Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.CCN(CC)CC.CO>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:20](=[O:21])[NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:23])[F:22])[CH:14]=1)[C:9]#[N:10]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: N#CCC(=O)c1ccc[nH]1
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CC(C(=O)Nc1cccc(C(F)(F)F)c1)C(=O)c1ccc[nH]1

Procedure:
Reaction of 2.0 g of 2-pyrroloylacetonitrile with 3.0 g of 3-(trifluoromethyl)-phenyl isocyanate in the presence of 1.8 g of Et3N in 25 ml of glyme similarly to the previous examples and recrystallization of the crude product from methanol gives β-oxo-α-(3-trifluoromethylphenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 210°-212°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([O:26]C)[CH:20]=[C:19]3[C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=C3C(=CC=2)N=C(OC)C=C3C2SC(C)=CC=2)(C2N(C)C=NC=2)O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[C:19]3[C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ccc(Cl)s2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Agent: COc1cc(-c2ccc(C)s2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3ccc(Cl)s3)c2c1
Yield: 94.4 %

Procedure:
The same procedure was used as that in example 2, except that (4-chloro-phenyl)-[2-methoxy-4-(5-chloro-thiophen-2-yl)-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (0.194 g, 0.391 mmol) was used in the place (4-chloro-phenyl)-[2-methoxy-4-(5-methyl-thiophen-2-yl)-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol, to give title compound as a white solid (0.178 g, 0.369 mmol, 94% yield).
Reaction SMILES: C1([C:7]2[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[CH:8]=2)C=CC=CC=1.Br[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][C:29](Br)=[CH:28][CH:27]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[C:7]1([C:14]2[CH:13]=[CH:12][C:11]3[N:10]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([S:35]([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)(=[O:37])=[O:36])[C:26]6[C:31]([C:32]=5[CH:33]=4)=[CH:30][C:29]([N:10]4[C:9]5[CH:8]=[CH:7][C:19]([C:11]7[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=7)=[CH:18][C:17]=5[C:16]5[C:11]4=[CH:12][CH:13]=[CH:14][CH:15]=5)=[CH:28][CH:27]=6)[C:9]4[C:17]([C:16]=3[CH:15]=2)=[CH:18][CH:19]=[CH:7][CH:8]=4)[CH:19]=[CH:18][CH:17]=[CH:9][CH:8]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: c1ccc(-c2ccc3c(c2)[nH]c2ccccc23)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1c2ccc(-n3c4ccccc4c4cc(-c5ccccc5)ccc43)cc2c2cc(-n3c4ccccc4c4cc(-c5ccccc5)ccc43)ccc21

Procedure:
8.0 g (42.2 mmol) of copper(I) iodide and 11.7 ml (97.5 mmol) of trans-cyclohexanediamine are added to a vigorously stirred suspension of 56.9 g (234 mmol) of 2-phenylcarbazole, 54.4 g (117 mmol) of 3,6-dibromo-9-(phenylsulfonyl)-9H-carbazole and 416.4 g (1961 mmol) of potassium phosphate in 1170 ml of dioxane, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol. Yield: 80 g (101 mmol), 86%.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=O.P(Cl)(Cl)([Cl:18])=O>C(O)C>[ClH:18].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCOC(=O)C(=O)c1csc(=NC=O)[nH]1
Solvent: CCO
Product: CCOC(=O)C(=O)c1csc(N)n1
Product: Cl

Procedure:
To a suspension of ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (31.3 g.) in ethanol (600 ml.) was dropwise added phosphorus oxychloride (41.9 g.) under ice-cooling and stirring, and the mixture was stirred for 30 minutes at 50° C. After the reaction, the solvent was distilled off. The residue was washed with diethyl ether and then dried to give ethyl 2-(2-amino-1,3-thiazol-4-yl)glyoxylate hydrochloride, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate hydrochloride, in quantitative yield, mp. 263° to 264° C. (dec.).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-])=O)=[C:11](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[N:10]([CH3:31])[C:9]1=[O:32])(=[O:3])[CH3:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)=O.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[CH:18][C:11]=2[N:10]([CH3:31])[C:9]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(/C=C/c2cccc(OC(F)(F)F)c2)n(C)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)cc2n(C)c1=O
Temperature: 140 °C
Yield: 43.1 %

