Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[CH3:9][CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[CH:32]=[C:31]3[O:33][CH2:34][O:35][C:30]3=[CH:29][C:28]=2I)=[N:24][C:18]2[C:19]([NH2:23])=[N:20][CH:21]=[N:22][C:17]1=2)[CH3:11].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[C:28]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:29][C:30]3[O:35][CH2:34][O:33][C:31]=3[CH:32]=2)=[N:24][C:18]2[C:17]1=[N:22][CH:21]=[N:20][C:19]=2[NH2:23])([CH3:11])[CH3:9]
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2cccs2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 45.2 %

Procedure:
2-Thienylboronic acid (11.2 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 12.5:1) to give 12.4 mg (45%) of DZ2-395. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.33 (dd, J=1.4, 4.9 Hz, 1H), 7.07 (s, 1H), 7.04 (s, 1H), 7.00-7.02 (m, 2H), 6.09 (s, 2H), 4.12 (t, J=6.6 Hz, 2H), 2.95 (septet, J=6.6 Hz, 1H), 2.62 (t, J=6.8 Hz, 2H), 2.00 (m, 2H), 1.19 (d, J=6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.2, 152.0, 151.1, 149.4, 148.8, 148.4, 140.5, 132.9, 127.8, 126.9, 126.3, 119.2, 119.0, 114.6, 111.8, 102.3, 49.6, 42.5, 40.6, 27.8, 20.7; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O2S2, 469.1480; found. 469.1461; HPLC: method A Rt=6.38, method B Rt=7.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.O.[C:21](O)(=[O:23])C>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:8])[C:3]=1[OH:9])[CH:21]=[O:23]
Reactant: CC(=O)O
Reactant: Oc1c(F)cccc1F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C

Procedure:
2,6-difluorophenol (1 eq) and hexamethylenetetramine (2 eq) were dissolved in a water/acetic acid mixture (10:90). The reaction mixture was refluxed for 18 hours then cooled to room temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[O:12]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[O:12]2)=[CH:8][CH:9]=1
Reactant: O=C1Nc2ccccc2OC1=Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=C2Oc3ccccc3NC2=O)cc1

