Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[CH:32]([O:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][C:44]([C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)=[O:45])([CH3:34])[CH3:33].Cl>C1COCC1.CO>[CH:32]([O:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][C@@H:44]([C:46]1[CH:47]=[CH:48][N:49]=[CH:50][CH:51]=1)[OH:45])([CH3:34])[CH3:33]
Reactant: Cc1cccc(CC(=O)c2ccncc2)c1OC(C)C
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: Cl
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C[C@H](O)c2ccncc2)c1OC(C)C
Reaction time: 15 h

Procedure:
Under nitrogen, at −30° C. slowly add BF3.□Et2O (1.7 g, 12 mmol) to a solution of (−)-B-chlorodiisopinocampheylborane (6.1 g, 19 mmol) in THF (40 mL). Cool the solution to −40° and add 2-(2-isopropoxy-3-methylphenyl)-1-(4-pyridinyl)ethanone (3.2 g, 12 mmol). Allow the solution to slowly come to room temperature and stir for 15 hr. Add MeOH and 3M aqueous HCl to the reaction mixture and stir for an additional 45 min. Evaporate the solvent and dissolve the residue in 3M aqueous HCl and wash with heptane. Neutralize the aqueous fraction with 50% aqueous NaOH to pH 12 and extract with EtOAc. Wash the organic phase was with brine and dry over MgSO4. Evaporate the solvent to afford a yellow oil. Purify the oil by chromatography over SiO2 using EtOAc:heptane (1:1). Evaporate the product-containing fraction to give (S)-2-(2-isopropoxy-3-methylphenyl)-1-(4-pyridinyl)ethanol as an oil, 1.16 g (36%); 1H-NMR (CDCl3) δ 8.5-6.8 (m, 7H), 4.9 (m, 1H), 4.3 (m, 1H), 3.1-2.9 (m, 2H), 2.3 (s, 3H), 1.3 (d, 6H).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:25]=3)[C:20]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[C:19]2[CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([O:51]C)=[O:50])(=O)=O)C=CC=CC=1>>[CH2:1]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH:25]=2)[C:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[C:19]1[CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([OH:51])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Reactant: ClCc1ccccc1
Product: CC(C)(Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared under the conditions described in Step A and Step B of Example 38, but substituting benzyl chloride for the benzenesulfonyl chloride from Example 38 (Step A).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-]>ClCCl.N1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH:23]([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: Cc1ccccc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCC(C)OC(=O)c1ccc(OC(C)=O)cc1
Yield: 87 %

Procedure:
Thionyl chloride (25 ml) was added to 10 mmols of p-acetoxybenzoic acid, and the mixture was refluxed for 5 hours. Excess thionyl chloride was then completely removed. Thirty milliliters of toluene were added to the obtained chloride, and 7.1 mmols of R-(-)-2-hexanol and 3 ml of pyridine were added dropwise, followed by conducting the reaction overnight at room temperature. After the reaction, 50 ml of dichloromethane was added, and the organic layer was washed with a hydrochloric acid aqueous solution, a sodium hydroxide aqueous solution and water in this sequence. Subsequently, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed. The obtained composition was purified by silica gel column chromatography to obtain 1-methylpentyl p-acetoxybenzoate in a yield of 87%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[OH:23])[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:39][C:40]([NH2:42])=[O:41]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])[CH2:39][C:40]([NH2:42])=[O:41])=[C:4]([CH:22]([OH:23])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:3]=1
Reactant: COc1cccc(C(O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC)c(OC)c2)c1
Reactant: NC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cc(Cl)ccc2N(CC(N)=O)S(=O)(=O)c2ccc(OC)c(OC)c2)c1
Reaction time: 48 h
Yield: 50.9 %

Procedure:
To 0.7 g of N-{4-chloro-2-[(3-methoxyphenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzenesulfonamide dissolved in 5 ml of THF are added, at room temperature, 0.2 g of potassium tert-butoxide and 0.25 g of 2-bromoacetamide. After 48 hours at 20° C., the reaction medium is concentrated, taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 0.4 g of the expected product.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:33])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:34](N(CC)CC)[CH3:35].ICC>CN(C)C=O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:29][CH2:28]4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:33])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C4CCNCC4)[nH]c3-c3ccccc3)cc21
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCC(c2nc(-c3ccc4nc(N)n(S(=O)(=O)C(C)C)c4c3)c(-c3ccccc3)[nH]2)CC1
Yield: 76 %

