Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:39][CH:38]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: Nc1ccc(B(O)O)cc1
Product: Nc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure G using 4-aminophenylboronic acid (274 mg, 2 mmol) to give 5-{-4-[2-(4′-amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.C([O:21][C:22](=O)[C:23](=[O:34])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)C>C(O)C>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:22](=[O:21])[C:23]([OH:34])=[C:24]1[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1
Reactant: O=Cc1ccccc1F
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Solvent: CCO
Product: O=C1C(O)=C(c2c[nH]c3ccccc23)C(c2ccccc2F)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 2-Fluoro-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(1H-Indol-3-yl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[CH:7][CH:8]=2)[O:3]1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O.CCOCC.O>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=2)[O:3]1
Reactant: Cc1ccc2c(c1)OC(C)(C)CC2(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1cc2c(cc1C)OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To an ice-bath cooled solution of 1.96 g (9.6 mmol) of 2,2,4,4,7-pentamethyl-chroman (Compound 89) in 30 ml of nitromethane was added under argon 1.059 g (13.5 mmol) of acetyl chloride followed by 1.9 g (14.3 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 14 h and then cooled in an ice-bath and treated with 25 ml of conc. HCl. The mixture was warmed to room temperature and diluted with ether and water. The organic layer was separated and the aqueous layer extracted with ether. The organic extracts were combined and washed successively with water, saturated NaHCO3 solution, water again, and saturated NaCl solution, and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. PMR (CDCl3): 1.36 (6H, s), 1.37 (6H, s), 1.86 (2H, s), 2.49 (3H, s), 2.56 (3H, s), 6.65 (1H, s), 7.74 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[H][H]>[Ni].CCCCCC>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5]
Reactant: [H][H]
Reactant: N#Cc1c(F)cccc1F
Agent: [Ni]
Solvent: CCCCCC
Product: NCc1c(F)cccc1F
Yield: 94.6 %

Procedure:
To an autoclave of 1 l, 150 g of 2,6-difluorobenzonitrile, 150 g of hexane and 7.5 g of Ra—Ni were charged, replacement with hydrogen gas was carried out, and a reaction was carried out at a hydrogen pressure of from 30 to 40 kg/cm2 at a reaction temperature of 130° C. for 2.5 hours. After the completion of the reaction, the reaction mixture was subjected to filtration to separate off the catalyst, and hexane was recovered by distillation, followed by distillation under reduced pressure to obtain 146 g of 2,6-difluorobenzylamine (boiling point: 82° C./25 mmHg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O.CCCCCC.CCOC(C)=O>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[Cl:13]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: CCOC(=O)c1ccc(N)c(Cl)c1

Procedure:
Ethyl p-aminobenzoate, 49.50 g (0.30 moles) was dissolved in 500 ml of acetonitrile (CH3CH) and heated to ref lux. When the mixture became homogeneous, 42.0 g (0.315 moles) of N-chlorosuccinimide was added in several portions over one hour and the mixture was stirred at reflux overnight. By TLC (Hexane: EtOAc, 3:1), the mixture contained no starting material but only the desired product (Rf=0.55) and a minor impurity, which was probably dichlorinated material (Rf=0.65). The mixture was concentrated on a rotary evaporator and the residue was redissolved in 250 mL of dichloromethane (CH2Cl2) and washed twice with 100 mL of 5% sodium hydroxide (NaOH). The organic layer was dried over anhydrous potassium carbonate (K2CO3) and concentrated on a rotary evaporator to yield 62.0 g of a reddish brown solid. The solid was recrystallized from 1.25 L of boiling hexane to give 52 g of a brown solid. The solid was recrystallized twice more from 1 L of boiling hexane to give 45.5 g (76%) of tan solid ethyl 4-amino-3-chlorobenzoate (2), mp 82-83° C. and homogeneous by TLC. Additional material, 9.6 g (16%) of like quality, was obtained by repeated recrystallization from hexane. The total yield of pure ethyl 4-amino-3-chlorobenzoate (2) was 92%. 1H NMR (CDCl3) d 7.97-7.96 (t, 1H, J=0.7 Hz, ArH), 7.80-7.75 (dt, 1H, J=0.7 Hz, ArH), 6.77-6.73 (dd, 1H, J=0.5 Hz, ArH), 4.40-4.29 (q, 2H, J=2.8 Hz, OCH2), 1.41-1.34 (t, J=2.8 Hz, 2H, OCH2CH3). IR (KBr) cm−1, 3500, 3370 (NH2, m), 1695, (C═O, s) 1630. MS (El) m/e 199 (M+), 201 (M+2), Anal. Calc'd for C9H10NO2. Cl: C, 54.15; H, 5.05: N, 7.02. Fd. C, 54.14; H, 5.17, N, 6.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:11]=[C:10]([C:20](OC)=[O:21])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH2:30])[CH3:26]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:11]=[C:10]([C:20]([NH:30][CH2:29][CH2:28][N:27]([CH2:31][CH3:32])[CH2:25][CH3:26])=[O:21])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1
Reactant: COC(=O)c1nn(-c2ccccc2)c2c1CCc1cc(Cl)ccc1-2
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)c1nn(-c2ccccc2)c2c1CCc1cc(Cl)ccc1-2
Product: Cl

