Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].O(CC)[C:11]([S-])=[S:12].[K+].Cl>N1C=CC=CC=1>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:11](=[S:12])[O:8][C:7]=2[CH:6]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-amino-m-cresol (593.7 mg, 4.82 mmol) and potassium O-ethyl xanthate (850 mg, 5.30 mmol) in pyridine (10 mL) was stirred and heated to reflux for 2 h. It was cooled to rt, poured into a mixture of ice-water (40 mL), and concentrated HCl (4 mL). The solid was collected, washed with water, and dried in the hood overnight and then in a vacuum oven at 45° C. for 3 h. The product 6-methyl-1,3-benzoxazole-2(3H)-thione was obtained as beige powder (735 mg, yield 92.3%). 1H NMR (300 MHz, DMSO-d6) δ 7.10 (s, 1 H), 7.03 (d, 2 H), 2.42 (s, 3H); LC-MS ret. time 2.37 min (method 2), m/z 166.0 (MH+).
Reaction SMILES: [CH3:1][Si:2](C)([CH3:11])O[SiH](C)O[Si](C)(C)C.C[SiH](C)C=C[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][Si:25]([CH3:35])([O:32]CC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.Cl>>[C:26]1([Si:25]([CH3:35])([CH3:24])[O:32][Si:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([CH3:11])[CH3:1])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCO[Si](C)(C)c1ccccc1
Reactant: C[SiH](C)C=Cc1ccccc1
Reactant: C[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: O
Product: C[Si](C)(O[Si](C)(C)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Five millimoles of 1,1,1,3,5,5,5-heptamethyltrisiloxane, 5 mmol of dimethylphenylvinylsilane, and 5 mmol of dimethylethoxyphenylsilane were mixed. To the mixture were added 5 mmol of water, 5×10-4 mmol of a platinum-vinylsiloxane complex, and 0.1 mmol of hydrochloric acid, followed by stirring at room temperature for 3 hours. Quantitative determination of the reaction product by gas chromatography revealed that 2,2-di-trimethylsiloxy-5-phenyl-5-methyl-2,5-disilahexane was obtained in a yield of 99% as a hydrosilylation addition product and 1,3-diphenyl-1,1,3,3-tetramethyldisiloxane was obtained in a yield of 99% as an alkoxysilane condensation product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][CH:18]([CH3:24])[C:17]=2[CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:30]=[C:31]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][CH:18]([CH3:24])[C:17]=3[CH:25]=2)=[CH:10][CH:11]=[C:12]1[C:31]#[N:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1OCC(=O)Nc2ccc(-c3cccn3C(=O)OC(C)(C)C)cc21
Reactant: O=C=NS(=O)(=O)Cl
Product: CC1OCC(=O)Nc2ccc(-c3ccc(C#N)n3C(=O)OC(C)(C)C)cc21

Procedure:
tert-Butyl-2-cyano-5-(5-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate was prepared from tert-butyl-2-(5-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate according to the cyanation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.30 (s, 1H), 7.37-7.25 (m, 3H), 7.16 (d, J=8.26 Hz, 1H), 6.46 (d, J=3.77 Hz, 1H), 4.81 (q, J=6.14 Hz, 1H), 4.47 (d, J=16.42 Hz, 1H), 4.36 (d, J=16.44 Hz, 1H), 1.51 (d, J=6.48 Hz, 3H), 1.37 (s, 9H); MS (ES) m/z 366 ([M−H]−, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>[Pd].O.C(O)C>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:15]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(-c3cccc(F)c3)cc2)cc1
Yield: 145.4 %

Procedure:
