Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:45])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:44])[CH2:13][N:14]([C:16]([C@@H:18]2[CH2:22][C@@H:21]([S:23]CC3C=CC(OC)=CC=3)[CH2:20][N:19]2[S:33]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:35])=[O:34])=[O:17])[CH3:15])=[CH:7][CH:6]=1)C.[Li+].[OH-].COC1C=CC(CS[C@H]2CN(S(CCC3C=CC=CC=3)(=O)=O)[C@H](C(N(C)CC(NC3C=CC(C(O)=O)=CC=3)=O)=O)C2)=CC=1.C1(O)C=CC=CC=1>C(O)(C(F)(F)F)=O>[SH:23][C@H:21]1[CH2:20][N:19]([S:33]([CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:34])=[O:35])[C@H:18]([C:16]([N:14]([CH3:15])[CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:45])=[O:3])=[CH:6][CH:7]=2)=[O:44])=[O:17])[CH2:22]1
Reactant: CCOC(=O)c1ccc(NC(=O)CN(C)C(=O)[C@@H]2C[C@@H](SCc3ccc(OC)cc3)CN2S(=O)(=O)CCc2ccccc2)cc1
Agent: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)CC(=O)Nc3ccc(C(=O)O)cc3)N(S(=O)(=O)CCc3ccccc3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)Nc1ccc(C(=O)O)cc1)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)CCc1ccccc1
Yield: 37.1 %

Procedure:
157 mg (0.24 mmol) (2S,4R)-4-(2-{[4-(4-Methoxy-benzylsulfanyl)-1-(2-phenyl-ethanesulfonyl)-pyrrolidine-2-carbonyl]-methyl-amino}-acetylamino)-benzoic acid ethyl ester were treated with 0.1 M LiOH according to 5.2., the crude product (2S,4R)-4-(2-{[4-(4-Methoxy-benzylsulfanyl)-1-(2-phenyl-ethanesulfonyl)-pyrrolidine-2-carbonyl]-methyl-amino}-acetylamino)-benzoic acid was dissolved in 1 ml TFA and heated to 75° C. in the presence of 23 mg (0.24 mmol) phenol for 1.5 h. The solvent was evaporated, the oil dissolved in toluene and evaporated (twice), the residue was titurated from hexane to yield 45 mg (2S,4R)-4-[2-[[4-Mercapto-1-(2-phenyl-ethanesulfonyl)-pyrrolidine-2-carbonyl]-methyl-amino]-acetylamino]-benzoic acid as light yellow solid, MS: 506 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:26])[O:12][C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[CH:2]1.[H-].[Na+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][Br:38]>CN(C)C=O>[Br:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:26])[O:12][C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[CH:2]1
Reactant: BrCc1ccccc1CBr
Reactant: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)OC2=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(Cc4ccccc4CBr)c4ccccc34)C(=O)OC2=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 17.1 %

Procedure:
A suspension of 3-(indol-3-yl)-4-(1-methyl-indol-3-yl)-furan-2,5-dione (1.0 g, 3 mmol) and sodium hydride (154 mg, 3.5 mmol, 55-60% dispersion in oil) in dimethylformamide (20 mL) was stirred and cooled to 0° C., under a stream of nitrogen. After 35 min the solution was transferred to a dropping funnel and added slowly, over 40 min, to a solution of 1,2-bis-bromomethyl-benzene (3.8 g, 14.5 mmol) in dimethylformamide (6 mL). The resulting solution was stirred for 1 h at room temperature under a stream of nitrogen. The reaction was quenched by adding NaHCO3 (aq), and extracted with ethyl acetate. The organic phase was washed with several portions of water and dried (MgSO4). Evaporation followed by chromatography on silica (ethyl acetate:heptane, 3:7) afforded 270 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([N:7]1[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1)(=[O:22])=[O:21]
Reactant: Cc1ccc2c(c1)NCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)N(S(C)(=O)=O)CCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
6-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine (1.49 g, 10 mmol) was dissolved in dichloromethane (50 mL) and treated with triethylamine (1.14 g, 11 mmol) followed by the dropwise addition of methanesulfonyl chloride (1.26 g, 11 mmol). The mixture was stirred at ambient temperature for 18 h then evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The phases were separated and the organic phase washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure to give the title compound (2.09 g, 93%) as a brown solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:36])[C:18]2=[CH:19][C:20]3[N:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:22]4[C:27]([C:28]=3[CH:29]=[C:17]2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:19]=[C:18]3[C:10]([CH3:36])([CH3:9])[C:11]4[C:16]([C:17]3=[CH:29][C:28]2=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccccc4)c3cc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4ccccc4)c3cc21
Reaction time: 6 h

