Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]3=[C:17]([C:31](=O)[CH3:32])[CH:16]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCl.C(O)(=O)C>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH:31]([C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]=23)[CH3:32])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(C)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 40 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
A mixture of 1-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethanone (390 mg), acetic acid (25 μL), piperazine-1-carboxylic acid tert-butyl ester (158 mg) and sodium triacetoxy borohydride (270 mg) in dichloromethane (7.5 mL) was stirred at 40° C. overnight. Then additional triacetoxy borohydride (90 mg) was added. The reaction mixture was concentrated in a membrane pump vacuum, and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 4-{1-[6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (90 mg). This material was dissolved in methanol (5 mL), purged with argon, then with hydrogen and palladium (10% on charcoal, 8 mg) was added. The reaction mixture was stirred at 40° C. until the reaction was complete (according to HPLC/MS). The catalyst was filtered off and the filtrate was concentrated in a membrane pump vacuum. The residue was taken up in THF (2 mL), and conc. hydrochloric acid (1 mL) was added. The solution was stirred at r.t., then the solvents were evaporated and the residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) giving 3-fluoro-4-[3-methyl-4-(1-piperazin-1-yl-ethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol (30 mg, 9%).
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][O:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[O:11][CH3:10])[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: COc1cccc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cccc(OC)c1OC)OCC
Temperature: 140 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
2-bromo-1,1-diethoxyethane (0.097 mol) was added to a mixture of 2,3-dimethoxy-phenol (0.097 mol) and potassium carbonate (0.097 mol) in N,N-dimethylacetamide (200 ml). The reaction mixture was stirred for 24 hours at 140° C. The solvent was evaporated. The residue was partitioned between 1,1'-oxybisethane and a solution of NaOH in water. The organic layer was separated, washed with a saturated NaCl solution, dried (MgSO4), filtered and the solvent was evaporated, yielding 23 g (87.7%) of 1-(2,2-diethoxyethoxy)-2,3-dimethoxybenzene (interm. 1).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[F:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15](=S)[NH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1.[C:23]([C:25]1([NH:34][C:35](=[O:45])[CH:36]([NH2:44])[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]1)#[N:24].C(N(CC)C(C)C)(C)C>C1COCC1>[C:23]([C:25]1([NH:34][C:35](=[O:45])[CH:36]([NH:44][C:15]2[C:14]3[CH:21]=[CH:22][C:11]([F:10])=[CH:12][C:13]=3[O:18][C:17](=[O:19])[N:16]=2)[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH3:33])[CH2:29][CH2:30]1)#[N:24]
Reactant: O=c1[nH]c(=S)c2ccc(F)cc2o1
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CCC(C)(C)CC)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1CCC(C#N)(NC(=O)C(CCC(C)(C)CC)Nc2nc(=O)oc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
2-Chloro-1-methylpyridinium iodide (365 mg, 1.43 mmol, 1.00 eq) was added to a suspension of 7-fluoro-4-thioxo-3,4-dihydro-benzo[e][1,3]oxazin-2-one (280 mg, 1.42 mmol, 1.00 eq), 2-amino-5,5-dimethyl-heptanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (627 mg, 1.42 mmol, 1.00 eq), and N,N-diisopropyl ethylamine (1.00 mL, 5.74 mmol, 4.04 eq) in THF (10.0 mL). The reaction mixture was stirred at room temperature overnight, then concentrated, resuspended in ethyl acetate (50 mL) and washed with saturated Na2CO3 solution. The organic phase was dried (MgSO4) and concentrated and the resulting residue was chromatographed over silica gel using a gradient of methanol in dichloromethane as the eluant to provide 324 mg (47% yield) of the title compound; m/z calculated for C26H36F N5O3 485.6, found 486.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]=[CH:14][C:15]1[C:16]([NH:23][CH2:24][CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1C[CH2:35][CH2:34][CH2:33]1>>[CH:24]1([NH:23][C:16]2[C:15]([CH2:14][NH:13][C:3]3[C:4]([F:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[F:1])=[CH:20][N:19]=[C:18]([S:21][CH3:22])[N:17]=2)[CH2:35][CH2:34][CH2:33][CH2:25]1
