Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@H]1N
Reaction time: 0.67 h
Yield: 8.9 %

Procedure:
A mixture of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.7 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.62 g), DBU (0.43 g) and anhydrous acetonitrile (30 ml) was refluxed for 52 hours. After cooling, the resulting precipitate was collected by filtration, washed with chilled acetonitrile and this was added to concentrated hydrochloric acid-methanol (1:1, 5 ml) and stirred for 40 minutes at elevated temperature. The reacting mixture was collected by filtration, washed with chilled water sufficiently and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:3) to give the title compound (0.076 g) as pale yellow prisms, mp 268°-270° C. (decompd.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[CH:15][CH:16]=[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:12]3=[N:11][C:10]=2/[CH:24]=[CH:25]/[C:26]2[CH:35]=[CH:34][C:33]3[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=2)=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+:41]>>[Na+:41].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[N:14]=[CH:15][CH:16]=[C:17]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:12]3=[N:11][C:10]=2/[CH:24]=[CH:25]/[C:26]2[CH:35]=[CH:34][C:33]3[C:32]([C:36]([O-:38])=[O:37])=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2c(/C=C/c3ccc4c(C(=O)O)cccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1ccc(-c2c(/C=C/c3ccc4c(C(=O)[O-])cccc4n3)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 76b (28.2 mg, 0.056 mmol) was treated with NaOMe (0.11 mL, 0.056 mmol) using the procedures described in Example 73, Step H to obtain the title compound 148. 1H NMR (400 MHz, CD3OD): δ (ppm) 9.02 (d, J=9.1 Hz, 1H), 8.07 (d, J=5.6 Hz, 1H), 7.89-8.02 (m, 6H), 7.79-7.88 (m, 3H), 7.65-7.74 (m, 1H), 6.39 (d, J=6.0 Hz, 1H), 4.08-4.13 (m, 4H), 3.92-4.00 (m, 4H). Mass spectrum (LCMS, ESI pos.) Calcd. For C29H22N6O3: 503.2 (M+H). found 503.2.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](Cl)=[O:31]>>[C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH:15][C:30](=[O:31])[CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:33])[N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: Cc1ccccc1CC(=O)Cl
Product: Cc1ccccc1CC(=O)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 420 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin ylamine and o-tolylacetyl chloride.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:37]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:22]2[CH:23]=[C:24]([S:26]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)(=[O:28])=[O:27])[CH:25]=[CH:20][C:21]=2[CH3:37])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)CCc2ccccc2)cc1Br
Product: Cc1ccc(S(=O)(=O)CCc2ccccc2)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 2-bromo-1-methyl-4-[(2-phenylethyl)sulfonyl]benzene (Intermediate 70), the title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13][CH:14]2[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](O)[CH:32]=[CH:33][C:34]=1[F:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13][CH:14]2[CH2:16][O:17][C:32]2[CH:31]=[CH:30][C:29]([F:28])=[C:34]([F:35])[CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(CO)CN2C(=O)OCc1ccccc1
Reactant: Oc1ccc(F)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of alcohol 77 (0.84 g, 2.2 mmol) in benzene (15 mL) was treated with 3,4-difluoro-phenol (402 mg, 3.1 mmol) and triphenylphosphine (864 mg, 3.3 mmol). To this solution was added DIAD (0.65 mL, 3.3 mmol) and the reaction mixture was stirred at ambient temperature. After 16 h, the solution was concentrated, diluted with DCM, washed with 1M NaOH, dried over anhydrous Na2SO4, filtered and concentrated. The aqueous phase was back-extracted with Et2O and the combined organic extracts were absorbed on SiO2 and purified by flash chromatography (3:1 hexane/EtOAc to 1:1 hexane/EtOAc) to afford 78 (0.86 g) which was contaminated with DIAD-related impurities and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:5]2[N:6]([C:8]([C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30]C(C)(C)C)=[O:29])=[C:26]([F:37])[CH:25]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[Cl:1][C:2]1[CH:3]=[C:4]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:5]2[N:6]([C:8]([C:24]3[CH:36]=[CH:35][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:37])[CH:25]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1F

Procedure:
Compound 81a (30 mg, 0.05 mmol) was treated with TFA using the procedures previously described in Example 80 to afford the title compound 165. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.87 (d, J=8.6 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.02-8.12 (m, 2H), 7.99 (t, J=8.1 Hz, 1H), 7.84 (t, J=7.1 Hz, 1H), 7.71 (d, J=9.1 Hz, 1H), 7.58-7.66 (m, 2H), 6.46 (s, 1H), 4.05-4.14 (m, 4H), 3.85-3.95 (m, 4H), 3.18-3.25 (m, 1H), 3.08-3.16 (m, 1H), 2.22-2.30 (m, 1H), 2.16 (m, 1H); Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H24ClN5O3: 526.1 (M+H). found: 526.3.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([CH3:13])=[N:7]1.[C:14]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].ClCCl>C(#N)C.O>[C:14]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[CH:10]=[CH:9][C:8]([CH3:13])=[N:7]3)[CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: Cc1ccc(=O)n(CCCCBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1ccc(=O)n(CCCCN2CCN(c3cccc4ccccc34)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.7 %

Procedure:
A mixture of 2-(4-bromobutyl)-6-methyl-3(2H)-pyridazinone (2.3 g, 9.5 mmol), 1-naphthylpiperazine (1.7 g, 8 mmol), K2CO3 (1.12 g, 8 mmol), and KI (10 mg) in acetonitrile (50 mL) was stirred at room temperature for 48 hours. Thereafter, the solvent was eliminated at reduced pressure and the residue distributed between dichloromethane and water; the aqueous phase was extracted with dichloromethane (twice). The organic extracts were collected, dried over anhydrous Na2SO4 and concentrated to dryness. The obtained residue was purified by flash chromatography (CH2Cl2/MeOH 96:4), yielding 2-[4-(4-naphthylpiperazine-1-yl)-butyl]-6-methyl-3(2H)-pyridazinone (2.4 g). The product was dissolved in ethanol and by adding hydrochloric acid concentrated up to a pH=1 yielded a white solid, which was re-crystallised in methanol, yielding the hydrochloride of the title compound, presenting a M.P. higher than 260° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=2)[C:9]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=3)[CH:22]=[CH:24][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=CC=O
Product: Cc1ccc(-c2cccn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methylphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a brown powder (yield 13%), melting at 183-184° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Cl)[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1)(=[O:27])=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[N:30][CH:31]=2)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(NS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (103 mg, 0.32 mmol) and 6-(methylsulfonamido)nicotinic acid, intermediate 15, (84 mg, 0.39 mmol) in CH2Cl2 (2 mL) and DMF (2 mL) is added TEA (0.18 mL, 1.29 mmol) and HATU (159 mg, 0.42 mmol) at room temperature. The crude is stirred at room temperature for 2 hrs. The crude is quenched with saturated NaHCO3, diluted in EtOAc. The organic layer is washed with six times with water, brine, dried over MgSO4, filtered, and concentrated. The crude is purified via RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-ethyl 4-(biphenyl-4-yl)-3-(6-(methylsulfonamido)nicotinamido)butanoate as a white solid (4.1 mg). HPLC retention time=1.61 minutes (condition A); MS (m+1)=482.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (t, J=7.2 Hz, 3 H), 2.56 (t, J=4.8 Hz, 2 H), 2.84-2.92 (m, 1 H), 3.05 (dd, J=13.6, 6.1 Hz, 1 H), 3.16 (s, 3 H), 4.08-4.18 (m, 2 H), 4.57-4.71 (m, 1 H), 7.03 (d, J=8.3 Hz, 1 H), 7.10 (d, J=8.3 Hz, 1 H), 7.22 (d, J=8.3 Hz, 2 H), 7.26-7.31 (m, 1 H), 7.33-7.40 (m, 2 H), 7.44-7.54 (m, 5 H), 7.98 (dd, J=8.8, 2.3 Hz, 1 H), 8.52 (s, 1 H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:13])=[N:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][CH:12]=1.[CH:14]([O:16]CCCC)=[CH2:15].C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:13][C:5]1[N:6]=[C:7]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:2]([C:14](=[O:16])[CH3:15])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)c(-c2ccco2)n1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ncc(N)nc1-c1ccco1
Temperature: 122 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
To a stirred solution of 5-bromo-6-(2-furyl)pyrazin-2-amine (Preparation 2, 1.5 g, 6.3 mmol) in a mixture of DMF (16 mL) and water (4 mL) was added butyl vinyl ether (4.10 mL, 31.5 mmol), potassium acetate (3.80 mL, 7.56 mmol), 1,3-bis-(diphenylphosphino)propane (0.172 g, 0.416 mmol) and palladium(II) acetate (42.0 mg, 0.189 mmol)1. The mixture was subjected to three cycles of evacuation-backfilling with argon and heated at 122° C. under microwave irradiation. After 4 h, the mixture was cooled to room temperature and hydrolyzed by adding of HCl 2N (30 mL) for 30 min. The mixture was then neutralized with a saturated solution of potassium carbonate and diluted with dichloromethane. The organic layer was separated, dried (Na2SO4) and evaporated. The residue was purified by silica gel flash chromatography (2% methanol in dichloromethane). Concentration in vacuo of the product-rich fractions provided the titled compound as a pale-yellow solid (0.77 g, 60%). 1K. S. A. Vallin, M. Larhed, A. Hallberg, J. Org. Chem., 2001, 66, 4340.