Procedure:
9.51 g (54 mmol) of N-bromosuccinimide are added over the course of 15 min to a solution of 19.3 g (54 mmol) of 12,12-dimethyl-10-phenyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene in 80 ml of chloroform at RT under a protective-gas atmosphere and with exclusion of light. The mixture is stirred for 6 h, 80 ml of sat. Na2CO3 soln. are subsequently added, and the organic phase is separated off and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue is recrystallised, giving the product as a colourless solid in a yield of 20 g (45 mmol), 85%.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc2[nH]cnc2cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Br)ncn2C1CCCCO1
Yield: 74.1 %

Procedure:
A mixture of 5-bromo-6-methyl-1H-benzo[d]imidazole (2.0 g, 9.6 mmol), p-TsOH (17 mg, 0.1 mmol), and dihydropyran (8.1 g, 96 mmol) in THF (30 mL) was heated to reflux overnight. The solvent was concentrated in vacuo and EtOAc (50 mL) and water (50 mL) were added to the residue. The pH was adjusted to about 8 with K2CO3. The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (2:1) to afford 5-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole as a yellow solid (2.1 g, 71%). MS (ESI): m/z=295.2 [M+1]+.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].C(O)(=O)C(O)=O.[CH2:30]([NH:34][NH2:35])[CH2:31][CH2:32][CH3:33]>>[CH2:30]([N:34]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:35]1)[CH2:31][CH2:32][CH3:33]
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: CCCCNN
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Product: CCCCn1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Yield: 38.9 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and butylhydrazine oxalate (0.178 g, 1.0 mmol) to give 0.058 g of product as a pink solid
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][NH:11][CH3:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10][NH:11][CH3:12])=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CNCCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Product: CNCCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.63 [M+H]+ 326.00. 1H NMR (Me-d3-OD) δ 2.37-2.47 (2H, m), 2.66 (3H, s), 2.91 (2H, t), 4.05 (1H, t), 7.25-7.34 (6H, m), 7.54 (2H, d), 7.92 (2H, s), 8.51 (1H, br s—due to formic acid).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:8][C:7]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][OH:27])=[CH:6][N:5]=1)(O)=[O:2].[NH2:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:36][N:32]1[CH2:33][CH2:34][O:35][CH:30]([CH2:29][NH:28][C:1]([C:4]2[C:9]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=3)=[N:8][C:7]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][OH:27])=[CH:6][N:5]=2)=[O:2])[CH2:31]1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)cnc2C(=O)O)cc1Cl
Reactant: CN1CCOC(CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)cnc2C(=O)NCC2CN(C)CCO2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of (S)-2-carboxy-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (80 mg) obtained in Example 22 (5), 2-aminomethyl-4-methylmorpholine (31.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (43 mg), 1-hydroxybenzotriazole (30.3 mg) in N,N-dimethylformamide (3 ml) is stirred at room temperature for 18 hours. To the reaction mixture is poured water, and the mixture is extracted with ethyl acetate. The extract is washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel flesh column chromatography (solvent; ethyl acetate) to give (S)-2-[N-(4-methyl-2-morpholinyl)methylcarbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (80.5 mg), MS (m/z): 505 (MH+), IR (Nujol): 3295, 1635 cm−1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH3:25])=[N:23][N:24]=2)[N:21]=1>>[CH3:25][C:22]1[N:20]2[N:21]=[C:16]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Cc1nnc2ccc(Cl)nn12
Product: Cc1onc(-c2ccccc2)c1COc1ccc2nnc(C)n2n1
Yield: 41 %

