Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.[CH2:22]([Sn:26]([Li:35])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].Br[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>C1COCC1>[CH2:22]([Sn:26]([Li:35])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH3:25].[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: Brc1ncccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li][Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Temperature: 25 °C

Procedure:
(Example of the general procedure Tin-03, below) Tri-n-butylstannyl lithium was prepared at 0° C. in dry THF (20 mL) from tri-butyltin hydride (2.2 mL) and LDA (lithium diisopropylamide, 2M, 4.09 mL). The tri-n-butylstannyl lithium solution was then cooled to −78° C. and to it was added 2-bromopyrimidine (1 g). The reaction mixture was then allowed to warm up to room temperature over 8 hours. The reaction was then quenched with aqueous ammonium chloride solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography to afford 2-(tri-n-butylstannyl)-pyrimidine (190 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)=[O:17])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)N2CCN(c3ccc(CN)cc3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(N2CCN(C(=O)N[C@H]3CC[C@H](C(=O)O)CC3)CC2)cc1

Procedure:
400 mg of 1-(4-aminomethylphenyl)-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-piperazine-hydrochloride and 3 ml of a 1.4 molar aqueous lithium hydroxide solution in 3 ml of tetrahydrofuran and 2 ml of water is stirred at ambient temperature for 2 hours. Then 3.2 ml of 1N hydrochloric acid are added dropwise and some of the solvent is evaporated off under reduced pressure. The precipitate is suction filtered, triturated with acetone, suction filtered again and dried. Yield: 330 mg (94% of theory), Rf value: 0.47 (silica gel; methylene chloride/methanol/conc. ammonia=2:1:0.25) Mass spectrum: M+ =360
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.O>[C:12]([CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:13]
Reactant: CCOC(=O)CCCCBr
Reactant: N#CCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(C#N)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
In 125 ml of DMF was dissolved 12.54 g (75 mmol) of 1-naphthaleneacetonitrile. Then, 3.30 g (82.5 mmol) of 60% sodium hydride was added at room temperature and the mixture was heated to 60° C. and stirred for 30 minutes. After cooling to room temperature, 13.17 ml (82.5 mmol) of ethyl 5-bromovalerate was added. The reaction was further conducted at 60° C. for 30 minutes, after which the reaction mixture was cooled to <10° C. and diluted with 500 ml of pure water. The diluted mixture was extracted with 200 ml of ethyl acetate twice and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane-CH2Cl2 -ethyl acetate=4:2:1) to provide 17.16 g (yield 77.5%) of the title compound as light-yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.CCOCC>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(OCC2CN(c3ccc([N+](=O)[O-])cc3)C(=O)O2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OCC2CN(c3ccc([N+](=O)[O-])cc3)C(=O)O2)cc1
Yield: 85.2 %

Procedure:
A solution of 2.0 g of methyl 4-[3-(4-nitrophenyl)-2-oxooxazolidin-5-yl]methoxybenzoate (compound 50) obtained in Example 3 in 18 ml of acetic acid and 6 ml of concentrated hydrochloric acid was refluxed with heating for 12 hours. After ice-cooling the reaction solution, ether was added thereto and the crystals formed were collected by filtration. Thus, 1.64 g of the title compound (compound 81) was obtained (yield 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:5]=1[O:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O)([O-:3])=[O:2].C(Cl)Cl.O.NN.Cl>CO>[N+:1]([C:4]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:5]=1[O:6][NH2:7])([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 5 L four-necked flask equipped with an overhead stirrer, thermocouple and a condenser was charged with 2-(2,4-dinitrophenoxy)isoindoline-1,3-dione (I-36) (96 g, 291.6 mmol) and DCM (2 L). The stirred solution was cooled to 0° C. and a solution of hydrazine hydrate (36.46 g, 729 mol) in MeOH (300 mL) was added at 0° C. The reaction mixture rapidly became bright yellow and a precipitate formed. The suspension was stirred at 0° C. for 2 hours. 0.5 N HCl (2 L) was added at 0° C. and stirred for 30 minutes. The mixture was filtered and washed with DCM (2×200 mL). The organic layer was separated, dried over MgSO4, filtered and the solvent removed to give O-(2,4-dinitrophenyl)hydroxylamine (I-37) as a red-orange solid. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, 1 H), 8.44 (dd, 1 H), 8.07 (d, 1 H), 6.42 (sbr, 2 H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]([OH:10])[CH2:8][CH3:9])=[CH:5][N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1
Reactant: CCC(O)c1cnc(Br)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(=O)c1cnc(Br)s1
Reaction time: 2 h

