Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([S:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: SCc1ccccc1
Reactant: C[n+]1ncc(N)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[n+]1ncc(N)cc1SCc1ccccc1

Procedure:
24.4 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 200 parts of acetonitrile is stirred with 12.4 parts of benzylmercaptan and 20 parts of triethylamine for 3 hours at 80°C. The solvent is then distilled off at subatmospheric pressure, the residue is treated with about 300 parts of water and the sparingly soluble reaction product is suction filtered. 29.5 parts (89.2% of theory) of 1-methyl-4-amino-6-benzylmercaptopyridazinium perchlorate is obtained; C12H14O4N3SCl, melting point 139° to 141°C.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].O[Li].O.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CO.O>[CH2:1]([O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH2:10][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(C)C(=O)OCC
Reactant: C=CCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C=CCCCCCCCCOC(=O)C(C)OCC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
3,5 g of crude ethyl (RS)-2-allyloxy-propionate are introduced into 24 ml of MeOH/H2O=3:1, cooled to 0° C., and then 2.2 g (30 mmol) of LiOH·H2O are added in portions. The mixture is further stirred for 5 minutes before the ice cooling is removed and the mixture is stirred for a further 1 h at room temperature. Methanol is then removed on a rotary evaporator and the residue is taken up in water. The aqueous phase is firstly extracted with Et2O in order then to be acidified to pH 1 with 6N HCl. The aqueous phase is then saturated with NaCl and extracted three times with EtOAc. The combined organic phases are dried over Na2SO4, filtered and freed from solvent on a rotary evaporator. The resulting carboxylic acid is dissolved in 40 ml of toluene and treated with 4.7 g (30 mmol) of 9-decen-1-ol and 0.38 g (2 mmol) of p-toluenesulfonic acid. The mixture is then heated using a water separator until visible amounts of water no longer separate out. After cooling to room temperature, the reaction solution is once again wash ed with saturated NaHCO3 solution, then dried over Na2SO4, filtered and freed from solvent on a rotary evaporator. Flash chromatography (cyclohexane/EtOAc=20:1, Rf=0.31) over silica gel gives 2.8 g (52.2%) of dec-9-enyl (RS)-2-allyloxy-propionate as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:16]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:16]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(OCCOc3ccc(F)cc3)nn(C)c2N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(OCCOc3ccc(F)cc3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To 4-(tert-butyl)-N-{[4-(tert-butyl)phenyl]sulfonyl}-N-[3-[2-(4-fluorophenoxy)ethoxy]-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Preparation 25) (180 mg) in dioxan (5 ml) at room temperature was added 1N aqueous sodium hydroxide (5 ml) and the mixture was stirred and heated to 100° C. for 1.5 hrs. The reaction was partitioned between 2N aqueous hydrochloric acid (25 ml) and ethyl acetate (25 ml). The organic layer was separated, washed with water, then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel (20 g), eluting with a solvent gradient of pentane:ethylacetate (19:1 changing to 7:3), to yield the title compound as a glass (106 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[S:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[S:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCNCC4)s3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCN(CCCCO)CC4)s3)ccc21

Procedure:
The preparation was carried out as already described starting from 125 mg (0.35 mmol) of 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-thiadiazol-2-yl]piperidine and 76 μl (0.53 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][O:5][CH2:6][CH3:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1.O>[CH2:6]([O:5][CH2:4][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2][NH:1][C:23](=[O:24])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:7]