Procedure:
As described for example 86, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (100 mg, 0.53 mmol) was converted, using 6-chloro-3-methyl-1,2,4-triazolo[4,3-b]pyridazine instead of 6-chloro-1,2,4-triazolo[4,3-b]pyridazine, to the title compound (70 mg, 41%) which was obtained as a white solid. MS: m/e=322.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14]C)=[O:13])[C:7](=[O:22])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[Li+].[OH-].Cl>CO.C1COCC1>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])[C:7](=[O:22])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(C(=O)OC)c2ccccc2)C(=O)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN1CCN(C(C(=O)O)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of methyl (4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetate (2.5 g, 9.1 mmol) in 1:1 methanol/THF (40 ml) was added 1N LiOH (18.2 ml, 18.2 mmol). The reaction was warmed to rt and allowed to stir for 18 h. The reaction mixture was cooled to 0° C., adjusted to pH 2 with conc HCl, and concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to yield (4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetic acid (100%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:26])[NH:9][C@@H:10]([CH3:25])[CH2:11][C:12]1[C:20]2[CH:19]=[C:18]([OH:21])[CH:17]=[CH:16][C:15]=2[N:14]2[CH2:22][CH2:23][CH2:24][C:13]=12)([CH3:6])([CH3:5])[CH3:4].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br.O>CS(C)=O.C(OCC)(=O)C>[CH3:27][O:28][C:29](=[O:32])[CH2:30][O:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:22][CH2:23][CH2:24][C:13]3=[C:12]([CH2:11][C@@H:10]([NH:9][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:26])[CH3:25])[C:20]=2[CH:19]=1
Reactant: COC(=O)CBr
Reactant: C[C@@H](Cc1c2n(c3ccc(O)cc13)CCC2)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)COc1ccc2c(c1)c(C[C@H](C)NC(=O)OC(C)(C)C)c1n2CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
0.42 g sodium hydride 55-65% in oil was added to a solution of 3.3 g (S)-[2-(6-hydroxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester in 30 mL dimethylsulfoxide and the mixture stirred at room temperature for 30 min. 1.68 g bromoacetic acid methyl ester was added to the resulting solution and the mixture stirred at room temperature for 2 h. The mixture was distributed between water and ethyl acetate. The phases separated and the organic phase was washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The residue crystallised under hexane and was dried to constant weight to yield 3.61 g of (S)-[8-(2-tert-butoxycarbonylamino-propyl)-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-6-yloxy]-acetic acid methyl ester as off white crystals melting at 87-88° C.
Reaction SMILES: [CH:1]([N:3]1CCC[C:4]1=O)=C.[CH:9]([CH:11]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]1=[O:13])=C.CN(CCCC=C(C)C(N)=O)C.[C:31]([C:39](=[CH2:43])[C:40]([NH2:42])=[O:41])([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:32].OS(O)(=O)=O>C(O)C>[CH3:9][C:11]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:3]([CH3:4])[CH3:1])=[O:13])=[CH2:18].[C:31]([C:39](=[CH2:43])[C:40]([NH2:42])=[O:41])([CH2:34][C:35]([CH3:37])([CH3:38])[CH3:36])([CH3:32])[CH3:33]
Reactant: C=CN1CCCC1=O
Reactant: C=CC1CCCCNC1=O
Agent: C=C(C(N)=O)C(C)(C)CC(C)(C)C
Agent: CC(=CCCCN(C)C)C(N)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C=C(C)C(=O)NCCCN(C)C
Temperature: 68 °C

Procedure:
Vinyl pyrrolidone (VP) (55.6 g), vinyl caprolactam (VCL) (577.5 g), dimethylaminopropyl methacrylamide (DMAPMA) (42.6 g), tert-octyl acrylamide (18.3 g) and ethanol (848.2 g) were charged into a 2-liter water-jacketed resin flask. The reaction flask was equipped with a condenser, a thermometer, a septum (for catalyst addition), an anchor-type metal stirrer, and a nitrogen sparge tube. Nitrogen was bubbled the solution while the resin flask was heated to 68° C. using hot water circulating through the jacketed flask. After an additional half-hour of degassing at reflex, a first shot of Lupersol 11 (0.25 ml) was injected into the flask. Subsequently, Lupersol 11 additions were made at 10, 40, 70, 100 minutes after the first addition. The reaction temperature was increased to 74° C. and 2 shots of Lupersol 554 M75 (0.12 ml) was then added at 240 and 330 minutes. The contents were allowed to react for an additional 5 hours and cooled to 35°-40° C. After neutralization with 12.5 g of H2SO4 (conc) the product was discharged as a 45% solution in ethanol.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:10])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.C[CH2:12][O:13][CH2:14]C.C(Cl)OC>CCOCC.CN(C=O)C.O>[CH3:12][O:13][CH2:14][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:10]
Reactant: CCOCC
Reactant: Cc1ccccc1O
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil; 1.2 eq) in Et2O/DMF (5:1, 0.2M) a solution of o-cresol in Et2O (1 eq, 2M) was added dropwise over 15 min. A solution of MOMCl in Et2O (1.1 eq, 2M) was added and the mixture was stirred for 30 min then poured into H2O and extracted with Et2O. The combined organic extracts were washed with 1N NaOH, H2O and brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound. The product was used in the next step without further purification.
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[SH:39])[CH3:32]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:31][CH3:32])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:26][CH2:27]1)=[O:12])([CH3:7])([CH3:9])[CH3:8]
Reactant: CCc1ccccc1S
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CS(=O)(=O)[O-]
Product: CCc1ccccc1S[C@@H]1C[C@@H](C(=O)NC2(C#N)CC2)N(C(=O)OC(C)(C)C)C1

Procedure:
The reaction of the mesylate from experiment A2 with 2-ethylbenzenethiol yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2-ethyl-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless oil. MS: 414.4 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([C:16](O)=[O:17])[CH3:15].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[NH:13]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C@@H:14]([C:16]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:17])[CH3:15]
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CC#N
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1

