Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:18](=[O:20])[CH3:19])[CH:5]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(N)c(C(C)=O)c1
Temperature: 105 °C
Reaction time: 7 h
Yield: 81.4 %

Procedure:
To a solution of 4-amino-3-iodo-benzoic acid methyl ester (11.30 g, 40.77 mmol) in toluene (300 mL) were added tributyl(1-ethoxyvinyl)tin (16.5 mL, 48.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (9422 mg, 8.154 mmol) under nitrogen atmosphere, and the solution was stirred at 105° C. for 7 hours. After cooling to room temperature, water was added, the mixture was extracted with ethyl acetate-tetrahydrofuran, the organic layer was washed with water, and then, evaporated. The residue was dissolved in 280 mL of tetrahydrofuran, 2N hydrochloric acid (80 mL) was added thereto, followed by stirring for 3 hours at room temperature. The reaction mixture was cooled on an ice bath, an aqueous solution of 2N sodium hydroxide (80 mL) was added, an aqueous solution of saturated sodium bicarbonate was further added, and the solution was extracted with ethyl acetate. An aqueous solution of 10% potassium fluoride was added to the organic layer, and the solution was stirred for 3 hours at room temperature. The organic layer was separated, washed with brine, then evaporated, the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and title compound (6.42 g, 33.2 mmol, 81.4%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:15]([O:19][C:20](=[O:28])[NH:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH:24]=O)([CH3:18])([CH3:17])[CH3:16]>CCCCCC.CCOC(C)=O>[C:15]([O:19][C:20](=[O:28])[NH:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1ccccc1C1(O)CCCCC1
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(CCNc1ccccc1C1(O)CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The product is prepared analogously to intermediate product 1b starting from 1-(2-aminophenyl)cyclohexanol and tert-butyl(1,1-dimethyl-3-oxopropyl)carbamate. After column chromatography (silica gel, hexane/EtOAc 7:1) the product is obtained as a colorless oil. Yield: 2.65 g (66%); Rf=0.50 (silica gel, hexane/EtOAc 4:1).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)=[CH:11][CH:10]=1)(=O)=O.[NH2:24][C@@H:25]([CH3:35])[C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[OH:27].C(OCC)(=O)C>CN(C)C=O>[CH3:21][C:18]1([CH3:20])[C:17]([CH3:22])([CH3:23])[O:16][B:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][NH:24][C@@H:25]([CH3:35])[C@@H:26]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[OH:27])=[CH:14][CH:13]=2)[O:19]1
Reactant: CC1(C)OB(c2ccc(OCCOS(C)(=O)=O)cc2)OC1(C)C
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](O)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl methanesulfonate (1.20 g) and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (1.76 g) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 5 hrs. Ethyl acetate was added to the reaction mixture. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=1/1, methylene chloride/methanol=9/1) to afford the title compound (0.24 g).
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46]OC)([CH3:33])([CH3:32])[CH3:31].[NH2:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([C:58]2[CH:62]=[CH:61][O:60][CH:59]=2)=[C:55]([OH:57])[CH:56]=1>>[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46][NH:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([C:58]2[CH:62]=[CH:61][O:60][CH:59]=2)=[C:55]([OH:57])[CH:56]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NCc1ccc(-c2ccoc2)c(O)c1
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1ccc(-c3ccoc3)c(O)c1)C(=O)NC2=O
Yield: 50 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound (purified through chromatography) is prepared from 6-tert-Butyl-4-methoxymethylene-4H-isoquinoline-1,3-dione (˜15 mg, 0.058 mmol) and 5-Aminomethyl-2-furan-3-yl-phenol (40 mg, 0.21 mmol) in 50% yield: MS (ESI): 415.1 (M−1)−1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C[N:18](C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:18])=[O:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 4'methyl-[1,1'biphenyl]-2-carboxylic acid (20.0 g, 94.2 mmol) in dichloromethane (200 mL) at 0° C. was added dimethylformamide (0.5 mL) followed by oxalyl chloride (100 mL of 2.0M solution in dichloromethane, 200 mmol). The rate of addition was adjusted to maintain the internal temperature below 10° C. When the addition was complete, the mixture was allowed to warm to 25° C. and was stirred at that temperature for two hours, after which it was concentrated in vacuo. The semisolid residue was added portionwise to concentrated ammonium hydroxide solution (250 mL) at 0° C., stirred for 15 minutes, and diluted with water (200 mL). The resulting white precipitate was collected, washed with water, and dried in vacuo over phosphorus pentoxide to give the title compound (18.7 g, 90%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[N:8]([CH3:9])[CH:7]=[CH:6][S:5]1.C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][CH:4]1[N:8]([CH3:9])[CH:7]=[CH:6][S:5]1)(=[O:20])[CH:18]=[CH2:19]
Reactant: CN1C=CSC1CCO