Reactant: C1CCOC1
Reactant: CCNc1nc(SC)ncc1C=Nc1c(F)c(OC)cc(OC)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(OC)c(F)c(NCc2cnc(SC)nc2NC2CCCC2)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of 25.30 g (assume 0.0523 mol) of (5-[(2,6-difluoro-3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-ethyl-amine in 425 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The cooled mixture was treated dropwise via syringe with 78.50 mL (0.0785 mol) 1 M solution of lithium aluminum hydride in tetrahydrofuran which resulted initially with vigorous bubbling. The resulting mixture continued to stir at 0° C. for 1 hour under nitrogen atmosphere. The ice bath was removed and the reaction mixture was allowed to warm up to room temperature and continued stirring at room temperature overnight. The reaction mixture was cooled to 0° C. using an ice/acetone bath and quenched by the slow addition of 78.50 mL of water, 78.50 mL of 15% sodium hydroxide and 157 mL of water. The salts were filtered over a bed of Celite and removed the tetrahydrofuran in vacuo. The residue was redissolved in dichloromethane and filtered again. The layers were separated and dried the organic layer over sodium sulfate, filtered and evaporated. The crude product was purified using medium-pressure chromatography eluting with a gradient of 2:1 to 1:1 hexanes/ethyl acetate to give 16.34 g (76%) of title compound. MS (APCI) (m+1)/z 411.1.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH3:15])C.C(OC(=O)COC1C=CC=CC=1CCCOC)C.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)=[N:41][CH:42]=1>>[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([C:40]2[N:41]=[CH:42][C:37]([CH2:36][N:13]([CH3:14])[C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:16])=[C:8]([CH3:15])[CH:9]=3)=[CH:38][CH:39]=2)=[CH:48][CH:47]=1
Reactant: CCOC(=O)COc1ccc(NC)cc1C
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)nc1
Agent: CCOC(=O)COc1ccccc1CCCOC
Product: Cc1cc(N(C)Cc2ccc(-c3ccc(Cl)cc3)nc2)ccc1OCC(=O)O

Procedure:
A] The title compound was prepared in analogy to example 4, but using in step C] (2-methyl-4-methylamino-phenoxy)-acetic acid ethyl ester (prepared in analogy to example 5F])instead of [2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester and 5-chloromethyl-2-(4-chloro-phenyl)-pyridine instead of [rac]-3-(1-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as off-white crystals of mp. 174–76° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[N:6]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:51]=[C:49]1[C:48]2[C:47](=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:46](=[O:56])[N:50]1[CH2:2][CH2:3][CH2:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[N:6]=1
Reactant: Cc1ccc(-c2cc(CCCO)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(CCCN3C(=O)c4ccccc4C3=O)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reaction time: 8 h
Yield: 392.1 %

Procedure:
To a solution of alcohol 18c (0.1 g, 0.27 mmol), PPh3 (0.11 g, 0.40 mmol), and phthalimide (60 mg, 0.40 mmol) in 5 mL of THF was added dropwise DIAD (54 mg, 0.27 mmol) at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated, and the resulting solid was recrystallized from methanol to afford 0.53 g (87%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.84-7.76 (m, 1H), 7.70-7.65 (m, 1H), 7.34 (d, J=8.76 Hz, 1H), 7.11 (d, J=7.89 Hz, 1H), 7.00 (d, J=8.15 Hz, 1H), 6.33 (s, 1H), 4.96 (s, 1H), 3.85 (t, J=6.96, 6.96 Hz, 1H), 2.80 (t, J=7.47, 7.47 Hz, 1H), 2.35 (s, 1H), 2.24-2.13 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1I.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])#[CH:20]>CN(C)C=O.[Cu](I)I.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>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:20]#[C:19][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27]
Reactant: C#Cc1ccccc1F
