Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24]O)(C1C=CC(C)=CC=1)(=O)=O.S(Cl)(Cl)=O.[Na].[Cl-].[NH4+]>N1C=CC=CC=1.ClCCl.CO>[CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]=[C:12]1[NH:11][CH2:15][CH2:14][NH:13]1)=[CH2:24]
Reactant: Cc1ccc(S(=O)(=O)N2CCNC2=Nc2ccccc2CCO)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: C=Cc1ccccc1N=C1NCCN1

Procedure:
N'-Tosyl-2-[2-(2-hydroxyethyl)phenylimino]imidazolidine from Example 17, Step B (1.8 g) is dissolved in pyridine (25 ml) containing thionyl chloride (3 ml). The mixture is heated at reflux until thin layer chromatography shows starting material to be gone [silica gel=dichloromethane:methanol (19:1)], about three hours. The volatiles are evaporated in vacuo and the residue is partitioned between water and ether. The aqueous layer is extracted (3×50 ml) with ether and the combined extracts are washed with brine, dried over sodium sulfate and evaporated to off white crystals which can be purified by recrystallization from ethyl acetate (1.23 g, 72%). Ammonia (50 ml) is condensed in a cooled flask fitted with a dry ice condenser. The N-tosyl derivative (0.5 g) is added and when solution occurs, small pieces of freshly cut metallic sodium are added one at a time until a blue color persists. Solid ammonium chloride is added to remove the blue color and the ammonia is evaporated in a stream of nitrogen. The solid residue is partitioned between water and ether. The aqueous layer is basified to pH 14 and reextracted with dichloromethane (2×50 ml). The organic extracts are pooled, extracted with 2 N acetic acid (3×50 ml) and these extracts are combined, back-extracted with dichloromethane, and neutralized with dilute hydrochloric acid.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C:36]2=[O:47])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C:36]2=[O:47])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(CC3CCCCO3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(CC3CCCCO3)C2=O)sc1C(=O)O
Yield: 84 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-((tetrahydro-2H-pyran-2-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 84% yield: 1H NMR (300 MHZ, DMSO-4) δ 3.96-3.91 (m, 2H), 3.85-3.78 (m, 1H), 3.65-3.54 (m, 2H), 3.46-3.34 (m, 1H), 3.32-3.24 (m, 1H), 3.17-3.09 (m, 2H), 2.47 (s, 3H), 1.86-1.70 (m, 1H), 1.49-1.37 (m, 4H), 1.18-1.04 (m, 1H); MS (ES+) m/z 326.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH2:9][CH3:10])[CH:3]=1.C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([B:16]([OH:19])[OH:17])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1I
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 4-bromo-2-ethyl-1-iodobenzene (80 g, 0.25 mol) in tetrahydrofuran (800 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 188 ml, 0.3 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (153.7 g, 1.48 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, then dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylphenylboronic acid (26 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(Cl)CCl>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 56.2 %

Procedure:
19.8 gm (0.062 mol) of 4-hydroxy-2-methyl-2H-naphtho [2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 9.3 gm (0.093 mol) of 2-amino-thiazole in 500 ml of xylene analogous to Example 1 and yielded 13.5 gm (56% of theory) of 4-hydroxy-2-methyl-N-(2thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 248°-249° C (decomp.; from ethylene chloride).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:13])[NH:35][C:34]2[CH:36]=[CH:37][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Compound 7a (4.91 g; 17.1 mmol) is suspended in acetonitrile (25 ml) and N,N-diisopropyl ethyl amin (3.58 ml; 20.5 mmol) is added at 0° C. Bis(2-oxo-3-oxazolidinyl) phosphinic chloride BOP-Cl (5.22 g; 20.5 mmol) is added as a solid and after stirring for 30 min at 0° C. 4-chloroaniline (2.18 g; 17.1 mmol) is added to the reaction mixture. The mixture is stirred for 2 h at 0° C., evaporated to dryness and dissolved in ethyl acetate (ml). The organic phase is washed with 0.1 N HCl (2×ml), with saturated aquous Na2CO3 solution, water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. The crude product is purified by silica gel chromatography. Yield: 4.7 g (69.3%), ESI-MS: m/z=395 [M−H]−, Cl-pattern
