Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:23][OH:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Sulfur trioxide-pyridine complex (24.1 g, 152 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (8.30 g, 21.7 mmol), triethylamine (24 mL), and dimethyl sulfoxide (150 mL) in dichloromethane (100 mL) at room temperature, and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 15-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with ethyl acetate/diisopropyl ether to give the title compound as a pale yellow powder (6.82 g, 17.9 mmol, 82%).
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[F:37][C:34]([F:35])([F:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[N:18]=[N:19][C:14]([NH:13][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1][CH2:2][S:3][S:4]3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(CCCCC1CCSS1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use lipoic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (yield 8%). 1H NMR (300 MHz, CDCl3) δ 10.11, 8.37, 7.72, 7.61, 7.53, 7.35, 7.04, 4.08-3.84, 3.70-3.57, 3.56-3.46, 3.33-3.30, 3.17-3.02, 2.59, 2.39, 1.84, 1.78-1.56, 1.51-1.37. 13C NMR (300 MHz, CDCl3): 172.52, 167.57, 157.94, 150.00, 134.42, 132.38, 129.45, 127.79, 127.29, 127.14, 126.93, 126.88, 126.82, 121.92, 116.27, 56.34, 46.47, 45.65, 45.33, 41.25, 40.26, 38.49, 37.05, 34.74, 28.85, 25.14. MS (ES+) m/z 540.1 (M+1).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5]C.C1(C#C)C=CC=CC=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]#N>C(#N)C1C=CC=CC=1>[C:20]([C:16]1[O:15][CH:19]=[CH:18][CH:17]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccco1
Reactant: C#CCCCC
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CCCCC#Cc1ccco1
Reaction time: 4 h
Yield: 69 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-hexyne (0.450 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 4 h at 65° C. showed the presence of 1.38 mmol (69% yield) of 2-(1-hexynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[S:16]([NH:19][C:20]1[C:21]([F:52])=[C:22]([C:26]2[N:27]=[C:28]([C:48]([CH3:51])([CH3:50])[CH3:49])[S:29][C:30]=2[C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][NH:40]C(=O)OC(C)(C)C)[N:32]=2)[CH:23]=[CH:24][CH:25]=1)(=[O:18])=[O:17].CO>C(Cl)Cl>[NH2:40][CH2:39][CH2:38][NH:37][C:33]1[N:32]=[C:31]([C:30]2[S:29][C:28]([C:48]([CH3:51])([CH3:49])[CH3:50])=[N:27][C:26]=2[C:22]2[C:21]([F:52])=[C:20]([NH:19][S:16]([C:10]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=3[F:8])(=[O:17])=[O:18])[CH:25]=[CH:24][CH:23]=2)[CH:36]=[CH:35][N:34]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN)n2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.2 %

Procedure:
A 4 N solution of HCl in 1,4-dioxane (1.7 ml, 7.1 mmol) was added to a stirring solution of 1,1-dimethylethyl [2-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]carbamate (0.31 g, 0.47 mmol) (composite batches prepared as described in the previous step) in DCM (10 ml) at rt. MeOH (1 ml) was added to aid in solubility. The reaction was allowed to stir at rt for 3 h. The volatiles were removed and the residue was dried in vacuo to afford the title compound of Step B (0.31 g, quantitative yield) as a hydrochloride salt that was used without further purification; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 7.93-8.18 (m, 4H), 7.20-7.69 (m, 7H), 3.37-3.53 (m, 2H), 2.96 (d, J=5.1 Hz, 2H), 1.41 (s, 9H). MS (ES+): 563 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10]C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:28][CH:29]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(CO)CBr
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC(C)(C)CO)cc2)c2ccccc21
Temperature: 95 °C

Procedure:
(±)-Cis-N-(4-chloro-phenyl)-N-{1-[4-(3-hydroxy-2,2-dimethyl-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide (210 mg, 0.484 mmol) was dissolved in DMF (10 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propan-1-ol (813 mg, 4.84 mmol), the reaction was heated to 95° C. and stirred over night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate—70/30 dichloromethane/ethyl acetate) to afford the pure ester (110 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: O=C(O)c1ccncc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccncc3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and isonicotinic acid as brown solid (36%). MS 409 (MH+).
Reaction SMILES: O1CCOCC1.[OH-].[Na+].C([O:17][CH2:18][C@@H:19]1[O:24][C@@H:23]([O:25][CH:26]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH2:22][CH2:21][CH2:20]1)(=O)C1C=CC=CC=1>O>[OH:17][CH2:18][C@@H:19]1[O:24][C@@H:23]([O:25][CH:26]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1
Yield: 74.7 %

