Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[OH-].[K+:17]>CO>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:4][C:2](=[O:3])[C:1]([O-:6])=[O:5])=[CH:10][CH:9]=1.[K+:17]
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=Cc1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of pyruvic acid and p-fluorobenzaldehyde (24.8 g) in methanol (20 ml) was cooled to 15° C. and treated with a solution of potassium hydroxide (16.8 g) in (50 ml) methanol. After 2/3 of the addition was complete, the cooling bath was removed and the temperature was allowed to rise to 40° C. A yellow precipitate appeared and was filtered after standing overnight. The solid was washed well with methanol and ether. The title compound (34.5 g) was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:69]=[CH:68][C:53]2[NH:54][C:55]([C@@H:57]([NH2:67])[CH2:58][C:59]3[CH:64]=[C:63]([F:65])[CH:62]=[C:61]([F:66])[CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:69]=[CH:68][C:53]2[NH:54][C:55]([C@@H:57]([NH:67][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:60]=[C:61]([F:66])[CH:62]=[C:63]([F:65])[CH:64]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(3,5-difluorophenyl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.43 (silica gel: dichloromethane/ethanol=9:1); C28H25ClF2N4O2 (522.99); mass spectrum: (M+H)+=523/525 (chlorine isotope).
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[BrH:15].BrBr.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)(=O)C.C(O)C>[BrH:15].[BrH:15].[NH2:21][C:19]1[S:20][C:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][CH2:2][CH3:3])[CH2:9][C:10]=2[N:18]=1
Reactant: CCCN1CCC[C@@H]2CC(=O)CC[C@H]21
Reactant: NC(N)=S
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCO
Product: CCCN1CCC[C@H]2Cc3nc(N)sc3C[C@@H]21
Temperature: 0 °C

Procedure:
Five grams of trans-(±)-1-n-propyl-6-oxodecahydroquinoline were dissolved in 30 ml. of glacial acetic acid. Five and eight tenths milliliters of 37% by weight hydrogen bromide in glacial acetic acid were added followed by the dropwise additions of 1.5 ml. of bromine dissolved in glacial acetic acid. The reaction mixture was illuminated with ultraviolet radiation using a commercially available sunlamp. The illuminated reaction mixture was stirred for one-half hour after all the reactants had been added. Volatile constituents were removed from the reaction mixture in vacuo yielding, as a residue, trans-(±)-1-n-propyl-6-oxo-7-bromodecahydroquinoline hydrobromide. One hundredth mole of this salt was dissolved in 50 ml. of ethanol. Eighty-four hundredths grams of thiourea were added thereto. The resulting mixture was refluxed for about 18 hours under a nitrogen blanket. A colorless solid began to form after about 20 minutes. The reaction mixture was cooled to about 0° C. and the solid, which had continued to form, was separated by filtration. The filter cake was dried in vacuo. One and fifteen hundredths grams of trans-(±)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline dihydrobromide salt were obtained. The salt melted above 255° C., tlc (9:1 chloroform:methanol plus a trace of ammonium hydroxide) Rf =0.13.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:15]3[C:11]([O:12][CH:13]=[CH:14]3)=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.C(O)CC.O.[NH2:29][NH2:30]>C(Cl)Cl>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:9]1[N:10]=[C:11]2[N:15]([C:8]=1[C:5]1[N:6]=[N:7][C:2]([NH:29][NH2:30])=[CH:3][CH:4]=1)[CH:14]=[CH:13][O:12]2
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccc(Cl)nn2)c(F)c1
Reactant: NN
Solvent: CCCO
Solvent: O
Solvent: ClCCl
Product: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)nn1
Temperature: 100 °C
Yield: 77.2 %

Procedure:
To a flask was added 5-(6-chloropyridazin-3-yl)-6-(2,4-difluorophenyl)imidazo[2,1-b]oxazole (4.00 g, 12.0 mmol), 1-propanol (80 mL) and hydrazine hydrate (5.89 mL, 120 mmol). The reaction mixture was heated at about 100° C. for about 20 h. The reaction mixture was cooled to ambient temperature and then diluted with DCM (100 mL). The organic layer was washed with saturated aqueous NaHCO3 (80 mL), dried with MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.04 g, 77%) as a solid. LC/MS (Table 1, Method g) Rt=1.58 min; MS m/z: 329.1 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-chloro-4-fluorophenyl isocyanate (0.34 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light orange solid (0.39 g, 56% yield), mp=89–91° C.; MS (−) ESI m/z=352 (M−H)−; [α]D25=+24.0° (c=1, EtOH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C(N(CC)CC)C.[C:39]([CH2:43][C:44](Cl)=[O:45])([CH3:42])([CH3:41])[CH3:40].OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:44](=[O:45])[CH2:43][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1noc(C)c1C
Reactant: CC(C)(C)CC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)CC(C)(C)C)c1C
Reaction time: 0.08 h

