Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:8]3=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24].CN(C)C=O>CO>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:8]3=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2c(ccc3nc(-c4ccccc4)[nH]c32)n1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2c(ccc3nc(-c4ccccc4)[nH]c32)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 88 g. (0.32 m.) of 7-methyl-2-phenyl-9-imidazo[4,5-f]quinolinol (Example V D above) and 293 ml. (481 g. 3.2 m.) of POCl3 is added slowly 586 ml. of dimethylformamide. Following the completion of the addition, stirring is continued overnight at room temperature. It is then poured into 4 liters of ice. The crude product is precipitated by the addition of 1200 ml. of conc. NH4OH to pH 8.0. It is collected by filtration, washed with H2O and air-dried to give 154 g. m.p. 136°-250° C., slow decomposition. After dissolving the crude product in 5 liters of MeOH, the MeOH filtrate is concentrated to a volume of 750 ml. and chilled. The yield after oven-drying (100° C.) is 41 g. A second recrystallization from 2000 ml. of MeOH and followed by concentration to one-half its volume yields 28 g.
Reaction SMILES: [ClH:1].O(CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=C[CH:4]=1.Cl.[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47](OC)=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=1[CH2:3][CH3:4])[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: Cl
Product: CCc1ccccc1OCC(O)CNC(C)(C)Cc1ccc(OC)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M−15, 1), 237 (16), 236 (100), 163 (5), 121 (17), 114 (7), 91 (6), 77 (7).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[N:13]1([C:18]2[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][C@H:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH:19]=1)[CH3:25])=[O:8]
Reactant: C[C@H](N)c1cccc(-n2cccn2)c1
Reactant: O=C(O)C=Cc1ccccc1F
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-1-(3-pyrazol-1-yl-phenyl)-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([CH3:34])[C:24]=4[OH:23])[CH2:29]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(C)c4O)C3)c3ccccc3n2)cc1
Yield: 22 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 26 (22% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.81 and 3.04 (2t, 2H), 3.60 and 4.22 (2t, 2H), 3.93 (s, 3H), 4.49 and 5.09 (2s, 2H), 6.34-6.93 (m, 2H), 7.05-7.09 (m, 3H), 7.56-7.64 (m, 1H), 7.94-8.04 (m, 2H), 8.32-8.33 (m, 1H), 8.64-8.70 (m, 2H); MS (ESI) m/z 426 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH:16]=[CH:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][OH:9].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>N1C=CC=CC=1>[S:32]([O:1][CH2:2][CH2:3][O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH:16]=[CH:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][OH:9])([CH3:31])(=[O:34])=[O:33]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCO)[C@]2(O)C(=O)CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOS(C)(=O)=O)[C@]2(O)C(=O)CO

Procedure:
A solution of 3.0 g of 16α-(2-hydroxyethoxy)-11β,-17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acetate in 15 ml of pyridine is stirred with 0.75 ml of methane sulfonyl chloride at 0°C for 150 minutes. The mixture is poured into 1.5 liter of cold 1N hydrochloric acid, stirred for a short time, and filtered. The resulting solid is dissolved in chloroform, washed with water, dried, and evaporated in vacuo to give 4.0 g of crude 16α-(2-mesyloxyethoxy)-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acetate
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2[C:10]([NH:13][CH3:14])=[N:11][NH:12][C:6]=2[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]1=[O:23])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([N:11]1[C:10]([NH:13][CH3:14])=[C:7]2[C:6]([N:5]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:4](=[O:23])[N:3]([CH2:1][CH3:2])[C:8]2=[O:9])=[N:12]1)(=[O:26])[CH3:25]
Reactant: CCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(C)cc2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCn1c(=O)c2c(NC)n(C(C)=O)nc2n(Cc2ccc(C)cc2)c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 5-ethyl-3-methylamino-7-(4-methylbenzyl)-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.5 g, 1.6 mM) and acetic anhydride (0.33 g, 3,2 mM) in pyridine (5 ml) was stirred at 60° C. for 18 hours.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1>>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[NH2:21])=[O:9])=[CH:10][CH:11]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: COc1ccc(NC(=O)c2ccc(CN)cc2)c(N)c1
Yield: 35.4 %

