Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:16][C:17]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]=O>C(O)=O.O.[OH-].[Na+]>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:17]2[N:16]=[C:15]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:12]3[CH2:13][CH2:14][N:8]([CH3:6])[CH2:9][C:10](=[CH2:34])[C:11]=3[N:18]=2)=[CH:25][CH:24]=1
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccc(F)cc3)nc(-c3ccc(F)cc3)c2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: C=C1CN(C)CCc2c1nc(Cc1ccc(F)cc1)nc2-c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylic acid tert-butyl ester in formic acid was added paraformaldehyde (10 equiv.). The mixture was heated at 80° C. for 6 h. The mixture was diluted with water and basified to pH ˜10 with 1 M NaOH. The mixture was extracted with CH2Cl2, dried and concentrated. Chromatography on SiO2 (0-5% 2 M NH3 in MeOH/CH2Cl2) afforded the desired compound. 2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine was also obtained. MS (ESI): exact mass calcd. for C23H21F2N3, 377.17; m/z found, 378.4 [M+H]+. 1H NMR (CDCl3): 7.50-7.46 (m, 2H), 7.42-7.37 (m, 2H), 7.17-7.12 (m, 2H), 6.99-6.94 (m, 4H), 6.03-6.01 (m, 1H), 5.47-5.46 (m, 1H), 4.25 (s, 2H), 3.51 (s, 2H), 2.87-2.83 (m, 2H), 2.76-2.72 (m, 2H), 2.41 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[C:15]([CH2:14][N:8]2[C:7](=[O:12])[CH:6]=[C:5]3[C:10]([N:11]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[CH:9]2)[CH:16]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1cc2ccc(Br)nc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cc3nc(Br)ccc3cc2=O)c1

Procedure:
The alkylation of 7-bromo-3-hydroxy-8-azaisoquinoline (1.00 g, 4.46 mmol) using methyl 3-(bromomethyl)benzoate (1.53 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([O:25][CH3:26])(=[O:24])[C:22]#[CH:23]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:6]2[N:7]1[CH:8]=[CH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: Oc1c(-c2ccccc2)sc2c3sccc3cc[n+]12
Reactant: C#CC(=O)OC
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Reaction time: 1 h

Procedure:
ca) 22.9 g of 3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) and 13.6 ml of methyl propiolate were heated together under argon in 1000 ml of toluene until the starting material was completely taken up. The solvent was removed in vacuo and the residue was stirred in 500 ml of ether/methanol (9:1) for 1 hour. The yellow crystals obtained were removed by filtration under suction. There was obtained methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 153°-154° (dec.). An additional portion of product of m.p. 151°-152° (dec,) can be obtained by chromatography of the filtrate on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)[nH]1
Product: FC(F)(F)c1cc(Cl)nc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-4-trifluoromethyl-1H-pyridin-2-one (10.0 g, 37 mmol) and phosphoryl chloride (16.75 mL, 183 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as a light brown solid (10.14 g, 95%). MS (ISP) 292.1 [(M+H)+], 294 [(M+2+H)+] and 296 [(M+4+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:5]2=O.[C:20](=[N:26][Si](C)(C)C)=[N:21][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:5]2=[N:26][C:20]#[N:21]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccccc2)Oc2cc(F)c(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccc2)Oc2cc(F)c(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 6-bromo-7-fluoro-2-phenylchroman-4-one (400 mg, 1.25 mmol) in DCM (10 mL) was added TiCl4 (2.5 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.62 mL, 2.75 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(6-bromo-7-fluoro-2-phenylchroman-4-ylidene)cyanamide (327 mg, 78%). 1H-NMR (CDCl3): 3.19 (m, 1H), 3.49 (m, 1H), 5.34 (m, 1H), 6.81 (d, 1H), 7.41 (m, 5H), 8.27 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.S(=O)(=O)(O)[OH:17].[C:21](O)(=[O:23])[CH3:22]>>[C:21]([O:1][CH2:2][CH2:3][CH2:4][C:5]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1)=[O:17])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(C#CCCO)cc1
Reactant: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(=O)CCCOC(C)=O)cc1
Temperature: 140 °C