A mixture of 5.6 g (21.4 mmol) of 4-bromo-4′-ethylbiphenyl, 3.6 g (25.7 mmol) of 3-fluorophenyl dihydroxyborane, 4.4 g (32.2 mmol) of potassium carbonate, 0.3 g of 5%-Pd/C and 60 mL of a mixed solvent of toluene, ethanol and water (ratio: 1/1/1) was refluxed for 6 hours to obtain a reaction solution. After removing the catalyst by filtration, 50 mL of toluene was added to the reaction solution, which was then washed with water. The reaction solution having been washed with water was dried over anhydrous magnesium sulfate, and the solvent was distilled off from the reaction solution under reduced pressure to obtain 8.6 g of a residue. The residue was purified by silica gel column chromatography (eluent: heptane/toluene=4/1) to obtain 5.1 g of crude crystals of the compound (E-8). The crude crystals were dissolved in a mixed solvent of ethanol and ethyl acetate (ratio: 10/1) and recrystallized therefrom to obtain 4.5 g of purified crystals of the compound (E-8).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[N+:5]([O-:8])([OH:7])=[O:6].CC(OC(C)=O)=O>CCOC(C)=O>[N+:5]([O-:8])([O-:7])=[O:6].[N+:5]([O:1][CH2:2][CH2:3][NH3+:4])([O-:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])[O-]
Product: [NH3+]CCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Hydroxyethylamine (5 g, 81.9 mmol) in EtOAc (40 mL) was added drop-wise to a mixture of fuming HNO3 (18 g, 12 mL, 0.29 mol) and Ac2O (54 g, 50 mL, 0.53 mol) at −10° C. The reaction mixture was stirred at 0° C. for 10 minutes and at room temperature for 10 minutes. The solvent was evaporated in high vacuo at 40° C. The residue was sonicated with ether. The solid was filtered and washed with hexane to give the title compound as a white solid. Mp 92-94° C. 1H NMR (300 MHz, d6-DMSO) δ 7.71-8.25 (bs, 3H), 4.72 (t, J=5.0 Hz, 2H), 3.23 (d, J=5.0 Hz, 2H). 13C NMR (75 MHz, d6-DMSO) δ 70.9, 37.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNS(C)(=O)=O
Temperature: 0 °C
Yield: 37.4 %

Procedure:
A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (3.27 g, 8.7 mmol) and triethylamine (3.82 mL, 11.3 mmol) in chloroform (165 mL) was cooled to 0° C. A cold solution of methanesulfonyl chloride (1.37 mL, 9.6 mmol) in chloroform (10 mL) was slowly added. The reaction was allowed to warm to ambient temperature after 15 minutes. Additional triethylamine (3.74 mL) and methanesulfonyl chloride (2.12 mL) were added over the course of several days to drive the reaction to completion. The reaction was concentrated under reduced pressure, and the residue was partitioned between 1% aqueous sodium carbonate and chloroform. The aqueous layer was adjusted to pH 13 with the addition of saturated aqueous sodium bicarbonate and 50% aqueous sodium hydroxide. The precipitate was isolated by filtration, air-dried, and combined with material from another run. The crude product was recrystallized from isopropanol:water (15 mL/g:1.5 mL/g) and dried in a drying oven for several days to provide 1.48 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([OH:11])[CH3:10].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[S:20]([O:11][CH:9]([CH3:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:22])(=[O:21])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)Cc1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cc1ccccc1F)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
Under a nitrogen atmosphere, to a mixture of 2.15 g (14.0 mmol) of (+)-1-(2-fluorophenyl)-propan-2-ol and 2.34 ml (16.8 mmol) of triethylamine in 10 ml of dichloromethane, 1.19 ml (15.4 mmol) of methanesulfonyl chloride was added at 0° C. The resulting mixture was stirred overnight at room temperature and then treated with water and extracted 3 times with dichloromethane. The combined organic layer was then washed with water, solvent was distilled off and the residue was purified by silica gel chromatography, giving 2.68 g of the title compound. (Yield: 82%).
