Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH2:27][CH3:28])[C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc2c(c1)[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(C)cc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.64 g), iodoethane (0.20 mL) and cesium carbonate (1.26 g) in DMF (5 ml) was stirred at 50° C. for 4 h. After stirring at room temperature over weekend, the mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.68 g) as a brown oil.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][CH:20]([CH2:24][CH2:25][OH:26])[CH2:19]3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:29])[C@@H:20]([CH2:24][CH2:25][OH:26])[CH2:19]3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCNC(CCO)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCO)C1
Yield: 35.3 %

Procedure:
Combine 2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-ethanol (0.161 g, 0.433 mmol), formaldehyde (46 μL, 0.563 mmol, 37%), and sodium triacetoxyborohydride (0.138 g, 0.650 mmol) in dichloroethane (15 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 8% 2N ammonia-methanol in dichloromethane gives (S)-2-[4(2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulen-10-yl)-1-methylpiperazin-2-yl]ethanol (0.059 g, 0.153 mmol, 35%) as a yellow oil. Mass spectrum (APCI): m/z=386.4 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow oil in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulen-10-yl)-1-methylpiperazin-2-yl]ethanol dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Li+].[CH3:14]C([N-]C(C)C)C.CI>C1COCC1>[CH3:14][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)CCc1ccc(Cl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(Cc1ccc(Cl)cc1)C(=O)O
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 3-(4-chlorophenyl)propionic acid (1.85 g, 10 mmol) in 10 mL of THF was added to 16 mL of freshly prepared 1.5 M LDA (24 mmol) at dry ice-acetone bath temp. The reaction mixture was stirred 1 hr as it warmed to −30° C. and 1.6 mL (25 mmol) of methyl iodide was added. The resulting mixture was stirred at the same temp. for 0.5 h and the stirring was continued at RT overnight. The reaction was quenched with 1 N HCl, and diluted with ether. The solution was washed with water, 10% sodium thiosulfate and brine. The organic layer was dried over MgSO4. Solvent removal gave a mixture of the desired methylated product and the starting acid. Repetition of the above procedure on this residue gave the desired 2-methyl-3-(4-chlorophenyl) propionic acid contaminated with ˜5% of the starting acid as an oil. NMR: 1.5 (d, 3H), 4.78 (q, 1H). 6.84 & 7.26 (2d, 4H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:31])([CH3:30])[C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.C(#N)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:28]=[C:27]5[C:23]([C:24]([CH3:31])([CH3:30])[C:25](=[O:29])[NH:26]5)=[CH:22][CH:21]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)Nc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 180 °C
Yield: 66 %

