Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(=O)(O)[O-].[Na+].Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[S:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1nc2ccccc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12
Yield: 58.1 %

Procedure:
To a mixture of 7-aminocephalosporanic acid (23.1 g., purity 86.4%) and 2-mercaptobenzothiazole (14.7 g.) in water (800 ml.), sodium bicarbonate (13.5 g.) was added portionwise with stirring, and acetone (250 ml.) was added thereto. The mixture was stirred at 73° C. for 4.5 hours, cooled below 20° C. and adjusted to pH 3.4 with 6N hydrochloric acid. The precipitating crystals were collected by filtration, washed with water and acetone in turn and dried under reduced pressure to give 7-amino-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (18.7 g.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[H-].[Na+].CI.[C:25](OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[N:10]=[C:9]([C:11]([O:14][CH3:25])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(C)(C)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C

Procedure:
2-(5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)propan-2-ol 68 (175 mg) was cooled in DMF to 0° C. and then NaH was added at once. The reaction was allowed to warm to room temperature and stirred several minutes before addition of methyl iodide. Reaction was stirred several hours and monitored by LC-MS until complete. Ethyl acetate was added and the solution was extracted with saturated bicarbonate solution. Organic was collected and dried, filtered and concentrated to get crude 4-(5-chloro-2-(2-methoxypropan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine.
Reaction SMILES: CN(C1C=CC=CN=1)C.[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[NH2:22])([O-:12])=[O:11].[C:23]([O:27][C:28](OC([O-])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([O:27][C:28]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[C:16]([NH2:22])=[N:17]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1nc(N)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
Dimethylaminopyridine (4 g, 36 mmol) was added to a solution of 5-nitro-1H-indazol-3-ylamine (32.2 g, 181 mmol), tert-butyldicarbonate (39.4 g, 181 mmol) and triethylamine (25 mL, 181 mmol) in THF (1 L) at room temperature under nitrogen. After stirring for 30 minutes, the reaction mixture was concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The layers were separated and the organic phase washed with brine, dried (MgSO4), and concentrated to an orange solid. Recrystallisation from ethyl acetate provided the title product as a yellow solid (25 g, 50%). 1H NMR (400 MHz, DMSO) 1.60 (9H, s), 6.75 (2H, brs), 8.10 (1H, d), 8.36 (1H, d), 8.96 (1H, s); MS (ES−) m/e=277.
Reaction SMILES: C(O[C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH:6]([OH:30])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)[CH:13]=2)[CH:8]=1)C.C[O-].[Na+].Cl.[OH:38][NH2:39].CO.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].[OH:30][CH:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)[CH:13]=2)[CH:8]=1)[C:5]([CH3:31])([CH3:32])[C:4]([NH:39][OH:38])=[O:33]
Reactant: NO
Reactant: CCOC(=O)C(C)(C)C(O)c1ccc2cc(OCc3cc(C)nc4ccccc34)ccc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(COc2ccc3cc(C(O)C(C)(C)C(=O)NO)ccc3c2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
3-Hydroxy-2,2-dimethyl-3-[6-(2-methyl-quinolin-4-ylmethoxy)-naphthalen-2-yl]-propionic acid ethyl ester (1.35 g, 3.04 mmol) was added portion wise to a 50° C. solution of sodium methoxide/hydroxyl amine HCl/methanol ˜1.34 M (230 mL, 308 mmol) under nitrogen atmosphere. The reaction was stirred for 0.5 h, cooled to 0° C., made neutral with TFA, and concentrated in vacuo. The residue was taken up in water (800 mL) and the pH adjusted to 2–3 with TFA to give a solid precipitate. The product was purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient to give the title compound (0.98 g, 59%) as a white solid. MS found: (M+H)+=431.
Reaction SMILES: Br[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:18])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[N:3]=1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](B1OC(C)(C)C(C)(C)O1)=[CH:28][CH:27]=2.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([C:2]1[C:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:18])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=3)[N:3]=1)=[CH:28][CH:27]=2
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: COC(=O)c1ccc2nc(Br)c(N3CCCC[C@@H]3C)nc2c1
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: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a solution of (S)-methyl 2-bromo-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (200 mg, 0.55 mmol) in ethylene glycol dimethyl ether (7 ml) was added 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (141 mg, 0.55 mmol), sodium carbonate (116 mg, 1.09 mmol), water (2 mL), and Pd(PPh3)4 (32 mg, 0.03 mmol). The resulting solution was stirred for 3 h at 90° C. and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (142.1 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: Oc1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 3-bromo-4-chlorophenol (25.0 g, 120.5 mmol) in dichloromethane at 0° C. was added imidazole (9.0 g, 132.5 mmol) and t-butyldimethylchlorosilane (TBSC1) (19.0 g, 126.5 mmol). The solution was stirred at 0° C. for 30 min, then at room temperature for 14 h. The reaction mixture was diluted with deionized water, extracted with dichloromethane (2×200 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-10% ethyl acetate in hexanes) to afford (3-bromo-4-chlorophenoxy)-t-butyldimethylsilane as colorless oil (37.0 g, 115.0 mmol, 98%). MS: (ES) m/z calculated for C12H19BrClOSi [M+H]+ 321.0. found 321.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1.[NH2:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24].C(N(CC)CC)C>O1CCCC1>[CH:10]1[C:11]2[CH:12]=[CH:13][C:14]3[C:5](=[CH:4][C:3]([CH2:2][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:20]4[C:15]=3[CH:16]=[CH:17][CH:18]=[CH:19]4)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(N)(CO)CO
Reactant: BrCc1cc2c3ccccc3ccc2c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 6-bromomethylchrysene (4.82 g, 15 mmol), 2-amino-2-methylpropane-1,3diol (3.15 g, 30 mmol), and triethylamine (1.67 g, 16.5 mmol) was refluxed in tetrahydrofuran (75 mL) under nitrogen. After one hour all the solids had dissolved and NMR analysis indicated that the 6-bromomethylchrysene had been consumed. Water (150 mL) was added and the mixture was cooled to ambient temperature. The solids were collected by filtration, washed with water (3×30 mL), and dried in vacuo to give 3.67 g (71% yield) of 2-(6-chrysenylmethylamino)-2-methylpropane-1,3diol. 1H NMR (CDCl3) 1.19 (s, 3 H), 1.81 (br s, 1 H), 3.53 (d, J=5.0 Hz, 2 H), 4.39 (s, 2 H), 4.58 (t, J=5.0 Hz, 2 H), 7.78 (m, 4 H), 8.11 (m, 2 H), 8.45 (d, J=8.4 Hz, 1 H), 8.9 (m, 4 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27]>>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:26](=[O:27])[C:25]([CH3:30])([CH3:29])[CH3:24])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: CNCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: CC(C)(C)C(=O)Cl
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)C(C)(C)C
Yield: 65.3 %