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:25][C:26]1[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:28]=[CH:29][N:30]=1)[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.[CH:41]1([N:47]2[CH2:56][CH2:55][C:50]3([CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH:41]1([N:47]2[CH2:48][CH2:49][C:50]3([CH2:54][N:53]([C:20](=[O:21])[C:19]4[CH:23]=[CH:24][C:16]([O:15][CH2:14][CH:13]([CH2:12][C:8]5[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:39])[CH3:40])[CH:11]=[CH:10][N:9]=5)[CH2:25][C:26]5[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:28]=[CH:29][N:30]=5)=[CH:17][CH:18]=4)[CH2:52][CH2:51]3)[CH2:55][CH2:56]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C[Si](C)(C)CCOCn1ccnc1CC(COc1ccc(C(=O)O)cc1)Cc1nccn1COCC[Si](C)(C)C
Reactant: C1CCC(N2CCC3(CCNC3)CC2)CC1
Product: C[Si](C)(C)CCOCn1ccnc1CC(COc1ccc(C(=O)N2CCC3(CCN(C4CCCCC4)CC3)C2)cc1)Cc1nccn1COCC[Si](C)(C)C
Yield: 80.1 %

Procedure:
Except for using the compound (50 mg) produced in Example 103 in place of the compound produced in Example 68 and using 8-cyclohexyl-2,8-diazaspiro[4.5]decane (38 mg) in place of the compound produced in Example 91, the same operation as in Example 92 was performed to obtain the title compound (54 mg) having the following physical properties.
Reaction SMILES: [H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[OH:24].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: OCCCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled round bottom blask is added 4.2 g. of 57% sodium hydride in oil, 50 ml. of hexamethylphosphoramide and 15.8 g. of 2-naphthol. After 1/2 hour the mixture is allowed to warm to room temperature and 13.6 g. of 6-chlorohexan-1-ol is added. The mixture is heated at 110° C. overnight, cooled, diluted with water and extracted with ether. The ether extract is washed with sodium hydroxide solution, then with water, dried (magnesium sulfate) and the solvent removed under vacuum. The solid is dissolved in ether and the solution washed with sodium hydroxide solution. The ether layer is dried (magnesium sulfate) and the solvent removed under vacuum to give 15.9 g. of product, as crystals, m.p. 53°-56° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:18]O>>[NH2:5][C@@H:6]([C:14]([O:16][CH3:18])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:3]
Reactant: CO
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)[C@H](N)Cc1ccccc1
Reaction time: 8 h

Procedure:
To cold (−20° C.) and dry methanol (1 l) was added dropwise thionylchloride (130 ml). H—D-Phe-OH.HCl (147.6 g) was added and the reaction mixture was heated under reflux for 30 min and then kept at room temperature overnight. The mixture was concentrated in vacuo and coevaporated with methanol (3 times). The residue was crystallized from methano/diethyl ether yielding H—D-Phe-OMe.HCl as a white crystalline powder (187.4 g). TLC: Rf=0.54, silica gel, n-butanolacetic acid/water 10/1/3 v/v.
Reaction SMILES: CS(C)=O.[OH-].[K+].[I-].[CH3:8][S+](C)(C)=O.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C:19]([CH3:25])([CH3:24])[C:18](=[CH2:26])[C:17]2=[O:27]>O>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C:19]([CH3:24])([CH3:25])[C:18]1([CH2:8][CH2:26]1)[C:17]2=[O:27]
Reactant: C[S+](C)(C)=O
Reactant: C=C1C(=O)c2cc(Br)ccc2OC1(C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(Br)cc2C(=O)C12CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
A 3-necked-flask was charged with dimethylsulfoxide (17 ml) and potassium hydroxide (0.84 g, 15 mmol). Then trimethylsulfoxonium iodide (3.3 g, 15 mmol) was added and the mixture was stirred at room temperature for 30 minutes. To this mixture, 6-bromo-2,2-dimethyl-3-methylene-2,3-dihydro-4H-chromen-4-one (2.0 g, 7.5 mmol) and dimethylsulfoxide (3 ml) were added. The mixture was stirred at room temperature for 15 hours and then water (30 ml) was added. The mixture was extracted with a mixture of hexane (70 ml) and ethyl acetate (70 ml). The organic layer was washed with water (50 ml) twice and then with brine (30 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-silica gel, hexane/ethyl acetate=100:1-20:1) to afford 6-bromo-2,2-dimethyl-4H-spiro[chromene-3,1′-cyclopropan]-4-one (1.2 g).
