Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4](Cl)=[C:5](Cl)[C:6]=1[C:7](=[O:10])[CH2:8]Cl.C(C1C=CSC=1)(=O)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[C:7]([C:6]1[CH:5]=[C:4]([C:23](=[O:24])[CH2:22][Cl:21])[S:3][CH:2]=1)(=[O:10])[CH3:8]
Reactant: O=C(Cl)CCl
Reactant: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Agent: CC(=O)c1ccsc1
Product: CC(=O)c1csc(C(=O)CCl)c1
Yield: 41 %

Procedure:
General procedure described for compounds 1 and 2 starting from 3-acetylthiophene and chloroacetyl chloride. Purified by column chromatography column (hexane:ethyl acetate 2:1), yield 41% m.p.: 118-119° C., 1H-NMR (CDCl3): δ8.3 (s, 1H, Ar), 8.1 (s, 1H, Ar), 4.60 (s, 2H, CH2), 2.56 (s, 3H, CH3); 13C-NMR (CDCl3): δ191.6 (CO), 184.5 (CO), 143.3 (C—CO), 141.7 (C—CO), 139.7 (CH), 132.0 (CH), 45.4 (CH2), 27.4 (CH3); M/z (EI): 204, 202 (M+, 6, 17%), 153 (M-CH2Cl, 100%); HPLC: Delta Pak Column C18, 5 μm, 300 A, (150×3.9 mm), Purity 94%, r.t.=2.70 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][C:5]=1[CH2:28][NH:29][CH2:30][CH2:31][CH3:32])([O-])=O.O=[Si]=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][C:5]=1[CH2:28][NH:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCNCc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[Si]=O
Solvent: CO
Product: CCCNCc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N

Procedure:
A mixture of N-[3-(4-nitro-3-propylaminomethyl-benzenesulfinyl)-phenyl]-benzenesulfonamide (0.0019 mol) in methanol (100 mL) was hydrogenated with 10% Pd/C (0.5 g) as a catalyst. After uptake of H2 (3 equiv.), the reaction mixture was filtered over Dicalite, and the filtrate was evaporated. The residue was filtered over silica gel (eluent: 95:5 CH2Cl2:CH3OH), and then the purest product fractions were collected, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N#N.Cl>C1COCC1>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCCN(C(=O)c2ccccc2)C1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of ethyl 1-benzoylpiperidine-3-carboxylate (9.22 g, 35 mmol) in dry THF (55 mL) at −78° C. was added dropwise LDA (39 mmol, 1.1 eq) in 45 mL of dry THF. After addition, the reaction was stirred for 1 h. Then benzyl bromide (6.54 g, 39 mmol, 1.1 eq) was added dropwise under the an atmosphere of N2. The reaction was stirred for another 3 h. The solution was added dropwise 5% HCl at 0° C. and concentrated. The aqueous residue was extracted with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated to afford ethyl 1-benzoyl-3-benzylpiperidine-3-carboxylate (11.16 g, 91%). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, 3H), 1.50˜1.55 (m, H), 2.75 (m, 2H), 3.65 (m, 4H), 4.09 (m, 2H), 7.08 (m, 2H), 7.22 (m, 3H), 7.48 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[C-:12]#[N:13].[Na+]>CS(C)=O>[CH3:4][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:11])[CH2:2][C:12]#[N:13]
Reactant: CC(C)(CCl)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(CC#N)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-chloro-2-methyl-2-phenylpropane (150 g, 0.889 mol) and NaCN (54.46 g) in DMSO (250 mL) was heated at 100° C. for 3 weeks. The solution was concentrated to half the initial volume, H2O (400 mL) was added and it was extracted with Et2O (3×). The combined organic extracts were dried and concentrated to a crude product (115.1 g), which was directly used in the next step as obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:46])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39]C4CCCCO4)[CH:34]=3)[S:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])(=[O:22])=[O:21])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1.O1CCOCC1>[OH:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][N:19]([S:20]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21])[C:16]1[CH:15]=[CH:14][C:13]([CH:12]=[CH:11][C:10]([NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:46])=[CH:18][CH:17]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)NCCc3ccncc3)cc2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(C=CC(=O)NCCc3ccncc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of N-(2-pyridin-4-yl-ethyl)-3-{4-[[3-(tetrahydro-pyran-2-yloxy)-benzyl]-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylamide (0.059 g, 0.09 mmol) in 0.4 mL methanol and 0.1 mL tetrahydrofuran was added HCl (0.5 mL of a 4.0 M solution in 1,4-dioxane, 2 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. The residue was purified by preparative TLC (eluting with 10% methanol/methylene chloride) to afford 0.018 g of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-N-(2-pyridin-4-yl-ethyl)-acrylamide. 1H NMR (CDCl3) δ 8.32 (d, 2H, J=4.8 Hz), 7.27 (d, 1H, J=16.4 Hz), 7.18 (d, 2H, J=5.2 Hz), 7.03–6.98 (m, 4H), 6.90–6.86 (m, 4H), 6.69 (s, 2H), 6.60 (d, 1H, J=7.2 Hz), 6.24 (d, 1H, J=15.6 Hz), 4.67 (s, 2H), 3.62–3.57 (m, 2H), 2.88 (t, 2H, J=6.4 Hz), 2.41 (s, 6H), 2.24 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:18]O>>[Cl:6][C:7]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:18])=[O:10]
Reactant: CO
Reactant: Cc1c(Cl)ccc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(C)c1Cl