Procedure:
In a manner similar to that of Example 1(d), by reacting 500 mg (0.9 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethylene)thiazolidine-2,4-dione (prepared in Example 12(c)) with 0.3 ml (2.3 mmol) of 2,2-dimethylpropionyl chloride, 240 mg (65%) of the expected product are obtained.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:34])[C:13]2[O:19][C:18]3[C:20]([Cl:30])=[CH:21][C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:32])(=[O:31])[C:14]=2[CH:33]=1)=[O:9].N1C=CC=CC=1>ClCCl>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:34])[C:13]2[O:19][C:18]3[C:20]([Cl:30])=[CH:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([S:1]([CH3:4])(=[O:3])=[O:2])[CH2:28][CH2:29]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:32])[C:14]=2[CH:33]=1)=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(S(C)(=O)=O)CC3)cc(Cl)c1O2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Mesyl chloride (0.16 mL, 2.059 mmol) was added to a solution of 4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.687 mmol) in dichloromethane (20 mL) and stirred at 20° C. for 10 min. To this pyridine (0.3 mL, 4.12 mmol) was added and the reaction mixture was stirred further for 5 h. The reaction mixture was washed using aqueous hydrochloric acid 10% (15 mL), water and then brine solution. Solvent was removed and the crude product obtained was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 0.14 g, (38.45%); 1H NMR (DMSO-d6, 300 MHz): δ 2.63 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.22 (s, 4H, 2CH2); 3.31 (s, 4H, CH2); 3.85 (s, 3H, OCH3); 5.16 (s, 2H, CH2), 7.13 (d, 1H, Ar), 7.18 (s, 1H, Ar), 8.09 (t, 1H, Ar), 8.15 (d, 1H, Ar); MS: m/e (ES+) 515 (M+1); analysis: C21H23ClN2O7S2.H2O requires C, 47.32; H, 4.73; N, 5.26; Cl, 6.65; S, 12.03. found: C, 46.86; H, 4.18; N, 4.96; Cl, 7.11; S, 12.57%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:2]1[N:7]=[C:6]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: OC1(c2cccc(Br)n2)CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(C2(O)CCC2)n1
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (10 mL) solution of 293.1 mg of 1-(6-bromo-2-pyridinyl)cyclobutanol obtained in Example 69-1 was cooled to -78° C. in an acetone/dry ice bath in a nitrogen atmosphere, and 1.8 mL of 1.58 M n-butyllithium/hexane solution was gradually added thereto, and stirred for 30 minutes. Subsequently, tetrahydrofuran (2.0 mL) solution of 0.36 mL of tri-n-butyltin chloride was added thereto at −78° C., and the reaction solution was stirred for 30 minutes. This was processed with aqueous saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline water, and purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 48.7 mg of the entitled compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]([C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)[OH:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Clc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)s2)CC1

