Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([CH3:25])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:3]1.COCCN(S(F)(F)[F:36])CCOC>C(Cl)Cl.C1COCC1>[F:36][C:2]1([CH3:25])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC(C)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (100 mg, 0.28 mmol) in DCM (5 mL) was added deoxo-Fluor® (50% in THF, 0.26 mL, 0.7 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (30 mL), cooled in an ice water bath and quenched by dropwise addition of saturated aqueous NaHCO3 (40 mL). The resulting mixture was stirred for 10 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was purified via silica gel column chromatography (0-50% EtOAc/isohexane) to give tert-butyl 6-fluoro-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (70 mg, 70%) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.80 (s, 3H), 3.73-3.32 (m, 6H), 3.26-3.03 (m, 2H), 1.50 (s, 9H), 1.32 (d, J=20.1 Hz, 3H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:28]1>CS(C)=O.C(OCC)(=O)C.CCCCCC>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([N:36]2[CH2:37][CH2:38][N:39]([CH2:11][CH:12]3[O:25][C:16]4=[C:17]5[C:21](=[CH:22][CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:24])[CH2:18]5)[CH2:40][CH2:41]2)=[N:28]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=C1Cc2c(ccc3c2OC(CN2CCN(c4nsc5ccccc45)CC2)CO3)N1
Temperature: 25 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.7 mmole) and 1-(1,2-benzisothiazol-3-yl)piperazine (2.2 g, 10 mmole) are combined in 30 ml of dry DMSO and heated at 80°-90° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture is diluted with 500 ml of 1:1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate and with two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue is column chromatographed on silica gel using 0.5% methanol/CHCl3 as eluant to give the free base of the title compound. The product is crystallized from ethanol with the addition of one equivalent of fumaric acid to give the (S) enantiomer of the title compound as a fumarate salt.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]1[NH:32][C:33]2[C:38]([C:39]=1[CH3:40])=[CH:37][C:36]([OH:41])=[CH:35][CH:34]=2>CN(C=O)C>[CH3:30][C:31]1[NH:32][C:33]2[C:38]([C:39]=1[CH3:40])=[CH:37][C:36]([O:41][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:35][CH:34]=2
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 41.5 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (360 mg, 1.00 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (215 mg, 1.56 mmol) and 2,3-dimethyl-5-hydroxyindole (177 mg, 1.10 mmol), (Arch. Pharm. 1972, 305, 159), in DMF (8.0 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue purified by silica column chromatography eluting with methanol (2.5%) in dichloromethane. The resulting solid was recrystallised from tertbutyl methyl ether/acetonitrile, filtered and washed with diethyl ether to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (201 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=C[CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].C[N:29](C)C(C1N=CC(Br)=CN=1)=O.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[N:29][C:20]([C:23](=[O:27])[N:24]([CH3:25])[CH3:26])=[N:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ncc(Br)cn1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 5-bromo-pyrimidine-2-carboxylic acid dimethylamide (164a) (271 mg, 1.18 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (262 mg, 1.18 mmol) to give a white foam (110 mg, 25% yield). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2 H) 7.24-7.36 (m, 1 H) 7.20 (s, 1 H) 3.88 (s, 3 H) 3.17 (s, 3 H) 3.00 (s, 3 H) 2.95 (s, 2 H) 1.51 (s, 6 H); LCMS for C19H21N3O5 m/z 372.00 (M+H+).
Reaction SMILES: [N:1]([CH:4]([C:17]1[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[N:19][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:15][CH3:16])[O:14][CH2:13][CH2:12][O:11]1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[CH2:15]([C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH2:1])[C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[N:19][CH:18]=2)[O:11][CH2:12][CH2:13][O:14]1)[CH3:16]
Reactant: CCC1(CCCCCC(N=[N+]=[N-])c2cnc(-c3ccc4ccccc4c3)n2COCC[Si](C)(C)C)OCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC1(CCCCCC(N)c2cnc(-c3ccc4ccccc4c3)n2COCC[Si](C)(C)C)OCCO1