Procedure:
To 10.0 g (1 eq) of methyl 4-(4-hydroxy-1-butynyl)benzoate in 200 ml of 90% aqueous acetic acid and 2.4 g (0.15 eq) of mercuric acetate were added 1.0 ml of concentrated sulfuric acid. The mixture was refluxed for 2 hours at approximately 140° C., and cooled to room temperature to facilitate precipitation of mercury salts. The precipitated mercury salts were removed by filtration and the filtrate extracted three times with dichloromethane. The acidic extract was neutralized to pH 7 with solid sodium bicarbonate and the aqueous layer then extracted with dichloromethane. The extracts were dried over magnesium sulfate and evaporated under reduced pressure to yield the product which was further purified by flash chromatography eluting with 1:2 ethylacetate:hexanes. m.p. 61-62° C. M.S.: m/z=264 (M+, CI), 233.0812 (M+ --CH3O, calc. for C13H13O5 : 233.0814), 204 (M+ -AcOH), 176, 163 (100%), 143. 1H-N.M.R. (CDCl3, 300 MHz): δ=2.08 (s, 3H, CH3 --CO); 2.10 (quin, 2H, CH2 --CH2 --CH2, J=7.5 Hz); 3.12 (t, 2H, CH2 --CO, J=7.5 Hz); 3.96 (s, 3H, CH3O); 4.20 (t, 2H, CH2O, J=7.5 Hz); 8.02 (d, 2Harom., J=9 Hz); 8.18 (d, 2Harom., J=9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[C:9]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(F)cc1
Reactant: Cc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)c2ccc(F)cc2)nc1
Yield: 66.1 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (3.97 g), 2-bromo-5-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF (125 ml) was added sodium hydride (2.35 g, 60%) at 0° C. and the mixture was heated to reflux for 6 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 2-(α-cyano-4-fluorobenzyl)-5-methylpyridine (4.35 g) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
to a stirred solution of 4-hydroxybenzaldehyde (25.0 g, 205 mmol) in dry DMF (200 mL) was added imidazole (28.0 g, 410 mmol) and TBDMS-Cl (32.4 g, 215 mmol) under an argon atmosphere. The resulting mixture was stirred for 4 h at room temperature (rt) then water was added and the mixture was extracted with ether (2×300 mL) and dichloromethane (2×300 mL). The combined organics were dried (MgSO4), filtered and concentrated under vacuum. The crude oil was purified by filtration through silica gel (eluting with hexane-EtOAc, 95:5) to give the product as a colourless oil (48.0 g, 99%).
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[C:7]1([CH:13]([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=O)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C[O:26]CC1>>[C:7]1([C:13]2([CH3:14])[CH2:15][CH:17]([C:22](=[O:26])[CH:21]=[CH:20][CH2:19][CH3:18])[CH2:3][CH2:2][CH2:1]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C(=O)C1CCCCC1)c1ccccc1
Reactant: C1CCOC1
Agent: [K+]
Product: CCC=CC(=O)C1CCCC(C)(c2ccccc2)C1
Yield: 91.58 %

