Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC([O-])=O.[OH:13][C:14]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]2[C:15]=1[C:16](=[O:34])[N:17]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:18]=[N:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1>C(Cl)Cl>[CH3:25][O:24][C:22]1[CH:21]=[C:20]2[C:15]([C:16](=[O:34])[N:17]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])[CH:18]=[N:19]2)=[C:14]([O:13][CH:55]2[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]2)[CH:23]=1
Reactant: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC2CCN(C)CC2)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of di-(tert-butyl azodicarboxylate (1.7 g) in methylene chloride (5 ml) was added to a stirred mixture of 5-hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.5 g), triphenylphosphine (1.9 g), 4-hydroxy-1-methylpiperidine (0.675 g) and methylene chloride (20 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was washed with diethyl ether and dried under vacuum to give 7-methoxy-5-(N-methylpiperidin-4-yloxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.75 g); NMR Spectrum: (CDCl3): 1.2 (s, 9H), 2.05 (br s, 41, 2.3 (s, 3H), 2.3-2.42 (m, 2H), 2.7-2.8 (m, 2H), 3.9 (s, 3H), 4.48 (m, 1H), 5.9 (s, 2H), 6.5 (d, 1H), 6.71 (d, 1H), 8.18 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[NH:14]2)=[CH:9][C:8]=1[CH2:19][CH2:20]C(OCC)=O.[OH-:26].[Na+].Cl>CCO.C1COCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[NH:14]2)=[CH:9][C:8]=1[CH2:19][CH2:20][NH:14][C:13](=[O:18])[O:26][C:7]([CH3:16])([CH3:8])[CH3:6]
Reactant: [OH-]
Reactant: CCOC(=O)CCc1cc2c(c(C)c1CCOCOC)NC(=O)CC2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCOCCc1c(CCNC(=O)OC(C)(C)C)cc2c(c1C)NC(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10.81 g of ethyl 3-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}propanoate in 100 ml of EtOH and 100 ml of THF was added 100 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized by the addition of hydrochloric acid and then concentrated under reduced pressure to one third of the liquid amount, and the residue was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in 300 ml of t-butanol were added 9.0 ml of triethylamine and 7.0 ml of DPPA, followed by heating and refluxing for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc), and then the resulting solid was washed with HEX to obtain 8.006 g of t-butyl (2-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}ethyl)carbamate as a milky white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.Cl.Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:10]([C:8]1[O:9][C:5]3[C:4]([F:14])=[CH:3][C:2]([F:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:19]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc(F)cc(F)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(F)c2o1
Reaction time: 0.33 h

Procedure:
55 mg (0.28 mmol) of 5,7-difluoro-1-benzofuran-2-carboxylic acid, 50 mg (0.25 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 114.6 mg (0.3 mmol) of HATU, 117 mg (0.9 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to the general procedure (variant B). DMF is removed under reduced pressure and the crude product is dissolved in 1N aqueous sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure using a rotary evaporator. The crude product is taken up in methanol and, together with acidic ion exchange resin (Dowex WX2-200), shaken for about 20 min. The loaded ion exchanger is washed three times with in each case 30 ml of methanol, then with water, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed under reduced pressure using a rotary evaporator. 40 mg (52% of theory) of the title compound are isolated.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH3:13])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C#N)cc1[N+](=O)[O-]
Yield: 96.9 %

