Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21](Cl)=[CH:20][N:19]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:34].[K+].C(P(C(C)(C)C)C1(C(C)C)CC(C(C)C)=CC(C(C)C)=C1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:34][C:21]3=[CH:20][N:19]=[C:18]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[CH:17]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(-c3ccc(S(C)(=O)=O)cc3F)ncc2Cl)CC1
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C(C)(C)C)C(C)(C)C)C1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 110 °C

Procedure:
A mixture of 4-[5-chloro-2-(2-fluoro-4-methanesulfonyl-phenyl)-pyridin-4-ylethynyl]-piperidine-1-carboxylic acid tert-butyl ester (208 mg), potassium hydroxide (70 mg), Pd2(dibenzylidenactone)3*CHCl3 complex (10 mg), and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (14 mg) in a mixture of 1,4-dioxane (4 mL) and water (2 mL) is heated under an argon atmosphere in an oil bath at 110° C. for 1 h. The reaction mixture is mixed with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1) to give the title compound. LC (method 7): tR=1.41 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl-].C[Al+]C.CO[C:12]([C:14]1[S:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH2:25][O:26][CH3:27])=[O:13]>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:12]([C:14]1[S:18][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:16][C:15]=1[CH2:25][O:26][CH3:27])=[O:13]
Reactant: CNOC
Reactant: COCc1nc(-c2ccccc2)sc1C(=O)OC
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COCc1nc(-c2ccccc2)sc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A solution of N,O-dimethylhydroxylamine hydrochloride(13.3 g, 136.3 mmole, 6.0 eq) in dry CH2Cl2(250 ml) at 0° C. was treated dropwise with neat dimethylaluminum chloride (12.7 ml, 136.3 mmole, 6.0 eq) and the resulting mixture stirred at 0° C. for 2 hours then allowed to warm to RT. To this mixture was added dropwise a solution of the above-prepared 4-methoxymethyl-2-phenyl-thiazole-5-carboxylic acid methyl ester (5.98 g, 22.71 mmole, 1.0 eq) in CH2Cl2 (20 ml). The yellow mixture was then stirred at room temperature under nitrogen for one hour and re-cooled to 0° C. The mixture was quenched slowly by adding 2.0N NaOH dropwise, warmed to room temperature, and extracted with two portions of CH2Cl2. The organic phase was washed successively with 1.0N NaOH and brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil. Silica gel chromatography eluting with (4:1) hexanes-ethyl acetate to give 6.5 g (97%) of the title compound as a yellow waxy crystalline solid. 1H NMR (CDCl3): δ 3.35 (s, 3H), 3.5 (s, 3H), 3.7 (s, 3H), 4.95 (s, 2H), 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:20]=1[CH2:21]Br>C(O)C.O1CCCC1>[C:2]([NH:5][C:6]([CH2:21][C:20]1[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH3:17])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: COc1cccc([N+](=O)[O-])c1CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Cc1c(OC)cccc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
Sodium metal (1.15 g) was dissolved in absolute ethanol (500 mL), and to the resulting solution was added diethyl 2-acetylaminomalonate (9.1 g). After 15 min at room temperature, a solution of 2-methoxy-6-nitrobenzyl bromide (J. Med. Chem. 1977, 20, 190–196) (8.6 g) in tetrahydrofuran (25 mL) was added over 2 min. After 16 h stirring at room temperature the mixture was evaporated. The residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated and washed sequentially with water and brine before drying over anhydrous sodium sulfate. Evaporation was followed by silica gel chromatography eluting initially with dichloromethane, followed by ethyl acetate, to obtain diethyl 2-acetylamino-2-(2-methoxy-6-nitrobenzyl)malonate (10.8 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:26])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([C:20](=[O:24])[CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:25])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CC(C)=O>[OH:25][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[C:20](=[O:24])[CH2:21][C@@:22]2([CH3:23])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[C:4](=[O:26])[CH2:3][CH2:2][N:31]2[C:27](=[O:37])[C:28]3=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]3[C:30]2=[O:32])[CH2:13]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCCl)[C@@]3(C)CC(=O)[C@@H]12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCN4C(=O)c5ccccc5C4=O)[C@@]3(C)CC(=O)[C@@H]12
Yield: 63.3 %

