Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][P:25]([OH:28])([OH:27])=[O:26])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:29])[CH2:11]3)[CH:8]=[N:9][C:4]2=[C:3]([NH2:30])[N:2]=1.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)[OH:32].P(OC[C@H]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.OP(=O)(OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)OP(=O)(OP(=O)(O)O)O>>[P:17]([O:16][CH2:15][C@H:13]1[O:14][C@@H:10]([N:7]2[C:5]3[N:6]=[CH:1][N:2]=[C:3]([NH2:30])[C:4]=3[N:9]=[CH:8]2)[C@H:11]([OH:32])[C@@H:12]1[OH:29])([O:20][P:21]([O:24][P:25]([OH:28])([OH:27])=[O:26])([OH:23])=[O:22])(=[O:19])[OH:18]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
10 μL 25 mM dNTPs (25 mM each dATP, dCTP, dGTP, dTTP)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]=2[CH2:10]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:8][CH:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]=3[CH2:10]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2.99 g of potassium carbonate, 20 ml of ethyl acetate and 40 ml of water are added to 2.09 g of ethyl (+)-6-amino-5,6,7,8-tetrahydronaphthalene-2-acetate 1/2 (+)-D-dibenzoyltartrate, and a solution of 1.28 g of 4 -chlorophenylsulfonyl chloride in 20 ml of ethyl acetate is added thereto at room temperature under stirring. After the mixture is stirred at room temperature for 1.5 hour, the organic layer is separated therefrom, washed, dried and evaporated to revove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform) to give 2.10 g of ethyl (+)-6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as colorless viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O[C@H:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:24][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:10]3[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C@@H:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=2)=[N:23][N:22]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@@H]2CCNC2=O)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a stirring mixture of Methyl 3-hydroxy-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (2.5 g) (Intermediate 7) and (S)-(−)-3-hydroxy-2-pyrrolidinone (Intermediate 17) (0.8 g) in dry THF (70 mL) taken in round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (3.77 g) was added. Diisopropyl azodicarboxylate (DIAD) (2.1 mL) in dry THF (2 mL) was added drop wise to the above reaction mixture. The reaction was stirred at room temperature. Reaction was monitored by TLC for completion. After completion, reaction mixture was concentrated under vacuum to remove the solvents. Diluted with DCM and coated over silica gel and chromatographed to furnish the product as white solid (2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61]C(=O)C)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 63 °C
Yield: 85.1 %

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (483 mg) was suspended in dry methanol (3 mL). To this solution was added 4N HCl in dioxane. The mixture was heated at 63° C. for 3-4 hours. Upon complete conversion, the mixture was concentrated to dryness. The solid was re dissolved in DCM 10 mL and was washed with Na2CO3 to a pH of 8. The organic layer was washed with water, brine, dried (anhydrous Na2SO4) and concentrated to get a white solid. The solid was purified by column chromatography (silica, DCM-EtOAc, 90/1-60/40) to get the desired product as a white solid (393 mg). LCMS (m/z) 926.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH3:22][O:23][CH2:24][O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:6]=1[O:7][CH3:8])[C:1]([OH:12])=[O:11]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C(=O)O)ccc1OC
Yield: 76.5 %

Procedure:
In a similar manner to Step 1 of Example 347, isovanillic acid (5.00 g, 29.7 mmol) was suspended in dichloromethane (100 mL), and the suspension was treated with diisopropylethylamine (22.8 mL, 131 mmol) and chloromethyl methyl ether (4.96 mL, 65.4 mmol). The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50 mL) and treated with 4 mol/L aqueous potassium hydroxide solution (50 mL). The solvent was evaporated under reduced pressure. The residue was added with 4 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-methoxymethoxy-4-methoxybenzoic acid (4.82 g, yield 76%).
Reaction SMILES: S(O[CH2:6][CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH3:8])(=O)(=O)C.[NH2:24][CH2:25][CH2:26][OH:27]>O>[ClH:23].[OH:27][CH2:26][CH2:25][NH:24][CH2:6][CH:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)[CH3:8]
Reactant: CC(COS(C)(=O)=O)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: NCCO
Solvent: O
Product: CC(CNCCO)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Product: Cl

Procedure:
A mixture of 10 g (0.028 mol) of the mesylate of Example 34 and of 17 g (0.280 mol) of 2-aminoethanol is slowly heated to 170° C. The reaction mixture is allowed to return to ambient temperature and is taken up in water. After extracting the insoluble matter with diethyl ether, washing the organic phase with water and drying it over dry sodium sulphate, 8.7 g of a pale yellow oil are obtained after evaporation of the solvent. 8.4 g of this product, in ethyl acetate, are treated with a solution of hydrogen chloride in ether and the product is then purified by crystallisation from a mixture of ethyl acetate and anhydrous ethanol (7:2 by volume) to give 8.3 g of white flakes which are soluble in water to the extent of 200 g/l.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:15]I.O=O.[OH-].[Na+]>O.C(O)C>[CH3:15][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCS
Reactant: CI
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSCCCCCCCCCCC(=O)O
Yield: 58.7 %