Reactant: CCOCC(CN)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCC(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (1-amino-3-ethoxypropan-2-yl)carbamate (0.45 g, 2.6 mol) and sodium carbonate (0.29 g, 3.2 mol) in THF (5 mL) and water (3 mL) was added dropwise benzyl chloroformate (0.58 g, 3.4 mol) at 0° C. and then the reaction mixture was allowed to warm to ambient temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give benzyl tert-butyl (3-ethoxypropane-1,2-diyl)biscarbamate. MS ESI calc'd. for C18H29N2O5 [M+H]+ 353. found 353. 1H NMR (400 MHz, CD3OD) δ 7.36-7.35 (m, 5H), 5.09 (s, 2H), 3.52-3.49 (m, 1H), 3.42-3.32 (m, 6H), 1.45 (s, 9H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][C:33]([CH:34]=[O:35])=[C:27]3[N:26]=2)[CH:3]=1.[BH4-].[Na+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[C:4]([C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][C:33]([CH2:34][OH:35])=[C:27]3[N:26]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C=O)c2n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(CO)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A solution of (R)-tert-butyl 3-(4-fluoro-2-(1-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)propylcarbamate (85.0 mg, 0.176 mmol) in MeOH (2 mL) was first cooled to 0° C., then NaBH4 (4.04 mg, 0.176 mmol) was introduced, and the reaction was stirred at 0° C. for 1 hour. The reaction was diluted with brine and extracted with DCM in a phase separator cartridge. The combined organic extracts were concentrated to provide (R)-tert-butyl 3-(4-fluoro-2-(1-(3-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)propylcarbamate (86 mg, 101% yield) as beige solid. MS (apci) m/z=468.1 (M+H−H2O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:33])[CH2:30]CBr.C(=O)([O-])[O-].[K+].[K+]>>[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:18][N:16]1[CH:17]=[C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:13]=[CH:14][C:15]1=[O:19]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with methyl-3-bromopropionate in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=482.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[O:3]1.[Si](C=[N+]=[N-])(C)(C)[CH3:17].C(O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:17])=[O:13])[CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)CCc2cccc(C(=O)O)c2O1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2,2-dimethyl-3,4-dihydro-2H-chromene-8-carboxylic acid (300 mg, 1.45 mmol) in methanol (2.10 mL) and toluene (5.20 mL) cooled to 0° C. was added TMS-diazomethane (1.82 mL, 3.64 mmol) dropwise via a syringe. The reaction mixture was warmed to room temperature and stirred for 45 minutes. It was then cooled to 0° C., and acetic acid (2.00 mL) was added carefully. The solvent was evaporated under vacuum and the residue was re-dissolved in EtOAc (80.0 mL), washed with a saturated NaHCO3 solution (20.0 mL, dried over Na2SO4, filtered and concentrated under vacuum. The crude product was used directly to the next step without further purification.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[CH2:6]([O:13][C:14](=[O:27])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([O:13][C:14](=[O:27])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:1][C@@H:2]([OH:3])[CH2:4][OH:5])=[CH:22][CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: OC[C@H]1CO1
Solvent: CCO
Product: O=C(NCCCCc1ccc(NC[C@@H](O)CO)cc1)OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of (S)-(−)-glycidol (0.16 mL, 2.3 mmol) in ethanol (5 mL) was added dropwise to a stirring solution of N-[4-(4-aminophenyl)butyl]carbamic acid benzyl ester (0.59 g, 1.97 mmol) in ethanol (15 mL) at 70° C. The reaction mixture was stirred at 70° C. (oil bath) overnight. The solvent was removed under reduced pressure and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, chloroform/methanol/ammonium hydroxide, 15:1:0.1, v/v) to give 700 (0.29 g, 40%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.51 (m, 4H), 2.48 (t, 2H), 3.07 (m, 1H), 3.26 (t, 2H), 3.30 (m, 1 if), 3.57 (m, 2H), 3.80 (m, 1H), 5.00 (s, 2H), 6.59 (d, 2H), 6.99 (d, 2H), 7.33 (m, 5H). m/z (ESI) 373 [C21H28N2O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32]Br.[F:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[C:39]([F:43])[C:40]=1[O:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.[Pd](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:37]1[CH:36]=[C:35]([F:34])[C:40]([O:41][CH3:42])=[C:39]([F:43])[CH:38]=1
