Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:29].[Na+].OO>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]([NH2:24])=[O:29])[C:17](=[O:28])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1cccc(N2CC(c3cccc(OCc4ccccc4)c3)CC2=O)c1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc(N2CC(c3cccc(OCc4ccccc4)c3)CC2=O)c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a solution of 3-[4-(3-benzyloxyphenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile (1.3 g, 3.36 mmol) in 25 mL EtOH was added 25% NaOH (0.15 mL) followed by the slow addition of 1.5 mL H2O2 (30%). The reaction mixture was heated to 45° C. and stirred for 5 h. The mixture was then cooled down and concentrated under reduced pressure. The residue was dissolved in 100 mL EtOAc, washed with water and brine, dried over MgSO4 and concentrated again. The residue was purified by column chromatography on silica gel (EtOAc:Hexane=1:3) to give 1.3 g of the desired product. Yield: 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[N:27]=[C:26](/[CH:35]=[C:36](\[CH3:42])/[C:37]([O:39]CC)=[O:38])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[N:27]=[C:26](/[CH:35]=[C:36](\[CH3:42])/[C:37]([OH:39])=[O:38])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(C)=C/c1cc(-c2ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3cc(/C=C(\C)C(=O)O)nn3C3CCCCC3)cc2)c1

Procedure:
Ethyl ester 4.4 (55 mg, 0.094 mmol) was stirred with 1N LiOH (1 ml) in 4 ml of MeOH/THF (1:3) at rt for 24 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl and extracted with EtOAc (3×). The combined organic extracts were washed with H2O, brine, and dried (Na2SO4). Concentration gave a crude product which was purified by semi-preparative HPLC (gradient elution: 70 to 100% CH3CN/H2O+0.1% TFA) to give 4.5,47 mg (90%). HRMS (ESI) calc'd for C33H34ClN2O4 577.2207, found 557.2218 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=1.1, 1H), 7.39–7.25 (m, 7H), 7.19 (d, J=2.5, 1H), 7.00–6.95 (m, 3H), 6.47 (s, 1H), 4.95 (s, 2H), 4.14–4.05 (m, 1H), 3.88 (s, 3H), 2.24 (s, 3H), 2.10–1.98 (m, 2H), 1.94–1.87 (m, 4H), 1.27–1.22 (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[OH:12].Cl.[NH2:15][OH:16].CO.C[O-].[Na+].CO>O>[OH:16][NH:15][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[OH:12]
Reactant: COC(=O)c1ccc(CO)cc1O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NO)c1ccc(CO)cc1O
Reaction time: 3 h
Yield: 82.7 %

Procedure:
350 g of 2-hydroxy-4-(hydroxymethyl)benzoic acid methyl ester and 160 g of hydroxylamine hydrochloride were added to 700 mL of methanol. Under heating reflux, 1.11 kg of 28% sodium methoxide/methanol solution was added dropwise, and this was stirred for 3 hours. To this, 2.1 L of water was added and 850 mL of solvent was distilled off under atmospheric pressure. Then, 196 mL of hydrochloric acid was added at 40-50° C. The result was stirred for 30 minutes at the same temperature, and 116 mL of hydrochloric acid was added dropwise. After filtering solids, 291 g of N,2-dihydroxy-4-(hydroxymethyl)benzamide was obtained in the form of a pale yellowish-white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][O:12][C:13]=1[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:16][N:15]=1.[Br:23]C1C=CC(F)=NC=1>>[Br:23][C:20]1[CH:21]=[C:22]2[C:14]([C:13]3[O:12][N:11]=[CH:10][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[N:15][NH:16][C:17]2=[N:18][CH:19]=1
Reactant: Fc1cccc(-c2cnoc2-c2n[nH]c3ncccc23)c1F
Reactant: Fc1ccc(Br)cn1
Product: Fc1cccc(-c2cnoc2-c2n[nH]c3ncc(Br)cc23)c1F