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(C#Cc2ccccc2F)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.2 ml, 1.43 mmol) was added to a suspension of 1-Chloro-2-iodo-4-nitro-benzene 69 (Step 1) (100 mg, 0.354 mmol), 1-ethynyl-2-fluorobenzene (100 mg, 0.832 mmol), copper iodide (100 mg, 0.525 mmol), Pd(PPh3)2Cl2 (100 mg, 0.142 mmol) in dimethylformamide (2 ml) at room temperature, then stirred at 70° C. for 2 hours. Reaction was cooled to room temperature and extracted with ether (50 ml), washed with water (20 ml), dried (MgSO4), filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 20% v/v MeCl2/hexanes yielding title product 70 as pale yellow solid (80 mg, 82%).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1)=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[N:23]1[CH:22]=[CH:21][N:19]2[CH:20]=[C:15]([CH:14]3[CH2:8][CH2:9][CH2:10][CH2:11][S:12]3)[CH:16]=[CH:17][C:18]=12
Reactant: O=S(CCCCCl)Cc1ccc2nccn2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: c1cn2cc(C3CCCCS3)ccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
8.68 g of potassium t-butoxide was added to 80 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4:1 (v/v)] mixture, followed by the cooling with ice. A solution of 9.51 g of the 6-((4-chlorobutyl)sulfinylmethyl)imidazo[1,2-a]pyridine prepared in the Preparative Example 8 in 30 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4: 1 (v/v)] mixture was dropped into the obtained mixture. The obtained mixture was stirred for one hour, followed by the addition of ice-water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained oil was solidified by allowing to stand, followed by the addition of ether. The obtained mixture was filtered to give 5.84 g of the title compound as a dark-creamy powder (yield: 71%). The NMR spectroscopic analysis of this powder revealed that the powder was a mixture comprising two diastereomers at a ratio of about 2:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:12]1([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:11])[CH2:9][CH3:10])[CH2:14][CH2:13]1
Reactant: Br[Mg]C1CC1
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(Cl)cc1)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (8.90 mmol) of 1-(4-chlorophenyl)propan-1-one and 35.6 ml (17.79 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.42 g (76% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.Br[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:32]([O:31][CH2:30][CH2:29][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(c2c(F)cccc2OCCOCc2ccccc2)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (preparation described in example 413; 50 mg; 0.13 mmol), ((2-bromoethoxy)methyl)benzene (28 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Water was added, and the separated aq. layer was extracted with Et2O. The mixed organic layers were washed with water, dried over anh. MgSO4, filtered and concentrated to dryness under reduced pressure affording 5-(2-(2-(benzyloxy)ethoxy)-6-fluorophenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=1.04 min.; [M+H]+: 518.47 g/mol. A mixture of 5-(2-(2-(benzyloxy)ethoxy)-6-fluorophenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one 55 mg; 0.10 mmol), and platinum (IV) oxide hydrate PtO2 (24 mg; 0.10 mmol) in anh. MeOH (2 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 16 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 427.92 g/mol.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[NH2:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[C:22](=[O:23])[C:21]3[C:20](=[CH:28][C:27]([Cl:29])=[CH:26][CH:25]=3)[NH:19][C:17]2=[O:18])(=[O:15])=[O:14])=[CH:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C=CCOC(=O)c1ccc(S(=O)(=O)N=C=O)cc1
Product: C=CCOC(=O)c1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 37.6 %

Procedure:
1.10 g (4.15 mmol) of 4-allyloxycarbonylbenzene-sulfonylisocyanate and 712 mg (4.15 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 657 mg of the above-identified compound (yield 37.6%). Properties: colorless crystal, Melting point: 130°-132° C., PMR (δppm, DMSO-d6): 4.59 (2H,d), 5.18 (1H,d), 5.27 (1H,d), 5.87-5.94 (1H,m), 7.13 (1H,s), 7.22 (1H,d), 7.62-7.70 (2H,m), 7.86 (1H,d), 8.09 (2H,d), 11.63 (1H,br).
