Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[CH3:7].[C:21]([O-])(=[O:23])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH3:20])[C:13]1[CH:18]=[CH:17][C:16]([CH:21]=[O:23])=[CH:15][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CCN(CCOC(C)=O)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CCOC(C)=O)c1ccc(C=O)cc1

Procedure:
To 16.1 g of dimethylformamide was dropwise added 33.7 g of phosphoryl chloride while stirring under ice cooling. Further, 30 ml of a solution of 41.5 g of 2-(ethylphenylamino)ethyl acetate in dimethylformamide was added dropwise, and this mixture was stirred for 5 hours at 40° C. This reaction solution was poured into 1,000 ml of sodium acetate aqueous solution. An organic layer was extracted with ethyl acetate, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting coarse product was purified by silica gel column chromatography to obtain 35.3 g of 2-(ethyl(4-formylphenyl)amino)ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:19][C:20](=[O:22])[CH3:21])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Sc1cncc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)CSc1cncc(Br)c1

Procedure:
5-Bromo-pyridine-3-thiol (0.880 g, 4.63 mmol) in THF (100 mL) was cooled to 0° C. and Hünig's base (2.4 mL, 13.89 mmol) was added. Chloroacetone (0.371 mL, 4.63 mmol) was added and the ice bath was removed. After 15 minutes the reaction mixture was concentrated, diluted with EtOAc, and washed with H2O/brine. After drying over MgSO4 the mixture was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1-c1ccccc1

Procedure:
In 10 ml of acetonitrile, 1.0 g of o-phenylphenol and 1.29 ml of ethyl bromoacetate were added in the presence of 1.76 ml of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and the resultant mixture was refluxed for 8 hr. The reaction mixture was treated similarly to that in Example 28 (Process2) to give 1.46 g of ethyl o-phenylphenoxyacetate. The ester was dissolved in 30 ml of ethanol, mixed with 10.8 ml of 1N—NaOH aqueous solution and stirred for 12 hr. The reaction mixture was evaporated under reduced pressure, acidified by the addition of 1N-HCl and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and o-phenylphenoxyacetic acid was crystallized as DCHA salt from ether with the yield of 1.59 g.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]2[O:7][C:8]([CH3:23])([CH3:22])[C@@H:9](OS(C)(=O)=O)[C@H:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2].C1C=CC=CC=1>C(OCC)(=O)C>[C:1]([C:3]1[CH:25]=[CH:24][C:6]2[O:7][C:8]([CH3:22])([CH3:23])[CH:9]=[C:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1OS(C)(=O)=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=NC#N)NC1=CC(C)(C)Oc2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
To 15 g of 6-cyano-3,4-dihydro-3-methanesulfonyloxy-2,2-dimethyl-trans-4-[(N-cyano-acetimidoyl)amino]-2H-benzo[b]pyran obtained in Step (1) of Example 34, 300 ml of benzene and then 18 g of 1,8-diazabicyclo(5,4,0]-7-undecene were added, and the mixture was reacted under reflux for 3 hours. The reaction mixture was cooled to room temperature, then diluted by addition of 200 ml of ethyl acetate and then washed three times with water. The benzene/ethyl acetate extract solution was dried over anhydrous sodium sulfate. Then, benzene and ethyl acetate were distilled off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 9.3 g of the above identified compound in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]([NH2:35])[N:29]=2)=[CH:24][C:23]=1[CH3:36].CCN(CC)CC>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:13]([NH:35][C:30]3[N:29]=[C:28]([C:25]4[CH:26]=[N:27][C:22]([O:21][CH3:20])=[C:23]([CH3:36])[CH:24]=4)[C:33]([CH3:34])=[CH:32][CH:31]=3)=[O:15])[CH2:11][CH2:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1Cl
Reactant: COc1ncc(-c2nc(N)ccc2C)cc1C
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4cnc(OC)c(C)c4)n3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of 1-(3-chloro-4-methoxyphenyl)cyclopropanecarboxylic acid (45.3 mg, 0.2 mmol) in dichloromethane (2 mL) was added thionyl chloride (43.8 μL, 0.60 mmol) followed by DMF (1 drop) and the reaction was stirred at room temperature for 30 minutes and then the solvent was evaporated. Toluene (˜1 mL) was added and mixed with the residue and then evaporated. The residue was then dissolved in dichloromethane (1 mL) and a solution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (45.9 mg, 0.20 mmol) and Et3N (83.6 μL, 0.60 mmol) in dichloromethane (1 mL) was added. The reaction was stirred at room temperature for 12 hours and then the reaction was then concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99% acetonitrilein water) to yield 44 mg of the product. ESI-MS m/z calc. 437.1. found 438.1 (M+1)+. Retention time 2.10 minutes.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([OH:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:17][C:16]=1[NH:32][C:33](=[O:49])[CH2:34][CH:35]1[C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[O:42][C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(OCC)C.C(Cl)Cl>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:17][C:16]=1[NH:32][C:33](=[O:49])[CH2:34][CH:35]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=2[O:42][C:43]2[C:48]1=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCC(=O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 88.5 %