Procedure:
21-Chloromethyl-3α-hydroxy-5α-pregnane-11,20-dione (600 mg) in acetone was treated at reflux with potassium phthalimide (600 mg) for 10 hours, poured into water and the oily precipitate extracted into ether. The extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to a white foam (700 mg). Purification by preparative t.l.c. in ethyl acetate/petrol (1:1) gave a foam which on trituration with ether gave title compound (490 mg) as a white solid m.p. 187°-189° [α]D + 58.8° (c = 0.97).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccccc1CBr
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: Cc1ccccc1COc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-2-methyl-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(2-methyl-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.Cl>C1COCC1>[CH2:1]([N:8]1[C:12](=[O:13])[C@@H:11]([CH3:17])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](C(=O)O)N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of (R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid (1000 mg, 4.56 mmol) in 55 ml of THF 10.03 ml of a 1M lithium bis(trimethylsilyl)amide solution in THF (10.03 mmol) were added slowly at −10° C., and stirring was continued at this temperature for 1 h. Subsequently iodomethane (0.284 ml, 647 mg, 4.56 mmol) in 9 ml of THF were added (slight exothermic reaction), and the reaction was completed by stirring overnight at room temperature. The brown reaction mixture was acidified using 2M HCl, extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried over Na2SO4 and the solvent evaporated under reduced pressure. The title compound was obtained as a brown oil, which was reacted in the next step without further purification (890 mg of raw material, yield: 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].O.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1cccc(Br)c1
Reaction time: 48 h

Procedure:
A magnetically stirred solution of 3-bromobenzaldehyde (86.5 g, 0.468 mol) and malonic acid (107 g, 1.03 mol) in pyridine (200 ml) was treated with peiperidine (4.0 ml, 40.45 mmol) and heated at ~90° C. for 90 min then under reflux for 30 min. The cooled mixture was poured onto ice (200 g) and water (300 ml) then acidified to ph=1 with conc. hydrochloric acid. Filtration afforded a white solid which was washed with water (4×200 ml), dried by suction and placed in an oven at 70° C. for 48 h until constant weight was obtained (96.02 g, 90%); Vmax (nujol)/cm-1 3400-2000 (br. OH), 1684.5, 1631.5, 1587.0; δH (270 MHz) 6.45 (1H, d, 2-H, 3J2,3 =16,2 Hz); 7.28 (1H, t, 5'-H, Jo =7.8 Hz); 7.48 (1-H, dt, 4'-H, Jo =7.9, Jm =1.3 Hz); 7.54 (1-H, dt, 6'-H, Jo =7.9, Jm =1.0 Hz); 7.70 (1-H, t, 2'H, Jm =1.8 Hz); 7.71 (1H, d, 3-H, 3J3,2 =15.8 Hz).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][OH:19])[O:15][C:14]3=[O:20])=[CH:9][C:8]=2[F:21])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][S:30]([CH3:29])(=[O:32])=[O:31])[O:15][C:14]3=[O:20])=[CH:9][C:8]=2[F:21])[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCSCC2)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: -20 °C