Procedure:
A catalytic amount of Raney nickel was added portionwise with stirring to a mixture of 2-[(4-nitrophenyl)methylene]-2H-1,4-benzoxazin-3(4H)-one (0.57 g, 0.002 mol) and hydrazine hydrate (1 ml) in ethanol (20 ml). The reaction mixture was refluxed for 3 h, then filtered. The filtrate was evaporated to dryness under reduced pressure. The crude product was purified by re crystallization from ethanol.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([C:18]1[C:19]([CH2:33][CH2:34][CH3:35])=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]2)=[N:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[CH3:38][C:39]1([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=2)[NH:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>CN(C)C=O.O>[F:36][C:2]([F:1])([F:37])[C:3]([C:18]1[C:19]([CH2:33][CH2:34][CH3:35])=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:41]3[C:40](=[O:45])[C:39]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=4)([CH3:38])[NH:43][C:42]3=[O:44])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CCCc1cc(N2CCN(CCO)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(N2CCN(CCN3C(=O)NC(C)(c4ccc(OC(C)C)cc4)C3=O)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
2-(4-{5-[1,1,1,3,3,3-Hexafluoro-2-(4-methoxybenzyloxy)propan-2-yl]-4-propylpyridin-2-yl}piperazin-1-yl)ethanol (20 mg, 0.0373 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (34.3 mg, 0.138 mmol) and triphenylphosphine (34.5 mg, 0.132 mmol) were dried with a vacuum pump, dissolved in N,N-dimethylformamide (3 mL), added DEAD (51 μL, 0.111 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water (1.0 mL) and 2N aqueous solution of hydrochloric acid (1.0 mL), extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (30 mg (yield 99%)) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH2:4][Mg]Cl.[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([OH:26])[CH2:4][C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cccc(Cl)c1C[Mg]Cl
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Solvent: C1CCOC1
Product: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirred solution of 2-chloro-6-fluorobenzyl magnesium chloride (12.8 mL, 3.20 mmol, 3 equiv., available from Rieke Metals) in anhydrous tetrahydrofuran (15 ml) at 0° C. under nitrogen was added a solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (300 mg, 1.07 mmol, 1 equiv.) in tetrahydrofuran (5 ml) dropwise over 15 minutes. The reaction was then stirred at 0° C. for one hour. The reaction mixture was allowed to warn to room temperature over two hours and stirred for a further 18 h. The solvent was then evaporated “in vacuo” and the residue redissolved in dichloromethane (30 mL). The organic solution was washed with aqueous saturated solution of NaHCO3 (50 mL). The aqueous solution was extracted with dichloromethane using a hydrophobic phase separator. The dichloromethane was evaporated “in vacuo” and redissolved in methanol (2 mL). The sample was bound to SCX-2 (5 g) and washed with methanol (30 mL). The sample was eluted using 2M ammonia in methanol (30 mL). The solvent was then evaporated using a reacti-therm blow down station to give 450 mg of a yellow amorphous solid. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=426 @ Rt 3.27 min. major peak.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.Cl[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](CC)([O-])=O>[O:15]=[S:14]1(=[O:16])[C:3]2[CH:4]=[C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=2[NH:1][C:18](=[O:19])[NH:17]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of N-(4-amino-phenyl)-methanesulfonamide (Example 3b′, 90.7 g, 0.49 mol) in nitroethane (900 mL) was added dropwise over 1.5 h to a mechanically stirred solution of chlorosulfonylisocyanate (50.6 mL, 0.54 mol) in nitroethane (150 mL) at −20° C. The resulting suspension was stirred at −20° C. for 30 min, then aluminum chloride (77.9 g, 0.58 mol) was added in one portion over 1 min. The resulting brown solution was warmed to 25° C., and then was heated at 110° C. for 1 h (considerable gas evolution was noted during this time). After cooling to −5° C., water (300 mL) was added dropwise via addition funnel over 15 min, followed by the rapid addition of more water (700 mL). The resulting suspension was allowed to warm to 25° C. and vigorously stirred for 30 min, and then was filtered through medium paper using a Büchner funnel. The collected solid was washed with water (1×300 mL) and was air-dried to afford the desired product, N-(1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazin-7-yl)-methanesulfonamide (115.2 g, 0.40 mmol, 81% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 3.00 (3H, s), 7.22 (1H, d, J=8.5 Hz), 7.46 (1H, dd, J1=8.8 Hz, J2=2.7 Hz), 7.51 (1H, d, J=2.4 Hz), 9.92 (1H, s), 11.20 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CN(C)CCCN
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C

Procedure:
139 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) of Example 1a are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 50.1 g. of [3-(dimethylamino)propyl]amine are added dropwise. After the addition is completed, heating is continued for ten minutes. The solvent is removed in vacuo and the residue is suspended in 200 ml. of water. The aqueous mixture is made alkaline with 10% sodium hydroxide solution and extracted three times with 200 ml. portions of ethyl acetate. The organic layer is dried over calcium chloride, evaporated to dryness and crystallized with petroleum ether to obtain 4-[[3-(dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester, yield: 102 g. (59%); m.p. 20°.
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1)=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 2-naphthoyl chloride (112 mg, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under-reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (160 mg, 82%).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C1C=CC=CC=1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1-c1ccccc1
Reaction time: 1 h