Procedure:
To a solution of 1-(2-bromo-thiazol-5-yl)-propan-1-ol (180 mg, 0.79 mmol) in dichloromethane (10 mL) was added Dess-Martin periodinane (DMP) (330 mg, 0.79 mmol). The reaction was stirred for 2 hours, then diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The compound was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford 1-(2-bromo-thiazol-5-yl)-propan-1-one.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:30]([SH:33])(=[O:32])[CH3:31].[H-].[Na+]>CN(C)C=O>[C:30]([S:33][C@@H:10]1[CH2:9][N:8]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:11]1)(=[O:32])[CH3:31]
Reactant: CC(=O)S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](Cn2ccnc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](Cn2ccnc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C

Procedure:
A solution of (2S,4R)-2-(imidazol-1-yl)methyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.76 g) in dimethylformamide (2 ml) was added to a mixture of thioacetic S-acid (0.16 ml) and sodium hydride (62.8 % in oil suspension, 0.08 g) in dimethylformamide (5 ml) under nitrogen stream and the mixture was heated at 70°-75° C. for 5 hours. The mixture was poured into ice-water (70 ml), extracted with ethyl acetate (70 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98, V/V) to give (2S,4S)-4-acetylthio-2-(imidazol-1-yl)methyl-1-(-4-nitrobenzyloxycarbonyl)pyrrolidine (0.38 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][NH:8][C:9](=[O:11])[CH3:10].CC1C=CC=C(C)N=1.[Cl:20][C:21]1[CH:22]=[N+:23]([O-])[CH:24]=[C:25]([Cl:29])[C:26]=1[CH2:27][Cl:28].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:20][C:21]1[C:22]([N:8]([CH3:7])[C:9](=[O:11])[CH3:10])=[N:23][CH:24]=[C:25]([Cl:29])[C:26]=1[CH2:27][Cl:28]
Reactant: CNC(C)=O
Reactant: [O-][n+]1cc(Cl)c(CCl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(=O)N(C)c1ncc(Cl)c(CCl)c1Cl
Reaction time: 0.33 h

Procedure:
Oxalyl dichloride (45 μL, 0.47 mmol) was added dropwise to a solution of N-methylacetamide (36 μL, 0.47 mmol) and 2,6-dimethyl-pyridine (55 μL, 0.47 mmol) in anhydrous DCM (10 mL) at 0° C. After stirring for 20 min, 3,5-dichloro-4-chloromethyl-pyridine 1-oxide (10 mg, 0.047 mmol) was added to it and stirring was continued overnight at 45° C. Saturated aqueous Na2CO3 solution (20 mL) and DCM (40 mL) were added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (elution with EA/hexane 1:3) to give the title compound. MS (m/z): 267.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH3:7][S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O>>[CH3:7][S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COC(=O)CN
Reactant: CSc1ccccc1C=O
Product: COC(=O)CNCc1ccccc1SC
Yield: 50 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 2-(methylthio)benzaldehyde. Yield 50%. MS M+H calculated 226.1. found 226.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13]C)[C:10]([CH3:12])([CH3:11])O2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[C:10]([CH3:11])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:12])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COC1(c2ccc(F)cc2)OC1(C)C
Product: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Temperature: 130 °C

Procedure:
29.43 g (0.15 mol) of 2-(4-fluorophenyl)-3,3-dimethyl-2-methoxyoxirane and 52.3 g (0.60 mol) of morpholine are brought together, and the mixture is heated to reflux temperature (about 130° C.). After 23 hours the excess morpholine is distilled off. The residue is taken up with toluene, and the mixture is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and is extracted with toluene. The toluene solution is dried with K2CO3 and is concentrated. The residue, 34.0 g, crystallises out from ethyl acetate with a melting point of 63°-66° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20]C)[CH3:18].ClC(OC1C=CC=CC=1)=[S:26].N1CCCC1>O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:20]([N:19]3[CH2:22][CH2:23][CH2:18][CH2:17]3)=[S:26])[CH:7]=2)=[CH:10][C:11]=1[Cl:16]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: Nc1ccc(Oc2ccnc(NC(=S)N3CCCC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 19.8 %

