Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[N:32][CH:33]=2)[CH:12]=[CH:11][C:10]=1[C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=1.Cl>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][C:18]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[N:32][CH:33]=2)[CH:12]=[CH:11][C:10]=1[C:44]1[CH:45]=[CH:46][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:49]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)cc(-c2ccc(C(=O)NCCC(=O)O)nc2)c1CNc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C

Procedure:
A 3M aqueous NaOH solution (0.13 mL, 0.39 mmol) was added to a THF (2.0 mL) and MeOH (1.0 mL) solution of ethyl 3-(5-(2-(((2-chloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)-3-methyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (44 mg, 0.07 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][C:15]=2[C:22](=[O:33])[NH:23][C:24]2[CH:32]=[CH:31][C:27]3[N:28]=[CH:29][S:30][C:26]=3[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]([C:37]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=1)=[C:35]=S>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:22](=[O:33])[NH:23][C:24]3[CH:32]=[CH:31][C:27]4[N:28]=[CH:29][S:30][C:26]=4[CH:25]=3)=[CH:16][C:17]3[N:21]=[C:35]([NH:34][C:37]4[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=4)[NH:20][C:18]=3[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3ncsc3c2)CC1
Reactant: Cc1cccnc1N=C=S
Solvent: ClCCCl
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4ncsc4c3)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1

Procedure:
4-[4,5-diamino-2-(benzothiazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylic acid tert-butyl ester (see Example 163; 0.3 mmol) was reacted with 2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from 2-amino-3-methylpyridine and thiophosgene employing procedure described in Example 115) followed by cyclization in situ using EDC as described in general procedure B to provide 4-[6-(Benzothiazol-6-ylcarbamoyl)-2-(3-methyl-pyridin-2-ylamino)-3H-benzoimidazol-5-yl]piperazine-1-carboxylic acid tert-butyl ester. MS: m/z 585 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C@@H:11]([O:43][C:44]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:58][CH2:57][C:56]4[CH:59]=[CH:60][CH:61]=[CH:62][C:55]=4[NH:54][C:53]3=[O:63])[CH2:48][CH2:47]2)=[O:45])[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]>N1CCCCC1>[O:63]=[C:53]1[N:52]([CH:49]2[CH2:48][CH2:47][N:46]([C:44]([O:43][C@H:11]([CH2:10][C:4]3[CH:5]=[C:6]([Br:9])[C:7]([OH:8])=[C:2]([Br:1])[CH:3]=3)[C:12](=[O:13])[N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:45])[CH2:51][CH2:50]2)[CH2:58][CH2:57][C:56]2[CH:59]=[CH:60][CH:61]=[CH:62][C:55]=2[NH:54]1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Solvent: C1CCNCC1
Product: O=C(O[C@H](Cc1cc(Br)c(O)c(Br)c1)C(=O)N1CCC(N2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 200 mg (0.20 mmol) 9H-fluoren-9-ylmethyl 4-(1-{(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate (Example 133) in 4 mL piperidine was stirred for 30 min at RT. The reaction mixture was evaporated down i.vac. and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 80:20:2).
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([SH:20])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.[H-].[Na+].[C:24](Cl)(=[O:26])[CH3:25].C(O)C>O1CCCC1>[Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([S:20][C:24](=[O:26])[CH3:25])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Sc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
At room temperature, a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol in 20 ml of absolute tetrahydrofuran is admixed with stirring with 0.24 g (6 mmol) of sodium hydride (60% strength in paraffin oil) and stirred for 30 minutes. 0.72 ml (10 mmol) of acetyl chloride are then added and the reaction mixture is stirred at room temperature for a further 4 hours. The reaction mixture is then admixed with 1 ml of ethanol and concentrated under reduced pressure. The residue that remains is extracted repeatedly with dichloromethane. The combined organic phases are concentrated under reduced pressure. In this manner, 1.8 g (94% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-acetylmercapto-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:19][CH2:30][O:31][CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: CC(=O)OC[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1COC(C)=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
To a solution of (±)-cis-4-acetoxymethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (45.0 mmol, 12.3 g) in anhydrous DCM (100 mL) at room temperature was added N,N-diisopropylethyl amine (180 mmol, 31.4 mL). The reaction mixture was cooled to 0° C. using an ice bath. To this was added chloromethylmethyl ether (135 mmol, 11.4 mL) dropwise over 15 minutes. After completion of addition, the reaction was stirred for 12 hours while coming to room temperature. All volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 110 g SiO2 cartridge using ethyl acetate/hexanes gradient to give (±)-cis-4-acetoxymethyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (13.3 g).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]([CH2:13][O:14][CH2:15][CH2:16]O)([CH2:8][O:9][CH2:10][CH2:11]O)[CH3:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[S:24]([CH2:16][CH2:15][O:14][CH2:13][C:6]([CH2:5][O:4][CH2:3][CH2:2][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([CH2:8][O:9][CH2:10][CH2:11][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH3:7])([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: CC(COCCO)(COCCO)COCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CCOCC(C)(COCCS(=O)(=O)c2ccc(C)cc2)COCCS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 15 h
Yield: 50 %