Procedure:
The title compound (192 mg, 71% yield) was prepared as a grey solid from 4-cyano-benzoic acid (294 mg, 2 mmol) and 4-methoxy-o-phenylenediamine (331 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 272 (M+1).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].[CH3:15][NH2:16].O1CCCC1>ClCCl>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([NH:16][CH3:15])=[O:11])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1cc(S(N)(=O)=O)ccc1F
Reaction time: 16 h
Yield: 23 %

Procedure:
To a suspension of 5-(aminosulfonyl)-2-fluorobenzoic acid [prepared according to Chem. Pharm. Bull. 1995, 43(4), 582-7] (3.0g, 13.7mmol) in dichloromethane (100 mL) at room temperature under nitrogen was added 1-(3-dimethylaminopropyl)-3-ethylcarbodlimide hydrochloride (WSCDI) (2.89 g, 15.06 mmol) followed by a solution of methylamine in tetrahydrofuran (2 M, 8.21 mL, 16.42 mmol), dropwise and the reaction allowed to stir for 16 hours. The crude reaction mixture was then evaporated to dryness and the residue chromatographed on silica gel, eluting with dichloromethane:methanol:ammonia (84:14:2) as solvent to give the amide (732mg, 23%) as a white powder. 1H NMR (300 MHz, d4-MeOH): δ=2.97 (3 H, s), 7.40 (1 H, t), 8.05 (1 H, m), 8.29 (1 H, d). MS m/z 250 (MNH4)+
Reaction SMILES: C([Li])CCC.[Cl-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][C:9]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH:41]1([C:44]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[CH:45][CH:46]=O)[CH2:43][CH2:42]1>O1CCCC1>[CH:41]1([C:44]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)=[CH:45][CH:46]=[CH:14][C:11]2[CH:12]=[CH:13][C:8]([F:7])=[C:9]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:10]=2)[CH2:43][CH2:42]1
Reactant: O=CC=C(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(C=CC=C(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A stirred solution of 0.71 gram (4.4 mL-0.011 mole) of n-butyllithium (2.5M in hexane) in 50 mL of dry tetrahydrofuran was cooled to -78° C., and 4.98 grams (0.01 mole) of 4-fluoro-3-phenoxyphenylmethyltriphenylphosphonium chloride (prepared in Steps C-E) was quickly added. Upon completion of addition the reaction mixture was stirred at -78° C. for one hour, and then a solution of 2.03 grams (0.01 mole) of 3-cyclopropyl-3-(4-chlorophenyl)-2-propenal (prepared in Steps A and B) in 10 mL of dry tetrahydrofuran was added dropwise during a 10 minute period. Upon completion of addition the reaction mixture was stirred at -78° C. for one hour and then was allowed to warm to ambient temperature where it was stirred for two hours. The reaction was quenched with 10 mL of aqueous dilute hydrochloric acid, and the reaction mixture was extracted with diethyl ether. The ether extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 5% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure yielding 1.4 grams of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)-1,3-butadiene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CCOCC>CCO>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][CH2:8][OH:9]
Reactant: OCCC1CCCCN1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: CCOCC
Product: OCC[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 72 h
Yield: 6.2 %

