Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in DCM (20 mL) was added pyridine (0.0241 mL, 0.297 mmol) at room temperature followed by methanesulfonyl chloride (0.0120 mL, 0.149 mmol) and the reaction mixture stirred for 5 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 22 as described in general methods) to obtain N-(5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)methanesulfonamide (50.0 mg, 69.8%) as a white solid. LCMS (Condition 4): retention time 2.45 min, [M+1]=482.2. HPLC (Condition 28): retention time=6.83 min, purity 97.53%. 1H NMR (400 MHz, DMSO-d6) δ 2.97 (s, 3 H), 4.51 (d, J=4.8 Hz, 2 H), 5.06 (t, J=4.8 Hz, 1 H), 7.02-7.03 (m, 2 H), 7.22-7.28 (m, 3 H), 7.43-7.52 (m, 5 H), 7.68 (dd, J=2.4 Hz, J=5.6 Hz, 1 H), 7.72 (br s, 1 H), 7.87-7.90 (m, 2 H), 8.35 (br s, 1 H), 8.40 (d, J=1.6 Hz, 1 H), 10.25 (br s, 1 H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:18])([CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=[O:6].Cl>C(O)(C)C>[CH3:3][C:4]([CH3:17])([CH3:18])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[OH:6]
Reactant: CC(C)Cc1ccc(C(=O)C(C)(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Cc1ccc(C(O)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Sodium borohydride (4.72 g) was added to a solution of 2,2-dimethyl-4'-isobutylpropiophenone (22.7 g) in isopropyl alcohol (150 ml). The mixture was stirred at 50° C. for 2 hours and poured into ice water. After acidified with 6N-hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated to give 2,2-dimethyl-1-(4-isobutylphenyl)propanol as a colourless oil (21.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([OH:12])=O)=[CH:8][CH:9]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:12])[NH:28][CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: NCc1cccc2ccccc12
Reactant: COC(=O)c1ccc(C(=O)O)s1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(C(=O)NCc2cccc3ccccc23)s1
Reaction time: 0.17 h

Procedure:
1.9 g Thiophene-2,5-dicarboxylic acid monomethyl ester and 1.2 mL N-methylmorpholine is dissolved in 20 mL of CH2Cl2 at −10° C. To this solution is added 1.5 mL isobutyl chloroformate. After 10 min of stirring, 1.7 mL 1-(aminomethyl)-naphthalene in 5 mL of CH2Cl2 is added. The cooling bath is removed and the reaction mixture is allowed to reach rt. After 90 min, 10 mL of water and 10 mL 2N HCl are added. The phases are separated, and the organic phase is washed with water. After evaporation of the solvent there is obtained 4.4 g crude 5-[(naphtalen-1-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (1b) which is purified by recrystalisation from ethylacetate, petrol ether, yielding 58%, mp 125° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][CH:13]=[N:14][C:15]=2[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO[C:30](OC)([CH3:32])[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[OH:9][CH2:8][C@@H:5]1[C@H:6]2[O:7][C:30]([CH3:32])([CH3:31])[O:1][C@H:2]2[C@H:3]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:4]1
Reactant: COC(C)(C)OC
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
N-{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-6-yl}benzamide (0.643 g, 1.73 mmol), 2,2-dimethoxypropane (1.06 mL, 8.66 mmol), and para-toluenesulfonic acid monohydrate (0.333 g, 1.73 mmol) were dissolved in acetone (43 mL). The solution was stirred at room temperature overnight and then heated to 40° C. for 3 hours. Once cooled to room temperature, saturated sodium bicarbonate solution was added to the reaction mixture and then approximately half the solvent was removed in vacuo. The resulting solution was diluted with water and extracted four times with CH2Cl2. Combined organics were washed with brine and dried over Na2SO4. The crude material was purified by silica gel chromatography (0 to 5% MeOH/CH2Cl2) to isolate the title compound (0.419 g, 59%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH2:13].C[Al](C)C.[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:28](OC)=[O:29])=[N:26][CH:27]=1)(=[O:21])=[O:20].Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:28]([C:25]1[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][N:26]=1)=[O:29]
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cn1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2Cl)nc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-trifluoromethoxy-phenylamine (2.0 g, 9.29 mmol) in toluene (50 mL) was added to trimethylaluminum (2.0 M 4.65 mL) then methyl 5-(methylsulfonyl)picolinate 6 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give 5-methanesulfonyl-pyridine-2-carboxylic acid (2-chloro-4-trifluoromethoxy-phenyl)-amide 7 as a light yellow solid. Yield: 1.26 g, 65%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([O:23][CH3:24])[CH:10]=1)(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:10][C:11]=1[O:23][CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1c[nH]cn1
Reactant: COc1cc(CCCOS(C)(=O)=O)ccc1OCc1ccccc1
Product: COc1cc(CCCn2ccnc2)ccc1OCc1ccccc1
Yield: 57 %