Procedure:
To a stirring solution of 1,1'-biphenylcarboxylic acid (1.0 g, 4.6 mmol) in 10 ml of dry benzene, under argon was added oxalyl chloride (0.40 ml, 2.0 eq.). To this solution was added DMF dropwise in 10 minute intervals, until no gas was evolved and the solution turned slightly cloudy (two drops). The mixture was stirred for 1 hour, then reduced on the rotovap without heating. The crude product, white solid, was carried directly on to the next step.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[C:12]([OH:14])=[O:13].[CH3:15]O>>[CH3:15][O:13][C:12]([C@@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]1[NH2:5])=[O:14]
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (5.48 g, 46.1 mmol) was added dropwise to a solution of cis-2-aminocyclohexanecarboxylic acid (2.0 g, 14.0 mmol) in methanol (50 mL) at 0° C. The mixture was allowed to warm to room temperature and stir for 18 h. The clear solution was then evaporated to dryness, and the residual volatiles were removed on high vacuum. The crude product, cis-2-aminocyclohexanecarboxylic acid methyl ester, was isolated in quantitative yield and used in the next reaction without purification: 1H NMR (400 MHz, CDCl3) δ 8.50 (s br, 2 H), 3.78 (s, 3 H), 3.59 (s br, 1 H), 3.18 (s br, 1 H), 2.27 (m, 1 H), 2.08 (m, 1 H), 1.88 (m, 2 H), 1.45 (m, 4 H).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]([NH2:11])([CH3:10])[CH3:9].C([O-])(=O)C.[Na+]>CCOCC.C(OC(=O)C)(=O)C>[CH:8]([N:11]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])([CH3:10])[CH3:9]
Reactant: CC(C)N
Reactant: O=C1C=CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(C)N1C(=O)C=CC1=O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 8.4 %

Procedure:
A cooled (5° C.) stirred solution of maleic anhydride (29.4 g, 0.30 mole) in anhydrous ether (150 mL) under nitrogen was treated dropwise over 45 min with a solution of isopropylamine (35.5 g, 0.60 mole) in anhydrous ether (100 mL) at a rate to keep the pot temp <20° C. The mixture was then stirred at 10° C. for 15 min, filtered, and the filter cake rinsed with anhydrous ether and dried in vacuo to afford a white solid. This was taken up in acetic anhydride (250 mL), treated with anhydrous sodium acetate (12.3 g, 0.15 mole), and heated to 75° C. with stirring for 4.5 h, then at 100° C. for 1.5 h. The mixture was concentrated in vacuo and the residue taken up in methylene chloride (300 mL), washed with saturated aqueous sodium bicarbonate (200 mL), water (200 mL), dried (MgSO4), and concentrated in vacuo. The residue was distilled (approx. 5 mm pressure) to afford two products; one an N-isopropylmaleimide that distilled at 82° C. (13.0 g), the other an acetate adduct of N-isopropylmaleimide that distilled at 154° C. (12.9 g). The acetate adduct was dissolved in 4:1 acetonitrile/triethylamine (100 mL), heated to 65° C. for 4 h, then concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a pad of silica gel (eluted with methylene chloride) to afford an additional 3.5 g of N-isopropylmaleimide. Total yield was 16.5 g of N-isopropylmaleimide (40%).
Reaction SMILES: C(O)=O.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].C[O-].[Na+].Br[CH2:22][C:23](=[O:39])[CH2:24][C@H:25]1[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]1[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>CO>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:22][C:23](=[O:39])[CH2:24][C@H:25]3[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: CSc1cc2c(=O)[nH]cnc2cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Br)c(SC)cc2c1=O