Procedure:
To a solution of (E)-3-(3-methyl-5-nitro-2,6-dioxo-4-(3-(trifluoromethoxy)styryl)-2,3-dihydro pyrimidin-1(6H)-yl)propyl acetate (50 mg, 0.109 mmol) in HCOOH (3 mL) was added Na2S2O4 (114.0 mg, 0.655 mmol). The reaction was heated at 140° C. for 5 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (20 mg, 43.1% yield) as an oil. LCMS: MH+ 426 and TR=1.597 min. Used without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>ClCCl>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NCCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccc(Br)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a mixture of 2-(trifluoromethyl)benzoyl chloride (1.0 g, 5.3 mmol) in dichloromethane (5 mL) was added dropwise a solution of triethylamine (0.41 g, 4.0 mmol) and 4-bromophenethylamine (0.80 g, 4.0 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane and extracted with 1 N aqueous hydrochloric acid. The aqueous phase was separated and extracted with additional dichloromethane. The organic extracts were then combined, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography on a silica gel column eluted with 0 to 100% ethyl acetate:hexane to provide the title compound (1.10 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].CC1C=CC(S(O[CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:13][C:11]([C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:3]([CH2:1][CH3:2])[N:4]([CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:5]=1)=[O:12]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 96 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (8.20 g, 44.6 mmol, prepared using procedure in WO9849166), tert-butyl (2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (17.4 g, 49.0 mmol, prepared using procedure in WO9926944) and cesium carbonate (16.0 g, 49.2 mmol) in N,N-dimethylformamide (100 ml) was stirred at 20° C. for 4 days and then at 50° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (300 ml) and water (300 ml). The phases were separated, and the aqueous layer extracted with further EtOAc (2×200 ml). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was partially purified by column chromatography (DCM/MeOH, 100:0-91:9) and then the regioisomers were separated by further column chromatography (Et2O/EtOAc, 100:0-50:50) to afford the title compound of preparation 34 (1.23 g, 3.35 mmol, 7.5%); mp 68-75° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH2:25][NH:24][C:23]3=[O:28])[CH2:18][CH2:17]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Reactant: O=C1NCCCN1C1CCNCC1
Solvent: CCO
Product: CC(=O)Nc1ccc(OCC(O)CN2CCC(N3CCCNC3=O)CC2)cc1

Procedure:
A solution of 19.35 g of 1 -(p-acetamido-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 10 ml of abs. ethanol is heated to 95°C. The reaction product crystallises out at boiling heat after about 5 minutes. The crystal broth is diluted with 10 ml of abs. ethanol and heated for a further 5 hours. When the reaction is terminated the batch is evaporated in vacuo and the residue is recrystallised from abs. ethanol/ether to yield the 1-[3-(p-acetamido-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 218°-221°C.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].[OH:24][CH2:25][C:26]1[C:27](=[O:32])[NH:28][CH:29]=[CH:30][CH:31]=1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Si:10]([O:24][CH2:25][C:26]1[C:27](=[O:32])[NH:28][CH:29]=[CH:30][CH:31]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]cccc1CO
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
At RT, 0.65 g (9.59 mmol) of imidazole, 2.42 g (8.79 mmol) of t-butyldiphenylchlorosilane and 0.10 g (0.80 mmol) of DMAP are added to 1.00 g (7.99 mmol) of the compound from Example 2A in 19 ml of DMF, and the mixture is stirred for 18 h. 180 ml of water are then added, and the mixture is kept at 0° C. for 3 h. After filtration, the residue obtained is purified by chromatography on silica gel (ethyl acetate/ethyldimethylamine 1000:1). This gives 801 mg (27% of theory) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(C)C=CC=CC=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([CH:12]=[CH:11][C:10]([O:14][CH3:15])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: C=CC(=O)OC
Reactant: Nc1ccc(Br)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(N)cc1F
Temperature: 124.5 °C
Reaction time: 26 h
Yield: 36 %