Procedure:
Stir a mixture of 1-isopropylsulfonyl-2-amino-6-(2-(piperidin-4-yl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (0.574 g, 1.23 mmol), triethylamine (3.1 mmol), and iodoethane (1.54 mmol) in anhydrous dimethylformamide (5 mL) at room temperature for 6 hours. Partition the mixture between ethyl acetate and water. Extract the aqueous layer with ethyl acetate (3 times). Wash the combined organic layers sequentially with cold water (5 times) and saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography to provide the title compound in 76% yield. MS(ES+): m/z=493.2 (M+H)+
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:17][CH2:18][CH2:19][N:20]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]2[O:33][CH2:34][O:35][C:31]=2[CH:30]=1)C(OC(C)(C)C)=O)[C:7]1[S:11][N:10]=[C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:8]=1)C.[NH3:39]>CO.CCOC(C)=O>[O:33]1[C:32]2[CH:36]=[CH:37][C:29]([CH2:28][NH:20][CH2:19][CH2:18][CH2:17][N:6]([C:7]3[S:11][N:10]=[C:9]([N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)[N:8]=3)[CH2:5][C:4]([NH2:39])=[O:3])=[CH:30][C:31]=2[O:35][CH2:34]1
Reactant: CCOC(=O)CN(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Reactant: N
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of [[3-(benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid ethyl ester from Step 1 (115 mg, 211 μmol) and a 2.0 M solution NH3 in MeOH (10 mL) was stirred at r.t. for 24 h. The reaction mixture was concentrated to a yellow oil. The crude residue was dissolved in TFA/DCM (1:1, 3 mL) and stirred at room temperature for 30 min. The solvent was evaporated to afford an orange oil. The crude product was diluted with EtOAc (50 mL), washed with 1M NaOH (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to an oil. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 53 mg (60%) of 2-[{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetamide as a white solid. [M+H]+ 415.97; 1H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.72 (s, 1H), 7.63 (br s, 1H), 7.28 (br s, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 6.82 (m, 2H), 5.98 (s, 2H), 4.20 (br s, 1H), 3.60 (s, 2H), 3.33 (s, 2H), 2.54 (m, 4H), 1.80 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](=[O:16])[CH2:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1>C(O)C.[Pd]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C@H:10]([N:12]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13](=[O:16])[CH2:14][CH3:15])[CH2:11][C@@H:2]2[CH3:1])=[O:33])=[CH:29][CH:28]=1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21

Procedure:
(±)-Cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide was prepared from (±)-cis-N-[2-methylmethyl-1-(4-nitro-benzoyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. (±)-Cis-N-[2-methyl-1-(4-nitro-benzoyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (200 mg, 0.45 mmol) was dissolved in ethanol (20 mL). Palladium on carbon (10%) was carefully added and the resulting suspension was shaken under hydrogen gas (40 psi) over night. The suspension was filtered through Celite® to remove solids, and the filter cake washed three times with ethanol. Concentration of the solution afforded pure product (160 mg, 86%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([CH2:12][C:13]#[N:14])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:22][C:23]#[N:24].O>O1CCCC1>[NH2:24][C:23]1[N:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C:12]([C:13]#[N:14])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1
Reactant: N#CC=C(Br)c1ccccc1
Reactant: N#CCc1n[nH]c(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(-c2ccccc2)cc(N)n2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.2 %