Procedure:
60 ml of conc. sulfuric acid were added dropwise to a solution of 424.0 g (2 mol) of 2,4-dichloro-3-methylbenzoic acid and 1500 ml of methanol. The reaction mixture was refluxed for 5 hours, cooled, concentrated under reduced pressure and subsequently taken up in 1000 ml of methylene chloride. The organic phase was washed with water, then with 5% strength sodium bicarbonate solution and then once more with water, dried and concentrated under reduced pressure. 401.0 g of methyl 2,4-dichloro-3-methylbenzoate were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH:27]=O)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1.O1CCCC1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH2:27][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(Nc2ncc(CN3CCOCC3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 57 from 17 mg (0.19 mmol) morpholine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde using a solvent mixture of tetrahydrofurane (1 ml), and methylene chloride (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 43 mg (59%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(5-morpholin-4-ylmethyl-thiazol-2-yl)-amine as a yellow oil. MS ISP (m/e): 386.2 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.65 (s, 1H), 7.27 (s, 1H), 7.19 (d, 1H), 7.11 (s, 1H), 6.97 (d, 1H), 6.87 (s, 1H), 3.86 (s, 3H), 3.71 (t, 4H), 3.61 (s, 2H), 2.49 (t, 4H), 2.30 (s, 3H).
Reaction SMILES: C1(C2NC(=O)C(C)NC2=O)CC1.Cl.[NH2:14][CH:15]([CH2:27][CH3:28])[C:16]([NH:18][CH:19]([CH:24]1[CH2:26][CH2:25]1)[C:20](OC)=[O:21])=[O:17]>>[CH:24]1([CH:19]2[NH:18][C:16](=[O:17])[CH:15]([CH2:27][CH3:28])[NH:14][C:20]2=[O:21])[CH2:26][CH2:25]1
Reactant: CCC(N)C(=O)NC(C(=O)OC)C1CC1
Agent: CC1NC(=O)C(C2CC2)NC1=O
Agent: Cl
Product: CCC1NC(=O)C(C2CC2)NC1=O