Procedure:
A solution of 1,1,1-tris(hydroxyethoxymethyl)ethane (6.7 g, 0.026 mol) in 35 mL of anhydrous pyridine was cooled to -10° C. Then solid p-toluenesulfonyl chloride (16.6 g, 0.087 mol) was added in portions over 1.5 hrs. The mixture was kept at -10° C. for 15 hrs. The resulting slurry was partitioned between dichloromethane (100 mL) and water (50 mL) and the layers were separated. The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and evaporated to give a crude gum. This material was purified over silica gel using 1% methanol/dichloromethane as eluant to give 1,1,1-tris(tosylethoxymethyl)ethane (8.9 g, 0.013 mol, 47%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[OH:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[N:1]1[C:15](=[O:16])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]1=[O:17]
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccccc2C[C@H]1O
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A suspension of (1R,2R)-1-aminoindan-2-ol (1.40 g, 0.00938 mol), phthalic anhydride (1.39 g, 0.00938 mol), and N,N-diisopropylethylamine (1.63 mL, 0.00935 mol) in toluene (141 mL) in a 250 mL round bottom flask equipped with a Dean-Stark trap and condenser was stirred at reflux under an atmosphere of nitrogen 18 h. The reaction mixture was cooled to rt. TLC showed complete conversion of starting material to a higher Rf spot. 1H NMR of an aliquot sample partitioned between EtOAc and water confirmed that reaction was complete. The reaction mixture was concentrated to a pale white and pale brown solid, redissolved in EtOAc (25 mL), washed with 1N HCl (2×10 mL), aqueous saturated NaHCO3 (1×10 mL), and brine (1×10 mL), dried over Na2SO4, filtered, concentrated, and dried on high vacuum to give the product as an off-white solid (2.53 g, 97%). 1H NMR (CDCl3, 400 MHz, δ): 7.86-7.84 (m, 2H), 7.74-7.72 (m, 2H), 7.26-7.25 (m, 2H), 7.20-7.14 (m, 1H), 7.01 (d, J=7.5 Hz, 1H), 5.67 (d, J=6.3 Hz, 1H), 5.14 (m, 1H), 3.58 (dd, J=7.5, 16.1 Hz, 1H), 2.97 (dd, J=6.8, 15.8 Hz, 1H), 2.12 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:26](=[O:27])[C:25]5[CH:29]=[CH:30][C:22]([O:21][CH2:20][CH2:19][OH:18])=[CH:23][CH:24]=5)=[CH:10][CH:9]=4)[CH:5]=[N:6]3)=[CH:12][CH:13]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc(OCCO)cc1
Product: O=C(Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(OCCO)cc4)ccc32)cc1)c1ccc(OCCO)cc1

Procedure:
Compound 995 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-(2-hydroxyethoxy)benzoic acid. [M+H]+ calcd for C31H29N4O6: 553.21; found: 553.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[CH2:28][C@@H:29]2[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:34][C:31]1([CH3:35])[O:30][C@H:29]([CH2:28][O:15][C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH2:33][O:32]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)O1
Temperature: 90 °C
Yield: 104.7 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.00 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (343 mg, 1.20 mmol) in DMF (5 mL) was added Cs2CO3 (650 mg, 2.00 mmol). The mixture was heated at 90° C. for 4 hours. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness to yield (R)-2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (350 mg) which was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:12][O:13][CH:14]=[CH:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nccc(C=O)n1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: COC=Cc1ccnc(SC)n1