Procedure:
A solution of 0.18 g (0.001 mol) 5-phenyl-1H-1,2,4-triazole-3-acetonitrile in 7 ml tetrahydrofuran was treated at −70° C. with 1.56 ml (0.0025 mol) butyllithium (1.6 M in hexane). After one hour 0.21 g (0.001 mol) 3-bromo-3-phenyl-2-propenenitrile was added, stirring was continued for one hour, the mixture warmed to room temperature over night and water was added. Extraction with diethylether, chromatography on silicagel with dichloromethane/methanol 99/1 and crystallisation from diethylether gave 3.6 mg 5-amino-2,7-diphenyl-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitril as white cystals. MS m/e (%): 312 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][C:12]2([CH2:18][CH2:19][CH3:20])[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:24])C>>[CH3:8][C:7]1[C:2]([CH2:1][OH:24])=[N:3][CH:4]=[CH:5][C:6]=1[O:9][CH2:10][CH2:11][C:12]1([CH2:18][CH2:19][CH3:20])[O:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: CCCC1(CCOc2cc[n+]([O-])c(C)c2C)OCCCO1
Reactant: CC(=O)OC(C)=O
Product: CCCC1(CCOc2ccnc(CO)c2C)OCCCO1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
The 2,3-dimethyl-4-(2-(2-propyl-1,3-dioxan-2-yl)ethoxy)pyridine 1-oxide (3.9 g, 13.2 mmol) obtained in the step (8c) was mixed with acetic anhydride (16 ml). The mixture was stirred at 90° C. for 2 hours. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, methanol (20 ml) and a 5N aqueous sodium hydroxide solution (10 ml) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was separated by use of a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound (1.69 g, yield: 43.3%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]([NH:12][NH:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[C:19](=[O:27])[C:18]1=[O:28])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][C:9]([C:10]1[O:11][C:14]([CH2:15][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[C:19](=[O:27])[C:18]2=[O:28])=[N:13][N:12]=1)([CH3:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN1CCN(C(=O)CNNC(=O)[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)C1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCCCN1CCN(Cc2nnc(C(C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)C(=O)C1=O

Procedure:
A solution of 1-((2-((R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanoyl)hydrazino)acetyl)-4-butylpiperazine-2,3-dione from Step A (80 mg, 0.16 mmol) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (152 mg, 0.64 mmol) in 1.6 mL dichloroethane was heated in the microwave at 120° C. for 8 min. Concentration and flash chromatography (silica gel, 80-100% EtOAc/hexanes) gave 1-((5-(2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-4-butylpiperazine-2,3-dione. 1H NMR (CDCl3) δ 7.30 (m, 3H), 7.05 (m, 2H), 4.92 (m, 3H), 3.61 (m, 2H), 3.55 (m, 2H), 3.48 (m, 3H), 3.30 (d, 1H, J=13.6 Hz), 1.60 (s, 3H), 1.57 (m, 2H), 1.40 (s, 9H), 1.35 (m, 2H), 0.94 (t, 3H, J=7.3 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[F:14])(=[O:3])[CH3:2]>[Pd].CO>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([F:14])[CH:7]=1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(N)cc1F

Procedure:
198 g (1 mol) of 1-acetylamino-2-fluoro-4-nitrobenzene are transferred into a stainless steel autoclave together with 510 ml of methanol, about 3 g of palladium-on-charcoal (5%) are added and catalytic reduction is carried out in the course of 4 hours at 50° C. under a hydrogen pressure of 15 bar. After the catalyst has been removed, 450 ml of methanol are distilled off from the reaction solution in vacuo, the product which has precipitated is filtered off with suction and the residue is washed with a little methanol and dried at 50°-60° C. in a vacuum cabinet.
Reaction SMILES: CN(C1C=CC=CN=1)C.[O:10]=[N:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14].S(Cl)(C)(=O)=O.Cl.[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29]>O1CCCC1.ClCCl.C(N(CC)CC)C>[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:29][C:16](=[O:18])[C@H:12]([CH:13]([CH3:15])[CH3:14])[N:11]=[O:10]
Reactant: CC(C)[C@H](N=O)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N=O)C(C)C
Temperature: -20 °C

Procedure:
15.1 g of dimethylaminopyridine were added to a solution of 13.0 g of the ketovaline obtained in step a) in 100 ml of tetrahydrofuran. While stirring, 22.7 g of triethylamine were added dropwise, and the reaction mixture was cooled to -20° C. Subsequently a solution of 14.1 g of mesyl chloride in 50 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for a further 20 minutes. Then a solution of 20.4 g of leucine methyl ester hydrochloride in 150 ml of dichloromethane was added dropwise, and the mixture was again stirred for 20 minutes. The mixture was then allowed to warm slowly to room temperature, undissolved constituents were separated by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was taken up in distilled water and extracted with dichloromethane. The collected organic phases were then dried over sodium sulfate and, after filtration, the solvent was removed under reduced pressure. 14.7 g of the title compound remained as a yellow oil.
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13]S([O-])(=O)=O.[Na+].[CH:19]([Cl:22])([Cl:21])[Cl:20].C(O)CC(C)C>C(O)C(N)(CO)CO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>[C:12]1([OH:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:12]1([OH:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[CH:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Solvent: CC(C)CCO
Solvent: ClC(Cl)Cl
Product: Oc1ccccc1