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(Cl)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1c(F)cc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c(F)cc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl-benzene (0.30 g), 3,5-difluoro-4-methoxy-phenylboronic acid (0.21 g) and potassium carbonate (0.31 g) in acetone (3 mL) and water (1 mL) under argon is cooled in an ice-bath. Then palladium dichloride (5 mg) is added and the cooling bath is removed. The reaction mixture is stirred at ambient temperature overnight. Then brine is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate, and the solvent is removed in vacuo. The residue is taken up in methanol (5 mL) aqueous potassium hydroxide solution (1 mL, 4 mol/L) is added. The solution is stirred at ambient temperature for 0.5 h and then neutralized with 1 M hydrochloric acid. The methanol is evaporated, and the residue is diluted with brine and extracted with ethyl acetate. The organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->9:1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)coc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)coc2C1
Yield: 68.2 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (0.087 g), concentrated hydrochloric acid (0.037 ml), water (0.037 ml) and ethanol (20 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 37) (0.17 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]1[CH2:14][C:13](=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1.P(Cl)(Cl)([Cl:21])=O.CN(C)[CH:26]=[O:27]>>[Cl:21][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH:5]([C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([F:1])[CH:3]=2)[C:14]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccccc21
Product: O=CC1=C(Cl)c2ccccc2OC1c1cccc(F)c1
Reaction time: 2 h

Procedure:
As in example 1, but using 10 g 3'-fluoro-flavanone, 100 ml dimethylformamide and 15 ml phosphorous oxychloride. Reaction time is two hours at 50° C. After hydrolysis a precipitate formed which is filtered, washed with water and dried over phosphorous pentoxyde. The residual solid is recrystallised in a mixture of ethanol and water and pure yellow crystalline 4-chloro-3'-fluoro-3-formyl-flav-3-ene is obtained; m.p. 97°-99° C.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15](/[CH:17]=[C:18](\[CH2:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)/[C:19]([O:21][CH3:22])=[O:20])=[CH:16][C:11]=2[O:10][CH2:9]1>ClCCl.C(OCC)(=O)C>[CH3:35][O:34][C:26]1[C:25]2[C:14]3[C:15]([CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:23][C:24]=2[CH:29]=[C:28]([O:30][CH3:31])[C:27]=1[O:32][CH3:33])=[CH:16][C:11]1[O:10][CH2:9][O:8][C:12]=1[CH:13]=3
Reactant: COC(=O)/C(=C/c1ccc2c(c1)OCO2)Cc1cc(OC)c(OC)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc3c(cc2-c2c(cc(OC)c(OC)c2OC)C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Ferric perchlorate hexahydrate (342 mg, 0.74 mmol) and 0.5 ml of trifluoroacetic acid were added to a solution of methyl (E)-α-(1,3-benzodioxol-5-yl-methylene)-3,4,5-trimethoxybenzene- propionate [114 mg, 0.295 mmol; P. Magnus et.al., J. Am. Chem. Soc., 107, 4984, (1985)] in 5 ml of dichloromethane, followed by stirring at room temperature for 1 hour. The reaction mixture was dissolved in 20 ml of ethyl acetate. The resulting solution was washed successively with 2N-HCl, water and saturated NaHCO3, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Brown oil thus obtained (122 mg) was purified by TLC (silica gel: "MERCK #5744", eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 96 mg of the title compound were obtained as colorless oil (yield: 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([C@H:27]3[CH2:26][CH2:25][C@@H:24]([OH:23])[CH2:29][CH2:28]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CN([C@H]2CC[C@@H](O)CC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CN([C@H]4CC[C@@H](O)CC4)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(cis-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=553.9/555.9. 1H NMR (300 MHz, DMSO-d6) δ: 9.90 (s, 1H), 8.40 (s, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.08 (s, 1H), 4.57 (s, 2H), 4.48 (d, J=3.1 Hz, 1H), 4.13-4.01 (m, 1H), 4.00 (s, 6H), 3.91-3.85 (m, 1H), 2.03-1.91 (m, 2H), 1.85-1.73 (m, 2H), 1.67-1.42 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10](=[O:21])[CH2:11][N:12](C(OC(C)(C)C)=O)[CH3:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:24].C(OCC)C>O1CCOCC1>[ClH:24].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:21])[CH2:11][NH:12][CH3:13])=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: CN(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNCC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