Procedure:
Following the procedure for the preparation of 3-cyclopropyl-6-methylpiperazine-2,5-dione but substituting methyl [(2-aminobutanoyl)amino](cyclopropyl)acetate hydrochloride and making non-critical variations provided the title compound as a solid: 1H NMR (DMSO-d6) δ 0.29-0.48, 0.79-1.20, 1.69, 3.20, 3.93, 8.05.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[CH:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([Cl:33])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[N:10]1)(C)(C)C>Cl.C(O)C>[Cl:33][C:25]1[CH:24]=[C:23]([CH:16]([CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:34])[CH:28]=[CH:27][C:26]=1[S:29]([CH3:32])(=[O:30])=[O:31]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCOC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)Nc2ccn(CCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
In a flask containing N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionamide (138 mg, 0.25 mmol) was added ethanol (6 ml) and concentrated hydrochloric acid (5 drops) and was stirred at 25° C. for 2 h. The reaction was then concentrated in vacuo to remove the ethanol, diluted with ethyl acetate (50 ml) and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 5% methanol/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-(tetrahydro-furan-3-yl)-propionamide (76 mg, 69%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.45-1.57 (m, 1H, CH of CH2), 1.68-1.84 (m, 1H, CH of CH2), 1.88-2.02 (m, 2 H, 2×CH of 2×CH2), 2.06-2.22 (m, 1H, CH), 3.22-3.30 (m, 1H, OCH of OCH2), 3.31 (s, 3H, SO2CH3), 3.53-3.77 (m, 5H, ArCH, SiOCH2, and 2×OCH of 2×OCH2), 3.83-3.93 (m, 1H, OCH of OCH2), 3.97-4.02 (m, 2H, NCH2), 4.82 (t, J=5.4 Hz, 1H, OH), 6.42 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.60 (2×dd, Jo=8.3 Hz, Jm=1.7 Hz, 1H, Ar), 7.71, 7.72 (2×d, Jm=1.7 Hz, 1H, Ar), 8.01 (d, Jo=8.3 Hz, 1H, Ar), 10.81, 10.82 (2×s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[S:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][C:12](=[S:13])[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:8]
Reactant: CCOC(=O)NC(=S)Nc1ccc(Br)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)n1c(=S)[nH]c2ccc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
Compound 2a (12.3 g, 35.5 mmol) was dissolved in 150 mL of acetic anhydride and stirred at 60° C. for 4 hour. The mixture was slowly cooled to 4° C. under crystallization and the white crystals formed were filtered off, washed with cold acetic anhydride and dried under vacuum, to give 3a (10.8 g, 32.8 mmol, 93%). mp: 214.0° C.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9][CH2:10]Cl)=[O:8])=[CH:5][CH:4]=[C:3]([F:12])[CH:2]=1.[CH3:13][CH:14]1[NH:18][CH2:17][CH2:16][S:15]1.C([O-])(=O)C.[Na+]>C(O)C>[F:12][C:3]1[CH:4]=[CH:5][C:6]([C:7](=[O:8])[CH2:9][CH2:10][N:18]2[CH2:17][CH2:16][S:15][CH:14]2[CH3:13])=[CH:1][CH:2]=1
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: CC1NCCS1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1SCCN1CCC(=O)c1ccc(F)cc1
Yield: 84.1 %

Procedure:
3.73 g (0.02 mol) of β-chloro-4-fluoropropiophenone are added in little portions at room temperature to a suspension containing 2.06 g (0.02 mol) of 2-methylthiazolidine and 1.64 g (0.02 mol) of anhydrous sodium acetate in 20 ml of ethanol over 30 minutes under stirring. After stirring for an additional 3 hours, the reaction mixture is evaporated, saturated sodium hydrogen carbonate solution is added to the oily yellow residue and it is extracted twice with 30 ml of ether each. After drying and evaporating the extract, the oily yellow residue is dissolved in acetone and acidified by 48% hydrobromic acid. Thus, 4.26 g of a white crystalline product are obtained and recrystallized twice from ethanol to give 2.00 g (29.9%) of hydrobromide of the title compound, m.p.: 151°-152° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:30]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:31])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)C1CCCCC1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)C3CCCCC3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and cyclohexanecarbonyl chloride provided the title compound. ESMS [M+H]+: 414.4
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH:41]=1)OC1C=CC=CC=1)#[N:25]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:27]([NH:26][C:24]#[N:25])=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:41]=2)[CH3:17])=[CH:6][CH:7]=1
Reactant: CN(CCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CN(CCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.99 g (3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 1.17 g (3 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 98+2) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=630 ([M+H]+, 7), 230 (100); IR (KBr): 2164 cm-1 (C≡N).
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[CH:10]([C:21]3[C:22]([OH:30])=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)[C:9]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:32]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[C:10]3([CH2:38][O:30][C:22]4[CH:23]=[C:24]5[C:25](=[CH:29][C:21]3=4)[CH2:26][CH2:27][O:28]5)[C:9]2=[O:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1C(c1ccccc1)c1ccccc1)OCCO3
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 6-(diphenylmethyl)-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6′-(diphenylmethyl)-2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one was obtained (67%) as a colorless solid: MS (ES+) m/z 504.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[C:32]([F:34])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30]C)=[CH:19][N:18]=3)=[N:10]2)=[C:6]([F:35])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN1CCCC1=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:35])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[C:20]([OH:30])=[CH:19][N:18]=3)=[N:10]2)=[C:32]([F:34])[CH:33]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3c2CCC3)c(F)c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3c2CCC3)c(F)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
461 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 2-1-1 (0.964 mmol, 1.00 eq.) were dissolved in 42 mL of dry 1-methylpyrrolidin-2-one. 51 mg of potassium carbonate (0.366 mmol, 0.38 eq.) and 150 μL benzenethiol (1.45 mmol, 1.5 eq.) were added. The mixture was stirred for 1 h at 150° C. bath temperature. The reaction mixture was partitioned between aqueous half saturated ammonium chloride solution and DCM/isopropanol (4:1). The separated aqueous layer was extracted twice with DCM/isopropanol (4:1). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography provided 349 mg (0.75 mmol, 78%) of analytically pure target compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.CN[C@@H]1CCCC[C@H]1NC.[I-:32].[Na+]>O1CCOCC1.[Cu]I>[F:15][C:14]1([F:16])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9][C@@:8]1([C:6]1[CH:7]=[C:2]([I:32])[CH:3]=[CH:4][C:5]=1[F:21])[CH3:20]
Reactant: [I-]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(I)ccc2F)C1(F)F
Temperature: 110 °C
Reaction time: 15 h
Yield: 96.2 %

