Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:24]=[CH:23]/[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2CCSCC2)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCSCC2)c2ccc(O)cc2)cc1
Temperature: 85 °C

Procedure:
Reagents 36 (0.32 g, 0.886 mmol), t-butyl acrylate (0.78 mL, 5.31 mmol), Pd(OAc)2 (0.042 g, 0.186 mmol), P(o-tolyl)3 (0.12 g, 0.381 mmol) and Et3N (0.74 mL, 5.31 mmol) were added to a flask containing CH3CN (13 mL) and the reaction mixture was heated at 85° C. for 24 h. The reaction mixture was allowed to cool at RT and partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel using a hexanes:EtOAc gradient (100:0 to 50:50) to give compound 37 as a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (s, 9H), 2.65-2.66 (m, 5H), 6.45 (d, J=16 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.1 Hz, 2H), 7.49 (d, J=16.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 9.37 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].C([N-]C(C)C)(C)C.[Li+].[F:21][C:22]([F:27])([F:26])[C:23](=[O:25])[CH3:24].[Cl-].[NH4+]>O1CCCC1>[F:21][C:22]([F:27])([F:26])[C:23]([C:10]1[S:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=2[N:9]=1)([OH:25])[CH3:24]
Reactant: CC(=O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc2scnc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(c1nc2cc([N+](=O)[O-])ccc2s1)C(F)(F)F
Temperature: -100 °C
Reaction time: 0.67 h
Yield: 51.4 %

Procedure:
A solution of 5-nitrobenzothiazole (120 mg) in dry tetrahydrofuran (10 mL was cooled to -100° C. and then treated dropwise with lithium diisopropylamide (0.36 mL, 2.0M). The reaction mixture was stirred for 40 minutes at -100° C., and then treated with a solution of trifluoroacetone (75 mg) in dry tetrahydrofuran (1 mL). The reaction mixture was maintained at -100° C. for 30 minutes, treated with saturated aqueous ammonium chloride (10 mL), warmed to room temperature, and extracted with diethyl ether. The extracts were combined, washed (brine) dried (Na2SO4), and evaporated to leave a brown solid. Chromatography, eluting with chloroform, followed by chromatography, eluting with toluene, gave the title compound as a solid (100 mg); m.p. 66°-69° C.; NMR: 1.87 (s,3), 8.10 (s,1), 8.33 (dd,1), 8.46 (d,1), 8.87 (d,1); MS (EI, high resolution): 292.0144 (theoretical 292.01292). Analysis for C10H7F3N2O3S: Calculated: 41.10; H, 2.41; N, 9,59; Found: C, 39.32; H, 3.09; N, 8,26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:13]([CH2:26][O:27]C2CCCCO2)[CH2:12][N:11]1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1>Cl.CCO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]=[C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:13]([CH2:26][OH:27])[CH2:12][N:11]1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1
Reactant: COc1ccc(CN2CC(COC3CCCCO3)N(Cc3ccc(OC)c(OC)c3)C2=Nc2c(Cl)cccc2Cl)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(CN2CC(CO)N(Cc3ccc(OC)c(OC)c3)C2=Nc2c(Cl)cccc2Cl)cc1OC
Yield: 74.9 %

Procedure:
9.66 g (15 mmol) of (8) were treated for 6 hours with 30 ml of 2N HCl/EtOH solution (5:5). After extraction with EtOAc, 7.2 g of crude sample were obtained. After silica gel column separation, using EtOAc/Hexane (6:4) as solvent, 6.3 g of (9) (75% yield) were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:25][CH2:26][N:27]([CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCC(O)(c4ccc(Cl)cc4)CC3)CC2)cc1