Procedure:
5-Bromo-3-(4-(2,3-difluorophenyl)isoxazol-5-yl)-1H-pyrazolo[3,4-b]pyridine was prepared according to the method described for the preparation of 3-(4-(2,3-difluorophenyl)isoxazol-5-yl)-1H-pyrazolo[3,4-b]pyridine starting with 5-bromo-2-fluoropyridine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C:20]([OH:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:28](OC)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:28][O:21][C:20]([C@@H:10]1[C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)=[O:22]
Reactant: O=C(O)[C@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: COC(C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
To a white suspension of (3R,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid (72.31 g, 229 mmol) in methanol (725 mL) was added slowly sulfuric acid (25.8 ml, 457.9 mmol). The resulting dark brown solution was stirred for 19 h at 60° C. After cooling to 0° C., tert-butylmethylether (1.6 L) was added and the solution was set to pH=9 with aqueous sodium carbonate (1M, 480 mL). The aqueous layer was separated and extracted with further tert-butylmethylether (410 mL). The organic layers were washed with brine (310 mL) and dried over sodium sulfate. Concentration afforded the title compound (74.18 g, 98%) as a light brown oil. MS m/e: 330.3/332.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.P([O-])([O-])([O-])=[O:16].[K+].[K+].[K+]>C(O)C>[OH:16][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10]
Reactant: CCCOC(=O)Cc1cccc(Cl)c1
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCOC(=O)[C@@H](O)c1cccc(Cl)c1
Reaction time: 0.03 h

Procedure:
Experimental description: 95 mg propyl 2-(3-chlorophenyl)acetate were dissolved in 500 μL ethanol and added to 250 mL potassium phosphate buffer pH 8.0. Var3-7 was added to the mixture at a final concentration of 1 μM. The mixture was split in 4 mL aliquots into 15 mL scintillation vials equipped with a stir bar. 500 μL of a 5 mM NADPH solution were added to each vial and stirred for 2 minutes. 500 μL of a cofactor regeneration solution containing 300 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 4 hours, the reaction mixtures were joined together and extracted with chloroform (3×100 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5% ethyl acetate:95% hexane) afforded the activated product ((S)-propyl 2-hydroxy-2-(3-chlorophenyl)acetate, 71 mg). 70 mg (0.3 mmol) of activated product were dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and added with 64 μL DAST (0.45 mmol). The reaction was stirred in dry ice for 12 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5% ethyl acetate:95% hexane) afforded the fluorinated product ((R)-propyl 2-fluoro-2-(3-chlorophenyl)acetate) (57 mg, 82% yield, colorless oil) in 89% ee, as determined by chiral GC analysis. 1H-NMR (300 MHz, CDCl3): δ 0.85 (t, J=7 Hz, 3H, —CH3), δ 1.56-1.68 (m, 2H, CH2), δ 4.12 (t, J=6 Hz, 2H, —O—(CH2), δ 5.72 (d, J=48 Hz, 1H, —CHF), δ 7.32 (br, 3H), δ 7.44 (br, 1H); 13C-NMR (75 MHz, CDCl3): 10.3, 21.9, 67.7, δ 88.7 (d, J=186.5 Hz), 124.8, 126.9, 129.9, 130.3, 134.9. 19F-NMR (282 MHz, CDCl3): δ −182.8 (d, J=48.7 Hz). HRMS (EI+): exact mass calculated for C11H12ClFO2 requires m/z 230.0510, found 230.0502.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:9])[CH2:3]1.[CH2:16]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:23])[CH:20]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:9])[CH2:3]1)[CH3:21])[CH3:17]
Reactant: O=C(N[C@@H]1CCNC1)c1ccc(Cl)s1
Reactant: CCOC(=O)C(C)Br
Agent: Cl
Product: CCOC(=O)C(C)N1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1