Procedure:
A mixture of 5 parts of methyl 7-chloro-1-phenyl-4,5-dihydro-1H-benz[g]indazole-3-carboxylate and 40 parts of 2-diethylaminoethylamine is heated at reflux for 3 hours. Excess amine is distilled off under reduced pressure and the reside is partitioned in ether and dilute aqueous hydrochloric acid. The aqueous layer is then separated and washed twice with ether and it is made alkaline with an aqueous sodium hydroxide solution. The resulting mixture is then extracted with ether and the ether extracts are dried over potassium carbonate. The ether solvent is removed under reduced pressure, the resulting oil is dissolved in anhydrous ethanol, and a slight excess of hydrogen chloride in 2-propanol is added. Anhydrous ether is then added until the mixture becomes turbid, and the mixture is cooled. The solid which forms is separated by filtration and recrystallized from a mixture of ethanol and ether to give 7-chloro-N-(2-diethylaminoethyl)-1-phenyl-4,5-dihydro-1H-benz[g]indazole-3-carboxamide hydrochloride melting at about 229°-231°C. The free base of this compound has the following formula ##SPC3##
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14][CH3:13])=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: NCc1ccccc1
Product: COc1ccccc1CNc1ccc2c(NCc3ccccc3)cccc2n1

Procedure:
The title compound, MS: m/e=370.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 2-methoxybenzylamine and benzylamine.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33]O)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(Cl)(=O)=O.C(N(CC)CC)C.[Br-:49].[Li+]>O1CCCC1.O>[Br:49][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:35]=[CH:36][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2ccccc2CO)cc1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2ccccc2CBr)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.7 %

Procedure:
To a solution of 3.5 g of 2-[4-(hexadecyloxy)phenoxy]-N-[2-(hydroxymethyl)phenyl]acetamide and 1.29 g of methanesulfonyl chloride in 60 ml of tetrahydrofuran is added 853.89 mg of triethylamine followed by stirring at room temperature for 2.5 hours. Also added is 6.11 g of lithium bromide followed by stirring at room temperature for 4 hours. The mixture is poured into water and extracted with ether. The organic layer is dried and passed through a pad of magnesium silicate. The solvent is evaporated to a residue which is crystallized from hexane to give 2.0 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[O:9]([CH2:16][CH:17]([OH:23])[CH2:18][NH:19][CH2:20][CH2:21][NH2:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[O:9]([CH2:16][CH:17]([OH:23])[CH2:18][NH:19][CH2:20][CH2:21][NH:22][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NCCNCC(O)COc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: OC(CNCCNc1ccc(Cl)nn1)COc1ccccc1