Procedure:
A suspension of 8.37 g of 4-hydroxy-3-nitrobenzonitrile, 27.64 g of anhydrous potassium carbonate and 6 mL of dimethyl sulphate in 60 mL of acetonitrile was stirred at reflux for 2 hours. The solvent was removed by evaporation in vacuo. The residue was taken up in 100 mL of water and extracted with 3×80 mL of chloroform. The combined organic layers were dried over sodium sulphate and the solvent was evaporated off to afford 8.8 g (98.8%) of Compound 18A as an ivory solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([S:11](Cl)(=[O:13])=[O:12])[CH3:10]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:11]([CH2:9][CH3:10])(=[O:13])=[O:12]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccccc1Br
Solvent: c1ccncc1
Solvent: O
Product: CCS(=O)(=O)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a solution of 2-bromoaniline (344 mg, 2.0 mmol) in pyridine (5 mL) was slowly added ethyl-sulfonyl chloride (257 mg, 2.0 mmol) at rt and the mixture was stirred at rt for 16 hours. The pyridine was removed under reduced pressure and resulting residue diluted with water (30 mL) and extracted with DCM (10 mL×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC to give the title compound (240 mg, 45%). MS (ESI): mass calcd. for C8H10BrNO2S 262.96 m/z found 264.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 7.71 (dd, J=4.8, 1.5, 1H), 7.59 (dd, J=4.8, 1.5, 1H), 7.32-7.28 (m, 1H), 7.08-7.05 (m, 1H), 6.77 (bs, 1H), 3.14 (q, J=7.2, 2H), 1.41 (t, J=7.5, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][S:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[C:5]2[CH2:10][S:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CSC2
Reactant: C[C@H]1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CSC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 2,4-dichloro-5,7-dihydrothieno[3,4-d]pyrimidine (300 mg, 1.45 mmol) and Et3N (294 mg, 2.9 mmol) in DMF (5.0 mL) at 0° C. was added 3-(S)-methylmorpholine (161 mg, 1.59 mmol) dropwise. After the addition was complete, the mixture was stirred overnight at rt. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give the crude product which was purified by preparative TLC (Eluent: petroleum ether/ethyl acetate=2/1) to provide 2-chloro-5,7-dihydro-4-((S)-3-methylmorpholino)thieno[3,4-d]pyrimidine as a light yellow solid (283 mg, 72%).
Reaction SMILES: [ClH:1].[NH2:2][C:3](=[N:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][CH:32]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[CH2:24][CH2:23]2)=[O:18])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.C(Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[ClH:1].[NH2:2][C:3](=[N:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][CH:32]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:29][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:24][CH2:23]2)=[O:18])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCc2cc(NC(=O)CCNCc3cccc(N=C(N)c4cccs4)c3)ccc21
Reactant: BrCc1ccccc1
Agent: Cl
Product: NC(=Nc1cccc(CNCCC(=O)Nc2ccc3c(c2)CCN3Cc2ccccc2)c1)c1cccs1

Procedure:
The experimental protocol used is the same as that described for compound 54, with benzyl bromide replacing iodomethane. A white solid is obtained. Melting point: 193-195° C.
Reaction SMILES: [Cl:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].[Br:16]Br>C(Cl)Cl>[Br:16][C:9]1[C:8](=[O:10])[N:7]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:6]2=[N:5][C:4]=1[CH:2]([Cl:1])[CH3:3]
Reactant: Cc1cccc2nc(C(C)Cl)cc(=O)n12
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cccc2nc(C(C)Cl)c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(1-chloroethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.16 g, 14.2 mmol) in methylene chloride (30 mL) was added drop-wise bromine (0.804 mL, 15.6 mmol) in methylene chloride (7 mL). The reaction mixture was stirred at room temperature for 2 h. The product precipitated out and was collected by filtration (2.42 g, 56.6%). LCMS calculated for C11H11BrClN2O (M+H)+: m/z=301.0. Found: 301.1.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:24]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2)[CH2:10][NH:11][C:12]([CH3:23])([CH3:22])[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:36]([C:39]1[S:43][CH:42]=[C:41]([C:44]([N:46]2[CH2:51][C:50]3([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[O:49][CH2:48][CH2:47]2)=[O:45])[CH:40]=1)([CH3:38])[CH3:37]>>[Si:1]([O:8][C@H:9]([C:24]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2)[CH2:10][NH:11][C:12]([CH3:23])([CH3:22])[CH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:16]([CH2:17][N:54]2[CH2:53][CH2:52][C:50]3([O:49][CH2:48][CH2:47][N:46]([C:44]([C:41]4[CH:40]=[C:39]([CH:36]([CH3:38])[CH3:37])[S:43][CH:42]=4)=[O:45])[CH2:51]3)[CH2:56][CH2:55]2)[CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1cccc(C=O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CC(C)c1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)CC3)C2)cs1

Procedure:
The subtitled compound was prepared using a similar method to that described in Example 14, step b) using (R)-3-(2-(2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)-2-methylpropyl)benzaldehyde (0.32 g) (Example 275, step h) and (5-isopropylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (0.21 g) (Example 275, step i)). The crude product was purified by flash silica chromatography, 8% methanol in dichloromethane with 1% 880 aqueous ammonia. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.31 g.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:16])[CH2:13][NH:12][C@@H:11]([CH2:14][OH:15])[CH2:10]1.[S:17](Cl)(Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:8][C:9]1([CH3:16])[CH2:13][N:12]2[S:17](=[O:19])(=[O:18])[O:15][CH2:14][C@H:11]2[CH2:10]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(C)CN[C@@H](CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
A solution of triethylamine (4.94 mL, 35.4 mmol) and (R)-(4,4-dimethylpyrrolidin-2-yl)methanol (2.29 g, 17.72 mmol) in DCM (89 mL) was cooled to −78° C. To this mixture was added sulfuryl chloride (1.0 M in DCM, 21.27 mL, 21.27 mmol) over 15 seconds. The reaction was maintained at this temperature for ˜3 h, allowed to warm to room temperature and stirred overnight (16 h). The mixture washed with aqueous 1 N HCl (30 mL×2), brine (40 mL), dried over MgSO4, filtered and concentrated affording crude product as a brown-orange oil that crystallized upon standing. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-60% EtOAc in heptane) affording (R)-5,5-dimethyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (708 mg, 3.70 mmol, 21% yield) as a white crystalline solid. MS (ESI) 192.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([N:31]=C=O)(=[O:30])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:23]([NH2:31])=[O:30])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1ccccc1C(=Cc1ccnc(N)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1C(=Cc1ccnc(NC(N)=O)c1)c1ccccc1
Temperature: 50 °C
Yield: 64.1 %

