Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1.Cl>[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:8]([CH:9]=2)=[O:11])=[O:12])[CH2:4][CH2:3]1
Reactant: CNCCc1ccc(O)c(O)c1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Product: CN1CCC2=CC(=O)C(=O)C=C21
Yield: 63 %

Procedure:
The above-detailed manganese dioxide oxidation was effected on 51 mg (0.20 mmol) 79% epinine hydrochloride, yielding a deep red solution of epinochrome. This was isomerized over a mixture of 0.56 g (2.5 mmol) of zinc acetate and 15 mL of ethyl acetate. After 45 min of rapid stirring, this mixture was yet slightly pink. It was again Schlenk-filtered under N2, then it was partitioned. Extractions and drying were performed as in Example 5. After an identical acetylation process, 31 mg (63% yield) of DAMI was collected.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.Cl[S:42]([C:45]1[CH:46]=[C:47]([CH:58]=[CH:59][CH:60]=1)[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])(=[O:44])=[O:43]>O1CCCC1.O>[C:20]([O:19][C:18]([N:17]([CH2:16][C:5]1[C:4]([F:3])=[C:8]([C:9]2[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[N:7]([S:42]([C:45]2[CH:46]=[C:47]([CH:58]=[CH:59][CH:60]=2)[C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])(=[O:44])=[O:43])[CH:6]=1)[CH3:25])=[O:24])([CH3:21])([CH3:22])[CH3:23]
Reactant: O=C(OCc1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)OCc3ccccc3)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoyl chloride (1.5 g) in tetrahydrofuran (12 mL) were added benzyl alcohol (712 mg) and pyridine (370 mg) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:16:1) to give benzyl 3-(chlorosulfonyl)benzoate as a colorless oil (yield 1.70 g, 87%). To a suspension of sodium hydride (60% in oil, 120 mg) in tetrahydrofuran (8 mL) were added dropwise a solution (12 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (646 mg) in tetrahydrofuran, 15-crown-5 (660 mg) and benzyl 3-(chlorosulfonyl)benzoate (684 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a pale-yellow oil (yield 1.09 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1cccc(N2CCOCC2)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 153.6 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 3-(1-tert-butoxycarbonylaminoethyl)phenyl ester (1.5 g, 4.08 mmol), morpholine (8 mL) Pd2(dba)3 (187 mg, 5 mol %), di-t-butyl-biphenylphosphine (243 mg, 20 mol %), potassium phosphate (1.21 g, 5.71 mmol) was stirred at 80° C. in a sealed tube for 10 hours. After cooling down, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (10 mL). The aqueous layer was extracted with dichloromethane (2×15 mL) and the combined organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography of Biotage with 30% ethyl acetate/hexanes to provide the title compound as a pale yellow solid (1.01 g, 81% yield).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[C@H:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].C([O-])(=O)[C@@H]([C@H](C([O-])=O)O)O.[C:39]1([S:45]([OH:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)(C)C.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH:42]1[CH:41]=[CH:40][C:39]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:44][CH:43]=1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1c1ccccc1Cl
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 2 h
Yield: 89.1 %

Procedure:
68.8 gm (0.122 mole, 95.2% de) R (+) amlodipine hemi L(+) tartarate mono DMSO solvate prepared as per example-2 was suspended in aqueous isopropanol (70 ml IPA: 250 ml distilled water) and a solution of benzene sulfonic acid (21.28 gm of 90% technical grade, 0.122 mole) in 1150 ml water was added. The reaction mixture was stirred for 2 hrs and the slurry was filtered, washed with distilled water, hexane, the solid was dried under vac. at 40° C. till constant weight to give R(+) amlodipine besylate (66.74 gm, 89.1% yield) 98.7 ee by chiral HPLC.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5](OCC)=[O:6])#[N:2]>CCO.[Ni]>[O:6]=[C:5]1[NH:2][CH2:1][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4]1
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.1 %