Procedure:
A solution of 31.39 g (0.2797 mol) of t-BuOK in 100 mL of THF was added dropwise to a solution of 55.00 g (0.2543 mol) of cyclohexyl 1-phenylethyl ketone and 26.4 mL (0.3052 mol) of alkyl bromide in 136 mL of THF (cooled in a wet ice acetone bath). THF washings (16 mL) were added to the reaction mixture. The cooling bath was removed after addition. After reaction completion (2 h), the reaction mixture was quenched with 300 mL of 1 N HCl (pH=0) and extracted with 300 mL of heptane. The heptane extract was washed with 10% NaHCO3 (aq) (pH=9), dried over MgSO4, gravity filtered and concentrated under vacuum to afford 59.70 g (91.58%) of title compound as an amber oil: 1H NMR (d6-DMSO): δ 7.32-7.42 (m, 2H, phenyl CH), 7.24-7.31 (m, 3H, phenyl CH), 5.34-5.47 (m, 1H, —CH═CH2), 5.02 (dd, J=17.1 Hz, J=2.1 Hz, 1H, —CH═CH—H (trans)), 4.97 (ddd, J=10.2 Hz, J=2.2 Hz, J=1.0 Hz, 1H, —CH═CH—H (cis, W-coupling)), 2.66 (ddd, J=14.2 Hz, J=6.9 Hz, J=1.0 Hz, 1H, —CH2CH═CH2), 2.59 (ddd, J=14.2 Hz, J=7.3 Hz, J=1.0 Hz, 1H, —CH2CH═CH2), 2.38-2.49 (m, 1H, cyclohexyl CH), 1.48-1.69 (m, 4H, cyclohexyl-CH2), 1.46 (s, 3H, —CH(CH3)Ph), 1.36-1.44 (m, 1H, cyclohexyl-CH2), 0.82-1.36 (m, 5H, cyclohexyl-CH2).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[C@@H:6]([CH3:21])[CH2:5][C:4]=2[CH:3]=1.C1(C)C=CC(S(O)(=O)=[O:29])=CC=1.[C:33]1(C)C=[CH:37][CH:36]=[CH:35][CH:34]=1>O1C=CCCC1.C(OCC)(=O)C>[CH3:21][C@H:6]1[CH2:5][C:4]2[CH:3]=[C:2]([O:1][CH:37]3[CH2:36][CH2:35][CH2:34][CH2:33][O:29]3)[CH:19]=[CH:18][C:17]=2[C@@H:16]2[C@@H:7]1[C@H:8]1[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]21
Reactant: Cc1ccccc1
Agent: C1=COCCC1
Solvent: CCOC(C)=O
Product: C[C@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]21

Procedure:
A suspension of 1.2 g of 3-hydroxy-7β-methyl-estra-1,3,5(10)-trien-17-one in 12 ml of toluene and 1.2 ml of dihydropyran is stirred with 5.6 mg of para-toluenesulfonic acid for 2 hours at room temperature. Then, it is diluted with ethyl acetate, washed with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. 1.22 g of 7β-methyl-3-tetrahydropyranyloxy-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([O:9][CH2:10][CH:11]1[CH2:15][O:14]C(C)(C)[O:12]1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([O:9][CH2:10][CH:11]([OH:12])[CH2:15][OH:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)OCC1COC(C)(C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)OCC(O)CO
Reaction time: 3 h

Procedure:
The solution from 2,2-dimethyl-[1,3]dioxolan-4-yl-methyl 2-acetoxybenzoate (5.7 g, 19.4 mmol) in dichloromethane (50 ml) is treated with trifluoroacetic acid (10 ml). After 3 h, the mixture is concentrated in vacuo, the residue is taken up in toluene (30 ml) and the solution is concentrated. The residue is purified by flash chromatography (gradient hexane/ethyl acetate=3/1→2/1 →1/1). Yield: 2.96 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[C:4]([CH:8]=[C:9]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:16][C:15]=3[NH:14][C:13]([CH3:25])=[C:12]2[C:26]#[N:27])[CH:10]=1)[C:5](O)=[O:6].[Cl-].[NH4+].C[N:41](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.O>[Br:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[C:4]([CH:8]=[C:9]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:16][C:15]=3[NH:14][C:13]([CH3:25])=[C:12]2[C:26]#[N:27])[CH:10]=1)[C:5]([NH2:41])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(N)=O)c1
Reaction time: 17 h