Procedure:
Piperidine-2-ethanol (127 g, 980 mmol) in 95% EtOH (260 mL) was added to (S)-(+)-camphorsulfonic acid (228.7 g, 1.0 eq.) in 95% EtOH (150 mL) and the resulting solution was warmed to reflux. To the warm solution was added Et2O (600 mL) and the solution cooled to room temperature and let stand 3 days. The resulting crystals were filtered and dried in vacuo (25 g): mp 173–173° C. (lit. 168° C.). The salt was then dissolved in NaOH (3M, 100 mL) and stirred 2 hours and the resulting solution was extracted with CH2Cl2 (5×100 mL). The combined organics were dried over Na2SO4, filtered, filtered and concentrated under reduced pressure to give (S)-piperidine-2-ethanol (7.8 g) a portion of which was recrystallized from Et2O: mp=69–70° C. (lit. 68–69° C.); [α]D=14.09° (CHCl3, c=0.2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21]C(C)(C)[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]#[N:51])[CH:45]=3)=[CH:38][CH:37]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:25])[O:26][C@H:27]2[C@H:34]3[C@H:30]([O:31][CH2:32][CH2:33]3)[O:29][CH2:28]2)[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]#[N:51])[CH:45]=3)=[CH:38][CH:37]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2cccc(C#N)c2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[[(4-aminophenyl)sulfonyl](isobutyl)amino]methyl}-4-{4-[(3-cyanobenzyl)oxy]benzyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate in 3 mL of dioxane was added 4M hydrochloric acid in dioxane (1.5 mL) and water (0.05 mL). The solution was stirred for 1 hour followed by neutralization with 10% aqueous Na2CO3. The solution was extracted with dichloromethane (3×15 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (8:2) as eluent to provide 17 mg (61%) of the title compound. 1H-NMR (DMSO-d6): δ 0.74 (3H,d), 0.81(3H,d), 1.18 (1H,m), 1.28 (1H,m), 1.89 (1H,m), 2.35 (1H,t), 2.54-2.60 (2H,m), 2.71 (1H,m), 2.86-2.93 (2H,m), 3.22-3.29 (1H,dd), 3.42-3.48 (1H,m), 3.53-3.59 (3H,m), 3.65 (1H,t), 3.82 (1H,q), 4.80 (1H,q), 4.93 (1H,d,b), 5.07 (2H,s), 5.47 (1H,d), 5.94 (2H,s,b), 6.54 (2H,d), 6.83 (2H,d), 7.08 (2H,d), 7.19 (1H,d), 7.33 (2H,d), 7.56 (1H,t), 7.74 (2H,t), 7.85 (1H,s). MS: 680 (M+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH3:14])[N:11]([CH3:15])[C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH:12]([CH3:14])[N:11]([CH3:15])[C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(c3ccccc3)CC(C)N(C)C2=O)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC1CC(c2ccccc2)(c2cccc(O)c2)C(=O)N1C
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
Product of Step 5 (5 g) was dissolved in dichloromethane (250 mL) and stirred at −60° C. under argon purging using dry ice and acetone. After 30 min at −60° C. and under argon purging, 1M boron tribromide in dichloromethane (45 mL) was added in drop wise manner. The reaction mixture was stirred for 3 hr at −60° C. under argon purging. Then, the reaction mixture was allowed to warm to 25° C. and stirred under argon for 2 hr at 25° C. The reaction was quenched with slow addition of methanol (50 mL) at 4° C. The reaction mixture was concentrated under vacuum and poured in cold 1N HCl (300 mL). The white precipitate was extracted with dichloromethane (500 mL). The organic layer was dried on anhydrous magnesium sulfate, was filtered and was concentrated under vacuum. The crude product was used without further purification.
Reaction SMILES: OO.C([C@@H]1COC(=O)N1[C:16](=[O:38])[C@H:17]([CH2:21][S:22]([N:25]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[S:33][C:27]=2[CH2:26]1)(=[O:24])=[O:23])[CH:18]([CH3:20])[CH3:19])C1C=CC=CC=1.O.[OH-].[Li+].S([O-])([O-])=[O:43].[Na+].[Na+]>O1CCCC1.O>[CH2:26]1[C:27]2[S:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[C:28]=2[CH2:29][CH2:30][N:25]1[S:22]([CH2:21][C@H:17]([CH:18]([CH3:19])[CH3:20])[C:16]([OH:43])=[O:38])(=[O:23])=[O:24]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCc2c(sc3ccccc23)C1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCc2c(sc3ccccc23)C1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Hydrogen peroxide (30% aqueous, 0.15 ml) was added to a solution of 4-(R)-benzyl-3-[2-(R)-(3,4-dihydro-1H-benzo[4,5]thieno[2,3-c]pyridine-2-sulfonylmethyl)-3-methyl-butanoyl]-oxazolidin-2-one (180 mg) in tetrahydrofuran (5 ml) at 0° C., followed by a solution of lithium hydroxide monohydrate (30 mg) in water (3 ml). The reaction was stirred for 16 h, allowing to warm slowly to room temperature. A solution of sodium sulfite (200 mg) in water (5 ml) was added then the mixture was evaporated under reduced pressure. The aqueous residue was washed with diethyl ether (20 ml), acidified with citric acid and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound (110 mg) in crude form.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3cccc(OC)c3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3cccc(OC)c3)n2)CC1