Procedure:
The azide (M5) (1 eq.) was dissolved in EtOAc and stirred in the presence of 10% Pd/C under an H2 atmosphere for 1 hr. The H2 atmosphere removed and N2 introduced. The reaction mixture was filtered and the catalyst washed with MeOH and the filtrates concentrated under reduced pressure. The residue was purified by column chromatography eluting with 70% EtOAc/Petroleum ether to afford the amine.
Reaction SMILES: C(O[CH:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37]CC4C=CC=CC=4)=[CH:33][CH:32]=3)[CH:24]=2)[O:6]1)(=O)C.N[C:46](N)=[S:47].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CI.CCN(C(C)C)C(C)C>C1COCC1.O1CCOCC1.[Pd]>[C:20]([O:19][C@@H:8]1[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([S:47][CH3:46])[O:6][C@H:7]1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC1O[C@@H](c2ccc(C)c(Cc3ccc(OCc4ccccc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(N)=S
Agent: [Pd]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
(3S,4R,5S,6S)-6-(3-(4-(benzyloxy)benzyl)-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (36, 5.29 g, 8.8 mmol) was hydrogenated over 10% Pd/C (50% wet) (0.93 g, 0.44 mmol) in THF (44 mL) under hydrogen at atmospheric pressure for 1 hour. The reaction was filtered through celite, concentrated under vacuum, azeotroped twice with toluene, and placed on the high vacuum to dry thoroughly. The resulting phenol was carried to the next step without further purification. It was combined with thiourea (2.01 g, 26 mmol) and dissolved in dioxane (44 mL). TMSOTf (4.8 mL, 26 mmol) was added. The reaction was heated at 80° C. for 3 hours and then cooled to room temperature. Methyl iodide (2.2 mL, 35 mmol) was added, followed by DIPEA (12 mL, 70 mmol). The reaction was stirred overnight, then quenched with saturated aqueous NaHSO4 (150 mL), stirred vigorously for 2 hours, diluted with EtOAc, washed with H2O and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient 0-50% EtOAc/hexanes) to give 3.88 g (88% yield) of the product 37 as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.10-7.19 (m, 2H), 7.03 (s, 1 H), 6.94 (d, J=8.6 Hz, 2 H), 6.68-6.77 (m, 2 H), 5.33 (t, J=9.3 Hz, 1 H), 5.21 (t, J=9.6 Hz, 1 H), 5.12 (t, J=9.6 Hz, 1H), 4.59 (s, 1 H), 4.52 (d, J=9.9 Hz, 1 H), 4.38 (d, J=9.9 Hz, 1H), 3.82-3.96 (m, 2 H), 2.21 (s, 3 H), 2.18 (s, 3 H), 2.10 (s, 3 H), 2.01 (s, 3 H), 1.75 (s, 3 H); MS (ES+) [M+NH4]+=520.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Mg].[Cl-:15].[Cd+2:16].[Cl-]>O1CCCC1>[Cl-:15].[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([Cd+:16])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: [Cd+2]
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc2cc([Cd+])ccc2c1

Procedure:
A solution is formed by dissolving 24 grams of 2-bromo-6-methoxynaphthalene prepared as in Example 7 above in 300 mL of tetrahydrofuran. The resulting solution is slowly added to 2.5 grams of magnesium turnings in 100 mL of tetrahydrofuran at reflux temperature. After the addition is complete, 20 grams of cadmium chloride is added, and the resultant mixture is refluxed for 10 minutes to yield a solution of 6-methoxy-2-naphthylcadmium chloride in tetrahydrofuran. A solution of 18 grams of ethyl 2-bromopropionate in 20 mL of tetrahydrofuran is then added to the cooled reaction mixture. After 24 hours at 20° C., the product is hydrolyzed by adding 200 mL of 5 weight percent methanolic sodium hydroxide followed by heating to reflux for 1 hour. The reaction mixture is then diluted with excess 1N sulfuric acid and extracted with ether. The ether phase is separated, evaporated to dryness and the residue is recrystallized from acetone-hexane to yield 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: Br[C:2]1C(Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])C)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C:19]2([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:29][CH2:31][CH2:7][CH2:2]2)=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)NCC1(Nc2nc(Cl)ncc2Br)CCCC1