Reaction SMILES: O[C@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=[O:13])[CH:5]=[CH:4][C:3]1=2.C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=[O:13])[CH:5]=[CH:4][C:3]1=2)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2c(c1)CCC[C@@H]2O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=N[C@@H]1CCCc2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(S)-5-Hydroxy-5,6,7,8-tetrahydronapthalene-2-carbaldehyde (19.73 mmol) was dissolved in 50 mL of toluene and cooled to 0° C. Diphenylphosphoryl azide (29.6 mmol, 1.5 eq) was added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (23.07 mmol, 1.2 eq). After stirring at room temperature overnight, the solvent was evaporated. The residue was purified by SiO2 chromatography (5→30% ethyl acetate in dichloromethane) to afford the title compound. MS (m/z): 204.2 (M+H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[Cl:19])=[C:10]([N:20]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]2)[N:9]2[N:27]=[CH:28][CH:29]=[C:8]2[N:7]=1.[CH3:30][S:31](OC)(=O)=S.Cl>ClCCl>[Cl:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[Cl:19])=[C:10]([N:20]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]2)[N:9]2[N:27]=[CH:28][C:29]([S:31][CH3:30])=[C:8]2[N:7]=1
Reactant: COS(C)(=O)=S
Reactant: CC1CCN(c2c(-c3ccc(F)cc3Cl)c(Cl)nc3ccnn23)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1cnn2c(N3CCC(C)CC3)c(-c3ccc(F)cc3Cl)c(Cl)nc12
Temperature: 0 °C

Procedure:
With stirring, 1.06 g of aluminium trichloride were initially added to 1 g of 5-chloro-6-(2-chloro-4-fluorophenyl)-7-(4-methylpiperidin-1-yl)pyrazolo[2,3-a]pyrimidine, the preparation of which is described, for example, in WO 02/048151, in 50 ml of dichloromethane, and 0.99 g of methyl methylthiosulphonate was then added dropwise. After 15 h of stirring at room temperature, the mixture was poured into ice-water and hydrochloric acid was added. The organic phase was separated off, and the aqueous phase was extracted two more times with in each case 15 ml of ethyl acetate. The combined organic phases were dried with sodium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using cyclohexane/ethyl acetate 4:1. This gave 0.65 g of an orange oil, logPs=5.73.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C@H:3]1[C:13]([OH:15])=[O:14].C(N(CC)CC)C.[Cl:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32])=[CH:27][CH:26]=1>ClCCl>[Cl:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][C:30]([CH3:34])([CH3:35])[C:31]([N:4]2[C@@H:3]([C:13]([OH:15])=[O:14])[C:2]([CH3:16])([CH3:1])[S:6][C@H:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:32])=[CH:27][CH:26]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CC1(C)SC(c2ccccc2)N[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Temperature: 0 °C

Procedure:
1.17 g (5 mmoles) of 5,5-dimethyl-2-phenylthiazolidine-4(S)-carboxylic acid and 0.7 ml of triethylamine are dissolved in 20 ml of dichloromethane while stirring and the solution is cooled to 0° C. Then, 2-(4-chlorophenoxy)-isobutyryl chloride dissolved in 4 ml of dichloromethane is added under stirring. After stirring for 3 hours, the solution is washed with water, dried over anhydrous magnesium sulphate and evaporated. The obtained syrup is recrystallized from methanol by adding water to give the title compound in a yield of 1.39 g (64%), m.p.: 177°-181° C., [α]D21 =0° (c=0.94, dimethylsulphoxide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[CH2:5][C:6]1[CH:7]3[O:19][CH:10]([C:11]=1[CH2:12]2)[C:9](=[CH2:20])[C:8]3=[CH2:21].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[CH:5]=[C:6]1[C:11](=[CH:12]2)[CH:10]2[O:19][CH:7]1[C:8](=[CH2:21])[C:9]2=[CH2:20]