Procedure:
A mixture of the 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (50 mg, 0.18 mmol), 6-amino-3,3-dimethylindolin-2-one (63 mg, 0.36 mmol), and acetonitrile (3 mL) was heated in a sealed tube via at 180° C. for 60 min. The mixture was treated with EtOAc (50 mL) and sat. aq. solution of NaHCO3. The organic layer was separated and washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography over silica gel to give a light yellow solid (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:21][CH2:20][NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 70 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
To a 2000 ml three-necked flask under N2 containing 3-Amino-4-hydroxy-benzoic acid methyl ester (31.35 g, 187 mmol) in anhydrous DMF (630 ml; 20 vols) at RT, was added K2CO3 (103 g, 4 eq.) in one portion followed by 1,2dibromoethane (65 ml, 4 eq.) in one portion. The reaction mixture was stirred at 70° C. for 12 h. Temperature was allowed to cool down to RT, and HCl1N was added until pH=8, and extraction was performed using diethyl ether (3*200 ml). The organic phase was washed with water (2*200 ml) and dried over MgSO4 and concentrated to afford a brown red oil with solid, which was taken up again in diethyl ether (450 ml) and THF (50 ml) and filtered to remove a white solid. To the filtrate was added HCl1N, and diethyl ether (130 ml) was added, suspension was stirred at RT for 5 minutes and filtered to give 27.6 g of crude product. The aqueous phases were again extracted with ethyl acetate to afford additional 6.23 g of product. The combined fractions (32 g) were recrystallised from EtOH (420 ml; 13 vols) to give after filtration and drying a white powder (19.47 g (16.37 g free base)), yield=40%.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C:24]1[S:25][C:26]([CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32])=[C:27]([CH3:29])[N:28]=1>C(Cl)Cl>[CH3:23][C:24]1[S:25][C:26]([C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])=[C:27]([CH3:29])[N:28]=1
Reactant: Cc1nc(C)c(C(O)C(C)C)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)C(C)C)s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask containing Dess-Martin reagent (2.5 g, 5.89 mmol) in DCM (50 mL) was cooled to 0° C. and then a solution of 1-(2,4-dimethylthiazol-5-yl)-2-methylpropan-1-ol (830 mg, 4.48 mmol, Intermediate 4: step a) in DCM (10 mL) was added. After 5 minutes, the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 45 minutes. The mixture was quenched with saturated aqueous NaHCO3 and 1 N aqueous NaOH (2 mL) and the aqueous portion (pH˜9) was extracted with DCM (3×75 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel (10% EtOAc-DCM) afforded the title compound as a colorless oil.
Reaction SMILES: O=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:13][OH:14]>N1C=CC=CC=1>[OH:14][N:13]=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: NO
Reactant: O=C1CCCc2ccncc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCCc2ccncc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 103.6 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-8-oxo-isoquinoline (850 mg) in pyridine (10 ml) was added hydroxylamine hydrochloride (803 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen-carbonate solution and brine. Evaporation of the dried (Na2SO4) organic layer gave 8-hydroxyimino-5,6,7,8-tetrahydroisoquinoline (970 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CC(O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([NH:9][C:12]2[CH:13]=[C:14]([NH2:18])[N:15]=[CH:16][N:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CN(C)c1cccc(Nc2cc(N)ncn2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of N,N-dimethyl-m-phenylenediamine (1.36 g, 10 mmol), 6-chloro-pyrimidin-4-ylamine (1.30 g, 10 mmol), 2-propanol (10 mL) and HCl conc. (0.45 mL, ˜5 mmol) is shaken for 16 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-concentrated Na2CO3 solution and ethyl acetate. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (ethyl acetate/CH3OH). The combined pure fractions are evaporated to afford the title compound. Beige solid, HPLC: tR=1.53 min (gradient F), ESI-MS: 230.3 [MH]+.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=O>O>[C:3]([NH:2][N:1]=[C:7]([CH3:9])[C:6]([OH:11])=[O:10])(=[S:4])[NH2:5]
Reactant: CC(=O)C(=O)O
Reactant: NNC(N)=S
Solvent: O
Product: CC(=NNC(N)=S)C(=O)O
Temperature: 70 °C

Procedure:
To a mixture of thiosemicarbazide (2) (4.55 g, 50.0 mmol) in water (90 mL) was added pyruvic acid (1) (4.40 g, 50.0 mmol). The mixture was heated at 70° C. for 20 min (while a white solid precipitated). After cooling to room temperature, the white solid was collected by filtration, washed with water and dried in air to give 2-(2-carbamothioylhydrazono)propanoic acid (3).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=[CH:19]3)(=[O:15])=[O:14])[CH2:9][CH2:8]1.[B:32](OC)([O:35]C)[O:33]C>CCCCC.C1COCC1>[C:28]([O:27][C:25]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([S:13]([N:10]3[CH2:9][CH2:8][N:7]([CH3:6])[CH2:12][CH2:11]3)(=[O:15])=[O:14])=[CH:24][CH:23]=2)[CH:19]=[C:20]1[B:32]([OH:35])[OH:33])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CN1CCN(S(=O)(=O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CC1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN1CCN(S(=O)(=O)c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of tert-butyllithium (1.7 M, 6.20 mL, 10.5 mmol, 2.00 equiv) in pentane was added to a solution of tert-butyl 5-[(4-methylpiperazin-1-yl) sulfonyl]-1H-indole-1-carboxylate (1-9, 2.00 g, 5.27 mmol, 1 equiv) in THF (150 mL) at −78° C. The resulting orange-colored reaction mixture was stirred at −78° C. for 1.5 hours before trimethyl borate (1.50 mL, 13.2 mmol, 2.50 equiv) was added. The mixture was warmed to 0° C. where it was stirred for 20 minutes, then partitioned between aqueous half-saturated ammonium chloride solution (200 mL) and EtOAc (2×200 mL). The organic layer was dried over sodium sulfate and concentrated to give 1-(tert-butoxycarbonyl)-5-[(4-methylpiperazin-1-yl)sulfonyl]-1H-indol-2-ylboronic acid (1-10) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, 1H, J=8.8 Hz), 8.02 (d, 1H, J=1.6 Hz), 7.71 (d, 7.71 (dd, 1H, J=8.6, 1.8 Hz), 7.49 (s, 1H), 3.05 (br m, 4H), 2.48 (br m, 4H), 2.25 (s, 3H), 1.75 (s, 9H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:17][CH2:18]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH2:17][CH2:18][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCCC1CCCCC1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(CCC2CCCCC2)cc1