Procedure:
catarrhalis cell pellet was resuspended in 20 mL Tris-EDTA (TE) buffer, pH 7.5. Pronase (final concentration 500 μg/mL) and SDS (final concentration 1%) were added and the suspension was incubated in a 37° C. water bath for 2 hours. DNA was isolated by sequential extractions with phenol (1 time), phenol-chloroform (1:1, 2 times), and chloroform-isoamyl alcohol (24:1, 1 time). Extracted DNA was dialyzed against 1M NaCl at 4° C. for 4 hours. This was followed by dialysis against TE buffer, pH 7.5, at 4° C. for 48 hours (3 buffer changes). DNA was ethanol precipitated from the dialysate. Large size DNA was collected by spooling on a glass rod. Air dried DNA was dissolved in 3 mL water. Small scale Sau3A (New England BioLabs) restriction digests of chromosomal DNA (final volume 10 μl) were done to establish conditions required to obtain maximal amounts of chromosomal DNA with a size range of 15-23 kb. Large scale digests were prepared once the optimal digestion conditions were defined. The large scale digests consisted of 50 μl chromosomal DNA (290 μg/mL), 33 μL water, 10 μL Sau3A buffer (New England BioLabs), 1 μL BSA (10 mg/ml, New England BioLabs) and 6.3 μL Sau3A (0.04 U/μL), and were incubated at 37° C. for 15 minutes. Reactions were stopped with the addition of 10 μL 10X loading buffer (100 mM Tris-HCl pH 8, 10 mM EDTA, 0.1% bromophenol blue, 50% glycerol). Digested DNA was applied to 0.5% agarose gels (prepared in Tris-acetate-EDTA (TAE)) and separated according to size at 50 V for 6 hours. The region of the gel encompassing DNA of size 15-23 kb was cut from the gel and placed in dialysis tubing (BRL) with 3 mL TAE. DNA was electroeluted from the gel slice overnight at a field strength of 1 V/cm. Electroeluted DNA in TAE was extracted once with phenol, once with phenol-chloroform (1:1), and finally precipitated with ethanol. The dried DNA pellet was dissolved in 5 μL water. Size-fractionated chromosomal DNA was ligated with BamHI cut EMBL3 arms (Promega) using T4 DNA ligase in a final volume of 9 μL. The entire ligation reaction was packaged into phage λ using a commercially purchased packaging kit following the manufacturer's (Amersham) protocol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]=[C:9]([C@H:11]([NH:19][C:20](=[O:41])[C@H:21]([NH:33]C(OC(C)(C)C)=O)[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[ClH:42]>C(OCC)(=O)C>[ClH:42].[CH2:1]([O:3][C:4]([C:6]1[N:10]=[C:9]([C@H:11]([NH:19][C:20](=[O:41])[C@H:21]([NH2:33])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1noc([C@@H](Cc2ccccc2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reaction time: 18 h

Procedure:
5-[(1R)-1-{(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionylamino}-2-phenylethyl]-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.41 g, 0.7 mmol) was suspended in a saturated mixture of hydrogen chloride in ethyl acetate (10 ml). After 18 h at 20° C., the reaction mixture was filtered to give 0.39 g of 5-[(1R)-1-{(2R)-2-amino-3-(2-naphthyl)propionylamino}-2-phenylethyl]-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:24])[C:11]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=2)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:6]([Cl:25])[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid methyl ester (62 mg) in THF (1.5 mL) and MeOH (0.3 ml) was treated with 1M aqueous LiOH (0.228 ml) and stirred for 2 h at 65° C. (bath-temperature). The organic solvents were evaporated in vacuo and the residue was diluted with water (2 ml) and acidified with 1M-HCl (0.3 ml). The precipitate was filtered and dried under high vacuum, leading to the title compound as a white solid (54 mg). MS (m/e, ISP neg. ion)=392.2 (M−H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: NN1CCOCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)NN2CCOCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), N-aminomorpholine (29 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (38 mg, 67% of theory).