Procedure:
tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate L using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 1.50-1.58 (m, 2H) 1.63-1.78 (m, 4H) 1.96-2.06 (m, 2H) 3.25 (d, J=6.15 Hz, 2H) 6.71 (s, 1H) 7.18 (t, J=6.29 Hz, 1H) 8.20 (s, 1H). LCMS (ESI) 405 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[N:20]1([C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][N:23]2[CH2:22][CH2:21][N:20]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=3)[CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that 4,4-bis(4-fluorophenyl)butyl bromide was used instead of 3,3-diphenylpropyl bromide and the compound prepared in step (a) of Example 80 was used instead of ethyl 3-piperazin-1-yl-benzoate. Thus, ethyl 4-[4-[4,4-bis(4-fluorophenyl)-1-butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:27])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (25.4 g, 147 mmol) in N,N-dimethylformamide (300 ml) were added triethylamine (22.6 ml, 162 mmol) and ethyl 3-chloro-3-oxopropionate (20.7 ml, 162 mmol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into ice water and the precipitated crystals were collected by filtration. These were washed with water and diisopropyl ether in sequence and then air-dried, thereby obtaining 37.1 g of title compound as yellow powder. Yield 88%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:14]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([O:10][CH2:24][C:14]2[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:16][O:17][C:13]=2[CH3:12])[CH:9]=1)=[O:4]
Reactant: Cc1onc(-c2ccccn2)c1CO
Reactant: COC(=O)c1cc(O)nn1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)nn1C
Temperature: 25 °C
Yield: 29.4 %

Procedure:
To a stirred solution of 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (355 mg, 2.28 mmol) and (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (432 mg, 2.28 mmol) in THF (10 mL) at 5° C. under argon was added triphenylphosphine (775 mg, 2.95 mmol), then diethyl azodicarboxylate (515 mg, 2.95 mmol) was added dropwise. The reaction mixture was warmed to room temperature overnight. Then the reaction mixture was evaporated and purified by chromatography (silica, heptane:ethyl acetate=1:1 to 7.5:2.5) to afford the title compound (220 mg, 30%) as a white solid. MS: m/e=329.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:16][N:17]([CH:19](OC)OC)[CH3:18]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[C:9]([C:8](=[O:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[CH:16][N:17]([CH3:19])[CH3:18])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1F

Procedure:
A mixture of ethyl 3-(2-fluorophenyl)-3-oxopropanoate (14.29 g, 68.0 mmol) and DMF-DMA (12.15 g, 0.102 mol, 1.5 eq.) in toluene (50 mL) was refluxed for 2 hours and concentrated to give 3-dimethylamino-2-(2-fluoro-benzoyl)-acrylic acid ethyl ester as a red oil in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1)([O-])=O.O.NN.[H][H]>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:8][CH:9]=1
Reactant: CCCn1c(=O)c2[nH]c(Cc3cccs3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3cccs3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 2-thiopheneacetic acid is reacted with 5,6-diamino -1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine.
Reaction SMILES: [CH2:1]([C:5]([CH:7]1[CH2:12][CH2:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH2:8]1)=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:15]([OH:17])C.C=O.[OH-].[K+]>CO.C(O)(=O)C>[CH2:1]([C:5]([C:7]1([CH2:15][OH:17])[CH2:12][CH2:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH2:8]1)=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC1=C(C)CC(C(=O)CC(C)C)CC1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC1=C(C)CC(CO)(C(=O)CC(C)C)CC1

