Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[C:13]=1[CH3:29]>N1C=CC=CC=1>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][O:18][C:14]2[C:13]([CH3:29])=[C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(N)cccc1OCCc1ccc(C#N)cc1
Solvent: c1ccncc1
Product: Cc1c(NS(=O)(=O)c2ccccc2)cccc1OCCc1ccc(C#N)cc1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Benzenesulfonyl chloride (0.24 mL; 1.9 mmol) was added to a stirred solution of amino-3-[2-(4-cyanophenyl)ethoxy]-2-methylbenzene (0.42 g ; 1.7 mmol; from step (iii) above) in dry pyridine (20 mL) under nitrogen. The reaction was left overnight at room temperature. After evaporation of the solvent the residue was partitioned between 10% aqueous HCl and EtOAc. The organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography afforded 0.47 g (72%) of the sub-title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:10][CH3:11].[N:13]([C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([S:24](Cl)(=[O:26])=[O:25])=[C:18]([F:28])[C:17]=1[F:29])=[N+:14]=[N-:15]>CO>[N:13]([C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([S:24]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([N:2]([CH3:12])[CH3:1])=[C:4]([O:10][CH3:11])[CH:5]=2)(=[O:26])=[O:25])=[C:18]([F:28])[C:17]=1[F:29])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(S(=O)(=O)Cl)c(F)c1F
Reactant: COc1cc(N)ccc1N(C)C
Solvent: CO
Product: COc1cc(NS(=O)(=O)c2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)ccc1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Dimethylamino-3-methoxyaniline (1.66 g, 10 mmol) is added to a solution of 4-azido-2,3,5,6-tetrafluorophenylsulfonyl chloride (3.47 g, 12 mmol) in MeOH (20 ml) at ambient temperature. After stirring at room temperature for 15 min, the reaction mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and filtered through a pad of silica gel. Concentration of the filtrate, followed by chromatography, provides the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2Cl.[CH3:17][N:18]([CH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:19].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:26][CH:25]=1
Reactant: CN(C)CC1CCC(N)CC1
Reactant: CS(=O)(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)cc1
Temperature: 90 °C
Yield: 66.4 %

Procedure:
To a suspension of 6-bromo-4-chloro-3-(methylsulfonyl)quinoline (250 mg, 0.78 mmol) in dioxane (8 mL) was added 4-((dimethylamino)methyl)cyclohexanamine (233 mg, 1.55 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (225 mg, 66%) as a yellow solid. ESI MS m/z 434 [C29H20BrN3O2+H]+
Reaction SMILES: C([BH3-])#N.[Na+].[ClH:5].[O:6]([C:13]1([OH:24])[CH:23]=[CH:22][C:16]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])=[CH:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.CCOCC>[ClH:5].[CH2:25]([NH:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]1[CH:15]=[CH:14][C:13]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:24])[CH2:23][CH:22]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(CN)C1=CCC(O)(Oc2ccccc2)C=C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(CNCc1ccccc1)C1=CCC(O)(Oc2ccccc2)C=C1
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (10 mg, 0.17 mmol) was added to a solution of 83 (30 mg, 0.11 mmol) and benzaldehyde (12 μl, 0.12 mmol) in MeOH (2 ml). After 1 hour stirring, the reaction mixture was diluted with ether and washed with water. The aqueous was extracted with ether and then combined organic layers were washed with water, and brine, then dried over MgSO4. The crude product was purified via flash SiO2 (eluted with hexane/ethyl acetate (10:1)) to give the protected amine as a white solid. The protected amine was dissolved in 3 N HCl solution in ethylacetate (2 ml) and the reaction mixture was stirred at ambient temperature for 15 hours. The crude reaction mixture was concentrated in vacuo and dried under high vacuum pressure to give 84 as a white solid (25 mg, 61% yield). 1H-NMR (400 MHz, DMSO-d6) δ 8.83 (brd s, 2H), 7.52-7.32 (m, 10H), 7.15 (d, J=7.6 Hz, 1H), 7.02-6.95 (m, 3H), 4.09 (s, 2H), 3.34 (s, 2H), 1.35 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CO)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C#N)c(F)c1
Reaction time: 1.5 h

Procedure:
2-Fluoro-4-hydroxymethylbenzonitrile (1.3 g, 8.6 mmol; see step (ii) above) was dissolved in 50 mL of CH2Cl2 and cooled on an ice bath. Triethylamine (0.87 g, 8.6 mmol) and methanesulfonyl chloride (0.99 g, 8.7 mmol) were added. After stirring for 1.5 h the reaction mixture washed with 1M HCl. The organic phase was dried (Na2SO4) and evaporated. The product could be used without purification. Yield of a colourless oil: 1.8 g (92%).
Reaction SMILES: ClC1C2C=C(C3CCN(C(OC(C)(C)C)=O)CC=3)NC=2N=CN=1.Cl[C:25]1[C:26]2[CH:33]=[C:32]([I:34])[NH:31][C:27]=2[N:28]=[CH:29][N:30]=1.[S:35]1[C:39]2[CH:40]=[C:41]([NH2:44])[CH:42]=[CH:43][C:38]=2[N:37]=[CH:36]1>>[S:35]1[C:39]2[CH:40]=[C:41]([NH:44][C:25]3[C:26]4[CH:33]=[C:32]([I:34])[NH:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH:42]=[CH:43][C:38]=2[N:37]=[CH:36]1
Reactant: Clc1ncnc2[nH]c(I)cc12
Reactant: Nc1ccc2ncsc2c1
Agent: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Product: Ic1cc2c(Nc3ccc4ncsc4c3)ncnc2[nH]1