Reaction SMILES: [F:1][C:2]([F:8])=[CH:3][CH2:4][C:5]([OH:7])=[O:6].N1(C2C=CN=CC=2)CCCC1.[O:20]([C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]O)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C>[O:20]([C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][O:6][C:5](=[O:7])[CH2:4][CH:3]=[C:2]([F:8])[F:1])=[CH:35][CH:36]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)CC=C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOCC
Product: O=C(CC=C(F)F)OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of 3.0 g of 4,4-difluorobut-3-enoic acid in 50 ml of diethyl ether is treated with 0.36 g of 4-pyrrolidinopyridine and 5.66 g of 2-(4-phenoxyphenoxy)ethanol, and the mixture is cooled to 0° C. A total of 5.58 g of N,N'-dicyclohexylcarbodiimide are added in portions at a temperature of between 0° C. and +5° C., the ice-cooling is removed, and the reaction mixture is allowed to come to room temperature in the course of 16 hours, with stirring. The N,N'-dicyclohexylurea which has precipitated as a solid is separated off and discarded. The supematant solution is evaporated. The residue obtained is purified by column chromatography on silica gel (eluent: hexane/ethyl acetate, 9:1). This gives pure 2-(4-phenoxyphenoxy)ethyl 4,4-difilorobut-3-enoate in the form of an oil (refractive index nD23 : 1.5315).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:28][OH:29]>O.CO>[OH:29][N:28]=[C:2]([CH3:4])[CH2:1][C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: NO
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cccc(C2=C(CC(C)=NO)C(=O)NCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The mixture of 7.0 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 3.88 g of potassium carbonate, 3.55 g of hydroxylamine hydrochloride, 5 ml of water and 60 ml of methanol is refluxed for 5 hours and then stirred at room temperature overnight. 80 ml of water are added, the precipitate collected and washed with ethanol and diethyl ether, to yield the 3-(2-hydroxyiminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, melting at 155°-158°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.N1CCCCC1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd]Cl.[Cu]I>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([C:36]#[C:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:3][N:4]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#Cc3ccccc3)c2c1
Reaction time: 20 h
Yield: 65 %

Procedure:
A solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.52 g, 1.5 mmoles), prepared as described in example 45, in dry DMF (10 ml) under N2 was added with piperidine (1 ml, 10 mmoles), phenylacetylene (0.15 g, 1.5 mmoles), PdCl2 (0.013 g, 0.075 mmole), triphenylphosphine (0.039 g, 0.15 mmole) and CuI (0.014 g, 0.075 mmole). The mixture was stirred for 20 hours, poured into saturated NHCl (10 volumes) and extracted twice with CH2Cl2, then washed with 5% HCl, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: CH2Cl2/ethyl ether 9:1). The resultant solid was triturated in ethyl ether to give 0.41 g of the title compound (yield: 52%). m.p.: 213.4-214.4° C. (dec.).
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:20])=[N:9][N:10]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:6][CH:5]=1.O1CCOCC1.CNCCNC>[Cu]I.CN(C=O)C>[I:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:20])=[N:9][N:10]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A pressure tube containing copper (1) iodide (37.57 mg, 0.20 mmol), sodium iodide (591.42 mg, 3.95 mmol) and 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (600 mg, 1.97 mmol) was flushed with nitrogen before the addition of 1,4-dioxane, DMF (3 ml each) and N,N′-dimethylethane-1,2-diamine (0.021 ml, 0.20 mmol). The vessel was sealed and stirred at 115° C. overnight. Reaction was cooled and added to ice water (15 ml) before extracting into DCM (2×20 mL). Combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Crude material purified by column chromatography (Elution with 2% MeOH-DCM to 12% MeOH-DCM) to give the title compound: 1H NMR (500 MHz, DMSO) delta 7.02 (3H, dd, J=5.5, 3.1 Hz), 7.73-7.53 (2H, m), 8.25 (1H, d, J=5.5 Hz), 9.25 (1H, s); LC-MS: m/z=+351.90 (M+H)+. This compound of 79% purity LC-MS was used for the next step without further purification
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)C>[CH3:11][N:10]([CH3:12])[C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[C:2]([Cl:1])[CH:9]=1
Reactant: CC[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc(N(C)C)cc1Cl)[N+](=O)[O-]

Procedure:
A solution of 36.8 g of 2-chloro-4-dimethylaminobenzaldehyde, 18 ml of nitroethane and 15 g of ammonium acetate in 150 ml of absolute ethanol is refluxed for 2 hours. The mixture is then poured into 1.5 l of water, whereupon the compound separates as a viscous red oil, which crystallizes on scratching. Recrystallization from ethanol yields 18.0 g of the compound, melting at 93°-94°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: SCc1ccccc1Cl
Agent: [Na]
Product: Clc1ccc(/C=C\C(SC(/C=C\c2ccc(Cl)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 73% yield following oxidation. 1HNMR (CDC13) δ4.56 (2H, s), 6.70 (1H, d, JH,H=12.05), 7.18-7.64 (8H aromatic+1H ethylenic).