Procedure:
A mixture of diethyl 3-cyano-3-phenylpentanedioate (8 g, 27.7 mmol) and Raney-Ni (4 g) in EtOH (240 mL) was stirred under H2 atmosphere (50 psi) at rt for 2 days. TLC and LC-MS showed that the reaction was completed, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by chromatography on a silica gel column eluting with PE/EtOAc=10:11:8 to give ethyl 2-(5-oxo-3-phenylpyrrolidin-3-yl)acetate (4.8 g, yield 71%) as white solid. 1H NMR (CDCl3 400 MHz): δ 7.33 (t, 2H), 7.24 (t, 1H), 7.18 (d, 2H), 5.79 (s, 1H), 3.97-3.88 (m, 3H), 3.72 (d, 1H), 2.86-2.70 (m, 4H), 1.03 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([P:16](Cl)(Cl)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[C:10]1([P:16]2(=[O:17])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH2:3][N:2]2[CH3:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNCc1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: CCOCC
Product: CN1Cc2ccccc2P1(=O)c1ccccc1

Procedure:
The procedure of Example 36 was employed utilizing N-methyl-N-benzylamine and phenyl phosphonic dichloride. The reaction of the dilithio compound and the phenyl phosphonic dichloride was conducted at -60° C. The residue produced as a result of the distillation process was slurried in ether to yield 1-phenyl-2-methyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a white solid. A second crop was obtained and the combined product yield was recrystallized from carbon tetrachloride and petroleum ether to yield 1-phenyl-2-methyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.25 g, 15% yield) having a melting point of 129°-130° C. and the following analysis:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:8]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH2:23][OH:24])=[O:20])=[CH:15][CH:14]=2)[CH:9]=1)(=O)[CH3:2].Cl.[NH2:34][OH:35]>N1C=CC=CC=1>[CH2:26]([O:25][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:34][OH:35])[CH3:2])=[CH:9][C:8]=1[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH2:23][OH:24])=[O:20])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)NCCO)cc2)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)NCCO)cc2)c1
Temperature: 60 °C
Yield: 56 %

Procedure:
A mixture of 4-[3-(5-acetyl-2-benzyloxyphenyl)propyl]-N-(2-hydroxyethyl)benzenecarboxamide (0.5 g) (example 2, compound 45) hydroxylamine hydrochloride (0.16 g) in pyridine (5 ml) was heated at 60° C. for 2 hours. The pyridine was removed and the residue subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate/hexane (4:1 v/v) to yield in the appropriate fractions, 4-[3-(2-benzyloxy-5-(1-hydroxyiminoethyl)phenyl)propyl]-N-(2-hydroxyethyl)benzenecarboxamide (m.p. 131°-2° C.; yield 56%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]4[CH:16]=[C:17]([CH2:21][NH2:22])[CH:18]=[CH:19][CH:20]=4)=[CH:14][C:9]=3[N:8]([CH3:23])[S:7]2(=[O:25])=[O:24])[CH2:4][CH2:3]1.F[C:27]1[N:34]=[CH:33][CH:32]=[CH:31][C:28]=1[C:29]#[N:30].CN1C(=O)CCC1.CCN(C(C)C)C(C)C>CO>[CH:2]1([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]4[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=4)[CH2:21][NH:22][C:27]4[N:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])=[CH:14][C:9]=3[N:8]([CH3:23])[S:7]2(=[O:24])=[O:25])[CH2:4][CH2:3]1
Reactant: CN1c2cc(-c3cccc(CN)c3)ccc2N(CC2CC2)S1(=O)=O
Reactant: N#Cc1cccnc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2cc(-c3cccc(CNc4ncccc4C#N)c3)ccc2N(CC2CC2)S1(=O)=O
Temperature: 100 °C

Procedure:
To a microwave vial was added 1-{3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]phenyl}methanamine hydrochloride (23-2) (0.037 g, 0.097 mmol), 2-fluoronicotinonitrile (0.18 g, 0.15 mmol), NMP (0.7 mL), and finally DIPEA (0.039 mL, 0.22 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 2-({3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]benzyl}amino)nicotinonitrile (24-1) as a tan solid. HRMS (M+H)+: observed=446.1642, calculated=446.1645.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+].Br[CH2:23][CH2:24][CH2:25][NH:26][C:27]1[C:36](=[O:37])[C:31]2[N:32]=[C:33]([CH3:35])[S:34][C:30]=2[C:29](=[O:38])[CH:28]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[C:36](=[O:37])[C:31]3[N:32]=[C:33]([CH3:35])[S:34][C:30]=3[C:29](=[O:38])[CH:28]=2)=[CH:5][CH:4]=1
Reactant: Cc1nc2c(s1)C(=O)C=C(NCCCBr)C2=O
Reactant: COc1ccc(CN)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNCCCNC2=CC(=O)c3sc(C)nc3C2=O)cc1
Temperature: 180 °C
Reaction time: 0.08 h

