Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].Cl.C([O:25][C:26](=[O:29])[CH2:27][NH2:28])C.[OH-].[K+].Cl>>[C:26]([CH2:27][NH:28][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20])([OH:29])=[O:25]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CNc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 75.5 %

Procedure:
A suspension of 2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.31 g 1.00 mmol) and glycine ethyl ester hydrochloride (0.69 g, 5.00 mmol) in a solution of 4M aqueous potassium hydroxide (3.8 mL, 15.0 mmol) was heated to 90° C. for 15 hours. The reaction mixture was cooled to room temperature and it was treated with 2M aqueous hydrochloric acid to adjust the pH to ˜5. It was partitioned with ethyl acetate (50 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the solvent gave 2-({4-[(carboxymethyl)amino]-3-nitrophenyl}carbonyl)benzoic acid (0.26 g, 76% yield) as a white residue. MS (EI) for C16H12N2O7: 342 (M−).
Reaction SMILES: [C:1](Cl)([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.[OH:21][CH2:22][C:23]1[CH2:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH3:31][O:30][C:26]1[C:27](=[O:29])[CH2:28][C:23]([CH2:22][O:21][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:24][CH:25]=1
Reactant: COC1=CN=C(CO)CC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CN=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
Trityl chloride (9.43 g) is added in one portion to a solution of 2-hydroxymethyl-5-methoxy-4-pyridone (5 g) and 4-dimethylaminopyridine (4.2 g) in dry dimethylformamide (80 mL) and the solution stirred at room temperature for 12 hours. The mixture is then heated on a steam bath for 3 hours and diluted with iced water (300 mL) to give a light brown solid. The solid is collected, washed with water and sucked dry. The solid is dissolved in hot ethyl acetate to give a clear solution which immediately deposits a granular off-white solid. The solid does not redissolve on further heating. After cooling the solid is collected, washed with ethyl acetate and diethyl ether and dried to give 5-methoxy-2-trityloxymethyl-4-pyridone (7.5 g) as an off-white solid, m.p. 185-7° C.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[SH2:14]>CCCCC>[SH:14][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:12][CH3:13])=[O:11]
Reactant: C=CCCCCCCCC(=O)OC
Reactant: S
Solvent: CCCCC
Product: COC(=O)CCCCCCCCCS

Procedure:
The resulting methyl 9-decenoate (156 g) is placed in a photochemical reactor comprising a reaction loop, with 100 g of pentane and 60 molar equivalents of liquefied hydrogen sulfide (1806 g condensed at 20° C. under a pressure of 17.5 bar).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCOC(C)=O>C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:15][CH:16]=1
Reactant: Nc1ccncc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1c(Nc2ccncc2)c(=O)c1=O
Yield: 9.9 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL) was added a suspension of 4-aminopyridine (2.77 g, 29.4 mmol) in ethanol (50 mL). The reaction mixture was refluxed for 4 hours then concentrated to give crude product. Chromatography (EtOAc) afforded 0.632 g (10%) of a white solid: mp 120°-125° C.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[C:6]=1[N:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2].[B:20](O)([OH:22])[OH:21].C1C=CC=CC=1>O>[B:20]([O:11][C:10]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([N:17]([CH3:19])[CH3:18])[C:7]([CH3:16])=[CH:8][C:9]=1[C:12]([CH3:13])([CH3:15])[CH3:14])([OH:22])[OH:21]
Reactant: OB(O)O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1N(C)C
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C(C)(C)C)c(OB(O)O)c(C(C)(C)C)c1N(C)C
Temperature: 85 °C
Yield: 84.3 %

Procedure:
A mixture of 2,6-di-tertiary-butyl-dimethylamino- p-cresol (131.5 gm, 0.5 mole), boric acid (31.0 gm, 0.5 mole), and benzene (450 ml.) was heated while stirring vigorously at 85° C. for twenty-two hours. Water (5.5 ml.) formed during reaction was collected by azeotropic distillation.At the end of the reaction, the unreacted, insoluble material was removed by filtration, and the benzene was removed under reduced pressure using a rotary evaporator. This gave a golden orange solid (129.5 gm) with a melting point of 75°-80° C.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].[Na]>ClCCl>[S:1]1[C:5]([CH2:6][NH:20][CH2:19][CH2:18][CH:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH3:12])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: CN1CCCC1CCN
Reactant: O=Cc1cc2ccccc2s1
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1cc2ccccc2s1
Yield: 26.6 %