Procedure:
Into a 3-neck round-bottom flask fitted with a condenser and an addition funnel were added 20 g of 11-mercaptoundecanoic acid, 13 g of methyl iodide and 200 mL of ethanol. A slow flow of nitrogen through the reactor was started to exclude oxygen because mercaptans can be converted into disulfides in the presence of air and strong alkali. A solution of 7.33 g of sodium hydroxide in 14.66 g of water was added dropwise to the reaction mixture via the addition funnel. Any unreacted methyl iodide, the ethanol and the water were removed using a rotovap. The residue was acidified using a mixture of concentrated hydrochloric acid and ice. After isolation the product was distilled. After a small amount of a low boiling fraction was collected, the crude product was collected at ~1 nun of Hg at 180° C. weighing 22.75 g. The crude product was distilled to yield 12.5 g of desired product representing 58.7% of theoretical based upon the weight of starting 11-mercaptoundecanoic acid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:32][C:31]1[CH:30]=[C:29]([CH3:33])[NH:28][C:27](=[O:34])[C:26]=1[CH2:25][NH:24][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:11]=1)=[O:15]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COc1ccc(-c2cc(C(=O)O)c3cnn(C(C)C)c3n2)cc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: COc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3n2)cc1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.225 mmol), DMSO(3 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (63.6 mg, 0.337 mmol) HCl salt, N-methylmorpholine (0.099 mL, 0.899 mmol), 1-hydroxy-7-azabenzotriazole (61.2 mg, 0.450 mmol), and EDC (86 mg, 0.450 mmol). The final product was collected as 89 mg (89%). LCMS E-S (M+H)=446.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.8 Hz, 6 H), 2.13 (s, 3 H), 2.23 (s, 3 H), 3.85 (s, 3 H), 4.41 (d, J=4.8 Hz, 2 H), 5.20-5.48 (m, 1 H), 5.91 (s, 1 H), 7.11 (d, J=8.8 Hz, 2 H), 8.11 (s, 1 H), 8.24 (d, J=8.8 Hz, 2 H), 8.34 (s, 1 H), 8.95 (m, 1 H), 11.58 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]=[CH:13][C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH2:15]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O.C1(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)C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: C=CC1(B(O)O)C=CC=CC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc(C=Cc2ccccc2)c1

Procedure:
Methyl 3-bromobenzoate (458 mg, 2 mmol), 1-styreneboronic acid pinacoyl ester (484 mg, 2.1 mmol), Na2CO3 (222 mg, 2.1 mmol), tetrakis(triphenylphosphino)palladium (116 mg, 0.1 mmol), water (4 mL) and 1,2-dimethoxyethane (6 mL) were stirred with reflux conditions for one hour, under nitrogen. The reaction mixture was diluted with water and was extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, dried over MgSO4 and concentrated. The product was purified by trituration with Et2O. White crystals were obtained (393 mg, 82%). NMR 1H (ppm, CDCl3): 8.19 (t, J4=1.6 Hz, 1H), 7.91 (dt, J3=7.7 Hz, J4=1.3 Hz, 1H), 7.67 (d, J3=7.8 Hz, 1H), 7.52 (d, J3=7.3 Hz, 2H), 7.42 (t, J3=7.9 Hz, 1H), 7.36 (t, J3=7.4 Hz, 2H), 7.30-7.26 (m, 1H), 7.19 (d, J3=16.3 Hz, 1H), 7.11 (d, J3=16.4 Hz, 1H), 3.06 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:13][C:14]1[N:19]=[C:18]([O:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)nc(N)n2)cc2oc(=O)[nH]c12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.20 g (1.15 mmol) 6-hydroxy-4-methylbenzo[d]oxazol-2(3H)-one and 0.19 g (1.16 mmol) 2-amino-4,6-dichloropyrimidine in 3.0 mL DMF were combined with 0.22 g (1.59 mmol) potassium carbonate and stirred overnight at 60° C. Then water was added and the precipitate formed was suction filtered, washed and dried. The substance was purified by preparative HPLC-MS. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][C:34]([CH3:45])([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36]>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]([CH3:33])([CH3:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.250 g, 0.573 mmol) in pyridine (3 mL) at 0° C. was treated with 2,2-dimethyl-3-phenylpropanoyl chloride (0.304 g, 1.55 mmol). The reaction mixture was stirred for 10 min at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. Solvent was removed under reduced pressure to dryness. Dichloromethane (15 mL) and saturated sodium bicarbonate solution (5 mL) were added to the solid. The layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure. The crude solid was purified by flash chromatography using 10% methanol in dichloromethane, then 15% (methanol with 5% ammonium hydroxide) in dichloromethane as eluent. The crude solid from the previous purification was recrystallized using ethyl acetate and heptane. The precipitate was filtered to give 0.201 g (59%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide. A hot solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide (0.201, 0.337 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.117 g, 1.011 mmol) in ethyl acetate. The precipitate was filtered under nitrogen, and dried under high vacuum to give 0.265 g of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide tri-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.46 (s, 1H), 8.241 (s, 1H), 8.107-8.086 (d, 1H, J=8.4 Hz), 7.248-7.183 (m, 7H), 6.170 (s, 6H), 4.697 (m, 1H), 3.883 (s, 3H), 2.931 (s, 3H), 2.9-2.75 (br. s., 4H), 2.671 (s, 3H), 2.104-1.990 (m, 7H), 1.588-1.5632(m, 2H), 1.226 (s, 7H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.413 min (95%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[CH2:16][CH2:15][CH2:14][CH:13]=1)=[O:11].[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:8][O:9][C:10]([C@:12]12[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:30][N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:25]2)=[O:11]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)C1=CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@]12CCC[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 82.5 %

