Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1([CH3:20])[NH:17][C:16](=[O:18])[NH:15][C:14]1=[O:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][C:13]1([CH3:20])[NH:17][C:16](=[O:18])[N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[C:14]1=[O:19]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)ccc1[N+](=O)[O-]
Yield: 25 %

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (1.55 g, 10 mmoles), 5,5-dimethylhydantoin (1.28 g, 10 mmoles), K2CO3 (1.38 g, 10 mmoles) in DMF (15 ml) is introduced into a vial intended to be placed in a microwave oven and irradiated at 100° C. for 70 minutes, under magnetic stirring. The reaction mixture is then poured into water (200 ml) and extracted with AcOEt (2×75 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a silica column (eluent: Heptane/AcOEt:7/3). The expected compound is obtained in the form of a white solid with a yield of 25% (666 mg). Melting point: 177-178° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:8]([CH3:10])=O)[CH:2]([CH3:4])[CH3:3].[C:22]1(=[O:45])[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])[C:25](=[O:40])[C:24]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:23]12>>[CH3:10][C:8]1[NH:38][C:36]([CH3:37])=[C:35]([C:34]([O:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[C:22](=[O:45])[C:23]3=[CH:44][CH:43]=[CH:42][CH:41]=[C:24]3[C:25]2=[O:40])=[O:39])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:21]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCC(C)C
Reactant: C/C(N)=C/C(=O)OCCCCCCN1C(=O)c2ccccc2C1=O
Product: CC1=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC(C)C)=C(C)N1

Procedure:
Prepared by a method analogous to that of Example 1(a) from 7.0 g (24 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid isobutylester and 8.0 g (24 mmol) of 3-amino-crotonic acid-(6-phthalimidohexyl)ester. 14.6 g (quantitative) of an orange yellow oil which is used for further reactions without purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)[CH2:8]1.CC(C)([O-])C.[Na+].Br[C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:32][N:31]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:37][NH:36][C:34](=[O:35])[C:33]1[CH:38]=[CH:39][C:30]([N:18]2[CH2:19][CH2:20][C:14]3[CH:13]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:22]=[CH:21][C:15]=3[CH2:16][CH2:17]2)=[N:31][CH:32]=1
Reactant: CNC(=O)c1ccc(Br)nc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNCC3)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(N2CCc3ccc(N4CC[C@H](N5CCC[C@@H]5C)C4)cc3CC2)nc1
Temperature: 85 °C
Yield: 92.3 %

Procedure:
7-((2S,3′S)-2-Methyl-1,3′-bipyrrolidinyl-1′-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (150 mg, 0.50 mmol) was added to a mixture of tris(dibenzylideneacetone)-dipalladium (6.88 mg, 0.007), R-BINAP (22.5 mg, 0.022 mmol), sodium tert-butoxide (69.8 mg, 0.72 mmol) and 6-bromo-N-methyl-nicotinamide (118 mg, 0.55 mmol) in 6 mL of toluene and the mixture was degassed (vacuum, 3×). The reaction mixture was heated at 85° C. for 17 h, and then it was partitioned between ethyl acetate and water. The aqueous phase washed with ethyl acetate and then the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to leave 200 mg of an oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[C:9]1[C:17]2[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[C-:30]#[N:31].[K+]>CS(C)=O>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:8]([C:9]1[C:17]2[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)[CH2:7][CH2:6][C:30]#[N:31]
Reactant: CSCc1cc(F)cc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1.36 g (2.86 mmol) of the compound from Example 58A and 372 mg (5.71 mmol) of potassium cyanide were dissolved in 65 ml of DMSO and stirred at 120° C. overnight. The mixture was concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 790 mg (68% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH2:13][S:14](Cl)(=[O:16])=[O:15])#[N:12].C(NS(CC#N)(=O)=O)C1C=CC=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:14]([CH2:13][C:11]#[N:12])(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCS(=O)(=O)Cl
Reactant: NCCCc1ccccc1
Agent: N#CCS(=O)(=O)NCc1ccccc1
Product: N#CCS(=O)(=O)NCCCc1ccccc1