Procedure:
Experimental condition analogous to Example 5, from benzo[b]thiophen-2-carbaldehyde 0.18 g (1.1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL dichloromethane. Purification using silica gel chromatography, elution with dichloromethane-methanol-ammonium hydroxide, 9-1-0.25, gave 73 mg of compound.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[C:8]([C:5]1[CH:11]=[CH:10][C:8]([CH2:9][CH2:12][CH:14]2[O:16][CH2:15]2)=[CH:7][CH:6]=1)([CH3:10])([CH3:9])[CH3:7]
Reactant: ClCC1CO1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(C)(C)c1ccc(CCC2CO2)cc1

Procedure:
reacting a 4-tert.butylbenzyl magnesuim halide with a stereochemically pure glycydyl tosylate or epichlorohydrin to form a single enantiomer of 4-(4'-tert.butylphenyl)-1,2-epoxybutane;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=[C:7]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1)=[O:4].[Br:36]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:9]([O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=[C:7]([CH:29]([Br:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nc(Cc2ccccc2)nc(OC(=O)c2ccccc2)c1OC(=O)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(C(Br)c2ccccc2)nc(OC(=O)c2ccccc2)c1OC(=O)c1ccccc1

Procedure:
A solution of methyl-5,6-bis(benzoyloxy)-2-benzylpyrimidine-4-carboxylate (B-6) (1.0 eq.) in carbon tetrachloride was heated up to 90° C. under nitrogen; N-bromosuccinimide (1.0 eq.) and benzoyl peroxide (0.1 eq.) were added as dry powder and mixture was refluxed for 3 h. After cooling, succinimide was removed by filtration and the filtrate was concentrated and purified by flash column chromatography (SiO2, 85/15 v/v petroleum ether/ ethyl acetate as eluent) to give the title product (B-7).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][C:22]4([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][O:25]4)[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:33]C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][C:22]4([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][O:25]4)[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][N:14]([CH3:33])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(c1cn(CC2CCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1′-{[6-chloro-1-(pyrrolidin-3-ylmethyl)-1H-indol-3-yl]carbonyl}-3H-spiro[2-benzofuran-1,4′-piperidine] in MeOH was treated with aq. H2CO (1.5 eq), AcOH (1.1 eq) and stirred for 15 min at room temperature, then treated with NaCNBH3 (1.1 eq) and stirred at room temperature for 1 h. Concentration and purification by preparative HPLC gave the desired product. ES-MS m/e (%): 464.2(M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[C:11]([CH3:22])([CH3:21])[N:12](C(OC(C)(C)C)=O)[CH2:13][C:9]=2[C:8]([NH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:7]1)=[O:5])[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[CH2:27]([O:26][C:24]([NH:23][C:8]1[C:9]2[CH2:13][NH:12][C:11]([CH3:22])([CH3:21])[C:10]=2[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Nc1nn(C(=O)OCC)c2c1CN(C(=O)OC(C)(C)C)C2(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)Nc1nn(C(=O)OCC)c2c1CNC2(C)C
Reaction time: 1 h