Procedure:
90 ml of dioxan and 20 ml of a 25% w/v aqueous solution of sodium hydroxide were added to 9.15 g of 1-[trans-β-(6-benzoyloxymethyltetrahydropyran-2-yloxy)-2,4-dichlorophenethyl]imidazole, and the mixture was refluxed for 6 hours. At the end of this time, the reaction mixture was cooled, diluted with water and extracted with diethyl ether. The ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through silica gel eluted with a 10:20:3 by volume mixture of benzene, ethyl acetate and ethanol, to give 5.34 g of the title compound as a liquid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40]C=2N=N1.[CH:49](N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:32]3[CH2:36][CH2:37][CH:38]([CH3:49])[CH2:39][CH2:40]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methyl piperidine(commercially available) and N,N-diisopropylethylamine in N,N-dimethyl-formamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:34])[NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][C:24]([CH3:34])=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCOCC1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (70.9 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 98.5 mg (79%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.28 (br s, 1H, NH), 11.68 (br s, 1H, NH), 9.12 (br s, 1H), 8.29 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31-7.36 (m, 2H), 3.56 (m, 4H, 2×CH2), 3.45 (m, 4H,2×CH2), 2.31 (s, 3H, CH3), 2.14 (s, 3H, CH3). MS 497 [M++1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH:25][P:26](=[O:29])([OH:28])[OH:27])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.CO.O.[OH-].[Li+:36]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH:25][P:26]([O-:28])([O-:29])=[O:27])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[Li+:36].[Li+:36]
Reactant: O=P(O)(O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=P([O-])([O-])Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Yield: 71.3 %

Procedure:
To a mixture of (3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)phosphoramidic acid (8.5 mg, 0.019 mmol) described in Example 2 and methanol (1 mL) was added a mixture of lithium hydroxide monohydrate (1.9 mg, 0.045 mmol) and water (4 mL) at room temperature, and the solvent was evaporated from the reaction mixture under a reduced pressure. The resulting residue was washed with methanol to obtain the title compound (6.1 mg, 70%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[NH2:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[F:22])[O:23][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1
Reactant: CC(=O)Nc1cn2nc(I)ccc2n1
Reactant: Nc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Temperature: 140 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (12 g, 39.7 mmol) in N,N-dimethylformamide (120 mL) were added 3-amino-4-fluorophenol (7.6 g, 59.6 mmol) and potassium carbonate (11.0 g, 79.5 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) to give the title compound (9.5 g, 79%) as a brown powder.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:31](=[O:32])[NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
To a methylene chloride solution (25 mL) of N-tert-butoxycarbonylpiperazine (2.50 g, 13.4 mmol), 4-phenoxyphenyl isocyanate (2.83 mL, 13.4 mmol) was added, followed by stirring at room temperature overnight. Methanol was added to the reaction solution, and the solvent was evaporated to give the target compound (5.71 g, 14.4 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:41][N:42]([CH3:47])[CH2:43][C:44]([O:33][C@@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:45]
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: CN(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)CN(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a mixture of (S)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl-1-(2-hydro-xylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.54 g, 1 mmol), N,N-dimethylglycine (0.206 g, 2 mmol, Alfa) and DMAP (0.244 g, 2 mmol, Aladdin) in 15 mL of CH2Cl2 at 0° C. was added EDC solid (0.575 g, 3 mmol, Aladdin) in portions. The mixture was continued to stir at 0° C. for 2 hrs, then the reaction mixture was warmed up to room temperature and stirred at rt for 20 hrs. The reaction mixture was diluted with 100 mL of CH2Cl2 and washed with 0.1 N HCl (10 mL×2), followed by saturated NaHCO3 (20 mL×2) and water (20 mL×8), and the aqueous phase was extracted with EtOAc(15 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to afford the title compound as a yellow solid (0.387 g, 61.6%).
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO[CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:44]=[CH:45][CH:46]=[CH:47][C:48](N2CCSC2=S)=[O:49])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38]OCCOC>O1CCCC1>[CH3:29][O:30][CH2:31][CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:44]=[CH:45][CH:46]=[CH:47][C:48]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:19][CH2:20]2)=[O:49])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:36][O:37][CH3:38]
Reactant: COCCOCOc1ccc(C=CC=CC(=O)N2CCSC2=S)cc1OCOCCOC
Reactant: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1ccc(C=CC=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OCCOC
Yield: 160 %