Procedure:
A catalytic amount of trifluoroacetic acid was added to a solution of 1-cyclopentene-1-carboxylic acid methyl ester (2.52 g, 20.0 mmol) and N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (5.00 g, 21.1 mmol) in dichloromethane (40 mL) at room temperature, and the mixture was heated with stirring at room temperature for 15.5 hours. The reaction solution was diluted with dichloromethane (100 mL) and washed with a saturated sodium bicarbonate solution (80 mL). The washed aqueous layer was further extracted with dichloromethane (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→90:10→80:20) to give 4.28 g (83%) of the title compound as a colorless transparent oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=3)[C:2]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)[CH2:26][CH2:27]3)=[N:3][N:4]=2)=[CH:14][CH:15]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc(-c2nnc(Cl)c3ccc(C)cc23)cc1
Product: COc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3ccc(C)cc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(4-methoxyphenyl)-6-methylphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15]>COC(C)(C)C.C(O)(C)C>[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH:15][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: CN(C)CCCN
Reactant: S=C=Nc1ccccc1
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CN(C)CCCNC(=S)Nc1ccccc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Phenyl isothiocyanate (5.283 g, 39.1 mmole) in 30 mL t-butyl methyl ether was added to a solution of 3-(dimethylamino)propylamine (3.993 g, 39.1 mmole) in 10 mL isopropanol. After stirring 2 hr at room temp., the solid which separated was filtered out and washed with t-butyl methyl ether to afford 6.51 g of 1-[3-(dimethylamino)propyl]-3-phenylthiourea (mp 112-114° C.), part of which (2.374 g, 10 mmole) was dissolved in ethanol (20 mL) containing conc. HCl (1.67 mL, 20 mmole) and added to 2-methylnaphthoquinone dissolved in warm ethanol (35 mL). After 4 days in a stoppered flask at room temp., the mixture was concentrated, and dissolved in ethyl acetate. The solid which separated after 16 hr was filtered out, but became sticky on the filter and was discarded. The filtrate was stored another 12 days at room temp. The powder which separated was filtered out to give 600 mg of pinkish-buff powder. Of this, 325 mg was recrystallized from 10 mL methanol+60 mL ethyl acetate containing a few drops of water to give 260 mg of the title compound, mp 238-240° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of p-toluenesulfonyl chloride (3.17 g, 19.3 mmol) in 20 mL of pyridine was added 2-(2-(2-methoxyethoxy)ethoxy)ethanol (4 g, 21 mmol), which was then stirred at 0° C. for 12 h and at RT for 2 h. To this suspension, water, hexanes, and ethyl acetate were added and separated. The organic layer was neutralized with dilute hydrochloric acid and separated again. The organic layer was dried over with magnesium sulfate and sodium bicarbonate, filtered, and concentrated under reduced pressure to give 4.87 g, 15.3 mmol (79%) of 2-(2-(2-methoxyethoxy)ethoxy)-ethyl 4-methylbenzene sulfonate as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:13]([C:14]#[N:15])=[C:12]([N:16]=[CH:17][N:18](C)C)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)N.C([O-])(O)=O.[Na+].C(OCC)(=O)C>CO>[CH2:1]([NH:8][C:9]1[C:13]2[C:12](=[N:16][CH:17]=[N:18][C:14]=2[NH:15][C:28]2[CH:27]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:29]=2)[NH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=Nc1[nH]nc(NCc2ccccc2)c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccccc4)c23)c1
Temperature: 50 °C

Procedure:
With the exclusion of moisture, 79.2 g (295 mmol) of N'-(3-benzylamino-4-cyano-1H-pyrazol-5-yl)-N,N-dimethylformamidine are suspended in 700 ml of methanol; 60.6 g (369 mmol) of 3-chloro-aniline hydrochloride are added and the reaction mixture is boiled under reflux for 22 hours. The resulting yellow reaction solution is cooled to ≈50° C. and poured onto 2 liters of ice-water, 200 ml of saturated NaHCO3 solution and 1 liter of ethyl acetate. The aqueous phase is separated off and extracted twice with ethyl acetate. The organic phases are washed twice with water, saturated NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation to a residual volume of ≈1.5 liters. Inoculation and dilution with 300 ml of diethyl ether yield crystalline 3-benzylamino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 214-217° C.; TLC: Rf =0.29 (ethyl acetate:hexane=1:1).