Reaction SMILES: C([O:3][C:4](=[O:47])[C:5]([CH:8]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][C:40]([Cl:46])=[CH:41][CH:42]=3)[N:37]=2)=[CH:30][CH:29]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][C:21]([Cl:27])=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)=[N:6][OH:7])C.[OH-].[Na+]>C1COCC1.CCO.O>[Cl:46][C:40]1[CH:39]=[C:38]2[C:43]([CH:44]=[CH:45][C:36]([CH2:35][O:34][C:31]3[CH:30]=[CH:29][C:28]([CH:8]([C:5](=[N:6][OH:7])[C:4]([OH:47])=[O:3])[C:9]4[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]5[CH:26]=[CH:25][C:24]6[C:19](=[CH:20][C:21]([Cl:27])=[CH:22][CH:23]=6)[N:18]=5)=[CH:13][CH:14]=4)=[CH:33][CH:32]=3)=[N:37]2)=[CH:42][CH:41]=1
Reactant: CCOC(=O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
To a solution in THF/EtOH/H2O (3:2:1, 35 mL) of bis(4-(7-chloro-2-quinolylmethoxy)phenyl)methyloximinoacetic acid ethyl ester (0.66 g, 1 mmol), prepared as in step 2, was added aqueous 1N NaOH (5 mL. The mixture was stirred at room temperature for 18 hours, concentrated in vacuo, diluted with water, and neutralized with 6N HCl. The precipitated solid was collected by filtration and slurried in Et2O/hexane (1:1, 50 mL), filtered, and dried in vacuo to provide bis(4-(7-chloro-2-quinolylmethoxy)phenyl)methyloximinoacetic acid (435 mg): mp 201°-202° C.; 1H NMR (300 MHz, DMSO-d6)δ4.55 (s, 2H), 5.39 (s, 2H), 5.44 (s, 2H), 7.08 (d, 2H, J=9 Hz), 7.15 (d, 2H, J=9 Hz), 7.31 (d, 2H, J=9 Hz), 7.41 (d, 2H, J=9 Hz), 7.68 (m, 3H), 7.72 (d, 1H, J=9 Hz), 8.80 (m, 4H), 8.49 (t, 2H, J=9 Hz); MS (DCI/NH3) m/e 638 (M+H)+. Anal. Calcd. for C35H25 Cl2N3O5 ×H2O: C, 64.12; H, 4.12; N, 6.41. Found C, 64.44; H, 3.96; N, 6.30.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[S:18][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(O)=[O:2].[C:23](N1C=CN=C1)([N:25]1C=CN=[CH:26]1)=O.CNC.C(NC(CC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1)=O)C.CNC(CCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1)=O.CN(C)C(CCCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1)=O>O1CCCC1>[CH3:23][N:25]([CH3:26])[C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[S:18][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(CC(=O)O)cc2)s1
Agent: CCNC(=O)Cc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: CN(C)C(=O)CCCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 8 h

Procedure:
5-(4-carboxymethylphenylsulfonyl)thiophene-2-sulfonamide (1.6 g) was dissolved in 50 ml of tetrahydrofuran and 0.72 g of carbonyldiimidazole was added. After stirring for one hour at room temperature excess aqueous dimethylamine was added and the mixture stirred overnight. The reaction mixture was concentrated under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum, giving an oil weighing 1.35 g, N.M.R. (acetone, d6) δ: 2.92 (3H, s), 3.08 (3H, s), 3.84 (2H, s), 7.02 (2H, s), 7.50 (3H, m), 7.65 (1H, d), 7.90 (2H, d). The following compounds were also made by similar procedures: 5-(4-ethylcarbamoylmethylphenylsulfonyl)thiophene-2-sulfonamide, 5-[4-(2-methylcarbamoylethyl)phenylsulfonyl]thiophene-2-sulfonamide, and 5-[4-(3-dimethylcarbamoylpropyl)phenylsulfonyl]thiophene-2-sulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][C:13](C)(C)[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.O1CCOCC1>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1cccc(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(C#N)c1

Procedure:
Combined tert-butyl 2-(3-cyanophenyl)acetate (500 mg, 2.301 mmol), ethanol (10 mL) and 4 N HCl in dioxane (0.288 mL, 1.151 mmol) and the solution heated at 60° C. for 22 h. The solution was concentrated in vacuo to give the title compound a yellow oil which was used without further purification. MS m/z 190 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ ppm 1.23-1.31 (m, 3H) 3.65 (s, 2H) 4.17 (q, J=7.1 Hz, 2H) 7.40-7.47 (m, 1H) 7.51-7.56 (m, 1H) 7.56-7.62 (m, 2H).