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (14 g, 45.3 mmol) was dissolved in dichloromethane (300 ml) and triethylamine (8.8 ml, 63.3 mmol) was added. It was cooled to −20° C. and methanesulfonyl chloride (4.22 ml, 54.4 mmol), dissolved in dichloromethane (50 ml), was added dropwise. The reaction mixture was allowed to warm to room temperature and was quenched with potassium phosphate buffer (pH 7). Dichloromethane was removed under vacuum and it was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The title compound (16.9 g) was precipitated from dichloromethane by addition of hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].[C:30]([N:38]=[C:39]=[S:40])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:39]([NH:38][C:30](=[O:37])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[S:40])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2nc3cc(NC(=S)NC(=O)c4ccccc4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (377 mg, 0.950 mmol) was reduced to the amine 8a as outlined above and the resulting ethanolic solution charged to a small, argon purged flask fitted with a magnetic stirbar. Anhydrous tetrahydrofuran (10 mL) added followed by dropwise addition of benzoyl isothiocyanate (178 mg, 1.093 mmol) and mixture stirred under Ar at ambient temperature for 3 hours then allowed to stand overnight at room temperature. 3-(Dimethylamino)propyl functionalized silica gel (205 mg, 0.286 mmol) added and mixture stirred for 1 hour, filtered and concentrated to yield crude. The product was purified using silica gel column chromatography eluting with 2.5% 2M NH3 in methanol/97.5% dichloromethane to afford a pale yellow oil. Trituration with diethyl ether/hexanes yielded an off white solid 20 N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]-imidazol-5-ylcarbamothioyl)benzamide. Yield: 160 mg (31.7%) 1H NMR (DMSO) δ: 0.80 (t, 6H, J=7.0), 1.30 (t, 3H, J=7.0), 2.34-2.50 (2×m, 6H), 3.98 (q, 2H, J=7.0), 4.16 (t, 2H, J=6.3), 4.27 (s, 2H), 6.87 (d, 2H, J=8.4), 7.18 (d, 2H, J=8.5), 7.34 (d, 1H, J=8.4), 7.44-7.59 (2×m, 3H), 7.62-7.69 (m, 1H), 7.94-8.03 (2×m, 3H), 11.48 (br s, 1H), 12.60 (br s, 1H). MS (ESI): 530 (MH+, 100%)
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH2:17][CH2:18][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:19])=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCOc1ccc(Br)cc1
Reactant: CCNC(=O)C(C)c1ccc(C2CCNCC2)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccc(OCC)cc3)CC2)cc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
60 mg (0.23 mmol) N-Ethyl-2-(4-piperidin-4-yl-phenyl)-propionamide (VI.1) are added to a mixture of 46 mg (0.23 mmol) 1-bromo-4-ethoxy-benzene, 91 mg (97%, 0.92 mmol) sodium tert-butyrat, 28 mg (0.09 mmol) 2-(di-tert-butylphosphino)biphenyl and 21 mg (0.02 mmol) tris-(dibenzylidenaceton)-dipalladium(0) in 1.0 mL 1,4-dioxane. The mixture is stirred for 1.5 h at 120° C. in a microwave oven. After that time, the solvent is removed in vacuo and the residue is purified by HPLC (column: Waters XBridge 50; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=1)[NH2:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=2)[NH2:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
4-Chlorophenylboronic acid (20.2 g, 0.13 mol) and tetrakis(triphenylphosphine)palladium (0) (3.7 g, 0.003 mol) are added to a solution of 5-bromo-2-methylaniline (20 g, 0.1 mol) in 1,2-dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 20° C., a solution of 20% aqueous sodium carbonate (300 ml) is added to the mixture, and the resulting mixture is refluxed for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 5-(4-chlorophenyl)-2-methylaniline (21.0 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH2:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:16])=[CH:18][CH:19]=3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Product: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtained in Example 150) (0.53 g, 2 mmol) and (S)-leucinol (0.30 g, 2.5 mmol) according to the procedure shown for Example 154 to give 0.53 g of a white solid; m.p. 90–91° C.; MS (ES) m/z: 363.3 (MH+); HRMS (ES) Calcd. for C20H31N2O4 (MH+): 363.2278. Found: 363.2275.
Reaction SMILES: CO[C:3]([CH:5]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8](=[O:15])(=[O:14])[N:7]([CH3:16])[C:6]1=[O:17])=[O:4].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[CH3:16][N:7]1[C:6](=[O:17])[CH:5]([C:3](=[O:4])[NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8]1(=[O:14])=[O:15]
Reactant: Nc1nccs1
Reactant: COC(=O)C1C(=O)N(C)S(=O)(=O)c2ccsc21
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2nccs2)c2sccc2S1(=O)=O

