Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([NH2:49])[CH:43]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:49][C:44]1[CH:43]=[C:42]([O:41][CH3:40])[CH:47]=[CH:46][C:45]=1[NH:48][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.9 %

Procedure:
6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-methoxy-o-phenylenediamine (166 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum. To the residue was added 5 ml of absolute ethanol. The solids were collected by vacuum filtration, washed with absolute ethanol and dried under vacuum to give the title compound (144 mg, 52% yield) as a brown solid. LC-MS (m/z) 278 (M+1).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:25][C@H:24]2[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:15](=[O:34])[N:14]2[CH2:35][C@H:36]([OH:38])[CH2:37][C@H:13]2[C:12](=[O:39])[NH:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl[C:41]1[N:42]=[C:43]2[C:48](=[C:49]3[C:54]=1[CH:53]=[C:52]([F:55])[CH:51]=[CH:50]3)[CH:47]=[CH:46][CH:45]=[CH:44]2.CC([O-])(CC)C.[Na+].Cl>CN(C)C=O>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:25][C@H:24]2[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])[C:15](=[O:34])[N:14]2[CH2:35][C@H:36]([O:38][C:41]4[N:42]=[C:43]5[C:48](=[C:49]6[C:54]=4[CH:53]=[C:52]([F:55])[CH:51]=[CH:50]6)[CH:47]=[CH:46][CH:45]=[CH:44]5)[CH2:37][C@H:13]2[C:12](=[O:39])[NH:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: Fc1ccc2c(c1)c(Cl)nc1ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccc(F)cc34)CN2C1=O
Agent: CCC(C)(C)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccc(F)cc34)CN2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (2c, 0.376 g, 0.660 mmol), 6-chloro-8-fluorophenanthridine (2b, 0.153 g, 0.660 mmol) and sodium 2-methylbutan-2-olate (0.218 g, 1.981 mmol) in dimethylformamide (6.6 mL) was stirred at room temperature for 2 h. The reaction mixture was added dropwise to 2N HCl (200 mL) and the resulting solid was collected by vacuum filtration, rinsed with water, and dried. The solid was purified by flash chromatography on silica gel, eluting with acetone/hexane, to provide the title compound (0.355 g, 70% yield) as a white solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([NH2:18])=[O:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH2:24]([O+](CC)CC)[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:12]1[C:10]2[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][N:7]([C:16](=[NH:18])[O:17][CH2:24][CH3:25])[CH2:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC[O+](CC)CC
Reactant: NC(=O)N1Cc2ccccc2-c2ccccc2C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.19 g of 5.7-dihydro-6H-dibenz[c,e]azepine-6-carboxamide are dissolved in 10 ml of methylene chloride, and the solution is treated with 1.14 g of triethyloxonium tetrafluoroborate and stirred at room temperature for 20 hours. The mixture is then poured on to 10% sodium carbonate solution/ice and the whole is extracted with methylene chloride. The combined extracts are washed with 10% sodium carbonate solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. In this manner there is obtained crude ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate which is purified by a filtration on silica gel [eluent: n-hexane/ethyl acetate (1:1)]; m.p. 74°-76° C. (crystallized from n-hexane).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]=[N+:17]=[N-:18])[CH2:5][N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]([CH3:40])([CH3:39])/[CH:23]=[CH:24]/[C@H:25]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][CH:27]2[CH:33]([O:37][CH3:38])[C:34](=[O:36])[O:35][C@H:26]12>C(O)(C)C>[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C@H:6]1[CH2:5][N:4]([CH3:19])[C:3](=[O:20])[C@@H:2]([NH:1][C:34](=[O:36])[C@@H:33]([C@H:27]2[C@H:26]([OH:35])[C@@H:25](/[CH:24]=[CH:23]/[C:22]([CH3:39])([CH3:21])[CH3:40])[O:30][C:29]([CH3:32])([CH3:31])[O:28]2)[O:37][CH3:38])[CH2:8][CH2:7]1)=[N+:17]=[N-:18]
Reactant: COC1C(=O)O[C@H]2C1OC(C)(C)O[C@@H]2/C=C/C(C)(C)C
Reactant: CN1C[C@H](OCCCCCCN=[N+]=[N-])CC[C@H](N)C1=O
Solvent: CC(C)O
Product: CO[C@@H](C(=O)N[C@H]1CC[C@@H](OCCCCCCN=[N+]=[N-])CN(C)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Yield: 59.1 %