Procedure:
A mixture of 3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-methoxy-benzyloxy)-benzoic acid (57 mg), ammonium chloride (18 mg), HATU (57 mg) and N,N-diisopropylethylamine (34 μl) in DMF (0.8 ml) was stirred for 17 h. The mixture was diluted with water and extracted with ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].[CH3:14]O>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1cc(O)c(CC(=O)O)cc1O
Reactant: CO
Product: COC(=O)Cc1cc(O)c(C)cc1O

Procedure:
A mixture of 145.6 g of 2,5-dihydroxy-4-methylphenylacetic acid and 45 g of dry sulfonic acid resin (IRN-77R) is heated under reflux in 4.38 liters of absolute methanol. The mixture is filtered and the filtrate evaporated. The white solid is recrystallized from a mixture of ethyl acetate and heptane (50:50), yielding white crystals with the following characteristics:
Reaction SMILES: C[C:2]([CH3:11])([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:3](O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:19])C=CC=CC=1.C([N:31]([CH2:34]C)CC)C>C1(C)C=CC=CC=1>[N:31]([C:2]([CH3:3])([CH3:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[C:34]=[O:19]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: COC(=O)CC(C)(C)C(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CC(C)(C)N=C=O
Temperature: 5 °C

Procedure:
A solution of 2,2-dimethyl-3-carbomethoxypropionic acid (LeMaul, Bull. Soc. Chim. Fr., 828 (1965), 20 g, 0.125 mol), diphenylphosphorylazide (34.3 g, 0.125 mol) and triethylamine was heated in toluene (150 ml) at 100° C. for 2 h. After cooling to 5° C., the toluene solution was washed successively with 0.5M HCl, aqueous NaHCO3 and brine. Evaporation of the dried solution gave a residue which was chromatographed on silica gel eluting with 60/40 hexane-ether. There was obtained 13 g of methyl 3-isocyanato-3-methylbutanoate as a mobile liquid. A solution of this material in toluene (20 ml) was treated with benzyl alcohol (13 ml) and the resulting mixture heated at reflux for 40 h. Evaporation of the toluene left a residue which was dissolved in methanol (125 ml) and then treated with a solution of NaOH (6.6 g, 0.165 mol) in 22 ml of water. After 5 h, the reaction mixture was partially evaporated, washed with ether and acidified with 6N HCl. Extraction with methylene chloride and evaporation gave 21 g of the desired product. NMR (300 MHz, CDCl3): 1.42 (s,6H), 2.78 (s,2H), 5.08 (s,2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][CH:29]=4)=[CH:23][C:22]=3[CH3:38])[N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].CO.Cl>C1COCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][C:21]3[C:22]([CH3:38])=[CH:23][C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([OH:36])=[O:35])=[CH:32][CH:33]=4)=[CH:25][C:26]=3[CH3:27])[N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2cc(C)c(Oc3nc(Nc4ccc(C#N)cc4)nc4c3ncn4C)c(C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of methyl 4′-(2-(4-cyanophenylamino)-9-methyl-9H-purin-6-yloxy)-3′,5′-dimethylbiphenyl-4-carboxylate (110 mg, 0.22 mmol) and lithium hydroxide (100 mg, 2.38 mmol) in) in a mixture of THF (3 mL), MeOH (1 mL), and H2O (1 mL) was stirred at rt for 3 h. The reaction mixture was diluted with H2O (5 mL) and acidified (1 N HCl). The resulting precipitate was collected by filtration to yield the desired compound (90 mg). MS (ESI): m/z 491 (M+1)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([N:22]3[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]3=[O:34])[C:19]([F:35])=[CH:18][C:17]=2[Cl:36])[N:10]=1)C1C=CC=CC=1.O>FC(F)(F)C(O)=O>[Cl:36][C:17]1[CH:18]=[C:19]([F:35])[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]=1[O:15][C:11]1[N:10]=[C:9]([OH:8])[CH:14]=[CH:13][N:12]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nccc(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nccc(O)n3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of 1 g of 4-benzyloxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine in trifluoroacetic acid was stirred for 2 hours at 70° C. This reaction solution was cooled to room temperature, then, poured into water, and filterated to obtain 0.3 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-pyrimidine.
Reaction SMILES: Cl.[S:2]1([CH2:8][CH:7]=[CH:6][CH2:5]1)(=[O:4])=[O:3].[C:9]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=1)(=O)[CH3:10].[CH3:21][OH:22]>>[S:2]1([CH2:8][CH:7]=[CH:6][CH2:5]1)(=[O:4])=[O:3].[CH2:21]([O:22][CH2:10][CH2:9][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=1)[CH3:5].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CO
Agent: Cl
Agent: O=S1(=O)CC=CC1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OCCOCC)cc1
Yield: 95 %