Procedure:
To a solution of 90 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-(3-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DCM, 0.3 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 15 mg
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.O.[Cl-].[Na+].[CH3:24]O>>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:24])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1cccc(O)c1)C1CC1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CC(c1cccc(O)c1)C1CC1
Temperature: 64 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxyphenyl)propanoic acid (99.0 g) in methanol (990 mL) was added conc. sulfuric acid (4.71 g), and the mixture was stirred at 64° C. for 2 hr. Water and sodium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (84.0 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:37])=[C:34]([Pb+3])[CH:35]=1>C(OCC)(=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:37])=[C:32]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:31]=1
Reactant: Cc1ccc(Cl)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 40 °C
Reaction time: 23 h

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (described in U.S. Pat. No. 5,089,046A) (0.504 g, 2.96 mmol) and N,N-dimethylaminopyridine (1.45 g, 11.84 mmol) is added anhydrous chloroform (40 ml). To this solution is added crude 5-chloro-2-methylphenyllead triacetate (2.26 g, 4.44 mmol) in one portion, and the mixture is then heated at 40° C. for 17 hours (analysis), then for a further 23 hours at 45-50° C. The mixture is allowed to cool to room temperature, then diluted with ethyl acetate (100 ml) and washed with dilute aqueous hydrochloric acid (3×30 ml). The organic phase is dried over anhydrous magnesium sulfate, then concentrated to give a yellow gum which is purified by column chromatography (ethyl acetate/hexane/acetic acid 8:18:1 ratio) then triturated with hexanes to afford 4-(5-chloro-2-methylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.53 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5](=[CH:10][C:11]=1[CH3:12])[CH2:6][C:7]([OH:9])=O.[CH:16]([NH2:19])([CH3:18])[CH3:17].C>C(O)C>[CH:16]([N:19]1[C:7](=[O:9])[CH2:6][C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[C:11]([CH3:12])[CH:10]=2)[C:13]1=[O:15])([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: Cc1cc(CC(=O)O)c(C(=O)O)cc1C
Agent: C
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)N(C(C)C)C(=O)C2
Temperature: 25 °C

Procedure:
A mixture of 4,5-dimethylhomophthalic acid (104 g., 0.5 mole) and isopropylamine (59 g., 1 mole) is heated by an oil bath until molten for 90 minutes. The hot mixture is then poured into 600 ml. of ethanol, treated with carbon black and filtered. The mixture is concentrated to about 300 ml. and slowly cooled to room temperature. 2-Isopropyl-6,7-dimethylisoquinoline-1,3(2H,4H)-dione precipitates and is collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])=[CH:15][CH:14]=1)#[N:12].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:19][C@H:18]([C:20]([OH:22])=[O:21])[CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C[C@H](Nc2ccc(C#N)c(Cl)c2)C(=O)O)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (0.90 g) in dimethyl sulfoxide (20 mL) were added 4-cyanophenylalanine (1.00 g) and cesium carbonate (2.23 g), and the mixture was stirred at 90° C. overnight. After warming to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 1.57 g, 92%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[F:22].Cl>O1CCOCC1>[F:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(Br)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
0.49 mol of diethyl malonate was added at 60° C. inside 2 hours to a mixture of 0.51 mol of NaH and 140 ml of 1,4-dioxane. The mixture was stirred for approximately 10 min at 60° C. and then 0.05 mol of Cu(I)Br was added. After 15 min, a mixture of 0.25 mol of 4-bromo-3-fluorotoluene and 10 ml of 1,4-dioxane was added. The reaction mixture was heated at 100° C. for approximately 15 hours and was then cooled to 15° C. After acidifying with 35 ml of 12N HCl at 15 to 20° C., the precipitate produced was filtered off. The filtrate was extracted and the organic phases, after separation, were dried and then freed from the solvent. 40 g of the title compound were obtained.