Procedure:
To a solution of (3S,6R)-3-amino-6-(6-azido-hexyloxy)-1-methyl-azepan-2-one (0.207 g, 0.73 mmol) in isopropanol (1 mL) is added (4R,4aR)-((E)-3,3-dimethyl-but-1-enyl)-7-methoxy-2,2-dimethyl-tetrahydro-furo[3,2-d][1,3]dioxin-6-one (0.3 g, 1 mmol) and heated to reflux for 18 h. The solution is evaporated under vacuum adsorbed on silica and chromatographed (CH2Cl2 to EtOAc gradient) to give 0.245 g (59%) of (R)-N-[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide as a solid. (ESI) 568.1 (M+H)+
Reaction SMILES: [CH2:1]([N:5]([CH3:16])[C:6](=[O:15])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[CH2:2][CH2:3][CH3:4].[Br:17]CC(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:16])=[O:15]
Reactant: CCCCN(C)C(=O)COCCCCCO
Reactant: BrCC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)COCCCCCBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 7.2 g of the product of Step C in 73 ml of methylene chloride, there were added at -10° C. 13 g of reaction tetrabromoethane and 10.3 g of triphenylphosphine and the reaction medium was stirred for one hour at 0° C. and chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 7.49 g of the desired compound.
Reaction SMILES: [CH3:1][NH2:2].O=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6][CH2:5]1>>[CH3:1][NH:2][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6][CH2:5]1
Reactant: N#CC1CCC(=O)CC1
Reactant: CN
Product: CNC1CCC(C#N)CC1

Procedure:
Following the procedure as described in Example 25, STEP D, methyl amine and 4-oxo-cyclohexanecarbonitrile were reacted to yield 4-methyamino-cyclohexanecarbonitrile as a white solid, as its corresponding hydrochloride salt.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]([NH:7][N:8]([CH2:16][C:17]([O:19]C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)=[O:6].O.P([O-])([O-])([O-])=O>CO>[CH3:15][C:11]1[CH:10]=[C:9]([N:8]2[CH2:16][C:17](=[O:19])[NH:4][C:5](=[O:6])[NH:7]2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CN(NC(N)=O)c1cccc(C)c1
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(N2CC(=O)NC(=O)N2)c1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A solution of sodium methoxide (2.17M in methanol; 3 ml) was added to a stirred solution of methyl [2-(aminocarbonyl)-1-(3-methylphenyl)hydrazino]acetate (0.5 g) in methanol (1 ml), and the mixture was stirred at 20° for 1.0 h. Water (20 ml) was added, followed by pH 6.5 phosphate buffer solution (30 ml), and the mixture was extracted with ethyl acetate (3×80 ml). The combined extracts were washed with water (2×80 ml) and saturated brine (80 ml), dried, and evaporated in vacuo to give a solid which was triturated with ether (30 ml) to give the title compound (261 mg), m.p. 245°-247°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[CH:17]=1)[CH3:13]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of 3-chloro-benzenesulfonyl chloride (2.68 g, 13.0 mmol) in toluene (10.0 ml) was warmed to 100° C. and treated with a solution of 3-amino-benzoic acid ethyl ester (2.00 g, 12.0 mmol) in toluene (10.0 ml). The mixture was stirred at 100° C. for 1 h, then cooled to 0° C. for 1 h. The precipitated solid was filtered, washing with toluene. Drying of the solid under high vacuum yielded 3-(3-chloro-benzenesulfonylamino)-benzoic acid ethyl ester (4.03 g, 98%) as an off-white solid, which was used crude in the following reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5](Cl)=[C:4]2[N:9]([CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:3]=12>CO.[Pd]>[CH3:16][O:15][C:13](=[O:14])[CH2:12][C:11]1[C:3]2[C:4](=[CH:5][N:6]=[CH:7][CH:2]=2)[N:9]([CH2:17][C:18]([OH:20])=[O:19])[CH:10]=1
Reactant: COC(=O)Cc1cn(CC(=O)O)c2c(Cl)ncc(Br)c12
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cn(CC(=O)O)c2cnccc12
Reaction time: 2 h