Reaction SMILES: [F-].[K+].[C:3]([O:7][CH3:8])(=[O:6])[CH:4]=[CH2:5].[F:9][C:10]([F:16])([F:15])[CH2:11][N+:12]([O-:14])=[O:13]>C(#N)C>[F:9][C:10]([F:16])([F:15])[C:11]([N+:12]([O-:14])=[O:13])([CH2:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH2:5][CH2:4][C:3]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])CC(F)(F)F
Reactant: C=CC(=O)OC
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCC(CCC(=O)OC)([N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 g (0.465 mol) of potassium fluoride (calcined) and 86 g (1 mol) of methyl acrylate are initially charged to 50 ml of acetonitrile at 0°-5° C. and 60 g (0.465 mol) of 2,2,2-trifluoronitroethane are added dropwise with stirring over a period of 60 min. The reaction is notably exothermic (up to about 60° C.). After being cooled to room temperature the reaction mixture is further stirred for 16 h. The mixture is filtered, the salt is washed with acetonitrile, and the solvent and unreacted starting material are stripped off on a rotary evaporator.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:9].CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:9]1[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: COC1CCC(OC)O1
Reactant: NC(c1ccccc1)c1ccccc1F
Solvent: CC(=O)O
Product: Fc1ccccc1C(c1ccccc1)n1cccc1
Yield: 69.3 %

Procedure:
To 100 ml of cooled (0° C.) acetic acid was added α-(2-fluorophenyl)benzenemethanamine (13.09 g). This mixture was then brought to room temperature and 2,5-dimethoxytetrahydrofuran (8.60 g) was added dropwise. The mixture was heated at reflux for 1.5 hours, after which time TLC (thin layer chromatography) showed absence of amine. The mixture was cooled and most of the acetic acid was removed by evaporation. The mixture was dissolved in ether and washed (3×H2O; 1×sat. NaHCO3), dried (sat. NaCl and anhydrous MgSO4), filtered and concentrated to yield a brown solid. Distillation (117° C.@0.15 mmHg) gave a slightly yellow solid (11.33 g). A sample was recrystallized from acetonitrile to give a white crystal, mp 81°-82.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[S:15]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](Cl)=O)=[CH:16]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:22]1/[CH:21]=[CH:20]/[C:17]1[CH:18]=[CH:19][S:15][CH:16]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccsc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccsc1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-(3-thienyl)acryloyl chloride (New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlemmer, R. F.; VanderMaelen, C. P.; Cipollina, J. A. J. Med. Chem, 1989, 32, 1147) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 303.39; mp: 135.5-136.0° C.; 1H-NMR (CDCl3) δ: 8.77 (1H, ddd, J=5.1, 1.8, 0.7 Hz), 8.03-7.95 (2H, m), 7.84-7.80 (1H, m), 7.54-7.43 (4H, m), 7.38-7.24 (4H, m), 6.97 (1H, d, J=15.7 Hz).