Procedure:
3.0 g (13.6 mmol) of 1-(4-nitrophenyl)-4-piperidone (cf. Taylor et al. Synthesis (1981) 606], 2.9 g (13.6 mmol) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 0.8 g (13.6 mmol) of acetic acid and 0.9 g (13.6 mmol) of sodium cyanoborohydride were reacted as in Example 1.
Reaction SMILES: COC1C=C(C(=O)C(C)CCC2C=CC(F)=CC=2)C=C(OC)C=1.C[Mg]Br.[Cl-].[NH4+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39](O)([CH:41]([CH3:51])[CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH3:40])[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1.OS(O)(=O)=O>CCOCC.C(O)(=O)C.[Pd]>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:39]([CH:41]([CH3:51])[CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)[CH3:40])[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1
Reactant: COc1cc(OC)cc(C(C)(O)C(C)CCc2ccc(F)cc2)c1
Agent: [Pd]
Agent: COc1cc(OC)cc(C(=O)C(C)CCc2ccc(F)cc2)c1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc(OC)cc(C(C)C(C)CCc2ccc(F)cc2)c1

Procedure:
3,5-Dimethoxy propiophenone (52.0 g.) was added to a suspension prepared from 13.9 g. 57% sodium hydride in mineral oil (which had been freed of mineral oil by washing with toluene) and 130 ml. toluene. The resulting mixture was refluxed 30 minutes, 51 g. of 2(p-fluorophenyl)ethyl bromide added and refluxed 21/2 hours. The mixture was worked up with water and HCl and the product distilled to give 66.4 g. 1-(3,5-dimethoxyphenyl)-2-methyl-4(p-fluorophenyl)-1-butanone b.p. 160 - 175/0.3mm. This ketone in 300 ml. ether was treated with 130 ml. of 3 molar methyl magnesium bromide in ether and worked up with ammonium chloride to give 71.0 g. 2(3,5-dimethoxyphenyl)-3-methyl-5(p-fluorophenyl)-2-pentanol. This alcohol was hydrogenated in acetic acid containing 2 ml. H2SO4 using palladium catalyst to give 55.0 g. of desired compound b.p. 150 - 155/0.3mm. Gas chromatography showed 2 isomers of ratio 63/37.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)[CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:7][CH:8]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][CH:26]=1)[CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)c1ccc(C(COc2ncnc3ccccc23)OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(C(O)COc2ncnc3ccccc23)cc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
4-(2-tetrahyropyranyloxy-2-(4-tert-butylphenyl)ethoxy)quinazoline (0.25 g, 0.615 mmol) is dissolved in 5 ml ethanol and pyridinium-p-toluenesulfonate (15.4 mg, 0.061 mmol) is added to it. The solution is heated to 55° C. and stirred at that temperature for 4 hours. The ethanol is removed and the crude is purified by flash chromatography (silica gel; ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[ClH:29].[Cl:30][CH2:31][C:32]([NH:34][C:35]1[C:36]([CH3:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41])=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:30].[ClH:29].[ClH:30].[NH2:21][C:19]([CH:14]1[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17][N:16]([CH2:31][C:32]([NH:34][C:35]2[C:36]([CH3:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])=[O:33])[CH2:15]1)=[O:20]
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)n1
Reactant: NC(=O)C1CNCCN1CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C(C(N)=O)C2)c(C)n1
Temperature: 70 °C
Reaction time: 15 h
Yield: 61.2 %

Procedure:
A mixture of 6.1 parts of 1-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 4.3 parts of 2-chloro-N-(2,4,6-trimethyl-3-pyridinyl)acetamide monohydrochloride, 3.7 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred for 15 hours at 70° C. The reaction mixture was filtered, washed with N,N-dimethylformamide and the filtrate was evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt was filtered off, washed twice with 2-propanone and once with 2,2'-oxybispropane and dried overnight at 100°-110° C., yielding 6.58 parts (61.2%) of 3 -(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-N-(2,4,6-trimethyl-3-pyridinyl)-1-piperazineacetamide trihydrochloride, hemihydrate; mp. 224.7° C. (compound 115).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[NH:39]1[CH2:44][CH2:43][CH:42]([NH:45]C(=O)OC(C)(C)C)[CH2:41][CH2:40]1>>[NH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]3[CH:12]=[CH:11][C:10](=[O:38])[N:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:14]=3[N:15]=2)[CH2:40][CH2:41]1
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(N2CCC(N)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and 1,1-dimethylethyl 4-piperidinylcarbamate: LC-MS m/z 573 (M+H)+, 1.90 min (ret time).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:14]
Reactant: O=C(Cl)CCCCCl
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(=O)CCCCCl
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Chlorovaleric acid (5.0 g, 0.037 moles) is dissolved in 40ml of dry methylene chloride in a round bottom flask under a nitrogen atmosphere. Freshly distilled oxalyl chloride (9.58 ml, 0.110 moles) is added and the mixture is stirred overnight. The solution is concentrated under vacuum to dryness to yield 5.15 g of chlorovaleryl chloride. Trimethylphosphite (3.9 ml, 0.033 mole) is slowly added to chlorovaleryl chloride (5.15 g, 0.033 mole) under a continuous flow of nitrogen. The mixture is allowed to stir overnight to yield 7.15 g of dimethyl chlorovalerylphosphonate.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:23])[C:10]1[S:11][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].C1COCC1.Cl>CO>[O:1]=[C:2]([CH2:8][C:9](=[O:23])[C:10]1[S:11][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(CCc2ccccc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)c1ccc(CCc2ccccc2)s1