Procedure:
4-Bromo-3-fluoroaniline (20.0 g) was dissolved in a mixed solvent of DMF (64 ml) and N,N-diisopropylethylamine (64 ml). Methyl acrylate (28.3 ml), palladium acetate (1.18 g), and tris(2-methylphenyl)phosphine (11.2 g) were added thereto in a nitrogen atmosphere. The obtained mixture was stirred at a bath temperature of 120 to 129° C. for 26 hours. Toluene was added to the reaction mixture, and the mixture was filtered through Cerite. The Cerite was washed with a mixed solvent of DMF and toluene (1:1, 80 ml). The filtrates were combined and concentrated under reduced pressure. The obtained residue was separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and toluene (70 ml) and n-heptane (10 ml) were added to the obtained residue. The precipitated solid was filtered off, and as a result, Compound 15a (3.74 g, 36%) was obtained as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:41])=[C:12]([CH2:14][O:15][C:16]2[CH:40]=[CH:39][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:18][CH:17]=2)[N:13]=1.O.Cl>O1CCCC1.C(O)C>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:41])=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:39][CH:40]=2)[N:13]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
Lithium hydroxide monohydrate (163 mg) was added to a solution of ethyl E-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate (670 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-[2-(2-furyl)-5methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoic acid (625 mg, yield 98%) as colorless crystals. m.p. 112-113° C.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.CCN(C(C)C)C(C)C.Cl.[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([C:47](Cl)=[O:48])[CH2:43][CH2:42]1.O>CN(C=O)C>[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:47]([N:44]6[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]6)=[O:48])[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)ccc21
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)N2CC=C(c3cc4c(Nc5ccc6c(cnn6C)c5)ncnc4[nH]3)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (78.1 mg, 0.172 mmol, 1 eq) in DMF (5 mL), DiPEA (180 μL, 1.0 mmol, 6 eq) was added. After cooling the suspension to 0° C., 4-methyl-1-piperazinecarbonyl chloride hydrochloride (28.6 mg, 0.170 mmol, 1 eq) in DMF (1.5 mL) was added and the reaction was stirred at 0° C. for 2 h. An additional 0.2 eq of 4-methyl-1-piperazinecarbonyl chloride hydrochloride (6.1 mg, 0.036 mmol) in DMF (1 mL) was added and the suspension was stirred again at 0° C. for 3 h. Still additional acid chloride was needed and 4-methyl-1-piperazinecarbonyl chloride hydrochloride (6.1 mg, 0.036 mmol, 0.2 eq) in DMF (1 mL) was added. After 5 h, the reaction was quenched/worked up as follows: reaction solution was added dropwise into water, filtered (M frit), washed with water and then EtOAc, and dried, giving the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=2.19 (s, 3H), 2.31 (s, br, 4H), 2.44-2.55 (m, 2H), 3.17 (s, br, 4H), 3.40 (t, J=5.2 Hz, 2H), 3.92 (s, br, 2H), 4.03 (s, 3H), 6.38 (s, br, 1H), 6.75 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 8.25 (s, 1H), 8.38 (s, br, 1H), 9.33 (s, —NH), 11.89 (s, —NH). MS (ES+): m/z 472.14 (9) [MH+]. HPLC: tR=1.68 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:14].P(=O)(O)(O)O.O>ClC1C=CC=CC=1Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[OH:14][C:8]1[CH:9]=[C:10]2[C:11](=[C:12]([CH3:13])[C:7]=1[CH3:6])[CH2:1][CH2:2][C:3]2([CH3:5])[CH3:4]
Reactant: Cc1cccc(O)c1C
Reactant: C=CC(=C)C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1c(O)cc2c(c1C)CCC2(C)C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
449 g of isoprene, stabilised with 1.3 g of phenothiazine, were added dropwise in the course of 7 hours to a solution of 732 g of 2,3-dimethyl-phenol, 76.5 g of 85% strength phosphoric acid and 6 ml of water in 1.44 liters of o-dichlorobenzene at 150° C. To complete the reaction, stirring of the mixture was continued overnight at 150° C. The acid phase was separated off and the organic phase was washed until neutral. Fractional distillation gave 526 g of 5-hydroxy-3,3,6,7-tetramethyl-indan; boiling point: 165°-167° C./15 mm Hg; melting point: 117°-118° C. ##STR7##
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=O.[OH-].[K+]>>[Cl:12][C:13]1[CH:14]=[C:15](/[CH:16]=[CH:2]/[C:1]([C:4]2[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[O:3])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(C)=O)cn1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)cn1