Procedure:
A mixture of [4-bromo-7-chloro-3-(2-methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]acetic acid from Step E (27.0 mg, 0.075 mmol) and 10% Pd/C (10 mg) in MeOH (5 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 2 h. The mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: Cl.[C:2]([C:6]1[C:7]2[CH2:8][C:9]([CH3:22])([CH3:21])[NH:10][C:11]=2[C:12]([CH3:20])=[C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]=12)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])O.[Na+].C(N(CC)CC)C.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C1COCC1>[C:2]([C:6]1[C:7]2[CH2:8][C:9]([CH3:22])([CH3:21])[N:10]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([F:35])=[CH:37][CH:38]=3)[C:11]=2[C:12]([CH3:20])=[C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]=12)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c2c(c(C(C)(C)C)c3c1NC(C)(C)C3)OC(C)(C)C2
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c2c(c(C(C)(C)C)c3c1N(C(=O)c1ccc(F)cc1)C(C)(C)C3)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
8-tert-Butyl-3, 5, 6, 7-tetrahydro-2,2,4,6,6-pentamethyl-2H-furo[2,3-f]indole hydrochloride (715.8 mg, 2.21 mmol) was suspended in THF (20 ml). To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and stirred for 1 hour at room temperature. After extracting with isopropyl ether followed by drying over magnesium sulfate, the solvent was removed under reduced pressure. The residue was dissolved in THF (20 ml). To the solution were added triethylamine (0.35 ml, 2.51 mmol) and p-fluorobenzoyl chloride (371.8 mg, 2.34 mmol) and stirred at room temperature for 5 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain 417 mg of the title compound as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=O.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:21][C:22]([F:30])([F:29])[C:23]([C:24]1[C:25]([CH3:26])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[CH:4][C:5]([I:8])=[CH:6][CH:7]=2)=[O:28]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(I)ccc2N)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(I)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 55 %

Procedure:
The title compound was prepared from (2-Amino-5-iodo-phenyl)-(4-methanesulfonyl-phenyl)-methanone [example A17] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 55%; MS: m/z=519 (M).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[S:32]1C=C[CH:34]=[C:33]1CC(O)=O.[CH3:41][O:42][C:43](=[O:58])[C:44]1[CH:49]=[CH:48][C:47]([CH2:50][OH:51])=[CH:46][C:45]=1[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:41][O:42][C:43](=[O:58])[C:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:51][C:33](=[S:32])[CH3:34])=[CH:46][C:45]=1[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(O)Cc1cccs1
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COC(C)=S)cc1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To triphenylphosphine (1.2 equivalents) in THF at −78° C. is added diethylazodicarboxylate (1.2 equivalents) in THF. After 10 min thiolacetic acid (1.3 equivalents) in THF is added followed by the resultant compound from Example 16B (1. equivalent) in THF. The reaction is stirred at −78° C. for 1 h and then at ambient temperature until it is judged to be complete by TLC analysis. The mixture is evaporated and the residue is taken up in methanol and is treated with K2CO3 (2 equivalents). When the reaction is judged to be complete by TLC analysis, the solvent is evaporated and the residue is chromatographed on silica gel to afford the title product.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.C(OCC)C.[C:13]([O:17][C:18]([NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[C:27]([OH:29])=[O:28])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=CC=CC=1>CO>[CH3:1][O:28][C:27]([C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]1[NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (5.0 mL, 10.0 mmol) was added over 10 min to a solution of (1S,2R)-2-tert-butoxycarbonylamino-1-cyclohexanecarboxylic acid (0.994 g, 4.09 mmol; purchased from NeoMPS) in a 1:1 mixture of benzene and methanol (50 mL) at 25° C. The resulting mixture was stirred at 25° C. for 30 min, and then was partitioned between half-saturated sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo to afford the desired product, (1S,2R)-2-tert-butoxycarbonylamino-1-cyclohexanecarboxylic acid methyl ester (1.00 g, 3.89 mmol, 95%), as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.44 (9H, s), 1.58-1.68 (3H, m), 1.72-1.81 (2H, m), 1.98-2.05 (2H, m), 2.77-2.80 (1H, m), 3.69 (3H, s), 3.82-3.90 (1H, m), 5.29-5.31 (1H, m). LC-MS (ESI) calcd for C13H23NO4 257.16, found 258.2 [M+H+].
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:26][NH:27][O:28][CH3:29]>CN(C=O)C.C(Cl)Cl>[CH3:29][O:28][N:27]([CH3:26])[C:6]([C:5]1[S:1][C:2]2[CH2:12][CH2:11][CH2:10][CH2:9][C:3]=2[CH:4]=1)=[O:7]
Reactant: O=C(O)c1cc2c(s1)CCCC2
Reactant: CNOC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2c(s1)CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (3.00 g, 16.5 mmol), methylene chloride (80 mL), and DMF (60 mg, 0.825 mmol) and cooled to 0° C. To the resulting solution, oxalyl chloride (2.31 g, 18.2 mmol) was added dropwise. After this addition was complete, the reaction was warmed to room temperature and stirred for 2 h. After this time, the reaction was concentrated to dryness under reduced pressure. The resulting white solid was dissolved in methylene chloride (80 mL) and the solution cooled to 0° C. Triethylamine (5.00 g, 49.5 mmol) and N,O-dimethylhydroxylamine (1.61 g, 16.5 mmol) were then added. After the addition was complete, the cooling bath was removed, and the reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (100 mL), followed by brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford an 88% yield of 105a (3.29 gm) as a white solid: mp 36-37° C.; 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 3.76 (s, 3H), 3.34 (s, 3H), 2.78 (t, 2H, J=6.0 Hz), 2.62 (t, 2H, J=6.0 Hz), 1.82 (m, 4H); MS (APCI+) m/z 226.3 (M+H)
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[Br:10][C:11]1[C:12]([CH3:22])=[N:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:15][CH:16]=1.[K].O>CN(C=O)C>[Br:10][C:11]1[C:12]([CH3:22])=[N:13][C:14]([N:17]([CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:15][CH:16]=1
Reactant: Cc1nc(NS(C)(=O)=O)ncc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N(COCC[Si](C)(C)C)S(C)(=O)=O)ncc1Br
Reaction time: 0.33 h