Procedure:
A solution of ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate (125 mg, 0.378 mmol), aqueous sodium hydroxide (1.2 mL, 1M, 1.2 mmol), and THF (5 mL) in methanol (5 mL) was stirred at rt overnight. The resultant mixture was treated with aq HCl (1.3 mL. 1M), and concentrated under vacuum. The residue was partitioned between brine and dichloromethane. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide off-white solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound. 1H NMR (CDCl3) δ 7.72 (d, J=3.1 Hz, 1H), 7.35-7.15 (m, 5H), 6.94 (s, 1H), 6.86 (d, J=3.1 Hz, 1H), 3.22 (d, J=8.1 Hz, 2H), 3.03 (d, J=8.1 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.Cl>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([N:8]2[C:20](=[O:21])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:22])[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N2C(=O)c3ccccc3C2=O)cc(C(C)(C)C)c1O
Yield: 77.5 %

Procedure:
A mixture of 8.8 g (40 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline and 5.9 g (40 mmol) of phthalic anhydride in 100 ml of tetrahydrofuran was refluxed for 24 hours. Concentrated hydrochloric acid (0.5 ml) was added and the mixture was refluxed for an additional seventeen hours and concentrated in vacuo. The resulting solid (13.2 g) was washed successively with water and hexane and then recrystallized from acetone-hexane to yield 10.9 g (31 mmol, 77%) of N-(3,5-di-tert-butyl-4-hydroxyphenyl)phthalimide, mp 196°-201° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:29]=[CH:28][C:11]([C:12]([NH:14][C:15]3[C:16]4[CH:22]=[C:21]([C:23]([O:25]CC)=O)[S:20][C:17]=4[NH:18][N:19]=3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:30][NH2:31].O.NN>C(O)C>[NH:30]([C:23]([C:21]1[S:20][C:17]2[NH:18][N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:29][CH:28]=3)[C:16]=2[CH:22]=1)=[O:25])[NH2:31]
Reactant: CCOC(=O)c1cc2c(NC(=O)c3ccc(N4CCN(C)CC4)cc3)n[nH]c2s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN)cc34)cc2)CC1
Yield: 36.5 %

Procedure:
Ethyl 3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylate (0.5 g, 1.03 mmol, 1 eq.) and ethanol (2 mL) are placed in a 15 mL round-bottomed flask, and a 1 M hydrazine solution (3.09 mL, 3.09 mmol) and 2 mL of hydrazine monohydrate are added. The reaction mixture is stirred at reflux for 5 hours, the solvent is then evaporated off and the residue is taken up in water. The white precipitate is filtered off, washed with water and then dried at a temperature in the region of 80° C. under vacuum. N-(5-Hydrazinocarbonyl-1H-thieno[2,3-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (0.15 g, 49%), Rf=0.32 (methanol/dichloromethane 10/90 (v/v)) is thus obtained, which product is used directly in the following step. Ethyl 3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylate may be obtained by deprotection of ethyl 1-(1-ethoxyethyl)-3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylate according to example 28.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:10][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:16]=4)[O:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:8][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([NH:42][O:43][CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][O:45]5)=[O:25])[CH:16]=4)[O:11]3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Yield: 81.1 %