Procedure:
Alternatively, intermediate 7 used in the synthesis of compounds of formula Ia can be prepared according to Schemes 2-4 below. 2-Methylsulfanyl-pyrimidine-4-carbaldehyde (8) can be condensed with (methoxymethyl)triphenylphosphonium chloride (Wittig reaction) to give 4-(2-methoxy-vinyl)-2-methylsulfanyl-pyrimidine (9). Oxidation of (9) with N-bromosuccinimide in methanol provides 4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (10). Condensation of (10) with 2-amino-3-chloropyrazine (1) in aqueous acid and a co-solvent such as acetone gives 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (11). Compound 11 can then be reacted with an appropriate amine (HNR1R2) either in excess or in the presence of another base, such as diisopropyl ethyl amine, in an appropriate solvent, such as ethanol or butanol, between room temperature to reflux to give the intermediate 7. Intermediate 7 can also be prepared via the ethyl homologs 9′ and 10′ according to Scheme 4 below. Compound 9′ (the ethyl homolog) can be prepared by the reaction ethyl ethynyl ether (13) with borane—tetrahydrofuran complex followed by palladium catalyzed coupling with 4-chloro-2-(methylthio)pyrimidine (12). Oxidation of 9′ with N-bromosuccinimide in ethanol provides the ethyl homolog 10′. Homolog 10′ can be converted to intermediate 7 in the same way as 10.
Reaction SMILES: [F:1][C:2]([F:23])([O:9][CH:10]([F:22])[C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:3]([F:8])([F:7])[CH:4]([F:6])[F:5].[CH3:24][N:25]1[C:32](=[O:33])[CH:31]([C:34](OCC)=[O:35])[C:29](=[O:30])[N:28]([CH3:39])[C:26]1=[O:27]>C1(C)C=CC=CC=1>[CH3:39][N:28]1[C:29](=[O:30])[CH:31]([C:34](=[O:35])[NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:21])([F:20])[CH:10]([O:9][C:2]([F:23])([F:1])[C:3]([F:7])([F:8])[CH:4]([F:5])[F:6])[F:22])=[CH:14][CH:15]=2)[C:32](=[O:33])[N:25]([CH3:24])[C:26]1=[O:27]
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Reactant: Nc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)F)cc1
Solvent: Cc1ccccc1
Product: CN1C(=O)C(C(=O)Nc2ccc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)F)cc2)C(=O)N(C)C1=O

Procedure:
14.50 g (40.6 mmol) of 4-(2-(1,1,2,2,3,3-hexafluoropropoxy)-1,1,2-trifluoroethoxy)-aniline were added to 9.26 g (40.6 mmol) of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid in 100 ml of toluene, the mixture was stired under reflux for 2.5 hours and concentrated and the residue was recrystallized from methanol.
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[C:11]([Cl:26])[S:10][C:9]=1[NH2:27])=[O:7])C>C1COCC1.[OH-].[Na+].CO>[Cl:26][C:11]1[S:10][C:9]2[NH:27][C:6](=[O:7])[C:8]([C:9]#[N:27])=[C:6]([OH:7])[C:8]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1
Reactant: CCOC(=O)COc1ccc(-c2c(Cl)sc(N)c2C(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c(O)c2c(-c3ccc(OCC(=O)O)cc3)c(Cl)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ambient suspension of NaH (235 mg, 5.89 mmol, 60% dispersion in mineral oil, washed with dry hexane) in dry THF (6 mL) was added 2-amino-4-(4-ethoxycarbonylmethoxy-phenyl)-5-chloro-thiophene-3-carboxylic acid ethyl ester (1.06 g, 2.36 mmol) as a solution in THF (6 mL). The reaction was stirred overnight at room temperature and was then diluted with 1N NaOH (10 mL) and MeOH (10 mL). After stirring an additional 1.5 h at room temperature, the reaction was concentrated under reduced pressure to ˜20 mL. The solution was acidified to pH ˜1 with 1N HCl and extracted with EtOAc (3×30 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a beije solid that was used without further purification. MS (ESI) m/e 375 (M−H)−; 1H NMR (300 MHz, BENZENE-d6) δ ppm 4.72 (s, 2H), 6.94 (d, J=8.48 Hz, 2H), 7.26 (d, J=8.48 Hz, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(O[Cl:15])(C)(C)C>CO>[Br:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[N:4]1[Cl:15]
Reactant: CC(C)(C)OCl
Reactant: CC1(CBr)COC(=O)N1
Solvent: CO
Product: CC1(CBr)COC(=O)N1Cl
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A solution of 4-(bromomethyl)-4-methyloxazolidin-2-one (1.33 g, 6.86 mmol) in MeOH (10 ml) was cooled to 0° C. and tert-butylhypochlorite (1.0 ml, 8.4 mmol) as added dropwise. The solution was stirred for 30 min, concentrated in vacuo, and the residue purified by flash chromatography (20% to 60% ethyl acetate in hexanes) to afford the title compound as a white solid (960 mg, 4.20 mmol, 61%). 1H NMR (CDCl3, 400 MHz) δ 1.57 (s, 3H), 3.45 (d, J=10.4 Hz, 1H), 3.60 (d, J=10.8 Hz, 1H), 4.20 (d, J=8.8 Hz, 1H), 4.51 (d, J=8.8 Hz, 1H). LRMS (ESI/APCI): 228 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:13][CH2:12][CH:11]([O:14][Si](C(C)(C)C)(C)C)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[NH2:7][C:8]1([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1
Reactant: COCCCC1(NC(=O)OC(C)(C)C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCC1(N)CCC(O)CC1
Temperature: 25 °C