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[N:39]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44][C@H:40]1[C:41](O)=[O:42].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:41]([C@@H:40]2[CH2:44][CH2:45][CH2:46][N:39]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:42])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Yield: 67.6 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (471 mg, 1.0 mmol), DIEA (Aldrich) (0.20 mL, 1.0 mmol), Boc-ProOH (Fisher Scientific) (323 mg, 1.5 mmol), HOAT (Aldrich) (232 mg, 1.70 mmol) and EDC (Aldrich) (544 mg, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (428 mg). MS (ESI, pos. ion) m/z: 633 (M+1); (ESI, neg. ion) m/z: 631 (M−1). Calc'd for C31H41ClN4O6S: 633.20.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>C(#N)C>[C:7]([C:6]1[CH:9]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:11]=[CH:12][C:5]=1[O:4][CH:2]([CH3:1])[CH3:3])#[N:8]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Reactant: CCOC(=O)CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 32) (100 mg, 0.204 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.07 ml, 0.408 mmol) and ethyl 5-bromopentanoate (0.06 mL, 0.408 mmol). The reaction mixture was heated to 80° C. overnight then was allowed to cool and the solvent evaporated. Purification of the residue by flash chromatography, eluting with (40-100% ethyl acetate in cyclohexane) gave the title compound as an off white solid (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(NS(=O)(=O)c2ccc(Cl)cc2)C(C)C)cc1
Yield: 38.8 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methylbutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (665 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.9 ml) and 1-methyl-2-chloropyridinium iodide (1.05 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-methylbutanamide (542 mg).
Reaction SMILES: [C:1]12([C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]=3F)=[N:12][OH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N#N.[H-].[Na+].O>CN(C=O)C>[C:1]12([C:11]3[C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:16][C:15]=4[O:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: ON=C(c1ccc(OCc2ccccc2)cc1F)C12CC3CC(CC(C3)C1)C2
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc3c(C45CC6CC(CC(C6)C4)C5)noc3c2)cc1
Temperature: 25 °C
Yield: 94550.1 %

Procedure:
1-adamantyl-(4-benzyloxy-2-fluorophenyl)methanone oxime (2.3 mg, 6 mM) in DMF (30 ml) was added at 0° C. dropwise under N2, to a stirred suspension of NaH (0.61 g, 18 mM, 60% oil dispersion) in DMF (10 ml). After the complete addition, the reaction mixture was allowed to warm to room temperature and poured into H2O. The precipitate was collected by filtration to give the expected product (2.06 g, 95%). mp 132° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[C:24]1[S:25][C:26]([NH2:29])=[CH:27][N:28]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[C:24]1[S:25][C:26]([NH:29][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][N:28]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COCCN(C)c1ncc(N)s1
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)s1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-thiazol-5-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-thiazole-2,5-diamine. LCMS calcd for C18H17F3N4O3S (m/e) 426, obsd 427 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24](F)[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.CN1C=CC(NC(C2C=C(OC3C=CC(C#N)=C([Cl:62])C=3)C3CC(C)(C)OC=3C=2)=O)=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24]([Cl:62])[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)c(Cl)c3)c3c(c2)OC(C)(C)C3)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(Cl)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(3-chloro-4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (189b) and used without further purification for the next step.
Reaction SMILES: [CH2:1]([C@:8]1([CH3:22])[C:13]([O:14][CH2:15][CH3:16])=[N:12][C@@H:11]([CH:17]([CH3:19])[CH3:18])[C:10]([O:20]C)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.C[Si](I)(C)C.C(NCC)C>ClCCl.C(O)C>[CH2:1]([C@:8]1([CH3:22])[C:13]([O:14][CH2:15][CH3:16])=[N:12][C@@H:11]([CH:17]([CH3:18])[CH3:19])[C:10](=[O:20])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1=N[C@@H](C(C)C)C(OC)=N[C@]1(C)Cc1ccccc1
Agent: C[Si](C)(C)I
Agent: II
Solvent: ClCCl
Solvent: CCO
Solvent: CCNCC
Product: CCOC1=N[C@@H](C(C)C)C(=O)N[C@]1(C)Cc1ccccc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
0.3 g of (2R,5S)-2-benzyl-2,5-dihydro-3-ethoxy-5-isopropyl-6-methoxy-2-methylpyrazine was dissolved in 15 ml of absolute dichloromethane and cooled under argon to -10° C. Then 25 mg of iodine and 0.16 ml of trimethylsilyl iodide were added. After 3 h, the solution was allowed to warm to room temperature and was stirred at 22° C. for 14 h. 5 ml of ethanol and 5 ml of diethylamine were added and the mixture was then evaporated under reduced pressure and the residue was chromatographed on silica gel (ether, Rf=0.44). 0.29 g (91%) of (2R,5S)-2-benzyl-3-ethoxy-5-isopropyl-1,2,5,6-tetrahydro-2-methyl-6-pyrazinone, melting point 125° C., was obtained.