Reactant: C=CC(=O)Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)OCCC1SC=CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 100 g of 2-(2-hydroxyethyl)-3-methylthiazole (0.70 mol.), 71 g of triethylamine (0.70 mol.), 500 g of chloroform and 3 g of phenothiazine. Next, 63 g of acryloyl chloride (0.70 mol.) was slowly added to the reaction over 1.5 hour via the addition funnel. The reaction was stirred for 2 hours at room temperature. The reaction mixture was extracted with NaCl(aq.), NH4OH(10%), NaCl(aq.) and dried over MgSO4. The chloroform was evaporated with a rotoevaporator to yield 113 g (82%) of a dark brown liquid. The compound was confirmed by IR and 13C NMR.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].[OH-].[Na+]>C(O)C>[CH2:16]([N:13]1[CH2:12][CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(CCCc2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C1=C(CCCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
A solution of 1.7 g (8.6 mmol) of 4-(3-phenylpropyl)pyridine and 1.5 mL of benzylbromide in 5 mL of ethanol was stirred at rt for 0.5 h. To the reaction mixture was added 10 mL of ethanol and the mixture was cooled to 0° C. To this mixture was added 0.5 g (13.2 mmol) of NaBH4 small portions over a period of 1 h. To the reaction mixture was then added 5 mL of a 1N NaOH solution and the mixture was partitioned between 200 mL of ether and 50 mL of H2O. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](O)=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)([Cl:31])=O)C=CC=CC=1.C(=O)(O)[O-].[Na+].C>CCCCCC.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:31])=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 29.6 g (95.7 mmol) of 7-benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (prepared essentially as described in Step A, above) and 53 mL of phenylphosphonic dichloride in a 250-mL round bottom flask was heated at 150° C. After 2 h, the reaction was judged to be complete by TLC analysis. The mixture was cooled to ambient temperature and poured onto 400 g of ice, transferring with about 500 mL of ethyl acetate. The aqueous layer was neutralized with solid sodium bicarbonate and the layers separated. The aqueous layer was extracted with two portions of ethyl acetate. The combined organics were washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to give a brown solid. The solid was boiled in 2 L of hexane with charcoal, filtered, and concentrated in vacuo to give the title compound as a yellow solid. LC-MS 328 (M+1).
Reaction SMILES: [OH-].[K+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4]1.[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[O:27])[CH3:26])[CH:15]([CH3:17])[CH3:16].Cl>O.CCO>[O:3]1[C:7]2[CH:8]=[CH:9][C:10](/[CH:12]=[CH:26]/[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:27])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)c1ccccc1OCC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)COc1ccccc1C(=O)/C=C/c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottomed flask was added EtOH (20 mL) and potassium hydroxide (320.0 mg, 8 mmol). The mixture was stirred until homogeneous before benzo[d][1,3]dioxole-5-carbaldehyde (0.83 mL, 4.0 mmol) and 1-(2-isobutoxyphenyl)ethanone (770 mg, 4 mmol) were added. The reaction was stirred at room temperature for 16 h, and 5 mL of water was added. The reaction mixture was acidified with 1N HCl until pH=6. The resulting orange precipitate was filtered and submitted to the next step without further purification. MS (EI) for C20H20O4: 325 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2].[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20]>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C

Procedure:
A slurry of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (2.24 g, 8.91 mmol) in CH2Cl2 (30 mL) was treated with isopropyl isocyanate (1.1 mL, 11 mmol). The reaction mixture was diluted with water, the CH2Cl2 was removed under reduced pressure, and the aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to the title compound as a white solid (2.6 g, 87%). MS (ES+) m/z 337 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=O)[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.6 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-[(cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (88 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=O>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2,6-Difluorobenzoyl chloride (1.28 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 2 days. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]#[C:3][CH3:4].