Procedure:
6.3 Using general procedure A 5-chloro-thiophene-2-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride was reacted with ethyl-2-bromopropionate to give 2-{(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidin-1-yl}-propionic acid ethyl ester. Oil. MS 329.1 ([M−H]−)
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8]CC)([OH:7])[CH2:5][CH2:4][NH:3]1.[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:11][C:12]1[CH:19]=[C:18]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: CCC[C@]1(O)CCN[C@H]1C
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (1.50 g), 2-chloro-4-fluorobenzonitrile (3.04 g) and lithium carbonate (1.04 g), the title compound was obtained as a colorless solid (yield: 1.70 g, yield: 72%).
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22][OH:23])=[CH:18][C:17]=4[CH:24]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C(Cl)Cl>[N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:18][C:17]=4[CH:24]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1
Reactant: OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a room temperature solution of 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzofuran-2-yl]-ethanol (200 mg, 0.91 mmol) in CH2Cl2 (10 ml) was added triethylamine (303 mg, 3 mmol) and methanesulfonyl chloride (525 mg, 4.56 mmol). The mixture was stirred at room temperature for 30 minutes. Water was added to the reaction and the organic layer separated. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were dried and concentrated to give methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester, which was used in the next reaction without further purification.
Reaction SMILES: [F:1][CH:2]([F:30])[C@@H:3]1[O:21][CH2:20][C@:6]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[N:7]=[C:8]([NH:11]C(=O)C3C=CC=CC=3)[S:9][CH2:10][C@@H:5]2[CH2:4]1.FC1C=C(F)C=CC=1[C@]12CO[C@@H](CF)C[C@H]1[C@@H](C)SC(NC(=O)C1C=CC=CC=1)=N2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](CF)C[C@H]1[C@@H](C)SC(N)=N2>>[F:30][CH:2]([F:1])[C@@H:3]1[O:21][CH2:20][C@:6]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[N:7]=[C:8]([NH2:11])[S:9][CH2:10][C@@H:5]2[CH2:4]1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(F)F)C[C@H]2CS1)c1ccccc1
Agent: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Agent: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Product: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(F)F)C[C@H]2CS1

Procedure:
N-[(4aR,6R,8aS)-6-(Difluoromethyl)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C24) was deprotected using the method described for conversion of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C19) to (4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (1) in Example 1; the product was isolated as a white solid. Yield: 1.46 g, 4.36 mmol, 96%. LCMS m/z 335.1 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.35 (ddd, J=9, 9, 7 Hz, 1H), 6.93-7.01 (m, 2H), 5.77 (td, J=55.6, 3.9 Hz, 1H), 4.11 (dd, J=11.1, 2.0 Hz, 1H), 3.81-3.92 (m, 1H), 3.73 (d, J=11.0 Hz, 1H), 2.87-2.97 (m, 2H), 2.69-2.75 (m, 1H), 1.88-1.99 (m, 1H), 1.59-1.66 (m, 1H).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:24]([C:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH:30]=1)[CH2:25][CH2:26][CH2:27][CH3:28].C(C1CCC(C(OC2C=CC(CCC3CCC(CCC=C(C)C)=CC3)=CC=2)=O)CC=1)CCCC>>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:24]([C:29]1[CH2:34][CH2:33][CH:32]([C:35]([O-:37])=[O:36])[CH2:31][CH:30]=1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC1=CCC(C(=O)O)CC1
Agent: CCCCCC1=CCC(C(=O)Oc2ccc(CCC3CC=C(CCC=C(C)C)CC3)cc2)CC1
Agent: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCC1=CCC(C(=O)[O-])CC1