Procedure:
To a solution of 3-Ethoxycarbonylamino-6,6-dimethyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (5.69 g, 14.4 mmol) in CH2Cl2 (10 mL) was added 4M HCl in 1,4-dioxane (20 mL). The solution was stirred for 1 h, at which time the volatiles were removed in vacuo to yield the desired product F1(i) as a white solid (4.8 g, 91%). Mass Spectrum: Calcd for C13H21N4O4(M+H): 297. Found: 297.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12](=O)[CH3:13])=[N:9][N:8]=2)[CH:2]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12](=[N:16][OH:17])[CH3:13])=[N:9][N:8]=2)[CH:2]=1
Reactant: NO
Reactant: CC(=O)c1nnc(-c2cccnc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=NO)c1nnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]ethanone (1.0 g, 4.68 mmol, prepared according to WO 2010/006713) in 50 ml EtOH was treated with hydroxylamine hydrochloride (0.345 g, 4.91 mmol) and potassium carbonate (0.686 g, 4.91 mmol), and stirred at room temperature, monitored by LCMS and TLC. After 3 hours, the mixture was concentrated in vacuo to approximately 10 ml. Addition of saturated ammonium chloride gave a precipitate which was filtered, and washed successively with water, isopropanol, and tertiary-butyl methyl ether. This yielded 1-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]ethanone oxime (577 mg, 51%) as a 5:1 mixture of isomers.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=O.C(O)(=O)C>C(O)C>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH:24]=[N:23][NH:22][C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]=4)[CH:15]=[C:11]3[N:10]=2)=[CH:27]1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3cnccn3)cc2n1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCO
Solvent: CC(=O)O
Product: C(=NNc1cc(N2CCOCC2)n2nc(-c3cnccn3)cc2n1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
To a solution of (7-Morpholin-4-yl-2-pyrazin-2-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (20 mg, 0.064 mM) in ethanol (2.0 mL), there were added 3-formyl-indole (19 mg, 0.13 mM) and acetic acid (5 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and then washed with ethanol to thus give the title compound (15 mg, yield: 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:22]1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27])[CH2:24][CH2:23]1>C(N(C(C)C)C(C)C)C>[CH:22]1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:28])=[O:27])[CH2:24][CH2:23]1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 90 %

Procedure:
1-[Bis(4-chlorophenyl)methyl]piperazine (10.00 g, 31.13 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (8.30 g, 34.63 mmol) were refluxed in N-ethyldiisopropylamine (50 ml) for 7 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (14.70 g) as an oil (yield based on 1-[bis(4-chlorophenyl)methyl]piperazine: 95.3%).
Reaction SMILES: O[CH2:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(Cl)[Cl:26]>>[Cl:26][CH2:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(c1ccccc1)N1c2ccccc2Oc2c(CO)cccc21
Reactant: ClCCl
Product: CC(c1ccccc1)N1c2ccccc2Oc2c(CCl)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-hydroxymethyl-N-(α-phenylethyl)phenoxazine (Example 4) dissolved in 50 ml of dry methylene chloride. The reaction mixture was stirred at room temperature under anhydrous conditions for 1 hour and the solvent removed under vacuo, to yield a solution of
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([CH3:41])([CH3:40])[CH3:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2C(C)(C)C)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29.3 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (960 mg, 0.005 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.00 g, 0.023 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-t-butyl-phenoxy)-but-2-enoic acid ethyl ester (1.60 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(2-t-butyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (585 mg, 28%) as yellow oil.
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:49])[CH:15]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:26]=1)[O:16][P:17]([C@@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22])([OH:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:49])[CH:15]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([NH:41][C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])=[N:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH:26]=1)[O:16][P:17]([C@@H:20]([NH:24][S:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9])[CH:21]([CH3:23])[CH3:22])([OH:19])=[O:18]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)C(OP(=O)(O)[C@@H](N)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OP(=O)(O)[C@@H](NS(=O)(=O)Cc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Alternatively, to a solution of benzylsulfonyl chloride (101.4 mg, 0.53 mmol) and 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-amino-2-methylpropyl)(hydroxy)-phosphinoyloxy)ethanoic acid methyl ester (301.4 mg, 0.54 mmol) in 4 mL of methylene chloride was added triethylamine (0.13 mL, 0.93 mmol). After stirring at ambient temperature for 1.5 hours, the reaction mixture was concentrated in vacuo to give a yellow oil, 2-(3-(N′,N″-di(t-butoxy-carbonyl)guanidino)phenyl)-2-((1R)-(1-(benzylsulfonyl)amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid methyl ester, which was used without further purification in the following step.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9]Br.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>CC(C)=O>[S:18]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:9][CH2:8]1
Reactant: BrCCBr
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2c(c1)NCCS2
Reaction time: 8 h
Yield: 66.1 %