Procedure:
To the title product of Step F in 300 ml of CH2Cl2 at 0° C., triethylamine (6.17 g, 60.96 mmol) was added and stirred for 5 minutes. To the mixture, t-butylacetyl chloride (3.98 g, 29.57 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hr. 100 ml 10% aqueous NaHSO4 was added. The aqueous layer was extracted with 100 ml CH2Cl2. The combined organic extracts were washed with 100 ml H2O, 50 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 60:40:1 hexane/EtOAc/AcOH to provide the title product of this Example (13.10 g, 80% for two steps) as a white solid. melting point=120-128° C. (amorphous).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CCN(C(C)C)C(C)C>CCO>[CH3:7][N:6]1[C:2]([N:18]2[CH2:19][CH2:20][C:15]3([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:13][CH2:14]3)[CH2:16][CH2:17]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC2(CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 130 °C
Yield: 72.1 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (150 mg, 0.93 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (244 mg, 1.02 mmol) and DIPEA (1 mL) in EtOH (3 mL) was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (50% EtOAc/isohexane) to give tert-butyl 8-(1-methyl-4-nitro-1H-pyrazol-5-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate as a yellow oil (245 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 3.76 (s, 3H), 3.49-3.39 (m, 2H), 3.30-3.00 (m, 6H), 1.90-1.60 (m, 6H), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][CH3:16])=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][CH3:16])=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cccc(CC)c2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cccc(CC)c2[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
7-Ethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (76.6 g, 0.24 mol) was dissolved in 450 mL dichloromethane and cooled to 0° C. Trifluoroacetic acid (150.0 mL, 1.96 mol) was added within 30 min. and after an additional 45 min. the reaction mixture was concentrated at a rotary evaporator. The residue was dissolved in 300 mL dichloromethane and poured cautiously onto 500 mL saturated aq. sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was suspended in 400 mL n-hexane and put in an ultrasonic bath for 15 min. The suspension was filtered and the filter cake was washed with 100 mL n-hexane. This procedure was repeated to give the desired product as a light brown solid (40.2 g, 76.6%). EI-MS: m/e 217.1 ([M]).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:29]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(Oc2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-phenoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 432.27 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[CH3:24])=[O:5])[CH3:2].[CH2:25]([O:27]C(=O)C(CC(C1C=CC(F)=CC=1)=O)C(=O)C)C.COC1C=CC(N)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([O:27][CH3:25])=[CH:20][CH:19]=2)[C:7]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1C
Solvent: COc1ccc(N)cc1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(OC)cc2)c1C

Procedure:
Prepared in analogy to that of 5-(4-fluoro-phenyl)-2-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 2-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester and 4-methoxyaniline. The title compound, ESI MS (m/z): 354 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[NH:33][CH:30]1[CH2:32][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(Cc4ccccc4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E.MS (ESI): predicted mass calcd. for C22H18FN5O2, 403.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1.[CH2:45]([O:52][C:53]1[CH:54]=[CH:55][C:56]([C@@H:64]([O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:70])[CH3:69])[CH2:65]Br)=[C:57]2[C:62]=1[NH:61][C:60](=[O:63])[CH:59]=[CH:58]2)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>O.CN(C=O)C.C(#N)C>[CH2:45]([O:52][C:53]1[CH:54]=[CH:55][C:56]([C@@H:64]([O:67][Si:68]([C:71]([CH3:72])([CH3:74])[CH3:73])([CH3:70])[CH3:69])[CH2:65][NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]3[CH:14]=[C:15]([S:19]([C:22]4[CH:23]=[C:24]5[C:29](=[C:30]([CH3:32])[CH:31]=4)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]5[NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=4)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:6][CH:5]=2)=[C:57]2[C:62]=1[NH:61][C:60](=[O:63])[CH:59]=[CH:58]2)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCN)cc5)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Temperature: 100 °C