Procedure:
A mixture of 3.0 g. 3,6-dichloropyridazine, 4.2 g. 1-phenoxy-3-(2-aminoethylamino)-propan-2-ol, 3.5 ml. N-ethyldiisopropylamine and 30 ml. toluene is stirred for 24 hours at 100° C. The reaction mixture is then evaporated and the residue is digested simultaneously with 100 ml. water and 100 ml. methylene chloride, followed by suction filtration and recrystallization from isopropyl alcohol, with treatment with fullers' earth. There are obtained 1.4 g. (21% of theory) of the desired product in the form of colorless crystals; m.p. 147°-149° C.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1(C(O)=O)[CH2:18][C@H:17]([CH3:19])[CH2:16][C@H:15]([CH3:20])[CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1)[NH2:25].CN1CC[O:40][CH2:39]C1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH:12]([C:39]([NH:25][NH:24][C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1)=[O:40])[CH:13]1[CH2:14][C@H:15]([CH3:20])[CH2:16][C@H:17]([CH3:19])[CH2:18]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@H](C)CC(CN(C=O)OCc2ccccc2)(C(=O)O)C1
Reactant: CN1CCOCC1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: C[C@@H]1CC(C(C(=O)NNc2nccc(C(F)(F)F)n2)N(C=O)OCc2ccccc2)C[C@H](C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a mixture of (3S,5R)-1-[(Benzyloxy-formyl-amino)-methyl]-3,5-dimethyl-cyclohexanecarboxylic acid (0.10 g, 0.31 mmol), 2-hydrazino-4(trifluoromethyl)pyrimidine (0.067 g, 0.37 mmol), NMM (0.095 g, 0.93 mmol) and HOAt (0.05 g, 0.37 mmol) in DMF (1 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.10 g, 71%). MH+480.
Reaction SMILES: [FH:1].[CH3:2][N:3]=[C:4]=[O:5].[CH3:6][N:7]([CH:10]=[O:11])[S:8]Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:2][N:3]([S:8][N:7]([CH3:6])[CH:10]=[O:11])[C:4]([F:1])=[O:5]
Reactant: F
Reactant: CN(C=O)SCl
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C=O)SN(C)C(=O)F
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
To a solution of 9.0 g hydrogen fluoride in 100 ml toluene cooled to -50° C. was added 25.6 g methyl isocyanate. After stirring for 45 minutes and allowing the mixture to warm to -10° C., 56.4 g of N-methyl-N-formylaminosulfenyl chloride dissolved in 300 ml toluene was added. Triethylamine 45.4 g was added dropwise over a period of 0.5 hr while the temperature was maintained between 0° to 8° C. by external cooling. After stirring for 0.5 hr at ambient temperature, the reaction mixture was diluted with 200 ml ice water. The organic layer was separated, washed with water, dried and concentrated. Distillation of the residue yielded 22.4 g of product. b.p. 60°-62° C./0.2 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([CH:13]=1)[O:8][CH2:9][C@H:10]1[CH2:12][O:11]1.C(N(C(C)C)C(C)C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:14][C:26](=[O:28])[CH3:27])=[C:7]([O:8][CH2:9][C@H:10]2[CH2:12][O:11]2)[CH:13]=1
Reactant: COc1ccc([N+](=O)[O-])c(OC[C@H]2CO2)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(C)=O)c(OC[C@H]2CO2)c1
Reaction time: 0.67 h
Yield: 23.8 %

Procedure:
A mixture of (2R)-2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane (620 mg, 2.75 mmol), Pd on charcoal (10%) (250 mg), N-ethyldiisopropylamine (0.941 mL), acetic anhydride (0.52 mL, 5.5 mmol) in ethyl acetate (25 mL) was hydrogenated at normal pressure for 40 min. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (0-60% ethyl acetate in petroleum spirit) to give the subtitled compound (155 mg).
Reaction SMILES: N[C@H](C=O)CCSC.[C:9](=[O:16])([O:13][CH2:14][CH3:15])OCC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=O)=[CH:20][CH:19]=1.C(OCC)C>C(O)C.C(O)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[CH2:25])[C:9]([O:13][CH2:14][CH3:15])=[O:16])=[CH:20][CH:19]=1
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: CSCC[C@H](N)C=O
Solvent: CCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=C(C(=O)OCC)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
Metal sodium (1.5 g) was gradually added to ethanol (50 ml) at room temperature, followed by stirring for 5 minutes, and diethyl carbonate (8.9 ml, 73 mmol) was added thereto at room temperature. Further, a solution of ethyl 4-chlorophenylacetate (10 g) in ethanol (10 ml) was added dropwise thereto with stirring, and the stirring was continued for 2 hours. The reaction mixture was concentreated, and diethyl ether (150 ml) and 10% aqueous acetic acid (150 ml) were added to the residue for extraction. The aqueous layer was further washed with diethyl ether (50 ml). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. To the resulting residue were added water (25 ml) and 37% aqueous formaldehyde (8 ml) at room temperature, followed by vigorous stirring at room temperature. After addition of an aqueous solution (36 ml) of potassium carbonate (6.5 g) over 5 minutes, the mixture reaction was stirred for 4 hours and extracted with diethyl ether (100 ml×2). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of ethyl 4-chlorophenyl-α-methyleneacetate (yield, 10 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH2:13][C:14](OCC)=[O:15])([O-:12])=[O:11].N1CCCCC1>C1(C)C(C)=CC=CC=1>[N+:10]([C:13]1[C:14](=[O:15])[NH:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([O-:12])=[O:11]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: Nc1ccccc1C=O
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: O=c1[nH]c2ccccc2cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 50.8 %