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH2:44]([NH:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([O:58][CH3:59])[NH:55]2)=[C:51]([NH2:60])[N:50]=1)[CH2:45][CH2:46][CH3:47].Br[CH2:62][CH2:63][CH2:64][CH2:65][CH:66]1[CH2:71][CH2:70][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1>>[NH2:60][C:51]1[N:50]=[C:49]([NH:48][CH2:44][CH2:45][CH2:46][CH3:47])[N:57]=[C:56]2[C:52]=1[N:53]=[C:54]([O:58][CH3:59])[N:55]2[CH2:62][CH2:63][CH2:64][CH2:65][CH:66]1[CH2:67][CH2:68][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73])[CH2:70][CH2:71]1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt and phenylmethyl 4-(4-bromobutyl)-1-piperidinecarboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[N:16][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]2)[CH:15]=[N:16][CH:17]=1
Reactant: CC(=O)N1CCC(O)CC1
Reactant: Oc1cncc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
1-(4-Hydroxy-piperidin-1-yl)-ethanone (200 mg, 1.4 mmol) and 5-bromo-pyridin-3-ol (248 mg, 1.4 mmol) are added to a solution of PPh3 (606 mg, 2.3 mmol) in THF (30 mL). Then diisopropyl azodicarboxylate (462 mg, 2.3 mmol) is added and the mixture is stirred at room temperature for 16 hrs. The mixture is then diluted with DCM, washed with water, dried over Na2SO4, filtered and concentrated. The residue is purified by flash column chromatography to give 250 mg of 1-[4-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.F[C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[C:17](=[O:26])[NH:18][CH:19]=[N:20]2.O>C1COCC1>[F:25][C:23]1[CH:22]=[C:21]2[C:16]([C:17](=[O:26])[NH:18][CH:19]=[N:20]2)=[C:15]([O:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:24]=1
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Reactant: OC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]cnc2cc(F)cc(OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (6.15 g) was added to a solution of 4-hydroxytetrahydropyran (2.94 g) in THF (40 ml) and the mixture was stirred at ambient temperature for 15 minutes. The resultant mixture was added to a stirred solution of 5,7-difluoro-3,4-dihydroquinazolin-4-one (5 g) in THF (60 ml) that was being heated to reflux. A further portion of THF (20 ml) was added and the reaction mixture was heated to reflux for 30 minutes. A second portion of potassium tert-butoxide (6.15 g) was added and the reaction mixture was heated to reflux for 40 minutes. A third portion of potassium tert-butoxide (1.52 g) was added and the reaction mixture was heated to reflux for 20 minutes. The reaction mixture was allowed to cool to ambient temperature. Water (50 ml) was added and the bulk of the organic solvent was evaporated. The residue was acidified to pH<2 by the dropwise addition of 2M aqueous hydrochloric acid. The resultant slurry was stirred for 15 minutes. The mixture was filtered and the isolated solid was washed with water (20 ml) and dried overnight in vacuo at 40° C. There was thus obtained 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (5.96 g; 96% HPLC purity using Method A, retention time 3.34 minutes); NMR Spectrum: (DMSOd6) 1.6-1.75 (m, 2H), 1.9-2.0 (m, 2H), 3.5-3.6 (m, 2H), 3.85-3.95 (m, 2H), 4.8 (m, 1H), 6.9 (m, 1H), 7.05 (m, 1H), 8.0 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[S:22][C:21]([S:23]([NH:1][C@H:2]([CH2:3][OH:4])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: CCC(CC)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 45.2 %

Procedure:
A mixture of (S)-2-amino 3ethyl pentan-1-ol (9) (200 mg) and methylene chloride (20 mL) was placed under argon, and cooled to 0° C. Triethyl amine (484 mg) was added followed by the drop wise addition of 5-chlorothiophene-2-sulfonyl chloride (347.2) in methylene chloride (5 mL) for 30 min to obtain (S)—N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol (1A) (45.2% overall yield and 98% ee).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7]C(O)=O.[CH2:14]([N:16](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH:14]1[C:4]2[C:5](=[CH:11][CH:12]=[CH:13][CH:3]=2)[CH:6]=[CH:7][N:16]=1