Procedure:
[2-(Chloromethoxy)ethyl]trimethylsilane (0.4 ml) was added to a solution of the product from step (i) in DMF (10 ml) and stirred for 20 min. The mixture was poured into water, extracted with ether, washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 20% EtOAc/isohexane. Yield 0.53 g.
Reaction SMILES: N([O-])=O.[Na+].Cl.N[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14].O(CC)C([S-])=[S:17].[K+].[OH-].[K+]>O.C(O)C>[OH:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:14])[C:7]=1[SH:17]
Reactant: CCOC(=S)[S-]
Reactant: Cc1cccc(O)c1N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(O)c1S
Temperature: 100 °C
Reaction time: 3 h

Procedure:
5.3 g (0.077 mol) of sodium nitrite in solution in 12 ml of water are added dropwise to a round-bottomed flask comprising 14 g of ice, 14 ml of 36% hydrochloric acid and 8.62 g (0.07 mol) of 2-amino-m-cresol. The mixture, kept at 0° C., is subsequently poured slowly into a solution of 15 g (0.093 mol) of potassium ethyl xanthate in 20 ml of water held at 40° C. The heating bath is removed and the mixture is stirred for 3 hours and then extracted with ethyl ether. The combined organic phases are washed with aqueous saline solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by fast chromatography on silica gel (eluent: cyclohexane/dichloromethane=65:35). The oil obtained is taken up in 20 ml of ethanol and the mixture is heated to 100° C. 20 ml of an ethanolic potassium hydroxide solution (7N) are then added dropwise. After 4 hours at 100° C., the mixture is cooled, concentrated under reduced pressure, acidified using hydrochloric acid (2N) and then extracted with ethyl ether. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil which is not isolated but is used directly in the following stage.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[S:26][C:27]([O:30][C:31]2[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:28][N:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCl.O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:24][C:25]3[S:26][C:27]([O:30][C:31]4[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=4)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:28][N:29]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cccc(Oc2cnc(N)s2)c1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A 1 L two necked round bottom flask maintained under inert atmosphere was charged with 2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (16 g, 47 mmol; preparation 4), ethyl 3-(2-aminothiazol-5-yl)oxybenzoate (13.6 g, 51 mmol; preparation 20), HOBt (7.6 g, 56 mmol) and EDCl (10.8 g, 56 mmol) in Dichloromethane (500 mL). The reaction mixture was stirred at 25° C. and added triethylamine (15.8 mL, 113 mmol). The resulting mixture was continued to stir for 16 hours at 25° C. Completion of reaction was confirmed by TLC. The reaction mixture was diluted with water (400 mL) and DCM (250 mL). The layers were separated. The aqueous layer was again extracted with DCM (2×200 mL). The combined organic layer was washed with 1N HCl (300 mL), brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained residue was purified by column chromatography using 5-40% ethyl acetate in hexanes as solvent system to get a pure product (16 g).