Procedure:
1 ml of a methylene chloride solution containing 16 mg (0.13 mmol) of oxalyl chloride was cooled to -78° C. 1.5 ml of a methylene chloride solution containing 20 mg (0.25 mmol) of dimethyl sulfoxide were then added to this solution. The resulting mixture was then stirred for 5 minutes, after which 1 ml of a methylene chloride solution containing 56 mg (0.11 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12) was added dropwise over a period of 5 minutes at the same temperature. The mixture was then stirred for 15 minutes, and then 1 ml of a methylene chloride solution containing 64 mg (0.64 mmol) of triethylamine was added dropwise to it. The mixture was stirred for 10 minutes, and then the reaction mixture was allowed to return to room temperature. The reaction solution was diluted with diethyl ether, and washed with dilute aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 10 g of silica gel. Elution with a 100:8 by volume mixture of methylene chloride and ethyl acetate afforded 51 mg (yield 91%) of the title compound as crystals, melting at 154°-155° C. (after recrystallization from a mixture of diethyl ether and hexane).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: CCC(=O)Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.061 mMol) propionyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:5]1[CH:34]=[CH:33][C:8]2[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][C:24]4=[O:32])=[CH:18][CH:17]=3)[C:10](=[O:12])[S:11][C:7]=2[CH:6]=1.[CH3:41][OH:42]>S(=O)(=O)(O)O>[OH:42][C:41]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][N:9]2[C:8]3[CH:33]=[CH:34][C:5]([C:4](=[N:3][O:2][CH3:1])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:6][C:7]=3[S:11][C:10]2=[O:12])=[CH:21][CH:20]=1)[C:24]([O:25][CH3:26])=[O:32]
Reactant: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC2C(=O)Oc3ccccc32)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(C(=O)OC)c2ccccc2O)cc1

Procedure:
1.5 g of the compound obtained in Step B, in 50 ml of methanol and 0.1 ml of concentrated sulphuric acid, are heated at reflux for 2 hours. The solvent is then evaporated off, the residue is hydrolysed and the precipitate obtained is chromatographed on silica gel (eluant: AcOEt/toluene 5/95).
Reaction SMILES: [Br-:1].[NH2:2][C:3]1[C:4]([C:11]([NH:13][CH2:14][CH2:15][N+:16]([CH2:19][CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)([CH3:18])[CH3:17])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.O.NN>CCO>[Br-:1].[NH2:21][CH2:20][CH2:19][N+:16]([CH2:15][CH2:14][NH:13][C:11]([C:4]1[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=1)=[O:12])([CH3:17])[CH3:18]
Reactant: C[N+](C)(CCNC(=O)c1nc(Cl)c(N)nc1N)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Agent: [Br-]
Solvent: O
Solvent: CCO
Product: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 40 °C

Procedure:
A mixture of {2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-dimethyl-ammonium bromide (47 g, 92 mmol) and hydrazine monohydrate (20 mL, 412 mmol) in EtOH (500 mL) is heated at 40° C. for 4 h. After cooling to RT the resulting solid is removed by filtration and washed with diethyl ether. The filtrate is concentrated in vacuo to afford the title product. [M+H]+ 302.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: COCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and 2-methoxyethylamine (3 ml) the subtitle compound was obtained (216 mg, 93%). MS 390 m/z (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]([CH3:36])([CH3:35])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C@@H:30]([CH3:34])[CH2:31][CH2:32][OH:33])[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH:13]=1.Cl[C:38]1[C:47]2[C:42](=[C:43]([CH3:50])[C:44]([O:48][CH3:49])=[CH:45][CH:46]=2)[N:41]=[C:40]([O:51][CH2:52][CH3:53])[CH:39]=1.C(O[K])(C)(C)C>CS(C)=O>[CH3:36][C:9]([CH3:35])([CH3:8])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C@@H:30]([CH3:34])[CH2:31][CH2:32][O:33][C:38]2[C:47]3[C:42](=[C:43]([CH3:50])[C:44]([O:48][CH3:49])=[CH:45][CH:46]=3)[N:41]=[C:40]([O:51][CH2:52][CH3:53])[CH:39]=2)[C:21]([CH:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH:13]=1
Reactant: C[C@@H](CCO)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Reactant: CCOc1cc(Cl)c2ccc(OC)c(C)c2n1
Agent: CC(C)(C)O[K]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCOc1cc(OCC[C@H](C)N(C(=O)C2CCC(C)CC2)c2cc(C#CC(C)(C)C)sc2C(=O)O)c2ccc(OC)c(C)c2n1
Reaction time: 0.25 h
Yield: 19.1 %