Procedure:
This compound was synthesized from 4′-hydroxyacetophenone and 2-cyclohexylethanol according to general method 5 described earlier.
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH:1](=[CH:10][C:11]([Cl:16])=[O:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=CC=Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C=CC=Cc1ccccc1
Yield: 94 %

Procedure:
8.7 g of cinnamylideneacetic acid was added to 100 ml of benzene and then an excessive amount of thionyl chloride (1.2 molar equivalent to cinnamylideneacetic acid) was added dropwise to the mixture while heating to 70°-90° C and stirring the mixture to form a cinnamylideneacetic acid chloride. By distilling off the solvent from the reaction product, yellow crystals having a melting point of about 60° C were obtained. The crystals were dissolved in 20 ml of methyl ethyl ketone and then 8 g of hydroxyethyl methacrylate was added slowly to the solution with stirring under ice-cooling. After further stirring under ice-cooling for about 20 minutes, 50 ml of pyridine was added slowly to the mixture as a hydrogen chloride accepting agent to conduct esterification. When the reaction product was treated with diluted (5%) hydrochloride acid, crystals were formed, which were recovered and recrystallized from hexane to provide crystals of a monomer having a melting point of 51°-52.5° C with a yield of 94%.
Reaction SMILES: C(OC(=O)NCC1C=CC2N(CCCC[F:36])C(CN3C4C(=CC=CC=4)C(=O)N(C4CC4)C3=O)=NC=2C=1)(C)(C)C.[C:40]([O:44][C:45](=[O:80])[NH:46][CH2:47][C:48]1[CH:79]=[CH:78][C:51]2[N:52]([CH2:73][CH2:74][CH2:75][CH2:76]O)[C:53]([CH2:55][N:56]3[C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:59](=[O:66])[N:58]([CH2:67][C:68]([F:71])([F:70])[F:69])[C:57]3=[O:72])=[N:54][C:50]=2[CH:49]=1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:80])[NH:46][CH2:47][C:48]1[CH:79]=[CH:78][C:51]2[N:52]([CH2:73][CH2:74][CH2:75][CH2:76][F:36])[C:53]([CH2:55][N:56]3[C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:59](=[O:66])[N:58]([CH2:67][C:68]([F:70])([F:71])[F:69])[C:57]3=[O:72])=[N:54][C:50]=2[CH:49]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCCO
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCCCF
Product: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCCF
Yield: 76 %

Procedure:
The procedure used to prepare [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(4-fluoro-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed starting from [2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-1-(4-hydroxy-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (67 mg, 0.12 mmol). Purification by flash chromatography (eluent 2%, 4% methanol in DCM) afforded [2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-1-(4-fluoro-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (51 mg, 76%) as a white solid:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:27]2\[C:28](=[O:39])[NH:29][C:30]3[C:35]\2=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)/[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17]/[C:18](=[C:27]2\[C:28](=[O:39])[NH:29][C:30]3[C:35]\2=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)/[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:40](=[O:42])[CH3:41])=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(CN)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)NCc1ccc(/C(Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-5-nitro-2-indolinone and acetic anhydride in dioxane.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[CH:2]3[C:3]([CH2:4][CH2:5][CH2:6][CH2:7]3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]2=[O:11])=[CH:20][CH:21]=1
Reactant: O=C1CCCCC1C(C(=O)O)c1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1C(c2ccccc2)=C2CCCCC2N1c1ccc(O)cc1
Yield: 82 %