Procedure:
The reaction between 4-(5-decyl-2-pyrimidyl)phenol (prepared essentially according to the procedure of H. Zaschke and R. Stolle, Z. Chem. 15, 441-43 (1975)) and 4-pentyl-3-cyclohexenylcarboxylic acid is essentially that used for the synthesis of ester 2J.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:25][CH2:26][CH3:27])=[C:12]([C:14]2[NH:15][C:16](=[O:24])[C:17]3[N:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:13]=1>>[C:1]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:25][CH2:26][CH3:27])=[C:12]([C:14]2[NH:15][C:16](=[O:24])[C:17]3[N:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:13]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOc1ccc(N)cc1-c1nc2cccnc2c(=O)[nH]1
Reactant: CC(C)C(=O)Cl
Product: CCOc1ccc(NC(=O)C(C)C)cc1-c1nc2cccnc2c(=O)[nH]1

Procedure:
The title compound was prepared using isobutyryl chloride and 2-(5-amino-2-ethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (Example 20), following the procedure of Example 12, and was obtained as a white solid (80%), m.p. 256-259° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.Cl.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12)(=[O:20])=[O:21]
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Reactant: CS(=O)(=O)c1cccc(CN)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(CNc2ccnc3cc(-c4ccccc4)oc23)c1

Procedure:
The title compound was prepared by procedure D using 7-chloro-2-phenyl-furo[3,2-b]pyridine (50.00 mg; 0.22 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and using 3-(methylsulfonyl)-benzylamine hydrochloride (57.92 mg; 0.26 mmol; 1.20 eq.) instead of N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide and was obtained as a waxy yellow solid (73 mg, 88%). (HPLC (method F): 98%, RT: 3.37 min); MS (m/z) 379 [M+H]+, RT: 2.2 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[NH:9]1[CH2:12][CH:11]([NH:13][C:14](=[O:39])[C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:12][CH:11]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[CH:19][C:18]([S:21]([N:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:25]4)(=[O:22])=[O:23])=[CH:17][CH:16]=3)[CH2:10]2)=[CH:3][CH:4]=1
Reactant: O=C(NC1CNC1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NC1CN(c2ccc(F)cc2)C1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Temperature: 100 °C
Yield: 23.9 %

Procedure:
Add 1-bromo-4-fluorobenzene (110 μL, 180 mg, 1.0 mmol, 2.0 equiv) to a mixture of N-azetidin-3-yl-4-(3-phenyl-indole-1-sulfonyl)-benzamide (216 mg, 0.501 mmol, 1 equiv), tris(dibenzylideneacetone)dipalladium(0) (12 mg, 0.012 mmol, 0.025 equiv), 2-(di-tert-butylphosphino)biphenyl (8 mg, 0.03 mmol, 0.05 equiv), and sodium tert-butoxide (58 mg, 0.60 mmol, 1.2 equiv) in anhydr toluene (2 mL). Heat the reaction mixture at 100° C. for 14 h. After cooling, dilute the reaction mixture with CH2Cl2 and transfer through a 0.45-μm filter disc to a column of silica gel (80 mm×20 mm dia.) and elute (10-35% EtOAc/hex) to yield 63 mg (24%) of N-[1-(4-fluoro-phenyl)-azetidin-3-yl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.C(N(CC)CC)C.[I-].[Na+].[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: C1COCCN1
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn(CCN3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 60 °C
Yield: 14.5 %