Procedure:
In substantially the same manner as in Reference Example 88, 3-(4-benzyloxy-3-methoxyphenyl)propyl methanesulfonate was reacted with imidazole to obtain 1-[3-(4-benzyloxy-3-methoxyphenyl)propyl]imidazole as an oil. The yield was 57%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[C:3]([NH:18][C@@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1nc(Cl)ncc1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (5 g, 22 mmol) and (R)-1-phenylethanamine (2.7 g, 22 mmol) in ethanol (50 mL) was added N,N-diisopropylethylamine (4.3 g, 33 mmol). The reaction solution was stirred at room temperature for 12 hours. The resultant mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1) to give (R)-5-bromo-2-chloro-N-(1-phenylethyl)pyrimidin-4-amine as a white solid (5 g, 74%). LRMS (M+H) m/z: calcd 310.98. found 310. 1H NMR (300 MHz, CDCl3): δ 8.10 (s, 1H), 7.41-7.25 (m, 5H), 5.73 (d, J=6.9 Hz, 1H), 5.39-5.34 (m, 1H), 1.61 (d, J=6.6 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:32]3[C:31](=[O:33])[NH:30][C:29](=[O:34])[NH:28][C:27]=3[N:26]=[C:25]([CH:35]([CH3:37])[CH3:36])[C:24]=2/[CH:38]=[CH:39]/[CH:40]=[O:41])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:32]3[C:31](=[O:33])[NH:30][C:29](=[O:34])[NH:28][C:27]=3[N:26]=[C:25]([CH:35]([CH3:37])[CH3:36])[C:24]=2/[CH:38]=[CH:39]/[CH:40]([OH:41])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8])=[CH:21][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)c1nc2[nH]c(=O)[nH]c(=O)c2c(-c2ccc(F)cc2)c1/C=C/C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccc(F)cc1

Procedure:
0.28 g (9.3 mmol) of 80% strength sodium hydride, 0.97 g (8.4 mmol) of methyl acetoacetate, 8.6 ml (14 mmol) of 15% strength butyllithium and 0.99 g (2.8 mmol) of the compound from Example 27 are reacted analogously to the procedure for Example 7.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)(=O)C.Cl>CO>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2OC(C)=O)c1
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2O)c1

Procedure:
A suspension was prepared of 46.5 g of 1-acetyloxy-2-(3-methoxyphenyl)-6-methoxynaphthalene and 40 mL of 5N HCl in 400 mL of MeOH. The reaction mixture was heated to reflux for eleven hours. The reaction mixture was evaporated to a clear oil. This yielded 38.6 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[N:6][CH:7]=1
Reactant: O=C1CCCN1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCCN1c1ncc(Br)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (11.3 g), pyrrolidin-2-one (5 g), and K2CO3 (27.4 g) in 1-methylpyrrolidin-2-one (100 mL) was heated to 80° C. under nitrogen and stirred at this temperature overnight. After cooling to room temperature, the reaction mixture was concentrated to give an oil which was poured into water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phase was concentrated to afford an oil, which was purified by column chromatography on silica gel to afford the title compound. Yield: 592 mg (4% of theory).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:45])=[C:39]([S:41]([O-:44])(=[O:43])=[O:42])[CH:40]=1.[Na+]>C(Cl)Cl.C1COCC1>[OH:45][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])=[CH:40][C:39]=1[S:41]([OH:44])(=[O:42])=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ccc(O)c(S(=O)(=O)[O-])c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@@H](CCC(=O)Nc1ccc(O)c(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) was dissolved in methylene chloride (1 ml) and THF (1 ml), and CDI (65 mg, 1.1 mmol) was added to the solution. The mixture was stirred for 30 minutes at room temperature. Sodium 5-amino-2-hydroxybenzenesulfonate (77 mg, 0.33 mmol) was added to the mixture and stirred overnight at room temperature. After the solvent was removed by distillation, the mixture was purified in accordance with the purification step A. The resulting intermediate was dissolved in 2 ml of TFA. After stirring for 3 hours at room temperature, the solvent was distilled off. The mixture was purified according to the purification step A to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([C:32]5[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(c2ccc(Cl)cc2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(c4ccc(Cl)cc4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 49 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic-acid (0.5 g) and 5-amino-2-[4-(4-chlorophenyl)piperazin-1-yl]benzonitrile (0.6 g), the title compound (0.5 g) was obtained, melting point: 265° C.