Procedure:
The crude 4-(2-phenyl-2-o-tolyl-vinyl)-pyridin-2-ylamine (251 mg) is dissolved in methylene chloride (5 mL). Then benzoyl isocynate (258 mg, 1.75 mmol) is added. The reaction mixture is sealed and heated at 50° C. for 16 hour. The solvent is then carefully removed and to the residue are added ethanol (5 mL) and potassium carbonate (182 mg, 1.32 mmol). The resulting mixture is heated at 80° C. for 45 min. Then solvent is removed and the residue is partitioned between water (45 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 185 mg of the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:7]([NH:11][CH:12]3[CH2:14][CH2:13]3)=[N:6][C:5]3=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:19]=4)=[N:17][N:4]3[C:3]1=2>C1COCC1.CO>[CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:7]([NH:11][CH:12]3[CH2:14][CH2:13]3)=[N:6][C:5]3=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:19]=4)=[N:17][N:4]3[C:3]1=2
Reactant: COC(=O)CCc1cc(-c2cc3nc(NC4CC4)c4ncn(C)c4n3n2)ccc1F
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cnc2c(NC3CC3)nc3cc(-c4ccc(F)c(CCC(=O)O)c4)nn3c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
A mixture of 1-methyl-4-cyclopropylamino-7-(4′-fluoro-3′-methoxycarbonylethylphenyl)-pyrazolo[5,1-b]purine (57.4 mg, 0.141 mmol) in THF/MeOH/1.0 N NaOH (3.5 mL, 4:2:1) was stirred at room temperature. After 3 days, neutralization with 1.0 N HCl precipitated a white solid. Filtration followed by wash with H2O and acetone furnished the title compound (26.9 mg, 49%) as a white solid. 1H NMR (d-MeOD, 400 MHz): 7.88 (d, J=7.34 Hz, 1H), 7.83 (s, 1H), 7.86-7.80 (m, 1H), 7.12 (t, J=9.78 Hz, 1H), 6.58 (s, 1H), 4.32 (s, 3H), 3.01 (t, J=7.83 Hz, 2H), 2.90 (m, 1H), 2.65 (t, J=7.82 Hz, 2H), 0.93 (m, 2H), 0.70 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:13][CH:10]2[CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH2:9]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2COC(c3ccccc3)OC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 2 liter round bottom flask was added 2-phenyl-1,3-dioxan-5-ol (50 g, 277 mmol), triethyl amine (42.1 g, 416 mmol), DMAP (3.39 g, 27.7 mmol) and dichloromethane (1 L). The reaction was cooled to 0° C. To this solution was added tosyl chloride (58.2 g, 305 mmol) and the reaction was stirred overnight at RT. The reaction was poured onto water (800 mL) and extracted into DCM. The organic layers were combined and concentrated to dryness. The crude mixture was recrystallized from EtOAc:Hex to afford 88 g (96% yield) of a white solid. 1H NMR (CDCl3, 400 MHz), δ: 2.44 (3H, s), 4.09 (2H, dd, J=13.6, 2 Hz), 4.27 (2H, dd, J=13.6, 1.6 Hz), 4.51 (2H, pseudo t, J=1.6 Hz), 7.33-7.36 (5H, m), 7.44-7.45 (2H, m), 7.85 (2H, d, J=8.39 Hz). Mass Spec (lo-res): Calc'd for C17H18O5S: 334.09; found: 335.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>C(O)C.O>[Cl:8][C:6]1[N:7]=[CH:2][N:3]=[C:4]([N:10]([CH3:9])[CH2:11][CH2:12][OH:13])[CH:5]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNCCO
Solvent: CCO
Solvent: O
Product: CN(CCO)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.8 g (0.1 mmol) 2,4-dichloropyrimidine in 120 ml ethanol and 20 ml water, cooled to 0° C., 11.3 g (0.15 mol) 2-(N-methylamino)ethanol is added. The resulting mixture is stirred at room temperature for ½ h., then concentrated to dryness and finally partitioned between CH2Cl2 and a NaHCO3 saturated solution.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N+:9]([O-:35])=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4]
Reactant: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Reaction time: 2.5 h