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (250 mg) as disclosed in WO 02/32872 was dissolved in tetrahydrofuran (5 ml) under a nitrogen atmosphere, and then triethylamine (0.185 ml) and phenyl chlorothioformate (0.184 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 2.5 hrs. To the reaction mixture were further added triethylamine (0.074 ml) and phenyl chlorothioformate (0.073 ml), followed by stirring at room temperature for 40 min. To the reaction mixture was added pyrrolidine (0.530 ml), followed by stirring overnight. Pyrrolidine (0.530 ml) was further added thereto, followed by stirring for 1 hr. The reaction mixture was warmed to 40° C. and stirred for 30 min, and warmed to 50° C. and stirred for 2.5 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:3). Fractions containing the target compound were concentrated to give a residue, which was dried in vacuum to provide the titled compound (73.2 mg, 19.8%) as a colorless solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[NH:10][CH2:9][S:8][CH2:7]1)=[O:5].Cl.[Cl:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[Cl:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([N:10]1[CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7][S:8][CH2:9]1)=[O:16]
Reactant: CCOC(=O)C1CSCN1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl
Product: CCOC(=O)C1CSCN1C(=O)c1cccnc1Cl
Yield: 77.5 %

Procedure:
Ethyl N-(2-chloronicotinoyl)thiazolidine-4-carboxylate is prepared as described in Example 5, from 23 g of ethyl L-thiazolidine-4-carboxylate hydrochloride and 20.4 g of 2-chloronicotinoyl chloride. 27 g of ethyl N-(2-chloronicotinoyl)thiazolidine-4-carboxylate are thus obtained in the form of a yellow oil, employed crude.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][C@H:50]([OH:62])[CH2:51][N:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1>C(Cl)Cl>[CH2:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:60][CH2:61][N:52]1[CH2:51][C@@H:50]([OH:62])[CH2:49][NH:48][C:18]([C:17]1[CH:21]=[CH:22][N:23]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)O)ccn2)CC1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccn2)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
To a solution of 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)isonicotinic acid (150 g, 0.47 mol) in DCM (1500 mL) was added HATU (178 g, 0.47 mol) and TEA (47 g, 0.47 mol) at 20° C., then the mixture was stirred at the temperature for 2 h. (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (113 g, 0.55 mol) was added to the solution, and the mixture was stirred at 20° C. for another 16 h, at which time TLC showed the completion of the reaction. The mixture washed with water (200 mL) and the combined organic phases were dried and concentrated. The residue was purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give the title compound as yellowish oil. Four batches were run in parallel and produced a combined product weight of 510 g, yield: 53.2%. LCMS (m/z): 510.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][CH2:9][C@H:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]1[OH:16]>N1C=CC=CC=1.CO.CCOCC>[C:1]([O:8][CH2:9][CH:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH:11]1[OH:16])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OC[C@H]1CC=CC[C@H]1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)C(=O)OCC1CC=CCC1O
Reaction time: 20 h
Yield: 92.9 %

Procedure:
Pivaloyl chloride (1.036 g, 1.1 equivalents) was added at -20° C. to a solution of 2-hydroxymethyl-cyclohex-4-eneol (7, 1.00 g, 7.81 mmol) in pyridine (10 ml). The reaction mixture was kept at -20° C. for 20 hours, diluted with methanol and ether (50 ml), and the organic layer extracted with 20 ml portions of 10% HCl containing copper sulfate until the blue color in the organic layer had disappeared. The ethereal layer was dried (magnesium sulfate), the solvent removed under vacuum, and the residue chromatographed on silica gel (hexane:EtOAc 7:3, Rf=0.43) to yield 2-pivaloyloxymethyl-cyclohex-4-eneol (8, 1.54 g, 93%) as a colorless oil. (IR, CCl4 1730 cm-1). 3,4-trans 1-Methoxy-3-pivaloyloxymethyl-4-(2'-hydroxyethyl)-tetrahydrofuran 9 and 1-Methoxy-3-pivaloyloxymethyl-4-(2',2'-dimethoxyethyl)-tetrahydrofuran.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](=[O:14])([O-])[O-].[Na+].[Na+].[C:17](Cl)(Cl)=O.C1(C)C=CC=CC=1>>[CH3:17][C:7]1[CH:8]=[C:2]2[C:1]([O:10][C:11](=[O:14])[NH:4][C:3]2=[CH:5][CH:6]=1)=[O:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 8 h