Procedure:
Under a nitrogen atmosphere in a flame dried flask at room temperature and with magnetic stirring, a suspension of 0.43 g (0.00136 mol) of 7-bromo-6-methylthioquinazolin-4(3H)-one formic acid salt in 5 ml of methanol was treated with two equivalents of sodium methoxide in methanol (approximately 1N). After 15 minutes 0.53 g (0.0016 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate was added in one portion. After being stirred for an hour, the reaction mixture was evaporated under reduced pressure, and the residue was taken up in about 15 ml of water. The aqueous solution was extracted three times with 15 ml portions of dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to afford the title compound: yield 0.61 g (86%). 1H-NMR(CDCl3): 1.3-2.0 ppm (multiplet, 4H, CH3OCHCH2CH2CH2N), 2.6 (singlet, 3H, CH3S), 2.8-3.0 (multiplet, 4H, COCH2CH and NCH2), 3.3 (broad singlet, 1H, CH2CHNCO), 3.4 (singlet, 3H CH3O), 4.0 (broad doublet, 1H, CHOCH3), 4.6 (broad doublet 2H, CH2CH=CH2), 4.8-5.1 (multiple peaks, 2H, NCH2CO), 5.2-5.4 (multiplet, 2H, CH2 =CH), 5.9 (octet, 1H, CH=CH2), 7.3 (singlet, 1H, aromatic H), 7.9 (singlet, 1H, aromatic H), 7.95 (singlet, 1H, N=CH--N).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22]C)=O)=[C:18]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.CC(O)=O>[CH3:33][N:31]1[CH:32]=[C:28]([C:18]2[C:19]3[C:20](=[O:22])[NH:27][CH2:26][C:24]=3[CH:25]=[C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[N:17]=2)[CH:29]=[N:30]1
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A solution of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (110 mg, 0.242 mmol) and palladium on carbon (2.58 mg, 0.024 mmol) in MeOH (5 mL) and HOAc (1 mL) was stirred at RT overnight under H2 atmosphere. After reaction, the mixture was filtered through Celite, the filtrate was evaporated, and the residue was diluted with MeOH and sat aq NaHCO3. The mixture was stirred at RT for 30 min and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 and preparative HPLC to give the title compound (60 mg, 58.1%). 1H NMR (500 MHz, CDCl3) δ ppm 1.26-1.87 (m, 17H), 3.91 (s, 3H), 4.25 (br s, 2H), 5.16-5.49 (m 2H), 6.23 (br s, 1H), 6.75 (br s, 1H), 8.18-8.44 (m, 1H), 8.76-9.05 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[CH3:27][S:28]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:30])=[O:29]
Reactant: Nc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
A stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (1 g; 3.6 mmol) and triethylamine (1.2 ml; 8 mmol) in dry THF (25 ml) was added methanesulfonylchloride (0.6 ml; 8 mmol) and stirred at rt. for 2 h. The reaction mixture was evaporated to dryness, resuspended in H2O/EtOAc and filtered. The filtrate was adsorbed onto silica gel. Column chromatography (CH2Cl2:acetone=9:1) gave 210 mg of product.
Reaction SMILES: [P:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][O:22][C:23](=[O:77])[C:24]1[CH:29]=[C:28](CC2C=CC=CC=2)[C:27]([NH:37][C:38]([C@H:40]2[C@H:44]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=3[F:52])[C@:43]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][C:56]=3[F:62])([C:53]#[N:54])[C@H:42]([CH2:63][C:64]([CH3:67])([CH3:66])[CH3:65])[NH:41]2)=[O:39])=[C:26]([O:68][CH3:69])[C:25]=1CC1C=CC=CC=1)=[O:19])([OH:4])([OH:3])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[P:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][O:22][C:23](=[O:77])[C:24]1[CH:29]=[CH:28][C:27]([NH:37][C:38]([C@H:40]2[C@H:44]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=3[F:52])[C@:43]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][C:56]=3[F:62])([C:53]#[N:54])[C@H:42]([CH2:63][C:64]([CH3:66])([CH3:67])[CH3:65])[NH:41]2)=[O:39])=[C:26]([O:68][CH3:69])[CH:25]=1)=[O:19])([OH:3])([OH:4])=[O:2]
Reactant: COc1c(Cc2ccccc2)c(C(=O)OCOC(=O)OCCOCCOCCOCCOP(=O)(O)O)cc(Cc2ccccc2)c1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCOC(=O)OCCOCCOCCOCCOP(=O)(O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 83.4 %

Procedure:
A solution of chiral dibenzyl 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-{2-[2-(2-phosphonooxy-ethoxy)-ethoxy]-ethoxy}-ethoxycarbonyloxymethyl ester (Example 49, 106.7 mg, 0.095 mmol) in ethyl acetate (10 mL) was treated with 10% palladium on carbon (58 mg) under 1 atm of hydrogen for 1 h. The reaction mixture was filtrated and the filtrate was concentrated to give chiral 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-{2-[2-(2-phosphonooxy-ethoxy)ethoxy]-ethoxy}-ethoxycarbonyloxymethyl ester as a white solid (75 mg, 82% yield). MS (ES+) m/z calcd. for C41H49Cl2F2N3O14P: [(M+H)+]: 946, found: 946.