To a solution of (N-t-butoxycarbonyl-N-methyl-amino)acetic acid p-nitrobenzyl ester (4.30 g, 133 mmol) (obtained as described in Reference Example 43(1)) was added a solution of 4N hydrogen chloride in 1,4-dioxane (4.3 ml) in an ice bath, and the mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, diethyl ether was added thereto and the reaction mixture was stirred for 30 minutes. The resulting reaction mixture was filtered and the obtained residue was washed with diethyl ether and dried to give sarcosine p-nitrobenzyl ester hydrochloride (3.04 g, yield 88%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2([Ti:20](Cl)(Cl)[C:21]3([CH3:30])[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([CH3:28])=[C:22]3[CH3:29])[CH:19]=[CH:18][CH:17]=[CH:16]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1([SH:40])[C:34]([SH:39])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH3:26][C:25]1[C:21]([Ti+3:20])([CH3:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24]=1[CH3:27].[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S-:39])[C:33]=3[S-:40])[CH:19]=[CH:18][CH:17]=[CH:16]2)=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4].[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S-:39])[C:33]=3[S-:40])[CH:19]=[CH:18][CH:17]=[CH:16]2)=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4].[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S-:39])[C:33]=3[S-:40])[CH:19]=[CH:18][CH:17]=[CH:16]2)=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4].[CH3:26][C:25]1[C:21]([Ti+3:20])([CH3:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24]=1[CH3:27]
Reactant: Sc1ccccc1S
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)C2(Cc3ccc(C(=O)OC(C)(C)C)cc3)C=CC=C2)C(C)=C1C
Product: CC(C)(C)OC(=O)c1ccc(CC2(c3cccc([S-])c3[S-])C=CC=C2)cc1
Product: CC1=C(C)C(C)([Ti+3])C(C)=C1C

Procedure:
The reaction was performed as described in Example 1, step 4, starting from ({[4-(tert-butoxycarbonyl)phenyl]methyl}cyclopentadienyl)dichloro(pentamethylcyclopentadienyl)titanium; i.e. reaction of the alkylated titanocene dichloride with benzenedithiol.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:24])[C:22]=1[F:23].C([O-])([O-])=O.[Na+].[Na+].O.C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[F:13][C:12]([F:15])([F:14])[C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[C:17]([F:16])[C:22]([F:23])=[C:21]([F:24])[CH:20]=2)[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=c1[nH]c2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1
Reaction time: 0.17 h

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-1,3-dihydrobenzoimidazol-2-one (1.12 g, 4 mmol, Example 6a), 3,4,5-trifluorophenylboronic acid (1.1 g, 6 mmol, Lancaster), PdCl2(PPh3)2 (35 mg, 0.05 mmol, Aldrich), Na2CO3.H2O (1 g, 8 mmol), dimethoxyethane (7 mL), H2O (3 mL) and EtOH (2 mL) was subjected to microwave irradiation at 120° C. with stirring for 10 min. Water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography, eluting with 35% EtOAc/hexane to give the title compound as a light-brown solid. MS (ESI, pos. ion) m/z: 333 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][C:20]=1[O:27][CH3:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:1][C:2]2[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[CH:21][C:20]=1[O:27][CH3:28])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(CCl)ccc1OCc1ccccc1
Reactant: Cc1nc(C)c(Cl)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(CNc2nc(C)nc(C)c2Cl)ccc1OCc1ccccc1

Procedure:
In analogy to the method described in example A1, 3.67 g (22.8 mmol) of 4-amino-5-chloro-2,6-dimethylpyrimidine, 6.0 g (22.8 mmol) of 4-benzyloxy-3-methoxybenzyl chloride and 0.91 g (23 mmol) of sodium hydride (60% suspension in liquid paraffin) are reacted in a total of 190 ml of N-methylpyrrolidone. After chromatography on silica gel (mobile phase: toluene/dioxane=10:1) and crystallization from petroleum ether, the title compound is isolated as a pale beige solid. Yield: 3.42 g (39% of theory). m.p.: 101-105° C.