Procedure:
To a mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.200 g, 0.373 mmol), triethylamine (0.052 mL, 0.37 mmol), and sodium iodide (0.056 g, 0.37 mmol) in DMF (5 mL) was added morpholine (0.039 mL, 0.45 mmol). The reaction mixture was heated at 60° C. for 60 h. Morpholine (0.100 mL, 1.15 mmol) was added and the reaction mixture was heated at 80° C. for 30 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration, washed with water (5 mL) and ether (10 mL), and dried in vacuo to afford a tan solid which was purified twice by silica gel chromatography (elution with 20% MeOH—CH2Cl2); the appropriate fractions were combined and concentrated to afford a beige solid which was triturated from ether and dried in vacuo to afford N2-{4-[4-amino-1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide as a white solid (0.048 g, 0.054 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.26 (1H, s), 8.11 (1H, d, J=8.0 Hz), 7.70 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=7.6 Hz), 7.29-7.35 (4H, m), 7.15 (1H, t, J=7.6 Hz), 4.48 (2H, t, J=6.4 Hz), 4.04 (3H, s), 3.96 (3H, s), 3.50-3.53 (4H, m), 2.82 (2H, t, J=6.2 Hz), and 2.47-2.51 (4H, m);); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.02 min. MS: M+527.3.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]([CH3:9])[CH2:5][CH:6]([CH3:8])[N:7]=1.Cl(O)(=O)(=O)=O.CO[CH:17](OC)[CH2:18][CH:19](OC)OC>>[CH3:8][CH:6]1[CH2:5][CH:4]([CH3:9])[N:3]2[CH:17]=[CH:18][CH:19]=[N:1][C:2]2=[N:7]1
Reactant: COC(CC(OC)OC)OC
Reactant: CC1CC(C)NC(N)=N1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC1CC(C)N2C=CC=NC2=N1

Procedure:
0.66 g 2-amino-4,6-dimethyl-1,4,5,6-tetrahydropyrimidine was refluxed to boiling point in a methanolic solution with the addition of perchloric acid with an equimolar amount of 1,1,3,3-tetramethoxypropane. Removing the solvent and coating the residue with a layer of diethyl ether yielded the 2,4-dimethyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine hydroperchlorate, which was filtered off and dried in a vacuum.
Reaction SMILES: [OH:1][N:2]([CH3:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C1COCC1.C(N(CC)CC)C>C(Cl)Cl>[S:18]([O:1][N:2]([CH3:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CN(O)C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)ON(C)C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
N-Tosyloxy-N-methylbenzamide was prepared by the following procedure. To a flask equipped with a stirrer were added N-hydroxy-N-methylbenzamide (1.39 g, 0.010 mol) from above, p-toluenesulfonyl chloride (1.91 g, 0.010 mol), 25 mL of THF and 2 mL of triethylamine. After 30 min at 0° followed by 1 h at room temperature, the reaction mixture was diluted with 50 mL of methylene chloride, and the solution was washed with water (4×50 mL) and dried. Evaporation of the solvent left 2.84 g of a golden oil which soon crystallized. Recrystallization from methylene chloride-hexane gave 2.04 g (69.4%) of fluffy white N-tosyloxy-N-methylbenzamide: mp 98°-99.5°; nmr (CDCl3) 7.8-7.0 (A2B2 and singlet at 7.36, 9H), 3.53 (s, 3H), 2.38 (s, 3H); ir (KBr) 1684 (vs), 1370 (s), 1180 (s), 1170 (s), 880 (m), 805 (m), 735 (m), 695 (s), 651 (m), 540 (s): uv (CH3CN) 227 (19,200), 265 (sh, 2020), 273 nm (sh, 1500); mass spectrum 305.0720 (calcd for C15H15O4NS: m+, 305.0720). Anal. Calcd for C15H15O4NS: C, 59.00; H, 4.95; N, 4.59; S, 20.96; O, 10.50. Found: C, 58.87, 58.75; H, 4.98, 5.02; N, 4.52, 4.43.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[OH-].[Na+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:4][CH2:3][CH2:1][OH:2])=[CH:10][CH:9]=1
Reactant: NCCO
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: OCCNCc1ccc(Cl)cc1

Procedure:
Ethanolamine (56.9 g, 931 mmol) and sodium hydroxide (7.44 g, 186 mmol) were mixed in isopmpanol (50 ml) and 4-chlorobenzyl chloride (30 g, 186 mmol) was added at such a rate that a mild reflux was achieved. The mixture was then refluxed for another 30 min. Evaporation of the solvent was followed by the addition of methylene chloride (50 ml). The solids were filtered off and the solvent was evaporated from the filtrate. The residual oil was distilled under oil pump vacuum and the fraction at 125-126° C. (0.1 mm Hg) was collected. Yield 27 g, 78%.