Procedure:
In analogy to example 170, step 1, 5-acetyl-2-methoxypyridine was reacted with 3,5-dichlorobenzaldehyde in the presence of potassium hydroxide to give the title compound as a colourless solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](O)=[O:11]>>[C:1]1([CH2:7][CH2:8][NH:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=CO
Product: O=CNCCc1ccccc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A mixture of phenylethylamine (20.0 g, 0.165 mol) and formic acid (49.4 ml, 1.309 mol) was slowly heated to 200° C. Excess water and formic acid were distilled off in the process. The mixture was then kept at 200° C. for 1 hour, and the product was distilled under reduced pressure, giving a colourless oil (22.0 g, 0.147 mol, 89%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([SH:11])[C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(N(C(C)C)CC)(C)C.O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([S:11][CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: CCn1cc(Cl)nc(S)c1=O
Reactant: O=C(CCl)Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(Cl)nc(SCC(=O)Nc2ccccc2)c1=O
Yield: 50 %

Procedure:
200 mg (1.05 mM) of 5-chloro-1-ethyl-3-mercaptopyrazin-2(1H)-one, 178 mg (1 mM) of 2-chloro-N-phenylacetamide and 135.6 mg (1.05 mM) of diisopropylethylamine in 5 ml of tetrahydrofurane were stirred overnight at room temperature. Water was added and the precipitate was filtered and washed with water, to give 170 mg of 2-[(6-chloro-4-ethyl-3-oxo-3,4-dihydropyrazin-2-yl)thio]-N-phenylacetamide. Yield: 50%.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2F)(=[O:28])=[O:27])=[CH:22][N:21]=1>CN(C)C=O.C(OCC)(=O)C>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])(=[O:28])=[O:27])=[CH:22][N:21]=1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1ccccc1F
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCCOc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(dimethylamino)-1-propanol (17 μL, 0.14 mmol) was dissolved in N,N-dimethylformamide (1 mL) and sodium hydride (60% dispersion in mineral oil; 6 mg, 0.14 mmol) added. After stirring at room temperature under nitrogen for 10 minutes, a solution of 2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1, 50 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) was added and the reaction stirred at room temperature under nitrogen for 3.5 days. The reaction was diluted with ethyl acetate and washed with water (×4) and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% methanol/0.5% ammonia/dichloromethane, to give the title compound which was dissolved in ethyl acetate and treated with ethereal HCl to give the hydrochloride salt (42 mg, 66%). δH (400 MHz, MeOD): 9.10 (1H, d, J=2.2 Hz), 8.29 (1H, dd, J=2.3, 8.4 Hz), 8.12 (1H, dd, J=1.6, 7.9 Hz), 7.98 (1H, d, J=16.2 Hz), 7.83 (2H, q, J=7.9 Hz), 7.75–7.67 (1H, m), 7.38 (1H, d, J=16.3 Hz), 7.23 (1 H, t, J=7.7 Hz), 7.18 (1H, d, J=8.3 Hz), 7.08–7.02 (2H, m), 4.22 (2H, t, J=5.7 Hz), 3.40 (2H, t, J=7.8 Hz), 2.97 (6H, s), 2.28–2.22 (2H, m); m/z (ES+) 459 [MH+].
Reaction SMILES: I[C:2]1[S:6][CH:5]=[C:4]([P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])CCC.[F-].[K+]>C1(C)C=CC=CC=1.[Cu]Cl>[CH2:10]([O:9][P:7]([C:4]1[CH:3]=[C:2]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:6][CH:5]=1)([O:12][CH2:13][CH3:14])=[O:8])[CH3:11]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sccc1P(=O)(OCC)OCC
Reactant: CCOP(=O)(OCC)c1csc(I)c1
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1csc(-c2sccc2P(=O)(OCC)OCC)c1
Yield: 84 %

Procedure:
At room temperature, 1.4875 g (4.3 mmols) of 5-iodo-3-(diethoxyphosphoryl)thiophene and 0.0994 g (0.086 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in 43 ml of toluene, to which 2.1899 g (4.3 mmols) of 2-tributylstannyl-3-(diethoxyphosphoryl)thiophene and 0.0347 g (0.39 mmols) of commercially available copper(I) chloride were added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 3.5 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 1 hour. Thereafter, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The resulting organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (gradiated with acetone from ethyl acetate) to obtain the specified substance in the form of a yellow oil at a yield of 1.5836 g (yield: 84%).