Procedure:
From 2-chlorothiophene (183 mg) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (300 mg) by procedure D. Yield: 180 mg (38%). Brown oil. MS (m/z): 332.1 ([M+H]+).
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH2:9])=[S:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O>>[CH:1]1([NH:6][C:7]2[S:8][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCC1
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Product: CC(C)c1ccc(-c2csc(NC3CCCC3)n2)cc1

Procedure:
Cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amine was prepared following procedure B using cyclopentyl-thiourea (1.6 g, 10.7 mmol) and 2-bromo-1-(4-isopropyl-phenyl)-ethanone (2.6 g, 10.7 mmol). Purification (Silica gel, ethyl acetate/hexane 5:95) provided the product (2.9 g). LCMS m/z: 287 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1>>[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH:21]([C:13]([C@@H:12]2[CH2:11][S:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[C:19](=[O:20])[O:18]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)C1C(=O)OC(C)(C)OC1=O
Yield: 89 %

Procedure:
A was prepared from (4R)-3-(tert-butoxycarbonyl)-1,3-thiazolidine-4-carboxylic acid (5.30 g, 22.7 mmol) and Meldrum's acid according to the previously described procedure used for Example 1C, giving the title compound as yellow solid (7.31 g, 89%). LCMS m/z 358 (M−H). 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 5.88 (m, 1H), 4.80–4.51 (m, 3H), 369 (m, 1H), 3.05 (m, 1H), 2.0–1.8 (m, 3H), 1.8–1.7 (m, 6H), 1.44 (s, 5H), 1.38 (s, 4H) ppm.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH:8]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH:8]1[S:4][CH2:1][CH2:2][S:3]1
Reactant: SCCS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(C2SCCS2)c1
Yield: 97.2 %