Procedure:
A mixture of 65.6 g (0.338 mole) of 3,4-dimethylcyclohex-3-enyl isobutyl ketone (Example XXII), 120 ml of ethanol and 109.6 g of 37% strength formaldehyde solution (=1.35 moles) is brought to a pH of 11-12 with a 15% strength solution of potassium hydroxide in methanol, and is then refluxed for 44 hours, the pH being checked. Thereafter the solution is brought to pH 5 with glacial acetic acid and the solvent is distilled off under reduced pressure. Water is added to the residue and after saturation with sodium chloride the mixture is extracted five times with toluene. The organic phases are dried over anhydrous sodium sulfate, the solvent is distilled off on a rotary evaporator and the residue is distilled under reduced pressure. 37.7 g of 3,4-dimethyl-1-hydroxy-methyl-cyclohex-3-enyl isobutyl ketone pass over at 112°-116° C./0.1 mm Hg.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:22]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[CH2:23].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:2]([N:9]1[C@@H:14]2[C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])[CH2:23][C@@:10]1([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:15])[CH:12]=[CH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1C=C[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (Description 1; 4.91 g, 14.3 mmol), phenyl vinyl sulphone (4.2 g, 25 mmol), triethylamine (2.8 ml, 20 mmol) and 1,4-dioxane (50 ml) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was poured onto saturated aqueous NaHCO3 and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (isohexane:diethyl ether 10-70%) to give the title compound (4.84 g, 78%) as a yellow-orange foam. Crystallisation from iso-hexane:diethyl ether gave the product as yellow rhombs.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[C:15]([Li])(C)(C)C.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:15][C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: [Li]C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At −78° C. a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (5 g, 23.8 mmol) in THF is treated with tert.-butyllithium (41 mL, 1.5 M in pentane). The mixture is stirred at −78° C. for 15 min before methyliodide (17.1 g, 120 mmol) is added dropwise. Stirring is continued at −78° C. for 30 min. The mixture is warmed to rt, diluted with water (400 mL), acidified with 10% aq. citric acid solution and extracted three times with EA. The combined organic extracts are dried over MgSO4 and evaporated. The remaining solid is suspended in heptane/diethyl ether, filtered and dried under HV to give 3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (4.01 g) as a beige powder; LC-MS: tR=0.97 min, [M+1]=225.13; 1H NMR (D6-DMSO): δ 12.49 (s br, 1H), 2.87 (t, J=6.7 Hz, 2H), 2.26 (s, 5H), 1.45 (t, J=6.7 Hz, 2H), 0.91 (s, 6H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[N:21][CH:22]=[N:23][CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: OB(O)c1cncnc1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3cncnc3)c2c1
Yield: 34 %

Procedure:
This compound was prepared from 6b using 5-pyrimidinylboronic acid according to method P. Yellow powder; Yield: 34%; mp>340° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 7.00 (d, J=2.6 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.36 (dd, J=9.0, 2.6 Hz, 1 H), 7.98–8.02 (m, 2H), 8.08 (s, 1H), 8.11 (dd, J=13.1, 2.2 Hz, 1H), 9.11 (s, 2H), 9.37 (s, 1H), 10.07 (s, 1H), 10.24 (s, 1H); MS (ESI) m/z 332 ([M−H]−), 334 ([M+H]+); Anal. Calcd for C19H12FN3O2: C: 68.47, H: 3.63, N: 12.61. Found: C: 65.37, H: 3.98, N:11.30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1conc1-c1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1conc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 0.79 g of Compound 8C, 3.5 mL of acetic acid and 3.05 mL of 37% HCl was refluxed for 4 h. After cooling to r.t., the solvent was evaporated to dryness at reduced pressure and the crude was taken up with 15 mL of water. The precipitate was filtered off and dried to give 0.632 g (85.9%) of the title compound. M.p. 170-174° C.