Procedure:
A suspension of (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (300 mg, 0.74 mmol) in DCM (9 ml) was treated with TEA (0.17 ml, 1.2 mmol) and then with EDC (235 mg, 1.23 mmol), HOBt (166 mg, 1.23 mmol) and NH2OTHP (115 mg, 0.982 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (280 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].O.[OH-].[K+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(COc2ccc3c(c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
In analogy to the method described by Gordon W. Gribble, Joseph H. Hoffmann Synthesis 1977, 859–860, the following reaction was performed. To a precooled solution of 22.3 g (0.1 mol) 5-benzyloxyindole in 270 ml acetic acid, 19 g (0.3 mol) NaCNBH3 were added. The solution was stirred at RT for 2 h, the volume was reduced to one third and poured into 300 ml water. KOH was added under cooling and the solution was extracted with ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated to yield 20.1 g (89%) 5-Benzyloxy-2,3-dihydro-1H-indole as colorless oil, MS: 225 (M).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2].[Sn](Cl)Cl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>CCO.O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSc2ccccc2)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSc2ccccc2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
[4-Methoxy-3-(4-nitro-2-phenylsulfanylmethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.4 g, 0.9 mmol) and tin(II) chloride (0.6 g, 2.7 mmol) were combined in EtOH (20 mL) and stirred overnight at 70° C. CH2Cl2, H2O, and sodium bicarbonate were added, and the mixture was filtered through Celite. The organic layer was separated and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>O1CCOCC1>[Cl:9][C:6]1[CH:7]=[CH:8][C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)=[C:3]([NH2:4])[CH:5]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Nc1cc(Cl)ccc1Br
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(Cl)cc2N)OC1(C)C
Temperature: 100 °C
Reaction time: 10.5 h
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-5-chloroaniline (20.0 g, 96.9 mmol) in 1,4-dioxane (200 ml) were added triethylamine (54.0 ml, 487 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (3.96 g, 4.84 mmol), and under a nitrogen stream, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (42.3 ml, 290 mmol) was added dropwise. The mixture was stirred at 100° C. for 10.5 hr. The mixture was allowed to cool to room temperature and filtered through celite. To the filtrate was added dropwise methanol (25 ml) at 0° C. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1) to give 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (16.5 g, yield. 65%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])[C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[OH-].[Li+]>>[CH3:34][C:33]([CH3:35])([CH3:36])[C:32]#[C:31][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:22]([C@H:24]2[CH2:25][CH2:26][C@H:27]([CH3:30])[CH2:28][CH2:29]2)=[O:23])[C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)[CH2:15][CH2:16]2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2ccnn2)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](n3ccnn3)CC2)c(C(=O)O)s1

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-[1,2,3]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.27 g, 0.52 mmol) is hydrolysed with lithium hydroxide as previously described (example 1, step VI) to give after HPLC purification 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-[1,2,3]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.CO.Br[CH2:30][CH2:31][CH2:32][Cl:33]>CN(C)C=O>[Cl:33][CH2:32][CH2:31][CH2:30][O:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1
Reactant: COC(=O)c1ccc2cc(O)c(C(=O)OC)cc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCCCCl)c(C(=O)OC)cc2c1

Procedure:
3.1 g of 2-hydroxy-3,6-dimethoxycarbonyl naphthalene was suspended in 30 g of N,N-dimethylformamide and 1.6 g of 1-bromo-3-chloropropane, 1.5 g of sodium carbonate and 0.1 g of polyethyleneglycol (average molecular weight 3000) were added thereto and reacted for 15 hours at 50° C. Then, the reaction mixture was poured into a mixed solution of 400 g of water and 100 g of methanol, about 1 hour after, the precipitates were collected by filtration. The filtrate was washed well with methanol and water and dried to give 2-(3′-chloropropyloxy)-3,6-dimethoxy carbonyl naphthalene as 2.6 g of pale yellow powder(melting point: 115° C.).