Procedure:
92.8 g of 2-(2-oxo-cyclohexyl)-2-phenyl acetic acid and 44 g of 4-aminophenol in 800 cm3 of xylene were stirred and heated under reflux, as indicated in Example 1a), until the water formed in the reaction has been totally eliminated. This took 2 hours (volume collected: 14.2 cm3 ; theoretical: 14.4 cm3). After the distillation of 400 cm3 of solvent, the residue was cooled. The precipitate produced was collected and recrystallized from methylcellosolve to give 100 g (82%) of 1-(4-hydroxyphenyl)-2-oxo-3-phenyl-2,4,5,6,7,7a-hexahydro-indole (m.p. 241° C).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH2:13][C:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.[OH-].[K+].C(O)C>O>[CH2:16]([C:14]1[C:13]([O:12][CH3:11])=[CH:4][C:3]2[C:2](=[CH:9][C:8]([Br:10])=[CH:7][CH:6]=2)[N:1]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cc(Br)ccc1C=O
Reactant: COCC(=O)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2ccc(Br)cc2nc1Cc1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
A mixture of 3.3 g of 2-amino−4-bromobenzaldehyde, 3.3 g of 1-methoxy-3-phenylacetone, an aqueous potassium hydroxide solution (10 g of potassium hydroxide was dissolved in 10 ml of water) and 20 ml of ethanol was heated under stirring at 100° C. for 4 hours in a sealed tube. After cooling as it was, the reaction solution was poured into water and the mixture was extracted with diethyl ether. The organic phase was washed with brine and the solvent was removed. The residue was crystallized from hexane/ethyl acetate, to give 3.7 g of the target compound.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>[Cu]I.O1CCCC1>[C:7]([C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCCCCCCCCC
Reactant: Ic1cccs1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cccs1
Temperature: 55 °C
Reaction time: 7 h
Yield: 739 %

Procedure:
To a solution of 2-iodothiophene (31.5 g), 1-dodecyne (2.5 g), triethylamine (105 ml), and tetrahydrofuran (100 ml) was added (bis)triphenylphosphine palladium(II)chloride (1.73 g) followed by copper(I)iodide (0.24 g). The reaction mixture was warmed to 55° C. and stirred for 7 hr. The solution was allowed to cool to room temperature and stirred overnight. The mixture was filtered, and the precipitate was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled to afford 27.6 g (74%) of product, bp 145°-150° C. at 0.7 mm Hg.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:32][CH2:28][CH2:29][CH2:30][CH3:31])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCCN
Solvent: CC#N
Product: CCCCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), butan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 333 (M+, 2), 290 (6), 87 (7), 86 (bp), 85 (4), 70 (7).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:22]=[O:23])(=O)=O>CN(C)C=O>[C:29]1([CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=2[CH2:18][N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(CN2CCN(c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of N-phenylpiperazine (200 mg) and diiosopropylethylamine (130 mg) in dimethylformamide (1 ml) was added 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (320 mg). After stirring at room temperature for 3 hours the reaction mixture was partially concentrated under reduced pressure and the residue was purified by flash chromatography column using petroleum ether:diethyl ether (1:3) as eluant. The pure fractions were combined and evaporated under reduced pressure to give a gum which was crystallized from diethyl ether to give 4-phenylmethoxy-3-[[(4-phenyl)-1-piperazinyl]methyl]benzaldehyde (320 mg) as white crystals. 1H NMR (CDCl3) δ9.95 (s, 1H, CHO); 5.23 (s, 2H); 3.80 (s, 2H); 3.30 (m, 4H); 2.78 (m, 4H). TLC (silica gel): Rf=0.7 (petroleum ether:diethyl ether, 1:4).