Procedure:
Following the General method for the reaction of amines with tert-butyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate to generate compounds of Formula I-B-Boc, but using 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine and benzothiazol-6-ylamine, one obtained the title compound. MS (ES+): m/z 393.88 (100) [MH+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][CH2:2][C:3]2[CH:18]=[CH:17][C:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[CH:5][CH:4]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCc2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
4-(4-Aminomethylbenzyl)-nitrobenzene (500 mg) was dissolved in dichloromethane (7 mL) and heated with 4-methoxybenzenesulfonyl chloride (426 mg) and triethylamine (0.3 mL). The mixture was stirred at room temperature for 15 hours, poured into dilute aqueous hydrochloric acid, and extracted with dichloromethane (3×). The solvent was evaporated to give 4-[4-(4-methoxyphenyl)sulfonylaminomethylbenzyl]-nitrobenzene as a yellow solid (851 mg, ˜100%), and was used in the next step without further purification.
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([NH:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])=[O:12])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc(Br)cc1
Temperature: 150 °C

Procedure:
A microwave vial containing 4-bromo-benzoic acid ethyl ester (1 g, 4.36 mmol) and N,N-dimethylethylenediamine (2.37 g, 21.38 mmol) was heated under microwave radiation (150° C., 10 min). The volatiles were removed under rotary evaporation and the crude was used in the next step without further purification. Yield: 1.18 g, 100%. LCMS method: 2, RT: 1.93 min; MI: 271-273 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture of 82 (0.5 g, 1.9 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 hr, the reaction was cooled and then diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4 and concentrated to give a solid. The solid was triturated with CH2Cl2 and filtered to give a solid (0.20 g, 47%); Mp=216–218° C.; 1H NMR (DMSO-d6) δ 9.95 (br s, 1 H), 7.74 (d, 2 H, J=8.8 Hz),7.66 (d, 1 H, J=1.9 Hz), 7.59 (d, 1 H, J=8.8 Hz), 7.27 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 7.17 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz); MS 243/245 [M−H]−
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](OCC)=O)=[CH:22][CH:21]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:32])[F:33])=[CH:25][CH:24]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(C(F)(F)F)cc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 57.5 %

Procedure:
Sodium (622 mg) was dissolved in ethanol (45 mL) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0 g, 13.5 mmol), followed by ethyl 4-trifluoromethylphenylacetate (6.27 g, 27 mmol) were added. The reaction mixture was refluxed overnight, cooled to room temperature, and the solvent was stripped. Water, followed by 2N HCl were added to the residue and the product was collected by filtration, recrystallized from ether and dried at 110° C. and 0.2 mm Hg to afford 3.03 g of 1-cyclopentyl-3-ethyl-6-(4-trifluoromethylphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 212-213° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:22]([CH:26]([CH3:28])C)[CH:23]([CH3:25])C.ClC(OCC(C)C)=O.N1CCCC1>C(Cl)Cl>[O:19]=[C:17]([N:22]1[CH2:23][CH2:25][CH2:28][CH2:26]1)[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccncc1)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
N-Boc-(5)-3-(pyridin-4-yl)alanine (0.500 g, 1.88 mmol) was dissolved in CH2Cl2 (15 mL) and DIEA (361 μL, 2.07 mmol) was added. The mixture was cooled to 0° C. and isobutyl chloroformate (270 μL, 2.07 mmol) was added. The mixture was stirred for 10 min and pyrrolidine (267 mg, 3.76 mmol) in CH2Cl2 (5 mL) was added. This mixture was stirred for 15 min at 4° C., 12 h at 25° C., washed successively with NaH2PO4, saturated sodium hydrogen carbonate, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue obtained was purify by column chromatography (SiO2) using a gradient of MeOH 0-10% [v/v] in EtOAc to give tert-butyl(R)-1-oxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate EBE 06172 (146 mg, 24% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH:35]=[CH2:34])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: O=C(O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)O)cc2)c1
Reaction time: 18 h