Procedure:
N-3-Phenyl-n-propyl cyanomethylsulfonamide was prepared with 3-phenyl-n-propylamine and cyanomethylsulphonyl chloride under the similar conditions as described for N-benzyl cyanomethylsulfonamide (Part A, EXAMPLE 12).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(Cl)c2)CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(c2ccc(F)c(Cl)c2)CCNC1
Yield: 87.9 %

Procedure:
Preparation according to Preparation 15. Tert-butyl-3-(3-chloro-4-fluorophenyl)-3-methoxypyrrolidin-1-carboxylate (1.81 g, 5.5 mmol), methylene chloride (20 mL) and trifluoroacetic acid (5 mL). Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (1.11 g, 88%). MS m/z (rel. intensity, 70 eV) 214 (38), 199 (73), 187 (bp), 157 (40), 133 (39).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:36])[C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24](S(C5C=CC=CC=5)(=O)=O)[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.CO.O1CCCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:36])[C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: Cc1cc(Cl)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(Cl)nn2c(-c3ccnc4[nH]ccc34)c(-c3ccc(F)cc3)nc12
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Added to a suspension of 0.50 g (0.97 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-[1-(phenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine in 10 ml of a mixture of methanol and a few ml of tetrahydrofuran is 0.32 ml (1.9 mmol) of a 6N aqueous solution of sodium hydroxide. The mixture gradually become homogeneous and the reaction is stirred for 30 minutes. The reaction medium is diluted with 100 ml of water and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The orange solid obtained is then chromatographed over a silica gel column (35 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.293 g of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine in the form of a yellow powder after trituration in isopropyl ether, chilling, filtration and drying.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])=[S:14])=[O:11])[CH:7]=[C:6]([Cl:25])[N:5]=1.[CH3:26]I>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13](=[N:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])[S:14][CH3:26])=[O:11])[CH:7]=[C:6]([Cl:25])[N:5]=1
Reactant: CI
Reactant: O=C(NC(=S)Nc1ccc(F)c(F)c1F)c1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC(=Nc1ccc(F)c(F)c1F)NC(=O)c1cc(Cl)nc(Cl)c1
Reaction time: 0.25 h

Procedure:
NaH (2.70 g, 0.06747 mol) was added carefully to a cooled solution (0° C.) of intermediate D9 (28.5 g, 0.04498 mol) in THF (200 ml). The mixture was stirred for 15 minutes and then CH3I (6.38 g, 0.04498 mol) was added. The ice-bath was removed and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, the mixture was quenched with H2O and extracted with CH2Cl2 (3×100 ml). The combined organic layers were washed (brine), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (eluent: heptane/EtOAc gradiënt from 80/20 to 50/50). The desired fractions were collected and the solvent was evaporated. Yield: 5.7 g of intermediate D10 (32%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:11]>C(O)CCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:11])[C:7]=1[CH2:8][CH3:9]
Reactant: N
Reactant: CCc1c(Cl)ncnc1Cl
Solvent: CCCCO
Product: CCc1c(N)ncnc1Cl
Temperature: 100 °C
Yield: 55 %