Procedure:
2-Aminobenzaldehyde (1.75 g, 14.5 mmol) was dissolved in xylene (87.5 mL). To this, ethyl 2-nitroacetate (6.43 mL, 58.0 mmol) and piperidine (1.58 mL, 16.0 mmol) were added and the mixture was stirred with heat at 150° C. for 1.5 hours and successively stirred with cooling in an ice bath for 0.5 hour. The precipitate was collected by filtration and dried under reduced pressure. Thus, 3-nitroquinolin-2(1H)-one (1.40 g, yield: 51%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C[Al](C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#N.ClCCl.C[OH:27]>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:27]
Reactant: Cc1ccccc1N
Reactant: COc1cccc(C#N)c1
Reactant: CO
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)Nc2ccccc2C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500 mL 3-neck round bottom flask was added o-toluidine (4.50 g, 42.0 mmol) and 150 mL toluene. The solution was cooled in an ice bath under nitrogen. Trimethylaluminum (2.0 M in toluene, 29.4 ml, 58.8 mmol) was added dropwise via dropping funnel. The reaction mixture was stirred at room temperature for 2 hours under nitrogen. Next, 3-methoxybenzonitrile (7.27 g, 54.6 mmol) in 50 mL toluene was added and the reaction mixture was heated to 70° C. overnight under nitrogen. The reaction mixture was cooled in an ice bath and poured onto a stirring slurry of silica gel in 2:1 dichloromethane/methanol. The silica gel was filtered and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid. The solid was triturated with hexane, filtered, washed with hexane (6 g, 59%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[CH3:6][N:7]([CH3:34])[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:17]=2)[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:34][N:7]([CH3:6])[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:4][CH2:3][O:2][CH3:1])=[CH:29][CH:30]=3)[CH:17]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COCCBr
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2C)cc1
Temperature: 25 °C

Procedure:
2-Bromoethyl methyl ether (0.033 ml) was added to a stirred suspension of N-(3-dimethylaminophenyl)-3-(4-hydroxybenzamido)-4-methylbenzamide (0.9 g) and anhydrous potassium carbonate (0.064 g) in DMF (10 ml) and the resultant mixture was stirred at 80° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.073 g); NMR Spectrum: (DMSOd6) 2.28 (s, 3H), 2.87 (s, 6H), 3.31 (s, 3H), 3.67 (m, 2H), 4.18 (m, 2H), 6.43 (d, 1H) 7.12 (m, 5H), 7.37 (d, 1H), 7.78 (d, 1H), 7.97 (m, 3H), 9.87 (s, 1H), 9.96 (s, 1H); Mass Spectrum: M+H+448.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][P:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[O:6].Br[CH2:21][C:22]([CH3:45])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]2[C:28]([CH2:29][O:30][C:31]2=[O:41])=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([P:5]([O:7][CH2:8][C:9]([F:12])([F:10])[F:11])([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[O:6])[CH2:21][C:22]([CH3:45])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])=[C:32]2[C:28](=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44])[CH2:29][O:30][C:31]2=[O:41]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CBr)C(=O)OC2
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)P(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (186 μL, 0.88 mmol) in anhydrous THF (2 mL) was added a solution of 1N NaN (TMS)2 in THF (0.88 mL, 0.88 mmol). The solution was stirred at room temperature for 30 minutes, whereupon a solution of 6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture was stirred overnight when a precipitate was observed. The reaction mixture was worked up by addition of a saturated aqueous solution of ammonium chloride and extraction of the product with EtOAc. The organic extract was dried and the product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 72 mg (48%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.22 (t, 3H, J=7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H, J=4, 12, 23 Hz), 3.40 (d, 2H, J=7 Hz), 3.65 (s, 3H), 3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm; MS (m/z) 701.2 [M+Na]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>C(Cl)Cl>[Cl:2][C:3]1[N:4]=[C:5]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH2:15][CH2:14]3)=[CH:9][C:7]=2[N:8]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
To 2-Chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine HCl salt from General Procedure B-3 (50 mg) in dry DCM (3 ml) and triethylamine (3.5 equiv., 60 ul) was added ethanesulfonyl chloride (1.1 equiv., 10 ul) at 0° C. and the reaction mixture was allowed to warm up to room temperature overnight. Extraction with DCM/brine gave 2-chloro-6-(4-ethanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a crude product (67 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and ether trituration gave 291. NMR (CDCl3): 1.40 (3H, t, J=7.4), 2.65-2.69 (4H, m), 3.00 (2H, q, J=7.4), 3.37-3.41 (4H, m), 3.86 (2H, s), 3.89-3.91 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 9.35 (2H, s). MS (ESI+): MH+ 505.15 (100%)