Procedure:
Intermediate 94 (206 mg, 0.258 mmol) was combined with (R)-8-(benzyloxy)-5-[2-bromo-1-[(tert-butyldimethylsilyl)oxy]ethyl]quinolin-2(1H)-one (115 mg, 0.235 mmol), sodium iodide (20 mg, 0.133 mmol), and K2CO3 (97 mg, 0.705 mmol) in a mixture of anhydrous acetonitrile (1.0 mL) and anhydrous DMF (0.5 mL) and was heated to 100° C. in a microwave for 2 h. The reaction was poured into H2O and extracted repeatedly into EtOAc. Flash chromatography (0-15% MeOH/CH2Cl2) gave the title compound as a yellow solid, 98 mg. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.54 (br s, 1H), 10.45 (s, 1H), 9.09 (s, 1H), 8.36 (d, J=1.7 Hz, 1H), 8.29-8.34 (m, 2H), 8.27 (d, J=10.0 Hz, 1H), 8.21 (dt, J=7.8, 1.3 Hz, 1H), 8.02-8.05 (m, 1H), 7.85-7.89 (m, 1H), 7.78 (br s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.54-7.58 (m, 2H), 7.33-7.40 (m, 2H), 7.27-7.33 (m, 1H), 7.14-7.20 (m, 3H), 7.11 (t, J=8.1 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.62-6.68 (m, 2H), 6.54 (d, J=9.9 Hz, 1H), 6.50-6.54 (m, 1H), 5.26 (s, 2H), 5.09-5.17 (m, 1H), 3.60 (s, 3H), 2.72-2.86 (m, 3H), 2.71 (s, 3H), 2.59-2.68 (m, 3H), 0.78 (s, 9H), 0.00 (s, 3H), −0.21 (s, 3H). ES/MS calcd. for C57H61N6O8Ssi+ 1017.4. Found m/z=1017.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][C:3]=1[N+:30]([O-])=O>CO.C1COCC1.[Pd]>[NH2:30][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:2]=1[CH3:1])[C:6]([NH:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[N:11][C:10]=1[C:25]([NH2:27])=[O:26])=[O:7]
Reactant: Cc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1N
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a mixture of 5-(4-methyl-3-nitrobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.07 g, 0.15 mmol) in MeOH-THF (10 mL, 1:1) was added 10% Pd/C (0.014 g) under N2-atmosphere. The mixture was stirred for 16 hrs under hydrogen atmosphere. The insoluble material was then filtered off, and the filtrate was concentrated under reduced pressure to give 0.032 g (49% yield) of the titled compound.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O:24][C:25](=[O:31])[C@H:26]([CH:28]([CH3:30])[CH3:29])[NH2:27]>CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:27][C@H:26]([C:25]([OH:31])=[O:24])[CH:28]([CH3:30])[CH3:29])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
Z-Phe-OAt is reacted with valine methyl ester in DMF in accordance with the procedure described in Example 33 to form Z-Phe-Val.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:11])[CH:12]=[CH:18][C:14]2[NH:13][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(=O)C=Cc2ccc[nH]2)cc1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a solution of 10.1 g (0.18 mole) of potassium hydroxide in 2.18 L of water was added 176.4 g (1.32 mole) of 4-methylacetophenone and 50 g (0.53 mole) of pyrrole-2-carboxaldehyde. The mixture was heated to 40°-45° C. with mechanical stirring under a nitrogen atmosphere overnight. The solid precipitate was filtered, washed with water and 2-propanol, and air dried to give 42.1 g (38% yield) of the title compound as a solid, mp 158.5°-159.5° C.
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](O)=[O:16])[CH:10]=[C:11]([CH3:13])[CH:12]=1>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][OH:16])[CH:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(CBr)cc(CC(=O)O)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1cc(CBr)cc(CCO)c1
Reaction time: 0.17 h

Procedure:
Borane dimethyl sulfide complex (2M in THF, 8.6 mL) was added dropwise to a solution of 2-(3-(bromomethyl)-5-methylphenyl)acetic acid [Aromatic Intermediate 23, step a] (2.1 g) in THF (50 mL) at 0° C. and the mixture stirred for 10 minutes at this temperature and then at room temperature for 1 hour. The reaction mixture was quenched by dropwise addition of methanol, the solvents were evaporated under reduced pressure and the residue was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 1.40 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[I-].ClC1C=[CH:28][CH:27]=[CH:26][N+]=1C.C(O)(C)C.C(N(CC)CC)C>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([O:16][CH:27]([CH3:28])[CH3:26])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)OC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Temperature: 25 °C
Reaction time: 10 h
Yield: 43.9 %

Procedure:
1.0 g of 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetic acid, 1.0 g of 2-chloro-1-methylpyridinium iodide and 0.24 g of isopropanol are dissolved in 30 ml of tetrahydrofuran, and 0.8 g of triethylamine is added dropwise thereto. The mixture is stirred at room temperature for 10 hours. Water is added to the mixture, and the aqueous mixture is evaporated under reduced pressure to remove tetrahydrofuran. The residue is extracted with ethyl acetate, and the extract is washed with an aqueous 20% citric acid solution, an aqueous sodium bicarbonate solution and water, successively. Then, the extract is dried and then evaporated under reduced pressure to remove solvent. The residue is recrystallized from ethanol, whereby 0.5 g of isopropyl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate is obtained. Yield: 43.6%
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]1[O:7][N:6]=[C:5]([C:8](OCC)=[O:9])[CH2:4]1.[BH4-].[Na+].[NH4+].[Cl-]>CCO>[F:14][C:2]([F:1])([F:13])[CH:3]1[O:7][N:6]=[C:5]([CH2:8][OH:9])[CH2:4]1
Reactant: CCOC(=O)C1=NOC(C(F)(F)F)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCC1=NOC(C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of ethyl 5-(trifluoromethyl)-4,5-dihydroisoxazole-3-carboxylate (1.0 g, 4.74 mmol) in EtOH (10 ml) was slowly added at 0° C. sodium borohydride (197 mg, 5.21 mmol) and the suspension was stirred at 0° C. for 4 h. The suspension was treated with half saturated aqueous NH4Cl, stirring was continued for 10 minutes, the mixture was extracted with diethylether, the organic layers were dried and evaporated (70 mbar/40° C.) to give crude (5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)methanol (803 mg) as a colorless oil which was used without further purification. MS: m/z=169 [M]+.