Procedure:
9.9 g of ethane 1,2-dithiol are added to 18.6 g of 2-chloro-5-nitrobenzaldehyde and 0.5 g of p-toluenesulfonic acid in 250 ml of toluene and the mixture is refluxed for 5 hours under a water separator. After the mixture has been cooled, the solvent is removed, the residue is stirred with petroleum ether and the product is filtered off and dried. 25.5 g of 4-chloro-3-(1,3-dithiolan-2-yl)-nitrobenzene (mp. 130-131° C.) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.CN(C=O)C.[H-].[Na+].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:11]=[CH:10][N:9]=1
Reactant: Brc1ccccc1-c1ncc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1Br
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
2-(2-bromophenyl)-1H-imidazole (WO 9407486; 1.0 g, 4.48 mmol) was dissolved in THF (11 mL) and DMF (11 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 197 mg, 4.93 mol) was added and the reaction stirred for 20 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (0.79 mL, 4.93 mmol) was added and the reaction stirred overnight at room temperature. The reaction was quenched with MeOH then partitioned between water and Et2O. The organic layer was dried (MgSO4) and concentrated in vacuo and the residue was purified by flash column chromatography to afford 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole as an off-white solid (1.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])/[C:5](/Br)=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P([Pd-4](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)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])/[C:5](/[C:19]1[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=1)=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCOC(=O)/C(Br)=C/C1CCCC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/C1CCCC1)c1ccc(SC)cc1
Yield: 85.6 %

Procedure:
Following the method of example 54c, reaction of (Z)-2-bromo-3-cyclopentyl-acrylic acid ethyl ester (56.8 g, 229 mmol) with 4-(methylthio)benzene boronic acid (46.3 g, 276 mmol) and tetrakis(triphenylphosphino)palladium(0) (10.4 g, 3 mol %) in a mixture of toluene (1600 ml), ethanol (421 ml) and 2 M aqueous sodium carbonate solution (420 ml) affords the title compound as an oil (56.9 g). MS (m/e): 291.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:12]([CH3:14])[CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)c1ncc[nH]1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nccn1-c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 64.1 %

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene 1.01 g, 2-isopropylimidazole 634 mg, N,N-diisopropylethylamine, 1.46 mL and acetonitrile 12 mL was heated under reflux for 15 hours. The solvent was distilled off and water was added to the residue which was then rendred acidic with diluted hydrochloric acid. After washing the same with diethyl ether, the aqueous layer was rendered alkaline with aqueous sodium hydroxide solution and extracted twice with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and removed of the solvent by distillation to provide 0.98 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14](C)=[N:15][N:16]=[C:9]1[CH:8]=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])([O-:3])=[O:2].I([O-])(=O)(=O)=[O:26].[Na+]>[Ru](=O)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7](=[O:26])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:11]=1[N:10]1[CH:14]=[N:15][N:16]=[C:9]1[CH3:8]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc([N+](=O)[O-])ccc3n12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-nitro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate with ruthenium dioxide to give 2'-chloro-5-nitro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@H:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:36]2N(O)N=[N:39][C:37]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N)C.C(N(CC)CC)C>CN(C=O)C>[CH2:37]([NH:39][C:29]([CH2:28][C@@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]4[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:11]4)[C:27]=3[C:26]1=2)=[O:31])[CH3:36]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)O)CC4)CC1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
A 25-mL round-bottom flask was charged with intermediate 22.4 (200 mg, 0.43 mmol, 1.00 equiv), HOBt (90 mg, 0.67 mmol, 1.54 equiv), EDCI (191 mg, 1.00 mmol, 2.31 equiv), ethanamine hydrochloride (45 mg, 0.55 mmol, 1.27 equiv), triethylamine (135 mg, 1.34 mmol, 3.08 equiv) and 10 mL of distilled DMF. The resulting solution was stirred for 4 h at room temperature under nitrogen. The reaction was then quenched with water and extracted with 3×25 mL of ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) and purified to provide the desired tert-butyl N-(4-[[(3S)-3-[(ethylcarbamoyl)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (24.1, 165 mg, 78%) as a white solid. MS: m/z 470 (M+H)+.