Procedure:
200 mg of the crude [4-(tert-butyl-dimethyl-silanyloxy)-1-(3-methoxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (33, step a) were dissolved in 10 mL of dichloromethane and treated with 370 μL of trifluoroacetic acid. After stirring at room temperature until complete conversion was achieved, 2M aqueous hydrochloric acid was added, the mixture stirred for further 60 min and the aqueous phase evaporated. The crude aminoalcohol was lyophilized from water and used crude as hydrochloride in the next reaction. Rt=0.18 min, 0.37 min (Method C). Detected mass: 188.3 (M+H+).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[CH:31](OCC)=[O:32].Cl>C1COCC1>[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[C:18]=1[CH:31]=[O:32]
Reactant: CCOC=O
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Br)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A 2.59 M hexanes solution of n-BuLi (1.13 mL, 2.92 mmol) was added dropwise to a, 0° C., THF solution (4 mL) of 2,2,6,6-tetramethylpiperidine (0.50 mL, 2.92 mmol). After 5 min at 0° C., the solution was cooled to −78° C. and 1-bromo-3,5-bis(trifluoromethyl)benzene was added dropwise over 2 min. The resulting brown amber colored solution was stirred at −78° C. for an additional 20 min. Ethyl formate (0.587 mL, 7.30 mmol) was then added dropwise at −78° C. over 1 min. After 30 min at −78° C., 1 M aqueous HCl was added, the layers were separated and the organic layer was washed with 0.1 M aqueous HCl and 1 M aqueous. The organic layer was dried (Na2SO4), concentrated, and short path vacuum distilled to provide the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:15](Cl)[CH2:16]Cl.C1C=CC2N(O)N=NC=2C=1>C(O)C>[CH2:15]([O:13][C:12](=[O:14])[CH:2]([NH2:1])[CH2:3][CH2:4][C:5]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:11])[CH3:16]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)O
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CCO
Product: CCOC(=O)C(N)CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A dry 250 mL round-bottomed flask was charged with 2.200 g (10.800 mmol) H-Glu(O-t-Bu)-OH (41a) dissolved in 100 mL ethanol. To this was added 4.4 g (22.9 mmol) EDC and 3.2 g (23.7 mmol) HOBt. The reaction mixture was stirred at ambient temperature for 22 h. The reaction mixture was followed to completion according to the LC-MS data. The solvent was removed under reduced pressure and the resulting oil was dissolved in dichloromethane 300 mL and extracted with H2O 300 mL. The H2O-phase was adjusted to pH 9.5. The crude product was extracted into dichloromethane 400 mL, dried over NaSO4, filtrated and evaporated.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][C@H:13]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:12]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:21]1[C:16]([O:15][C@H:13]2[CH2:14][C@H:9]([OH:8])[CH2:10][CH2:11][C@@H:12]2[C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)=[CH:17][C:18]([F:44])=[C:19]([S:23]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:20]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC[C@@H](O)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 24.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (59.0 mg, 0.0791 mmol) prepared in Example 160b, triethylsilane (0.050 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), to yield the title compound (9.5 mg, 25%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]([NH2:15])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13](=[S:25])[NH2:15]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)/C=C/c1cc([N+](=O)[O-])ccc1Cl
Solvent: C1CCOC1
Product: NC(=S)/C=C/c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution composed of 5.0 g of (E)-3-(2-chloro-5-nitrophenyl)-2-propenamide, 4.4 g of Lawesson's reagent and 100 ml of tetrahydrofuran was stirred under a positive argon atmosphere at room temperature for 16 hr. The volatiles were then removed in vacuo and the residual materials slurried with 100 ml of methylene chloride to yield (E)-3-(2-chloro-5-nitrophenyl)-2-propenethioamide as a orange solid; m.p. 236°-238° C. from acetonitrile.