Procedure:
0.15 G. of 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[ 2,3-e] 1,2-thiazine 1,1-dioxide and 0.071 g. of 2-aminothiazole are dissolved in 30 ml. of absolute xylene and the solution is heated for half an hour under the reflux. After cooling, the crystals are removed by filtration, recrystallized from glacial acetic acid, and 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)2H-thieno[ 2,3-e] 1,2-thiazine 1,1-dioxide, melting point 236° C. to 238° C. (decomposition), is obtained.
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]([OH:35])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37](C)([O-])[CH3:38].[K+].C(Br)C=C>C1COCC1>[C:1]([O:20][CH2:21][C@@H:22]([O:35][CH2:38][CH:37]=[CH2:36])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(COCC[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCO[C@@H](CCOCc1ccc(OC)cc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a solution of Compound 5 (10 grams, 21.4 mmoles) in dry THF (250 ml), a solution of 1M of potassium t-butoxide (Aldrich) (27.8 ml, 27.8 mmoles) in THF was added, under argon atmosphere. The mixture was stirred at room temperature for 5 minutes and, thereafter, allyl bromide (Aldrich) (7.4 ml, 85.5 mmoles) was added. The mixture was stirred for 18 hours at 55° C. The solvent was thereafter evaporated to dryness and the residue was extracted with ethyl acetate (250 ml) and washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The resulting yellowish oily residue was purified by silica gel chromatography, using 1:2 (v:v) ethyl acetate:hexane as eluent. 10.75 grams (99% yield) of Compound 6 were obtained as an oil.
Reaction SMILES: Cl[CH:2]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[CH:3]([N:5]1[C:9](=O)CCC1=O)O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[N:34]C(N)=[N:32][CH:31]=2)=[CH:26][C:25]=1[F:37]>C(O)CCC>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][C:9]3[N:34]([C:2]([CH2:12][C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)=[CH:3][N:5]=3)[N:35]=2)=[CH:26][C:25]=1[F:37]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Solvent: CCCCO
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)ccc1Br
Temperature: 110 °C
Reaction time: 18 h
Yield: 6.7 %

Procedure:
1-(2-Chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 228 g, 0.74 mol, 1.1 equiv) and 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (7, 181 g, 0.673 mol) were suspended in 1-butanol (1800 mL) and the resulting suspension was heated to 110° C. and stirred at 110° C. for 18 h (the reaction mixture becomes homogeneous at this point). The reaction mixture was then gradually cooled down to room temperature before being further cooled down to 10° C. in an ice bath. The resulting yellow solid was collected by filtration (save the 1-butanol filtrates), washed with cold 1-butanol (3×100 mL) and dried by suction. This solid was then suspended in the saturated aqueous sodium bicarbonate solution (NaHCO3, 500 mL) and the resulting suspension was stirred at room temperature for 1 h to neutralize the corresponding hydrochloride salt. The free base was then filtered, washed with water (500 mL) and dried in a vacuum oven at 45° C. for 18 h to afford the first crop of the crude 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 125.1 g, 292.3 g theoretical, 42.8% yield). The 1-butanol filtrates were then concentrated under the reduced pressure and the resulting solids were dissolved in dichloromethane (CH2Cl2, 2 L). The solution was wash with the saturated aqueous sodium bicarbonate solution (NaHCO3, 1 L), dried over sodium sulfates (Na2SO4), and concentrated under the reduced pressure. The residue was then purified by flash column chromatography (SiO2, 0-10% MeOH—CH2Cl2 gradient elution) to afford the second crop of 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)-quinoline (12, 19.7 g, 292.3 g theoretical, 6.7% yield; total 144.8 g, 292.3 g theoretical, 49.5% yield) as yellow solids. For 12: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 9.11 (dd, 1H, J=4.98, 1.55 Hz), 8.85 (d, 1H, J=8.09 Hz), 8.25-8.18 (m, 2H), 8.12-8.00 (m, 3H), 7.93-7.86 (m, 3H), 4.70 (s, 2H); C21H13BrFN5 (MW 434.26), LCMS (EI) m/e 434.00/435.95 (M++H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Si:23]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 73.4 %

Procedure:
4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (7.34 g, 39.2 mmol) in N,N-dimethylformamide (200 mL) was stirred with imidazole (4.80 g, 70.6 mmol) and tert-butylchlorodimethylsilane (7.70 g, 51.0 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=25/1→4/1 (v/v)) to give the title compound as a colorless oil (8.68 g, yield 73%).