Procedure:
To a mixture of 4-[3-(2-benzyloxy-5-hydroxyphenyl)propyl]- benzoic acid (150 mg) (prepared as described in Example 4) and potassium carbonate (125 mg) in DMF (5 ml) was added allyl bromide (0.076 ml). The mixture was stirred for 18 hours, then potassium carbonate (125 mg) and allyl bromide (0.076 ml) were added and the mixture stirred for a further 18 hours. The mixture was poured into water (50 ml) and extracted with ethyl acetate (2×20 ml). The combined organics solutions were washed with brine (25 ml) and sodium bicarbonate (25 ml), dried (magnesium sulphate) filtered and evaporated. There was thus obtained allyl 4-[3-(2-benzyloxy-5-(allyloxy)phenyl)propyl]benzoate (150 mg).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCN1CCCC1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCCN3CCCC3)cccc2c1Nc1ccccc1C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry dimethylformamide (100 ml) at 100° , 1-(3-chloropropyl)pyrrolidine hydrochloride (3.6 g, 20 mmol) added, and stirring continued for 1 hour. The mixture was diluted with water and extracted with ether, and the ether extracts dried and evaporated. Chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and recrystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(1-pyrrolidinyl)propoxy)quinoline (0.35 g, 8.5 %), m.p. 101°-103°.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1nccc2c1[nH]c1cc(OCc3ccccc3)ccc12
Yield: 70 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (0.500 g, 1.59 mmol) in presence of cesium carbonate (1.410 g, 4.33 mmol) and 1-bromomethylbenzene (0.432 g, 2.53 mmol) as described here above.
Reaction SMILES: O1C2C=CC(O)=CC=2OC1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=2[CH2:13][CH2:12]1.C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[C:37]1([CH:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46](=[O:53])[C:45]2=[O:54])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:55]1([CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([OH:53])([C:17]3[C:18]([OH:20])=[CH:19][C:14]4[CH2:13][CH2:12][O:11][C:15]=4[CH:16]=3)[C:45]2=[O:54])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: Oc1ccc2c(c1)CCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCO2

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-5-ol, (Alabaster, R. J., et al.; Synthesis (1988), 12:950-2) and 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, the title compound was obtained: MS (ES+) m/z 472.2 (M+23).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:34][O:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:19]([N:18]([C:26]1[N:31]=[CH:30][C:29]([N:38]2[CH2:39][CH2:40][CH:36]([O:35][CH3:34])[CH2:37]2)=[CH:28][N:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Reactant: COC1CCNC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCC(OC)C2)cn1

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and 3-methoxypyrrolidine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:14][C:15]#[N:16]>CN(C)C=O>[C:15]([CH2:14][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)#[N:16]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC#N)c1
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
To a solution of ethyl 1H-pyrazole-4-carboxylate (0.98 g, 7.0 mmol) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.42 g, 10.5 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 20 min. Bromoacetonitrile (0.63 mL, 9.10 mmol) was added to the reaction mixture, the ice bath was removed and the mixture was stirred for 4.5 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (1.14 g, 90%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[Cl:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.O>C1COCC1>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([O:11][C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[CH:13][CH:14]=2)[C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: Cn1c(Oc2ccc(N)cc2)nc2ccccc21
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(Oc2ccc(Nc3ncnc(Cl)c3[N+](=O)[O-])cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (0.30 g) and TEA (0.26 ml) in THF (15 mL) was added 4,6-dichloro-5-nitropyrimidine (0.24 g) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5%-50% AcOEt in hexane) to give 6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine (0.24 g) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]([NH2:15])=[N:13][C:12]2[C:7]1=[N:8][C:9]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[N:10][C:11]=2[I:16])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:20]([O:19][C:17]([C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:14]([NH2:15])[N:6]2[CH2:5][C:4]([OH:27])=[O:3])=[C:11]([I:16])[N:10]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cn1c(N)nc2c(I)nc(C(=O)OCc3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2c(I)nc(C(=O)OCc3ccccc3)nc2n1CC(=O)O
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
To a suspension of [2-(benzyloxycarbonyl)-amino-6-iodo-purine-9-yl]-acetic acid ethyl ester (10.02 g, 20.8 mmol) in tetrahydrofuran (50 mL) and water (50 mL) was added lithium hydroxide hydrate (2.83 g, 20.8 mmol) at 10° C. The resulting reaction mixture was stirred for 30 min. Then the mixture was acidified to pH=3 by adding 1N HCl. The precipitated solid was filtered off, washed with water and ethyl ether, and dried in vacuo to give the title compound (9.81 g). 1H-NMR (500 MHz; DMSO-d6) δ 10.75 (s, 1H), 8.44 (s, 1H), 7.50˜7.30 (m, 5H), 5.17 (s, 2H), 4.97 (s, 2H).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[S:17])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]1[C:2](=[O:8])[C:3](=[O:5])[N:15]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[C:16]1=[S:17]
Reactant: CC(C)(C)CNC(=S)Nc1cccnc1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)CN1C(=O)C(=O)N(c2cccnc2)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
Ethyl chlorooxoacetate (0.33 mL, 2.90 mmol) was added to a stirring solution of the above thiourea (0.50 g, 2.24 mmol) and K2CO3 (0.31 g) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.50 g (81%) 1-(2,2-dimethyl-propyl)-3-pyridin-3-yl-2-thioxo-imidazolidine-4,5-dione as a yellow solid: mp 111.4–112.8° C.; IR (KBr): 3500, 2980, 1770 cm1; MS (m/z) 378 (M+H+).