Procedure:
To a mixture of 4,6-Dichloro-5-ethylpyrimidine (22.5 g, 0.12 mol) in 1-butanol (70 mL) in a 1L glass pressure tube was added aqueous ammonia (26%, 150 mL) at RT. The vessel was sealed and heated to 100° C. for 12 h. The reaction mixture was cooled to RT, the resulted solid was filtered, washed with water (50 mL) and dried under vacuum to afford the titled compound (11.0 g, 55%) as white solid. LCMS: Mass found (M+, 158.0). 1H NMR (400 MHz, CDCl3) 8.02 (s, 1H), 7.10 (bs, 2H), 2.57-2.50 (m, 2H), 1.03-0.99 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]([F:11])=[CH:7][C:6]=1[CH3:12]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(F)cc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (15 g, 81.5 mmol) in conc. sulfuric acid (100 mL) at 0° C. was added powdered KNO3 (8.3 g, 82.2 mmol) in several portions. The reaction mixture was stirred for 1 hour at 0° C. and was then poured into ice water and extracted with ethyl acetate (3×100 mL). The extracts were washed with water and brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide carbonic acid 4-fluoro-2-methyl-5-nitrophenyl ester methyl ester (2.0 g, 11% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.14 (d, J=6.9, 1H), 7.60 (d, J=12.0 Hz, 1H), 3.86 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])CO)[CH3:16]>C1(C)C(C)=CC=CC=1.[O-]CCCC.[Ti+4].[O-]CCCC.[O-]CCCC.[O-]CCCC>[C:6]([O:8][CH2:9][CH:17]([CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH3:14])=[O:12])=[CH:3][CH:4]=1
Reactant: CCCCC(CC)CO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1C
Product: CCCCC(CC)COC(=O)c1ccc(C(=O)OC)cc1

Procedure:
A 2000 ml multi-neck flask stirring apparatus, composed of an intensive condenser, which is attached to a thermostat, and a distillation bridge, is charged with 1 mol of dimethyl terephtalate in 1.2 l of xylene at 40° C., and a mixture of 340 mg of titanium(IV) butoxide and 1 mol of 2-ethyl-1-hexanol is added dropwise.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C[O:20][C:21](=O)[C:22]1[C:27]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:26][CH:25]=[C:24]([Cl:34])[C:23]=1[CH2:35]Br.C(N(CC)CC)C>CN(C=O)C>[Cl:34][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([CH:31]2[CH2:32][CH2:33]2)=[O:30])=[C:22]2[C:23]=1[CH2:35][N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:21]2=[O:20]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 27.9 %

Procedure:
To a solution of (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.4 g, 5.1 mmol) in DMF (20 ml) was added 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.6 g, 4.6 mmol) and triethyl amine (2.0 ml, 14 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×2), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give (1S)-cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (650 mg, 30%): mp, 197–199° C.; 1H NMR (CDCl3) δ 0.89–0.93 (m, 2H, c-CH2), 1.08–1.12 (m, 2H, c-CH2), 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65–1.69 (m, 1H, c-CH), 2.97 (s, 3H, CH3SO2), 3.70 (dd, J=5, 15 Hz, 1H, CHH), 3.87(s, 3H, OCH3), 4.05–4.23 (m, 4H, NCH+CH+OCH2CH3), 4.41 (d, J=17 Hz, 1H, CHH), 5.75–5.81 (m, 1H, CHN), 6.86–6.96 (m, 3H, Ar), 7.39 (d, J=9.0 Hz, 1H, Ar), 8.45(d, J=9.0 Hz, 1H, Ar), 10.36 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.5, 14.7, 16.2, 41.6, 46.9, 51.3, 55.5, 56.0, 64.7, 111.7, 112.3, 118.6, 119.3, 119.7, 121.8, 129.1, 133.2, 136.8, 139.0, 149.0, 149.9, 169.2, 172.6; Anal Calcd for C24H27ClN2O6S: C, 56.86; H, 5.37; N, 5.53. Found: C, 56.81; H, 5.26; N, 5.56.
Reaction SMILES: [CH3:1][C:2]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=S>C1COCC1.[Ni]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:1])[CH2:3][N:4]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CN1C(=S)C(C)(CC(=O)OCC)c2c1cccc2[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(C)(CC(=O)OCC)c2c(N)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (±)-diethyl 2,2′-(3-methyl-4-nitro-2-thioxo-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step C (900 mg, 6.31 mmol) in THF (40 mL) was added activated Raney nickel (ca. 4 g) and the reaction mixture was stirred at ambient temperature for 10 min. The reaction mixture was filtered through a pad of Celite, washing with THF. EtOAc (100 mL) was added to the filtrate and the mixture was concentrated under reduced pressure to a volume of about 100 mL. This mixture was diluted with EtOAc (300 mL) and washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=321 (M+1).
Reaction SMILES: C([C:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C=C.C([Mg]Cl)(C)C.Cl>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CCOCC>[CH2:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCC(Cc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To an ether solution (7.5 ml) containing tetraisopropoxytitanium (0.284 g, 1.0 mmol) and diethyl allyl(benzyl)malonate (0.145 g, 0.5 mmol) was added dropwise at −50° C. 1.53 ml of 1.31M ether solution containing isopropylmagnesium chloride (2 mmol). Upon stirring at −40° C. for 1 hour, the reaction liquid turned from yellow into brown. With 1N hydrochloric acid added, the reaction liquid was stirred at room temperature for 15 minutes. After treatment and purification as in Referential Example 1, there was obtained diethyl benzylmalonate in deallylated form (yields: 97%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=3)[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
100 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propanal (80 mg, 0.312 mmol), 1-phenylpiperazine (0.047 mL, 0.312 mmol), DIPEA (0.081 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH2:1]([OH:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH3:11]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1](=[O:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCC=CCC=C/C=C/CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCC=CCC=C/C=C/C=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 59.5 %

