ppm): 7.01 (m, 3H), 4.35 (m, 1H), 2.66 (m, 2H), 2.36 (m, 2H), 2.34 (s, 3H), 2.19 (s, 3H), 2.03 (m, 2H), 1.85 (m, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][N+:7]=1[O-:14].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[C:11]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([CH3:13])=[CH:8][N+:7]=1[O-:14]
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 ml of fuming nitric acid (d=1.5) were added dropwise while cooling to 210 ml of concentrated sulfuric acid. 96.5 g of 2,3,5-trimethylpyridine 1-oxide were subsequently added portionwise at 0°-5°, whereupon the mixture was stirred at room temperature for 1 hour, then heated to 90° within 3 hours and left at this temperature overnight. After cooling the solution was poured on to 1.5 kg of ice, whereupon the mixture was adjusted to pH 3 with concentrated sodium hydroxide solution and extracted three times with 500 ml of methylene chloride. The combined organic phases were washed with 1 l of water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ether/petroleum ether and there was obtained 2,3,5-trimethyl-4-nitropyridine 1-oxide of melting point 76°-78°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](OC)[N:8]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=1)=[O:4].P(Cl)(Cl)([Cl:20])=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:20])[N:8]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C(=O)OC)cc(OC)n1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OC)cc(Cl)n1
Temperature: 85 °C
Yield: 78 %

Procedure:
Mix 6-methoxypyridine-2,4-dicarboxylic acid 2-ethyl ester 4-methyl ester (239 mg, 1.0 mmol), phosphorous oxychloride (0.46 mL, 4.93 mmol) in DMF (1.9 mL) and heat to 85° C. for 24 h. Cool to room temperature and quench with saturated aqueous sodium acetate solution (5 mL). Extract with ethyl acetate, wash with water, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (190 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH:14]([CH3:17])[CH:15]=C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[O+][O-].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH:14]([CH3:17])[CH2:15][OH:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CC(C)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(CO)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1-methylallyl)piperidine-1-carboxylic acid 1-tert-butyl ester (25.5 g) in chloroform/methanol (250 ml/250 ml) cooled to −78° C. was flowed ozone air for 30 minutes. To the reaction mixture was added sodium borohydride (7.5 g) in small batches, and the mixture was warmed to room temperature. To the mixture was added 5% aqueous sodium bicarbonate solution (250 ml), and the mixture was extracted with chloroform (125 ml). The separated aqueous layer was extracted with chloroform (125 ml) again. The combined organic layer was sequentially washed with a mixed aqueous solution of sodium bicarbonate/sodium thiosulfate (12.5 g/25.0 g, 275 ml), water (125 ml) and 10% aqueous sodium chloride solution (125 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 2/3) to give the titled compound (21.9 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:39]=[CH:38][C:37]([CH:40](O)[CH3:41])=[CH:36][N:35]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:35]=[CH:36][C:37]([CH2:40][CH3:41])=[CH:38][N:39]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)O)cn2)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Oc2cccc(OC)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 4-tert-butyl-N-[6-{2-(5-(1-hydroxyethyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (150 mg) in methylene chloride (3 ml) is added thionyl chloride (90 mg), and the mixture is reacted at room temperature for 0.5 hour. The reaction solution is concentrated to dryness under reduced pressure, and to the residue are added 10% palladium-carbon (30 mg), triethylamine (76 mg) and ethanol (3 ml), and the mixture is stirred at room temperature for two hours under hydrogen atmosphere (1 atm). The catalyst is removed by filtration, and the filtrate is concentrated to dryness under reduced pressure. The residue is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=10:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-[6-{2-(5-ethylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (137 mg) as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[C:24]([C:28]#[N:29])=[C:23]([CH3:30])[N:22]=1.CCN(CC)CC>CN(C=O)C>[NH2:20][C:21]1[N:22]=[C:23]([CH3:30])[C:24]([C:28]#[N:29])=[C:25]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:18])[N:26]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1C1CCOCC1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2CCOCC2)c1C#N
Temperature: 90 °C
Reaction time: 8 h
Yield: 6.6 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (271 mg, 1.05 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (194 mg, 1.149 mmol) and Et3N (0.29 mL, 2.1 mmol) in DMF (5 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The product was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the product were combined and lyophilized to give the title compound as a white solid (27 mg, 6.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.53 (m, 3 H), 1.58-1.86 (m, 3 H), 1.91-2.11 (m, 1 H), 2.18-2.29 (m, 3 H), 2.99-3.17 (m, 1 H), 3.37-3.61 (m, 2 H), 3.75-3.90 (m, 3 H), 3.90-4.10 (m, 2 H), 5.63-5.80 (m, 1 H), 6.44-6.57 (m, 1 H), 6.97-7.25 (m, 2 H), 7.32-7.45 (m, 1 H), 7.55-7.65 (m, 1 H), 7.83-7.97 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H25N2O, 392; found 392.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][C:24]([S:30][CH3:31])=[N:25][CH:26]=2)[N:21]1[CH3:32].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][C:24]([S:30]([CH3:31])=[O:9])=[N:25][CH:26]=2)[N:21]1[CH3:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccccc1-n1c(=O)c2cnc(SC)nc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccccc1-n1c(=O)c2cnc(S(C)=O)nc2n1C
Reaction time: 1 h