Procedure:
The 5-(3,3-dimethyl-but-1-ynyl)-3-[(3-hydroxy-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid TFA salt (100 mg, 0.239 mmol) and 4-chloro-7-methoxy-2-ethoxy-8-methyl-quinoline (301 mg, 1.195 mmol) were dissolved in DMSO (3 mL). To this solution tBuOK (107 mg, 0.956 mmol) was added in one portion at rt. The reaction was run at it for 15 min and then cooled in an ice bath. The reaction was quenched with a 20% (v/v) solution of acetic acid in water. The reaction was partitioned between water and EtOAc. The phases were separated and the organic phase was extracted with brine. The organic phase was extracted with brine and then concentrated. The residue was suspended in MeOH and remaining solids were removed by filtration. The filtrate was concentrated, suspended in MeOH and filtered again. The filtrate was clarified with a small amount of EtOAc and 5-(3,3-dimethyl-but-1-ynyl)-3-[[3-(2-ethoxy-7-methoxy-8-methyl-quinolin-4-yloxy)-1-(S)-methyl-propyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (29 mg, 16%) was isolated as the TFA salt by reverse phase HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[O:50])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]6)=[O:50])=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CN1CCN(C(=O)Cc2ccc(Br)cc2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CC(=O)N4CCN(C)CC4)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(4-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-ethanone (130 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-methyl-piperazin-1-yl)-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-183) as a yellow powder (35 mg, 19%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[C:18](OCC)=[O:19].O.[OH-].[Na+]>C1COCC1>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[C:10]=1[CH:17]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=1)[CH2:18][OH:19]
Reactant: CCOC(=O)C(NCc1ccc(OC(F)(F)F)cc1)c1c(OC)cccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC)c1C(CO)NCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A cooled (0° C.) mixture of LiAlH4 (6 mg; 0.15 mmol) in anh. THF (1 ml) was treated dropwise with a solution of ethyl 2-(2,6-dimethoxyphenyl)-2-((4-(trifluoromethoxy)benzyl)amino)acetate (65 mg; 0.15 mmol) in anh. THF (1 ml). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Water (6 μl), 15% aq. NaOH (6 μl), and water (18 μl) were then successively added, and the heterogeneous mixture was filtered. The filtrate was concentrated to dryness under reduced pressure, and the oily residue was further dried under HV affording 2-(2,6-dimethoxyphenyl)-2-((4-(trifluoromethoxy)benzyl)-amino)ethanol as a yellow oil. LC-MS (conditions E): tR=0.59 min.; [M+H]+: 372.10 g/mol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C#N)cc1
Yield: 94.3 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.502 g, 1.83 mmol), α-bromo-p-tolunitrile (0.538 g, 2.75 mmol), KI (65 mg, 0.40 mmol), and DIPEA (0.72 mL, 4.13 mmol) in DMF (9 mL) was heated at 60° C. for 16 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.66 g (94%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a white solid. 1H NMR (CDCl3) δ 1.60-1.73 (m, 3H), 2.02-2.12 (m, 1H), 2.18-2.34 (m, 2H), 2.41 (s, 6H), 3.56 (s, 2H), 4.14 (d, 2H, J=10.5 Hz), 6.64 (d, 2H, J=8.1 Hz), 6.95 (dd, 2H, J=7.5, 4.8 Hz), 7.10 (d, 2H, J=7.8 Hz), 7.22 (d, 2H, J=7.2 Hz), 8.37 (d, 2H, J=3.9 Hz); ES-MS m/z 383 (M+H).
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Br.C(=O)(O)[O-].[Na+].[NH2:14][C:15]1[N:16]=[N:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21]>O.C(O)C>[CH3:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]2[N:16]([CH:3]=[CH:4][N:14]=2)[N:17]=1
Reactant: Cc1cc(C)c(N)nn1
Reactant: COC(CBr)OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2nccn2n1
Reaction time: 16 h
Yield: 44.6 %

Procedure:
A mixture of 25 g (148 mmol) of bromoacetaldehyde dimethyl acetal, 5 mL of water and 5 mL of 48% HBr was refluxed 2 h. After cooling, it was poured into 50 mL of ethanol. Solid sodium bicarbonate was added until bubbling ceased. The mixture was filtered and to the filtrate was added 7.5 g (61 mmol) of 3-amino-4,6-dimethylpyridazine. After stirring 16 h, the ethanol was removed with a rotary evaporator. The residue was triturated with ethanol to give a brown solid which was dissolved in water and washed with dichloromethane. The aqueous layer was brought to pH 9 with sodium bicarbonate and extracted with dichloromethane. Drying (Na2SO4) and solvent removal with a rotary evaporator gave 4 g of the title compound as a brown solid, m.p. 70°-74° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1C#CCCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperazine-1-carboxylate (0.0315 g, 0.0596 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[4-(piperazin-1-yl)but-1-ynyl]benzofuran-3(2H)-one (0.0120 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1
Reactant: COc1cc(O)ccc1-c1nc2ncncc2[nH]1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Oc1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
Prepared analogously to Example 1 from 8-(2'-methoxy-4'-hydroxy-phenyl)-purine and ethanesulfonic acid chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.3 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 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 4-[4-bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (38 mg, 29%)