Procedure:
To a solution of trans, trans, trans-2,4,7-undecatrien-1-ol (3.4 g) in chloroform (300 ml) was added manganese dioxide (30 g). The reaction mixture was stirred for 60 hours at ambient temperature. After the manganese dioxide was removed by filtration, the resultant mixture was concentrated under reduced pressure to give a yellowish oily residue, which was subjected to a column chromatography on silica gel (developing solvent: chloroform) to give colorless oily trans, trans, trans-2,4,7-undecatrienal (2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 39.8 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (77 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (39 mg, 40% over 2 steps) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.39 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 6.87 (s, 1H), 4.49 (s, 1H), 4.02 (s, 1H), 3.93 (s, 3H), 2.84 (s, 1H), 2.22 (s, 1H), 1.97 (s, 1H), 1.75 (s, 2H), 1.23 (s, 4H); ESI MS m/z 544 [C30H30ClN5O3+H]+; HPLC 99.7% (AUC), tR=10.68 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19](=[O:35])[CH:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>>[NH2:18][C:19](=[O:35])[CH:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:2]2[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)[N:7]=2)=[CH:30][CH:29]=1)[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22]
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: CC(C)OC(=O)C(Cc1ccc(N)cc1)C(N)=O
Product: CC(C)OC(=O)C(Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(N)=O
Yield: 78.3 %

Procedure:
Following general procedure A1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.063 g, 0.24 mmol) was reacted with isopropyl 3-amino-2-(4-aminobenzyl)-3-oxopropanoate (0.060 g, 0.24 mmol) to afford the title compound (0.090 g, 78%) as a light brown foam. MW=478.97. APCI MS m/z 479 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:19]1[C:20]([OH:28])=[CH:21][C:22]3[O:26][CH2:25][CH2:24][C:23]=3[CH:27]=1)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C.O=S(Cl)Cl>ClCCl.C(O)(=O)C.O1CCCC1.[Zn]>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:19]1[C:20]([OH:28])=[CH:21][C:22]3[O:26][CH2:25][CH2:24][C:23]=3[CH:27]=1)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C1(O)c1cc2c(cc1O)OCC2
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: O=C1C(c2cc3c(cc2O)OCC3)c2c(Br)cccc2N1Cc1ccccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 138.3 %

Procedure:
To a solution of 4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (1.12 g, 2.48 mmol) in anhydrous dichloromethane (25.0 mL) was added triethylamine (1.40 mL, 9.91 mmol) and SOCl2 (0.40 mL, 4.96 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and quenched with water (30.0 mL). The organic layer was separated, washed with water (3×30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give a gummy material. The residue was dissolved in acetic acid/tetrahydrofuran (3.00 mL/22.0 mL) followed by the addition of zinc dust (0.81 g, 12.4 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 16 h. After the solid was filtered, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with water (3×30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (1.50 g, 77%) as a gummy material: MS (ES+) m/z 437.3 (M+1).