Procedure:
To a solution of 650 mg (1.2 mmol) of N-(3-benzhydroxypropyl)piperazine in dry tetrahydrofuran (5 ml) was added a solution of 966 mg (2.0 mmol) of N-[5-[3,4-di(β-methoxyethoxymethoxy)phenyl]2,4-pentadienoyl]thiazolidine-2-thione in dry tetrahydrofuran (6 ml), and the mixture was reacted at room temperature for 14 hours. The reaction mixture was concentrated by evaporation under reduced pressure, diluted with chloroform and washed, in turn, with 2N aqueous solution of sodium hydroxide and water. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with 1% methanol in chloroform, to give 1.09 g (1.6 mmol) of N-[5-[3,4-di(β-methoxyethoxy)phenyl)-2,4-pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[CH2:9][C:8]1([CH3:20])C(O)=O)=[O:5])C.FC1C=C2C(=CC=1)NC(C)(C(O)=O)C2.[C:35](=[O:38])([O-])[O-].[K+].[K+].C(OCCBr)(=O)C.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)=[C:53]([CH:56]=1)[C:54]#[N:55]>CN(C)C=O>[C:54]([C:53]1[CH:56]=[C:49]([NH:48][C:35]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:7]([CH2:6][C:4]([OH:3])=[O:5])[C:8]=2[CH3:20])=[O:38])[CH:50]=[CH:51][C:52]=1[N:57]1[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]1)#[N:55]
Reactant: CCOC(=O)CN1c2ccc(F)cc2CC1(C)C(=O)O
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Agent: CC(=O)OCCBr
Agent: CC1(C(=O)O)Cc2cc(F)ccc2N1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCC(O)CC3)c(C#N)c2)c2cc(F)ccc2n1CC(=O)O

Procedure:
By the reaction and treatment in the same manner as in Example 3 using 1-(ethoxycarbonylmethyl)-5-fluoro-2-methyl-indole-2-carboxylic acid (3 g) obtained by reacting 5-fluoro-2-methyl-1H-indole-2-carboxylic acid with potassium carbonate and bromoethyl acetate in dimethylformamide and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (3.2 g), the title compound (1.4 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5](C(O[Si](C)(C)C)(C#N)[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl.O.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:20]([C:19]([OH:22])=[O:21])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: C[Si](C)(C)OC1(C#N)CCOc2cc(F)ccc21
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1CCOc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
7-Fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile (750 mg, 2.83 mmol) and SnCl2 dihydrate (2551 mg, 11.3 mmol) were diluted with glacial acetic acid (3 mL) and concentrated HCl (3 mL). The reaction was heated in an oil bath at 130° C. and stirred overnight. The reaction was allowed to cool, diluted with water and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (465 mg, 83.9% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[Cl:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:10])[C:3]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Br)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c(Br)cccc1CBr
Reaction time: 2 h
Yield: 45.9 %

Procedure:
1-bromo-2-chloro-3-methylbenzene (10 g, 48.7 mmol) was dissolved in CCl4 (100 mL), and then N-bromosuccinimide (13.0 g, 73.0 mmol) and benzoyl peroxide (5.9 g, 24.3 mmol) were added. The mixture was stirred for 2 hours at reflux. The solid was removed by filtration, and the filtrate was washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in DCM and purified on silica gel using 10% hexane/AcOEt to afford 1-bromo-3-(bromomethyl)-2-chlorobenzene (6.36 g, 46% yield); 1H NMR (400 MHz, CDCl3): δ 4.62 (s, 2H), 7.12 (t, J=7.8 Hz, 1H), 7.39 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 7.60 (dd, J=1.6 Hz, J=8.0 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1.CC[N:16](C(C)C)[CH:17]([CH3:19])C.CC([N:26](C)C)=O>CS(C)=O>[NH2:16][CH2:17][CH2:19][NH:26][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)N(C)C
Reactant: O=c1[nH]nc(CCl)c2ccccc12
Solvent: CS(C)=O
Product: NCCNCc1n[nH]c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 4-chloromethyl-2H-phthalazin-1-one (13 mg, 0.067 mmol) in DMA (400 μL) were added the amine (e.g., N-(2-amino-ethyl)-acetamide (8 mg, 0.08 mmol)) and DIPEA (14.3 μL, 0.08 mmol). The mixture was stirred overnight at RT, diluted with DMSO (400 μL) and purified by preparative HPLC to yield 4-[(2-amino-ethylamino)-methyl]-2H-phthalazin-1-one and the dialkylated compound. The purity was determined by RPLC/MS.