Procedure:
160 μl (1.22 mmol; 1.1 equivalent) of 4-methoxybenzylamine, 213 μl (1.22 mmol; 1.1 equivalent) of diisopropylethylamine and a spatula tip's worth of sodium iodide are added to 0.35 g (1.11 mmol) of 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione in solution in 15 ml of dimethylformamide. The reaction mixture is maintained under stirring under microwaves for 5 minutes at 180° C. Then the solvent is evaporated off under reduced pressure and the reaction residue is taken up in dichloromethane, followed by washing with 3 times 50 ml of water. The organic phases are combined, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. The expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5) and obtained in the form of a red oil.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10](Br)[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6]1)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:6][N:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH:9]=[CH:10]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)N1CCC(Br)C(OC(C)=O)C1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)N1CC=CC(OC(C)=O)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A mixture of Compound 239A (371 mmol) and DBU (92 g, 604 mmol) was heated to 90-110° C. for 30 min. After cooling to room temperature, the mixture was diluted with toluene and stirred for an additional 30 min. The precipitate was removed by filtration and rinsed with toluene. Combined filtrates were washed with 1.0 N HCl, water and dried over anhydrous anhydrous MgSO4. Concentration in vacuo afforded 67.56 g (yield: 85.4%) of 239B as an oil. 1H-NMR (400 MHz, CDCl3): 6.00 (bs, 1H), 5.90 (bs, 1H), 5.20 (m, 1H), 4.20 (q, J=7.08, 2H), 4.19 (m, 1H), 3.85 (m, 1H), 3.80 (m, 1H), 3.55 (m, 1H), 2.08 (s, 3H), 1.28 (t, J=7.08, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.CCN(CC)CC>C1COCC1>[O:14]=[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)Nc1ccccn1

Procedure:
The compound 2-aminopyridine (5 g; 53.02 mmol) is dissolved in 80 ml of THF and heated at 80° C. for 15 hours in the presence of succinic anhydride (5.3 g; 53.08 mmol) and a catalytic amount of Et3N (0.7 ml). A white solid is observed with precipitates in the reaction mixture and is suction-filtered off, corresponding to the title product.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]2[CH2:24][C:25]([O:27]C)=[O:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1>C1COCC1.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]2[CH2:24][C:25]([OH:27])=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: COC(=O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCc3ccccc3C2CC(=O)O)cc1
Reaction time: 8 h

Procedure:
A 6 M aqueous NaOH solution was added to a mixture of methyl 2-(2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (15.22 g, 40.54 mmol) in THF (200 ml) and water (120 ml), and stirring was carried out overnight at room temperature. The solvent was then removed under reduced pressure, and a 6 M aqueous HCl solution (125 ml) and DCM (400 ml) were added. The phases were separated and then the organic phase was washed with concentrated NaCl solution, dried over sodium sulfate and concentrated. Yield: 14.65 g (100%)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]([CH2:19][CH:20]([OH:22])[CH3:21])[S:15]([CH3:18])(=[O:17])=[O:16].C(N(CC)CC)C>ClCCCl>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]([CH2:19][CH:20]([O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:21])[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: Cc1cccc(C)c1N(CC(C)O)S(C)(=O)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
31.4 ml (46.6 g, 0.4 moles) of methanesulfonyl chloride are added dropwise, within one hour, to a solution of 94.5 g (0.368 moles) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-propanol and 55.3 ml (40.5 g, 0.4 moles) of trietyl amine in 600 ml of 1,2-dichloroethane. During the addition the mixture is cooled with ice to maintain its temperature at 10°-12° C. The mixture is stirred at room temperature for additional 4 hours and then washed thrice with 100 ml of water, each. The dichloroethane solution is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and the thick, oily residue is triturated with 120 ml of isopropanol. The resulting crystals are filtered off, washed with ice-cold isopropanol and dried. 93.2 g (75.8%) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-methanesulfonyloxy-propane are obtained as a white, crystalline substance melting at 111°-114° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:15])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4](Cl)[N:3]=1.O.[NH2:18][NH2:19]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:15])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: NN
Reactant: Cn1c(=O)n(CCO)c2nc(N)nc(Cl)c21
Solvent: CCO
Solvent: O
Product: Cn1c(=O)n(CCO)c2nc(N)nc(NN)c21
Temperature: 105 °C
Yield: 88.9 %