Procedure:
At 0° C., 68 mg of m-chloroperbenzoic acid was added to a chloroform solution of 91 mg of 2-(2-methoxyphenyl)-1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 1 hour. Aqueous saturated sodium hydrogencarbonate solution was added thereto, and extracted with chloroform to obtain crude 2-(2-methoxyphenyl)-1-methyl-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]=1[CH:19]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)C>[Cl:6][C:7]1[C:8]([CH:19]=[CH2:1])=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1c(Cl)cccc1-c1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
Under a dry argon atmosphere n-butyllithium (1.3 g, 0.020 mole) was added slowly to a stirred ice cold mixture of (methyl)triphenylphosphonium bromide (7.3 g, 0.0203 mole) in 30 ml of tetrahydrofuran. The mixture was warmed to room temperature, stirred for two hours, and 3-chloro-[1,1'-biphenyl]-2-carboxaldehyde (4.4 g, 0.0203 mole) in 30 ml of tetrahydrofuran added. The reaction mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then cooled. The reaction mixture was diluted with 300 ml of diethyl ether and washed with 100 ml of water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to give a residue. Distillation of the residue at 88°/0.05 mm gave 3-chloro-2-ethenyl-[1,1'-biphenyl] (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9].[OH-].[K+].[CH2:20](Br)[CH:21]=[CH2:22].O>CS(C)=O>[CH2:22]([NH:10][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[O:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=1)[CH:21]=[CH2:20]
Reactant: NC(=O)c1cccnc1Oc1cccc(Cl)c1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCNC(=O)c1cccnc1Oc1cccc(Cl)c1

Procedure:
To a stirred solution of 2(3-chloro-phenoxy)-nicotinamide (0.084 g, 0.34 mmole) in methylsulfoxide (2 ml) was added potassium hydroxide powder (0.074 grams, 1.32 mmole) followed by allyl bromide ((0.082 grams, 0.68 mmole). After 1 hour the mixture was poured into water and extracted with methylene chloride. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a clear film (0.011 g). 1H NMR (400 mhz, CD3OD) d 4.37 (q, J=7.26 Hz, 1H), 4.82 (d, J=5.60 Hz, 1H), 5.26 (d, J=10.58 Hz, 1H), 5.40 (d J=17.0 Hz, 1H), 6.05 (m, 1H), 7.03 (m, 1H), 7.13 (m, 1H), 7.21 (m, 2H), 7.38 (t J=8.1 Hz, 1H), 8.30 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21]>C1COCC1>[C:4]1([C@H:7]2[NH:10][C:20](=[O:21])[CH2:19][O:9][CH2:8]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: NC(CO)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COC[C@@H](c2ccccc2)N1
Reaction time: 1 h

Procedure:
(R)-Phenylglycinol (0.20 g, 1.46 mmol) in dry THF (10 mL) was treated with triethylamine (0.18 g, 1.75 mmol) in one portion at 0°, under an atmosphere of nitrogen. Chloroacetylchloride (0.20 g, 1.75 mmol) was added dropwise over 15 minutes at 0°. The mixture was allowed to reach room temperature over 1 hour then quenched with water (5 mL) and EtOAc (5 mL). The organic layer was washed with brine (10 mL), dried (MgSO4) and evaporated in vacuo to a white solid. NMR shows the precursor to the product (non ring closed). The solid was dissolved in dry THF (5 mL) and 10M NaOH was added slowly at 0°. The suspension was allowed to reach room temperature over 1.5 hours. The suspension was diluted with water (10 mL) and EtOAc (10 mL) and the organic layer was further washed with water (10 mL), then dried (MgSO4) and evaporated in vacuo to a crude yellow solid, which was taken to the next step without any purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C@H:13]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]1=[O:25])[CH3:2].[Cl:27]N1C(=O)CCC1=O>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:11]([Cl:27])=[CH:10][N:9]=[C:8]([NH:12][C@H:13]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]1=[O:25])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1ccnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-[3-(1-azidomethyl-2-phenyl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester (5.8 g, 16.3 mmol) in dichloroethane (90 ml) was added N-chlorosuccinimide (2.17 g, 16.3 mmol) and the reaction mixture was stirred at 85° C. for 1 h 30 and at room temperature for 18 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 20% diethyl ether in hexane to 45%) to give (S)-[3-(1-azidomethyl-2-phenyl-ethylamino)-6-chloro-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester as a thick syrup. 1H NMR (CDCl3, 400 MHz): δ 7.38–7.20 (m, 5H); 6.85 (s, 1H); 6.10 (bd, J=8.8 Hz,1H); 4.92 (A of AB, d, J=17.7 Hz, 1H));); 4.86 (B of AB, d, J=17.7 Hz, 1H)); 4.40–4.30 (m, 1H); 4.25 (q, J=7 Hz, 2H); 3.52 (A of ABX, dd, J=12.4, 4.6 Hz, 1H); 3.40 (B of ABX, dd, J=12.4, 4.6 Hz, 1H); 3.00 (A of ABX, dd, J=13.5, 6.4 Hz, 1H); 2.92 (B of ABX, dd, J=13.5, 7.4 Hz, 1H); 1.29 (t, J=7 Hz, 3H).