Reactant: CCN(CC)CC
Reactant: COc1cccc(C=CC(=O)O)c1
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc2cnccc2c1
Temperature: 210 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of 3-methoxy cinnamic acid (11.04 g, 62 mmol) and triethylamine (12.52 g, 124 mmol) in acetone (80 mL) was added ethyl chloroformate (approximately 1.5 equivalents) dropwise at 0° C. After stirring at this temperature for 1 h, aqueous NaN3 (6.40 g, 100 mmol in 35 mL H2O; appropriate precautions must be taken when using sodium azide) was added dropwise and the reaction mixture was stirred for 16 h at the ambient temperature. Water (100 mL) was added to the mixture and the volatile was removed in vacuo. The resulting slurry was extracted with toluene (3×50 mL) and the combined organic layers were dried over MgSO4. This dried solution was added dropwise to a heated solution of diphenylmethane (50 mL) and tributylamine (30 mL) at 190° C. The toluene was distilled off as added. After complete addition, the reaction temperature was raised to 210° C. for 2 h. After cooling, the precipitated product was collected by filtration, washed with hexane (2×50 mL), and dried to yield the desired product as a white solid (5.53 g, 51%) (Nicolas Briet et al, Tetrahedron, 2002, 5761–5766).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].CN(C=O)C.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1C(=O)c2cccnc2N(Cc2ccccc2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of 4.0 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 100 ml of dry DMF was added 1.2 g of 50% NaH in mineral oil. The resulting solution was heated to 60° C. for one hour. The dark red solution was cooled to 30° C. and 2.5 ml of benzyl bromide was added and stirred overnight under nitrogen. Methanol was added slowly until bubbling ceased, and the reaction mixture was then poured into 400 ml of water. The product was extracted with ether, dried over MgSO4, then concentrated and purified by column chromatography over silica gel. Elution of the material with 2% ethyl acetate/methylene chloride gave a white solid, which was recrystallized from methylene chloride/ether/petroleum ether to give 2.2 g (39% of theory) of 6,11-dihydro-11-benzyl-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazapin-5-one, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12]2)[N:4]=1.[O-:21]Cl.[Na+].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:19]2[C:14]([C:13]([OH:12])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[N:4]=1
Reactant: [O-]Cl
Reactant: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)nc(C(=O)c2cccnc2C(=O)O)n1
Temperature: 50 °C

Procedure:
(Table E, cpd. no. 63) 490 mg of 5-(4,6-dimethoxy-2-pyrimidinyl)-furo [3,4-b]pyridine-7(5H)-one is dissolved in 50 ml of methanol and the mixture heated with stirring at 50° C. until a homogenous solution is formed (ca 1/2 hr). 2.6 g of NaOCl is added dropwise and the solution heated for a further 1/2 hr at 55° C. 0.208 g of 50% NaOH is added at 55° and the mixture heated for a further 1/2 hr at this temperature and then cooled in an ice-bath and acidified with 1 ml conc. HCl. The solvent is evaporated and the residue partitioned between 50 ml of CH2Cl2 and 50 ml of water. The organic phase is concentrated to give a white solid, m.p. 71°-73°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[CH3:15][NH:16][CH3:17]>C1COCC1>[CH3:15][N:16]([CH3:17])[CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a seal tube was added 4-(2-bromoethoxy)-2-nitroaniline (4.5 g, 17 mmol), THF and 40 mL of 2M dimethylamine in THF. The mixture was heated to 80° C. and was stirred overnight. The suspension was concentrated, and the residue was triturated with ether to give 3.5 g of 4-(2-(dimethylamino)ethoxy)-2-nitroaniline which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.24 (s, 1H), 6.91 (d, 1H), 6.61 (d, 1H), 5.85 (bs, 2H), 4.04 (t, 2H), 2.78 (t, 2H), 2.27 (s, 6H). MS (EI): 226 (MH+).