Procedure:
A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one obtained in step 3 (8 g, 32.9 mmol), Hydrazine hydrate (16 ml, 32.9 mmol) and ethanol (300 ml) were heated at 100-110° C. for 16 hours. The reaction mixture was concentrated and solid obtained was filtered off and dried to obtain 2-amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyl-purin-8-one (7 g, 89%) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1>CN1CCCC1=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N[C@H]3CC[C@H](O)CC3)c21
Temperature: 150 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 555 mg (4.82 mmol) of trans-4-aminocyclohexanol was added. The mixture was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 91 mg (73% of theor.) of the target compound was obtained.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:53][C:54](=[O:67])[C@H:55]([OH:66])[C@H:56]([NH2:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:64])[CH2:50][CH2:51][CH3:52]>C(Cl)Cl>[CH2:49]([O:53][C:54]([C@H:55]([OH:66])[C@H:56]([NH:65][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:64])=[O:67])[CH2:50][CH2:51][CH3:52]
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Reactant: CCCCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Reaction time: 0.17 h
Yield: 39 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (300 mg, 1.4 mmol, 1.0 eq.) was combined with DIPEA (803 μL, 3.2 eq.) and HATU (548 mg, 1.4 mmol, 1.0 eq.) in DCM (30 mL). The mixture was stirred for 10 min and (2R,3R)-3-amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid butyl ester (412 mg, 1.4 mmol, 1.0 eq.) was added. The reaction was quenched after 1 hour by adding saturated NH4Cl and the product was extracted with DCM, dried and evaporated. AcOH (1 mL) was added and the resulting product was purified by preparative HPLC to yield the title compound (260 mg, 99% purity). MS m/z [M+H]+ calc'd for C25H30ClNO6, 476.18. found 476.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=2[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([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)=CC=1>[CH3:20][N:16]1[C:15]2[CH:21]=[C:11]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:13][C:14]=2[O:18][C:17]1=[O:19]
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1c(=O)oc2ccc(-c3cccnc3)cc21
Yield: 39.8 %

Procedure:
A mixture of pyridin-3-ylboronic acid (61.5 mg, 0.5 mmol), 5-Bromo-3-methyl-3H-benzooxazol-2-one (114 mg, 0.5 mmol), polymer-supported Pd(PPh3)4 (0.11 mmol/g, 114 mg, 0.0125 mmol), Na2CO3 (2 M in water, 0.5 mL, 1 mmol) in DME (3 mL) was heated to reflux for 6 hrs. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 1-3%) and yielded the title compound as pale yellow solid (45 mg). 1HNMR(CDCl3, 400.342 MHz): δ 3.47 (s, 3H), 7.13 (s, 1H), 7.30 (m, 2H), 7.38 (dd, J=4.8, 7.9 Hz, 1H), 7.85 (m, 1H), 8.62 (dd, J=1.5, 4.8 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9][CH2:8]2>C1COCC1.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([CH3:1])[CH2:10][CH:9]=[CH:8]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C=CCC2C
Yield: 51 %

Procedure:
Methyllithium (1M solution in THF; 27 ml, 27 mmol) was added slowly to a solution of 6-methoxy-1-tetralone (3.16 g, 18 mmol) in THF (15 ml) under N2. The reaction mixture was allowed to react under N2 at RT overnight (12 h). It was then diluted with ethyl acetate and quenched with ice-cooled HCl (2M). The aqeous phase was extracted further with ethyl acetate, dried, and concentrated in vacuo. Chromatographic purification of the crude material on silica gel, using 5% ether in petroleum ether as eluent, gave the title compound as a gum (1.6 g, 52%). 1H-NMR (250 MHz CDCl3): 2.1 (t, 3H, Me), 2.2 (m, 2H), 2.8 (t, 2H), 3.8 (s, 3H, OMe), 5.8 (t, 1H), 6.8-7.2 (m, 3H), 13C-NMR (250 MHz, CDCl3) 19.3, 23.2, 28.9, 55.2, 110.8, 113.7, 122.9, 123.9, 129.1, 131.8, 138.1, 158.4; Mass Spectrum (M+1) m/e=175.