Procedure:
K2CO3 (4.4 g, 31.9 mmol) and 1,2-dibromoethane (0.69 mL, 8.0 mmol) were added to a solution of 2-aminothiophenol (1.0 g, 8.0 mmol) in 20 mL of acetone at room temperature. The reaction mixture was stirred overnight. The insoluble material was filtered off and the solvent was removed under reduced pressure. The residue was purified on silica gel column to provide 3,4-dihydro-2H-1,4-benzothiazine (0.8 g, 66%). MS (ES+): 152 (M+1). (208b) K2CO3 (5.2 g, 37.7 mmol) and methyl 4-(bromomethyl)benzoate (2.8 g, 12.6 mmol) were added to a solution of 208a (1.9 g, 12.6 mmol) in 20 mL of anhydrous DMF. The reaction mixture was heated to 80° C. overnight. After cooling down, the solid was filtered off and rinsed with DMF. The solvent was removed under reduced pressure and the residue was purified on silica gel column to provide methyl 4-(2,3-dihydro-4H-1,4-benzothiazin-4-ylmethyl)benzoate (3.02 g, 80%). MS (ES+): 300 (M+1). (208c) A solution of Oxone® (2.2 g, 3.54 mmol) in 20 mL of H2O was added slowly to a solution of 208b (2.12 g, 7.1 mmol) in 20 mL of MeOH. Upon completion of the reaction, the solution was diluted with ethyl acetate, washed with saturated NaHCO3 and dried over MgSO4. After filtration and concentration, the residue was purified on silica gel column to provide methyl 4-[(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoate (1.39 g, 65%). MS (AP+): 316 (M+1). (208d) A solution of KOH (1N, 7.5 mL) was added to a solution of 208c (1.25 g, 3.8 mmol) in 40 mL of MeOH and 40 mL of H2O. The reaction mixture was heated to 60° C. overnight. Upon completion, the aliquot was neutralized with HCl (1N, 1.2 mL). The solvent was removed and the residue was dissolved in MeOH. After filtration and concentration, 4-(2,3-dihydro-4H-1,4-benzothiazin-4-ylmethyl)benzoic acid was obtained in quantitative yield. MS (AP+): 318 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6](C(OC(C)(C)C)=O)[C:5]2=[CH:14][S:15][C:16]([C:17]3[S:18][C:19]([C:26]4[S:27][CH:28]=[C:29]5[C:33]=4[NH:32][C:31](=[O:34])[N:30]5C(OC(C)(C)C)=O)=[C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=34)=[C:4]2[NH:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[O:1]=[C:2]1[NH:6][C:5]2=[CH:14][S:15][C:16]([C:17]3[S:18][C:19]([C:26]4[S:27][CH:28]=[C:29]5[C:33]=4[NH:32][C:31](=[O:34])[NH:30]5)=[C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=34)=[C:4]2[NH:3]1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2c(-c3sc(-c4scc5c4[nH]c(=O)n5C(=O)OC(C)(C)C)c4c3OCCO4)scc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1[nH]c2csc(-c3sc(-c4scc5[nH]c(=O)[nH]c45)c4c3OCCO4)c2[nH]1
Reaction time: 3 h

Procedure:
To the obtained tert-butyl 4-[7-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)-2,3-dihydrothieno[3,4-b]-1,4-dioxin-5-yl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate was added 40 equivalents of trifluoroacetic acid, and then a reaction was performed at 25° C. for 3 hours. The resulting reaction liquid was dropped slowly to a saturated aqueous sodium carbonate solution to neutralize, thereby stopping the reaction. Ethyl acetate was added to the reaction liquid and stirred, and then an organic layer was taken and the solvent was distilled off. The residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 4-[7-(2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)-2,3-dihydrothieno[3,4-b]-1,4-dioxin-5-yl]-2,3-dihydro-1H-thieno[3,4-d]imidazol-2-one was obtained. The yield based on the charged tert-butyl 4-[7-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)-2,3-dihydrothieno[3,4-b]-1,4-dioxin-5-yl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate was 90%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:14]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCc1nccnc1Cl)[C@H]1CC[C@H](O)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Temperature: 25 °C

Procedure:
The total harvest of (trans)-N-((3-chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide (10 mmol, 2.7 g) and 4-dimethylaminopyridine (1.0 mmol, 0.12 g) were dissolved in pyridine (25 ml), acetic anhydride (10.51 mmol, 0.994 ml) was added and the mixture was stirred at room temperature. After 1 hour the reaction was quenched in 185 mL of 2N hydrochloric acid (pH becomes four) and extracted with ethyl acetate three times. The combined organic layers were dried (sodium sulfate) and concentrated to give 2.8 g of (trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl acetate.