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[O:31]([C:38]1[CH:60]=[CH:59][C:41]([O:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]3[CH:49]=[C:50]([C:52]4[CH:53]=[C:54]([CH:56]=[CH:57][CH:58]=4)[NH2:55])[O:51][C:44]=23)=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[O:31]([C:38]1[CH:60]=[CH:59][C:41]([O:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]3[CH:49]=[C:50]([C:52]4[CH:53]=[C:54]([NH:55][C:1](=[O:5])[C:2]#[C:3][CH3:4])[CH:56]=[CH:57][CH:58]=4)[O:51][C:44]=23)=[CH:40][CH:39]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Reactant: CC#CC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC#CC(=O)Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a 20-mL glass vial was added but-2-ynoic acid (7.57 mg; 0.09 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (28.66 mg; 0.11 mmol), and N,N-diisopropylethylamine (0.05 ml; 0.30 mmol) suspended in dioxane (3.00 ml). The reaction mixture was stirred at room temperature for 1 hour. 3-[7-(4-phenoxyphenoxy)furo[3,2-b]pyridin-2-yl]aniline (29.60 mg; 0.08 mmol.) was added. The reaction mixture was then stirred at room temperature overnight. The mixture was purified using preparative HPLC to afford the title compound as a white solid (30.00 mg, 87%). HPLC (method F): 100%, RT=4.400 min. 1H NMR (DMSO-d6) δ [ppm] 10.79 (s, 1H), 8.40 (d, 1H), 8.24 (s, 1H), 7.70 (d, 1H), 7.66 (d, 1H), 7.62 (s, 1H), 7.47 (t, 1H), 7.41 (t, 2H), 7.38 (d, 2H), 7.16 (m, 3H), 7.08 (d, 2H), 6.77 (d, 1H), 2.05 (s, 3H). MS: m/z=461 [M+H]+, RT=4.52 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[O:8])=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1
Reactant: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
The product from step (b) (0.7 g) and 1,1′-carbonyldiimidazole (0.62 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature for 1 hour. tert-Butyl 4-(2-aminoethyl)-1-piperazinecarboxylate (2.73 g) was added, the solution stirred for 16 hours and then evaporated to leave a gum. Dichloromethane and sodium bicarbonate solution were added, the organic phase was separated, dried and concentrated to a gum which was purified by chromatography (ethyl acetate:triethylamine, 10:1) to give the product as a solid (0.62 g), m.p. 139-140° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][C:24]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])=[CH:34][CH:33]=4)=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:45]([N:41]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:24]2[O:23][C:19]3=[N:20][CH:21]=[CH:22][C:17]([NH:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:18]3[C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:37][CH:36]=1)([CH3:47])[CH3:46]
Reactant: CC(C)N(CCOc1ccc(-c2oc3nccc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)c3c2-c2ccccc2)cc1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCOc1ccc(-c2oc3nccc(NCCN4CCNCC4)c3c2-c2ccccc2)cc1)C(C)C
Temperature: 0 °C

Procedure:
A solution of 4-(2-{2-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 10a (0.075 g, 0.117 mmol) in dichloromethane (2.0 mL) was cooled to 0° C. Trifluoroacetic acid (1.0 mL) was added and the solution stirred under a nitrogen atmosphere at 0° C. and was allowed to warm to room temperature over 2 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford {2-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-yl}-(2-piperazin-1-yl-ethyl)-amine 10b as an off-white solid. MS (MH+) 542.3; Calculated 541 for C33H43N5O2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1cc2c(NCc3ccccc3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:37]=[C:1]([Br:5])[Br:2])=[CH:39][CH:40]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Carbon tetrabromide (78.1 g, 235.6 mmole) and triphenylphosphine (123.5 g, 471.2 mmole) were combined in 460 ml dichloromethane in a flame dried 1000 ml three neck round bottom flask under nitrogen at 0° C. The mixture was stirred 1 hour at 0° C. and was treated portionwise with 4-benzyloxybenzaldehyde (25 g, 117.8 mmole). The reaction was stirred 30 minutes at 0° C. and was washed successively with 1×100 ml water and 1×100 ml saturated sodium chloride. The organics were dried over magnesium sulfate and were poured into 3 liters hexane. The supernatant was collected and the residue was dissolved in a minimum amount of dichloromethane. This solution was also poured into 3 liters hexane and the process was repeated one more time. The combined supernatants were filtered through a 125 ml plug of silica gel (230-400 mesh) in a 600 ml coarse filter funnel. The plug was washed with 1 liter 15% ethyl acetate/hexane and the combined eluents were concentrated in vacuo to provide 38.2 g (89%) of 2-(4-Benzyloxyphenyl)-1,1-dibromo-ethene as a white solid. Melting Point: 97°-98° C. The dibromo-olefin (20 g, 54.3 mmole) was dissolved in 200 ml dry tetrahydrofuran in a flame dried 500 ml three neck round bottom flask under nitrogen. The solution was cooled to -78° C. and was treated slowly dropwise with butyllithium (70 ml, 108.6 mmole). The reaction was stirred 1 h at -78° C. followed by 1 hour at 0° C. The mixture was cooled to -78° C. and was treated with methyl-chloroformate (4.6 ml, 60 mmole). The reaction mixture was stirred for 20 minutes at -78° C. and then for 1.5 hours at 0° C. The reaction was quenched with 1×100 ml 1:1 saturated ammonium chloride/saturated sodium chloride. The layers were separated and the aqueous layer was washed with 2×100 ml diethyl ether. The combined organics were dried over magnesium sulfate and were concentrated in vacuo to a red oil. The oil was crystallized and then recrystallized from hexane to provide 9.2 g (75%) of methyl-4-benzyloxyphenyl-propiolate as orange tinged flakes. Melting Point: 78° C.