Procedure:
A mixture of 4.2 g (11 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acid methyl ester and 3.15 g (14.5 mmol) of m-chloroperbenzoic acid in 100 ml of methlene chloride was stirred at 0° for 2.5 hr. The mixture was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 224°-226°. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, mp 226°-227°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>CO>[F:12][C:13]([F:20])([F:19])[C:14]([NH:1][CH2:2][CH2:3][OH:4])=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCO
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NCCO)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
2-Aminoethanol (4 g, 65.48 mmol, 1 equiv) was dissolved in 200 mL of methanol, and triethylamine (9.94 g, 98.23 mmol, 1.5 equiv) was added, followed by adding ethyl trifluoroacetate (11.16 g, 78.59 mmol, 1.2 equiv). After the reaction mixture was stirred overnight at room temperature, the solvent was evaporated, and the residue was dissolved in DI water and extracted with ethyl acetate. The crude product was purified by silica gel column chromatography using ethyl acetate as eluent. The obtained product was a white solid (9.8 g, 62.42 mmol, 95% yield). 1H-NMR (600 MHz, CDCl3): δ 2.07 (s, 1H, CF3CONHCH2CH2OH); δ 3.5 (t, 2H, CF3CONHCH2CH20H); δ 3.8 (t, 2H, CF3CONHCH2CH2OH); δ 6.9 (s, 1H, CF3CONHCH2CH2OH).
Reaction SMILES: [C:1](O)(=O)C.[CH3:5][C:6]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[C:9]2[NH:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:12][C:13](=[O:14])[N:8]2[N:7]=1.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:1][N:7]1[N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[N:10]=[C:9]2[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[C:6]1[CH3:5]
Reactant: CC(=O)O
Reactant: Cc1ccccc1Cc1c(C)nn2c(=O)cc(-c3ccncc3)[nH]c12
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1Cc1c(C)n(C)n2c(=O)cc(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a solution of 2-methyl-3-(2-methylbenzyl)-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one acetate (500 mg, 1.281 mmol) in dichloromethane/methanol (30 mL/15 mL) was added trimethylsilyldiazomethane (1.3 mL, 2.561 mmol). The mixture was stirred at room temperature for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by a silica gel chromatography to give the titled compound (223 mg, 51%); LC/MS: MS (ES+) m/e 345 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.27 (s, 3H), 2.42 (s, 3H), 4.04 (s, 2H), 4.24 (s, 3H), 6.51 (s, 1H), 7.10-7.20 (m, 4H), 7.88 (d, J=5.7 Hz, 2H), 8.70 (d, J=5.7 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C1COCC1.CC(C)([O-])C.[K+]>O>[O:24]=[C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:17]1[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Reactant: O=C(Cl)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(N3CCCCC3=O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.1 %

Procedure:
Part H. To tert-butyl-5-amino-1-indolinecarboxylate (1.90 g, 8.2 mmol) was added 5-bromovaleryl chloride (1.4 mL, 9.0 mmol) and 18 mL of THF. After stirring for 5 min at rt under N2, potassium tert-butoxide (9 mL, 9 mmol; 1.0 M in THF) was added in one portion, and the resulting brown solution was stirred under N2 for 30 min. A second portion of potassium tert-butoxide (9 mL) was added, and the resulting brown suspension was stirred for 15 min. An additional 0.10 mL-portion of 5-bromovaleryl chloride and a 4.5 mL-portion of potassium tert-butoxide were added, and the mixture was stirred for 30 min. The reaction was then poured into H2O (80 mL). The aqueous layer was washed with EtOAc (3×50 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the resulting residue was purified by radial chromatography (50% EtOAc in hexanes) to afford tert-butyl 5-(2-oxo-1-piperidinyl)-1-indolinecarboxylate as a pink solid (1.30 g, 50%). LRMS (AP+): 317.2 (M+H)+. 1H NMR (CDCl3) δ 7.40-7.80 (br m, 1H), 7.01 (s, 1H), 6.97 (d, 1H), 3.94 (t, 2H), 3.55 (br m, 2H), 3.09 (t, 2H), 2.49 (br m, 2H), 1.91 (br m, 4H), 1.52 (s, 9H).