Procedure:
A solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (200 mg, 546 μmol) in dioxane (2 ml) was treated consecutively with trans-N,N′-dimethyl-1,2-cyclohexanediamine (16.0 mg, 109 μmol), copper(I)iodide (10.6 mg, 54.6 μmol), and sodium iodide (165 mg, 1.09 mmol). The reaction mixture was stirred at 110° C. for 15 hours. Following TLC the reaction was incomplete. Another amount of copper(I)iodide (10.6 mg, 54.6 μmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (16.0 mg, 109 μmol), and sodium iodide (165 mg, 1.09 mmol) was added. Stirring was continued at 110° C. during the weekend. For the workup, the reaction mixture was evaporated at reduced pressure and the residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 90:60 as the eluent. The (R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one (217 mg, 96% yield) was obtained as light yellow viscous oil. MS (ISP): m/z=414.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:14]([C:15]([NH2:17])=[O:16])=[C:7]1[NH:6][C:5]2=[O:31].[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>>[C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[C:13]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[C:14]([C:15]([NH2:17])=[O:16])=[C:7]1[NH:6][C:5]2=[O:31])(=[O:35])[CH:33]=[CH2:34]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c(=O)c1cc(N)ccc12
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Nc1ccc2c(c1)c(=O)[nH]c1c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn12

Procedure:
Compound 78 was prepared from 7-amino-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide and acryloyl chloride according to the procedure similar to that for compound 8. 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.77 (s, 1H), 8.65 (s, 1H), 8.24 (d, J=8 Hz, 1H), 8.15 (d, J=8 Hz, 1H), 7.85 (d, J=7.6 Hz, 2H), 7.48-7.52 (m, 2H), 7.2-7.15 (m, 5H), 6.57 (dd, J=9.2, 18.0 Hz, 1H), 6.37 (d, J=18.0 Hz, 1H), 5.87 (d, J=9.2 Hz, 1H). MS (ESI, m/e) [M+1]+ 466.1.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.[O:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.O>O1CCCC1.CCCCCC>[CH2:2]([O:3][C:4](=[O:5])[C:6]([F:7])=[C:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)[CH3:1]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)=C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
Into a cooled (−10° C.) solution of 5.25 g (21.68 mmol) of 2-fluoro-2-phosphonoacetic acid triethyl ester in tetrahydrofuran (30 mL) under an atmosphere of argon was dropped 13.2 mL (19.87 mmol) of 1.5 mol/L n-butyllithium in hexane (available from KANTO KAGAKU). After stirring for 20 minutes at room temperature, 2.0 g (19.87 mmol) of tetrahydropyran-4-one was dropped thereto and stirred for 2 hours at about 55° C. The obtained mixture was left to cool to room temperature and then poured into water, followed by extraction with ether. The ether extract was washed with water (three times) and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by medium pressure liquid column chromatography on silica gel (developing solvent: hexane-ethyl acetate) to obtain 3.32 g (yield 88.8%) of fluoro-(tetrahydropyran-4-ylidene)acetic acid ethyl ester (IX-16) as colorless liquid. Its physical property is shown blow.