Procedure:
To mixture solution which is 20 mL of methanol and 30 mL of 1N hydrochloric acid was added poly(butadiene sulfone/4-acetoxy styrene) obtained from Stage 1(0.05 mole). And the resulting solution was reacted at about 50° C. for about 10 hours, thereby obtaining the entitled compound (yield: 95%).
Reaction SMILES: C1(SC[Cl:9])C=CC=CC=1.C1(S[CH2:17][N:18]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:19]2(=[O:21])=[O:20])C=CC=CC=1.S(Cl)(Cl)(=O)=O>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[Cl:9][CH2:17][N:18]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:19]1(=[O:21])=[O:20]
Reactant: O=C1c2c(-c3ccccc3)cccc2S(=O)(=O)N1CSc1ccccc1
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1c2c(-c3ccccc3)cccc2S(=O)(=O)N1CCl
Yield: 93 %

Procedure:
Following a procedure similar to that described in Preparation 1, the latter (0.33 g, 0.0012 mol) was reacted with 0.3 g (0.0019 mol) of chloromethyl phenyl sulfide in 15 ml of toluene in the presence of 0.08 g (0.0025 mol) of TBAB and the product, 2-phenylthiomethyl-4-phenylsaccharin (0.48 g, 100%), treated with sulfuryl chloride in MDC to give 0.36 g (95%) of 2-chloromethyl-4-phenylsaccharin.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl>O>[CH3:13][N:12]([CH3:14])[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:6]([OH:8])=[O:7])(=[O:16])=[O:15]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)ccc1N1CCNCC1
Reaction time: 1 h

Procedure:
264 Grams of 4-chloro-3-dimethylsulfamoylbenzoic acid (1.0 mole) and 345 g of anhydrous piperazine were heated at 130° C., while stirring, for 1 hour. Subsequently the reaction mixture was dissolved in 2 l of water and the pH value was adjusted to 7 with 5N HCl. After having stood over night, the crystalline precipitate was suction-filtered, washed with water and tetrahydrofurane and recrystallized from water.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:51]=[CH:52][CH:53]=1)[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH:19]2[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][CH2:42][N:41]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]=3[CH:50]=2)=[CH:14][CH:13]=1)=O)C.[NH3:54]>O1CCCC1>[C:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:51]=[CH:52][CH:53]=1)[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH:19]2[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][CH2:42][N:41]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]=3[CH:50]=2)=[CH:14][CH:13]=1)(=[O:3])[NH2:54]
Reactant: N
Reactant: CCOC(=O)Cc1cccc(OCc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3OCc3ccc4c(c3)N(CCCOC)CCO4)cc2)c1
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4cccc(CC(N)=O)c4)cc3)cc21

Procedure:
A solution of 0.114 g of benzyl 4-[4-(3-ethoxycarbonylmethylphenoxymethyl)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 348b), 5 ml of ammonia (7N in methanol) and 1 ml tetrahydrofuran is stirred in a Supelco bottle at 80° C. for 50 hours. After concentration by evaporation, the title compound is obtained as a yellow oil. Rt=4.96.