Procedure:
To an aqueous solution of anthranilic acid (100 g, 0.66 mol) and sodium carbonate (0.7 mol) a solution of phosgene in toluene (362 mL, 1.93 M, 0.7 mol) was added dropwise under vigorous stirring. The reaction becomes a suspension and is stirred for additional 8 hours and filtered. The residue was treated with aqueous Na2CO3 and filtered. Washed with water (4×150 mL) and dried.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1.Cl>CO.O1CCOCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][N:18]=[CH:17][C:16]=2[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc3sncc3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NOC[C@H](O)CO)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 4-(2-Fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-5-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (142 mg, 0.261 mmol) in MeOH (2 mL) was added a 4M HCl solution in dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 hours before being concentrated in vacuo. The resultant residue was taken up in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in ethyl acetate/cyclohexane to afford the title compound as a solid (73 mg, 56%). LCMS (method A): RT=8.97 min, [M+H]+=504. NMR (DMSO-d6, 400 MHz) 11.78 (1 H, s), 9.28 (1 H, s), 8.64 (1 H, s), 7.84 (1 H, dd, J=8.48, 0.92 Hz), 7.64-7.57 (2 H, m), 7.31 (1 H, dd, J=8.47, 1.83 Hz), 6.65 (1 H, t, J=8.71 Hz), 4.80 (1 H, s), 4.54 (1 H, s), 3.80 (1 H, t, J=6.46 Hz), 3.68-3.61 (2 H, m), 3.32 (2 H, s).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C([Li])CCC.C(NC(C)C)(C)C.[C:44]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:46])[CH3:45].N1C=CN=C1>C1COCC1>[C:48]([O:47][C:44](=[O:46])[CH2:45][C:17](=[O:19])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a solution of CBZ-L-tert-leucine (20.53 g, 77.4 mmol, 1 equiv) in THF (150 mL) was added 1,1'-carbonyldiimidazole (13.81 g, 85.14 mmol, 1.1 equiv) at 23° C. The resulting solution was stirred at 23° C. for 1 h. In a separate flask, n-butyllithium (101.59 mL of a 1.6 M solution in hexanes, 162.54 mmol, 2.1 equiv) was added to a solution of diisopropylamine (22.78 mL, 162.54 mmol, 2.1 equiv) in THF (100 mL) at -78° C. The reaction mixture was stirred for 15 min at -78° C., warmed to 0° C. for 5 min, then cooled back to -78° C. A solution of tert-butyl acetate (21.9 mL, 162.54 mmol, 2.1 equiv) in THF (10 mL) was added via cannula, and the resulting mixture was stirred at -78° C. for 10 min. The above imidazole solution was then added dropwise to the lithium enolate at -78° C. The resulting mixture was stirred at -78° C. for 1 h, quenched with 1 M HCl (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (150 mL), fried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to afford 4-benzyloxycarbonylamino-5,5-dimethyl-3-oxo hexanoic acid tert-butyl ester as a pale yellow oil (12.06 g, 44%): IR (cm-1) 1717, 1508, 1265, 739; 1H NMR (CDCl3) δ 1.09 (s, 9H), 3.50 (s, 2H), 4.29 (d, 1H, J=9.3), 5.03 (s, 2H), 5.35-5.42 (m, 1H), 7.34 (s, 5H).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=O)[CH2:4][C:5](OC)=[O:6].C(=O)(O)O.[NH2:16][C:17]([NH2:19])=[NH:18]>C(O)C>[NH2:19][C:17]1[N:18]=[C:5]([OH:6])[CH:4]=[C:3]([C:2]([CH3:11])([CH3:10])[CH3:1])[N:16]=1
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: CC(C)(C)c1cc(O)nc(N)n1
Yield: 75.4 %

Procedure:
Methyl 4,4-dimethyl-3-oxopentanoate (15.82 g) and guanidine carbonate (20.0 g) were mixed in 80 mL of ethanol, and the solution refluxed for 16 hours. The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added. The remaining mixture was acidified to pH 5 with acetic acid, affording a white precipitate. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (12.6 g), m.p. 285-288° C. (dec.).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].N1C=CC=CC=1.O1CCOCC1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:25]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(ON1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 25 °C

Procedure:
In a 3-L flask equipped with a stirrer and thermometer, 100 g (613 mmol) of N-hydroxyphthalimide, 53.3 g (674 mmol) of pyridine and 1100 g of 1,4-dioxane were placed and were stirred at room temperature. To the resulting mixture, 94.8 g (674 mmol) of benzoyl chloride was added dropwise over 1 hour, and the resulting mixture was stirred at room temperature for further 2 hours. Subsequently, 1100 g of pure water was added dropwise over 30 minutes to dissolve by-produced salts and thereby yielded a crystal of the target N-benzoyloxyphthalimide. The mixture was stirred and aged for further 1 hour, the crystal was filtrated using a Nutsche, was rinsed with an appropriate amount of water, was dried at 60° C. under a reduced pressure and thereby yielded 162 g (604 mmol) of N-benzoyloxyphthalimide in a yield of 98.6% on the basis of N-hydroxyphthalimide.