Reactant: C=C1C(=C)C2OC1C1=C2Cc2c(OC)ccc(OC)c2C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: C=C1C(=C)C2OC1c1cc3c(OC)ccc(OC)c3cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 2 g (7.1 mmol) of 1,2,3,4,9,10-hexahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene, 1.77 g (7.8 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 30 ml of benzene was stirred at room temperature under nitrogen for 30 minutes. The precipitate formed was filtered off and washed with benzene, the benzene solution was washed with two 30 ml portions of saturated aqueous sodium hydrogen sulphite solution and two 30 ml portions of water, dried over sodium sulphate and concentrated to dryness. By recrystallization from diethyl ether/tetrahydrofuran/methylene chloride (4:1:2) there were obtained 1.95 g (98%) of 1,2,3,4-tetrahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene of melting point 205°-206° C. in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:24])[CH3:23])=[CH:4][CH:3]=1.[CH2:27]([Mg]Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:24])[CH3:23])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1
Reactant: CC(=O)Nc1ccccc1C=Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1C(Cc1ccccc1)Nc1ccccc1Oc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
N-(2-([2-(4-Chloro-phenoxy)-phenylimino]-methyl)-phenyl)-acetamide (111 mg, assumed 100% pure, 0.3 mmol) was dissolved in THF (5 ml) and cooled to 0° C. under a N2 atmosphere, to this was added BF3OEt2 (0.04 ml, 0.3 mmol) and benzylmagnesium bromide (2 M in THF, 0.3 ml, 1.2 mmol). The resulting solution was stirred at r.t. for 18 h. The reaction was then quenched with sat. NH4Cl solution, extracted with EtOAc and dried (MgSO4). The crude product was purified by flash chromatography (0-20% EtOAc in DCM) to yield the desired product, 20 mg, 14% yield.
Reaction SMILES: C([Sn](CC)(CC)[C:4]1[O:5][CH:6]=[CH:7][N:8]=1)C.[CH2:13]([N:16]([CH2:30][CH2:31][CH3:32])[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27](I)[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:14][CH3:15]>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:30]([N:16]([CH2:13][CH2:14][CH3:15])[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([C:4]2[O:5][CH:6]=[CH:7][N:8]=2)[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:31][CH3:32]
Reactant: CC[Sn](CC)(CC)c1ncco1
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
A stirred solution of 2-triethylstannyloxazole (Chem. Mater. 1994, 6, 1023)(1.5 g, 5.5 mmol) and methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (1.8 g, 4.6 mmol) in dimethylformamide (12 mL) was degassed under reduced pressure for 15 min and purged with argon. Palladium(0) tetrakis(triphenylphosphine) (158 mg, 0.14 mmol) was added and the reaction mixture was degassed under reduced pressure for 15 min and then purged with argon. The reaction mixture was heated at reflux for 2 d, cooled to room temperature, diluted with ethyl acetate, washed with water (3×50 mL), dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided methyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (423 mg): 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.28 (s, 1H), 3.97 (s, 3H), 3.49 (br s, 2H), 3.18 (br s, 2H), 1.72 (d, J=7 Hz, 2H), 1.55 (d, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=O)=[O:11])=[CH:5][CH:4]=1.[H-].[Na+]>CN(C=O)C>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH2:13][O:12][C:10](=[O:11])[C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:17][CH:18]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(CC(=O)OCC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)COC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a 0° C. solution of 2-(4-(benzyloxy)phenyl)-2-oxo-ethyl 2-(4-methoxyphenyl)acetate (3.0 g, 0.007 mol) in DMF (20 mL) was added NaH (0.96 g, 0.01 mol). The reaction mixture was stirred at RT for 30 minutes and quenched with ice to obtain a solid precipitate. The solid precipitate was filtered and dried in vacuo to afford 4-(4-(benzyloxy)phenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (2.4 g, 84%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=N)[CH2:5][C:6]([OH:9])([CH3:8])[CH3:7])[CH3:2]>C(O)C>[CH2:1]([O:3][C:4]([O:9][CH2:6][CH3:5])([O:3][CH2:1][CH3:2])[CH2:5][C:6]([CH3:8])([OH:9])[CH3:7])[CH3:2]
Reactant: CCOC(=N)CC(C)(C)O
Solvent: CCO
Product: CCOC(CC(C)(C)O)(OCC)OCC
Reaction time: 72 h

Procedure:
A solution of 3-hydroxy-3-methyl-butyrimidic acid ethyl ester (4.40 g) in ethanol (50 mL) was left to stand for 72 hours. The mixture was filtered and the filtrate concentrated to dryness under vacuum affording 4,4,4-triethoxy-2-methyl-butan-2-ol which was used for the next step without further purification or analysis.