Procedure:
To 7.4 g H-Gly-OBzl.p-Tos-OH, 100 ml acetonitrile was added, and this was followed by cooling with ice, then 3.1 ml TEA, 3.78 g Boc-D-Ala-OH, 3.96 g HONB and 4.54 g DCC were added, and this was followed by agitation for one night. The resulting DCU was filtered, and the filtrate was concentrated, then the resulting residue was dissolved in 300 ml AcOEt. The resulting solution was washed with 4% aqueous NaHCO3 and 10% aqueous citrate, after which it was dried with Na2SO4. The dried product, after concentration, was crystallized with petroleum benzine and collected by filtration.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:12]([NH2:17])[CH:13]=[N:14]2)=[CH:9][CH:8]=1>ClCCl>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:18][CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[C:12]([NH:17][C:3](=[O:4])[CH2:2][Cl:1])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cnc2cc(Br)ccc2c1NCC1CCOCC1
Solvent: ClCCl
Product: O=C(CCl)Nc1cnc2cc(Br)ccc2c1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
Chloroacetyl chloride (5.2 mL, 65 mmol) was added to 7-bromo-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (55 mmol) dissolved in 273 mL of dichloromethane at 0° C. A solid formed after adding half of the chloroacetyl chloride at which point additional dichloromethane (100 mL) was added. The reaction was stirred for 1 hour at ambient temperature. The yellow suspension was quenched first with aqueous saturated sodium bicarbonate followed by 50% aqueous sodium hydroxide until a pH of 14 was reached. Filtration provided 10 g of N-{7-bromo-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl}-2-chloroacetamide as a tan solid. The filtrate was placed in a separatory funnel and the layers were separated. The aqueous layer was extracted with additional dichloromethane. The combined organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford additional N-{7-bromo-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl}-2-chloroacetamide as a yellow oil. The yellow oil was carried forward without further purification assuming a 50% yield (27.3 mmol). The oil was combined with ethanol (100 mL) and triethylamine (7.5 mL, 54 mmol). The resulting yellow solution was refluxed for 2 hours. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure to provide 7-bromo-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as a brown oil that was used without further purification assuming quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:26]([C:28]1[CH:42]=[CH:41][C:31]([S:32][C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1)[CH3:27]>ClCCl>[CH2:26]([C:28]1[CH:42]=[CH:41][C:31]([S:32][C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:8]([C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH3:7])=[O:10])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1)[CH3:27]
Reactant: CCc1ccc(Sc2ccc(CN)cc2)cc1
Reactant: Cc1nc(C)c(C(=O)O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCc1ccc(Sc2ccc(CNC(=O)c3oc(C)nc3C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a stirred mixture of 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (155 mg, 1.1 mM) and dichloromethane (20 ml) was added 1,3-dicyclohexylcarbodiimide (227 mg, 1.1 mM) at 0°-10° C., and the mixture was stirred for 30 min at the same temperature. To this was added dropwise a solution (10 ml) of 4-(4-ethylthiophenoxy)benzylamine (285 mg, 1.1 mM) in dichloromethane, and the mixture was stirred for 12 h at room temperature. The mixture was poured into ice water, and the mixture was extracted with dichloromethane. The extract was washed with saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-[4-(4-ethylthiophenoxy)benzyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide (164 mg, 39%) as colorless crystals, m.p. 60.0°-64.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CC=C(c2cccnc2F)CC1
Agent: O=[Pt]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(c2cccnc2F)CC1
Yield: 97.4 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(2-fluoropyrid-3-yl)-1,2,3,6-tetrahydropyridine (2.04 g) in 50 mL of ethanol was treated with platinum oxide (0.22 g) and the mixture was hydrogenated (3.4 bar hydrogen pressure) for 16 hours. At the end of this period, the reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was evaporated to afford the named material as a white solid (2.0 g); MS: 315; NMR: 1.6 (br, 2), 1.8-1.9 (d, J=14, 2), 2.8-3.1 (m, 3), 4.3 (b, 2), 5.1 (s, 2), 7.1-7.2 (m, 1), 7.2-7.4 (m, 5), 7.6 (m, 1), 8.1 (m, 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[N:8][N:9]([CH3:13])[C:10]=1[CH2:11]O)=[O:5])[CH3:2].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:11][C:10]1[N:9]([CH3:13])[N:8]=[C:7]([CH3:14])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c(C)nn(C)c1CO
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nn(C)c1CCl

Procedure:
This material was combined with the product of a second reaction (5.0 g of 4-ethoxycarbonyl-5-(1-hydroxymethyl)-1,3-dimethylpyrazole and 1.93 ml thionyl chloride), dissolved in dichloromethane, washed with brine, dried (MgSO4) and concentrated to give 10.7 g of a solid, mp. 81°-83° C.