Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]=2)[CH2:14]1)=O)C1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+].[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO.[C].[Pd]>[C:35]1([S:41]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]=3)[CH2:14]2)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)Cc1ccc2c(c1)CC(CNC(=O)OCc1ccccc1)C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 97 %

Procedure:
Dissolved in 30 ml of methanol were 1.80 g (4.90 mmol) of ethyl [2-(benzyloxycarbonylaminomethyl)indan-5-yl]acetate, and 500 mg of 10% palladium-carbon were added to the solution, followed by stirring for 2 hours under a hydrogen atmosphere. The catalyst was separated by filtration, and the filtrate was concentrated. The resultant residue was dissolved in 15 ml of ethyl acetate, and 10 ml of water and 1.18 g (8.51 mmol) of potassium carbonate were added to the solution. While vigorously stirring, 902 mg (5.11 mmol) of benzenesulfonyl chloride were then added dropwise. After the addition, the mixture was stirred for 1 hour, and an organic layer separated was taken out, dried and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to obtain 1.78 g of a colorless oily substance. Yield: 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].S([CH2:23][N+:24]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+]>COCCOC.CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:11])[C:23]#[N:24]
Reactant: COc1ccc(C(C)=O)c(Cl)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: COc1ccc(C(C)C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2′-chloro-4′-methoxyacetophenone (18.5 g, 0.10 mol) and tosylmethylisocyanide (TOSMIC, 21.5 g, 0.11 mol) in dry 1,2-dimethoxyethane (100 mL) was cooled to −10° C. A solution of t-BuOK (22.4 g, 0.20 mol) in dry t-BuOH (250 mL) was added slowly keeping the temperature below 5° C. The homogeneous orange solution was stirred for 2 h/0° C. and 1 h/25° C. The resulting suspension was evaporated to a slurry. Water (200 mL) was added and extracted with Et2O (3×150 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure leaving an orange oil. Yield: 19 g (97%). GCMS: >98%
Reaction SMILES: O[CH:2]1[O:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]1=[O:17].[CH3:18][C:19]([C:22]1[CH:26]=[CH:25][NH:24][N:23]=1)([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:18][C:19]([C:22]1[CH:26]=[CH:25][N:24]([CH:2]2[O:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[C:3]2=[O:17])[N:23]=1)([CH3:21])[CH3:20]
Reactant: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc[nH]n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccn(C2OCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-hydroxy-3-[3-(trifluoromethyl)phenyl]-4-oxazolidinone (1 g, 4.05 mmol) in tetrahydrofuran (20 mL) under nitrogen at ˜0° C., were added 3-(1,1-dimethylethyl)-1H-pyrazole (0.5 g, 4.05 mmol), triphenylphosphine (1.23 g, 4.7 mmol) and diisopropyl azodicarboxylate (0.88 mL, 4.46 mmol). After the addition, the reaction mixture was allowed to warm up slowly to room temperature and stirred at room temperature overnight. The reaction mixture was then concentrated, and the residue was purified by column chromatography (silica gel, ˜20% ethylacetate/80% hexanes) to give a crude product. The crude product was further purified by column chromatography (silica gel, ˜20% ethyl acetate/˜80% hexanes) to give the title compound, a compound of this invention, as a white solid (14 mg) melting at 95–98° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:67])[N:7](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([O:36]CC3C=CC([N+]([O-])=O)=CC=3)=[O:35])[CH2:25][N:24]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:22])[CH2:3]1.[ClH:68]>O1CCCC1.O>[ClH:68].[CH3:67][C:2]1([CH3:1])[NH:7][CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:3]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(C)(C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(C)(C)C4)C3)[C@H](C)[C@H]12

Procedure:
205 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3,3-dimethyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 5 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.23 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 200 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 35 mg of the title compound as a powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:20]([F:22])([F:21])[F:23])=[CH:10][C:9]3[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH:38]=[CH:37][CH:36]=[N:35]5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cccn3)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-morpholin-4-yl-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M32) (322 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (146 mg).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[OH:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>>[NH2:26]/[C:4](/[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Br:1])=[C:6]1\[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: N
Reactant: O=C(c1ccccc1Br)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1Br
Yield: 42 %

Procedure:
Prepared as in Example 1 from 2-(2-bromobenzoyl)-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated aqueous ammonia with a yield of 42% of theory. M.p. 143°-144° C. (petroleum ether/ethyl acetate 1:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)=[N:3][CH:2]=1.[H][H]>[Pd].CO>[N:8]1([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCN(Cc2ccncn2)CC1
Agent: [Pd]
Solvent: CO
Product: c1cc(CN2CCNCC2)ncn1

Procedure:
To 0.01 g (0.09 mmol) of 10% palladium on carbon was added a solution of 0.14 g (0.45 mmol) of the title compound from Step A in 5 mL anhydrous methanol. The resulting suspension was subjected to hydrogen at atmospheric pressure while stirring. After 4 h the mixture was filtered through a pad of Celite. The pad was washed with methanol (25 mL) and the combined filtrates were concentrated in vacuo to afford the title compound as a pale yellow residue without further purification. LC/MS: m/z (ES) 179.1 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18](=O)[C:19](OC)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)(C)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
A suspension of methyl 5-benzyloxyindol-3-ylglyoxylate (10 g.) and sodium borohydride (3.7 g.) in isopropanol (100 ml.) was stirred and refluxed for 5 hours. The cooled mixture was diluted with water and extracted with dichloromethane. Evaporation of the extract gave a pale yellow oil which crystallised from a mixture of toluene and petroleum ether to give 5-benzyloxy-3-(2-hydroxyethyl)indole as a white crystalline powder m.p. 97°-98°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[I-:14].[Na+].[Cl-].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1
Reactant: ClCCCCCOC1CCCCO1
Reactant: [I-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCOC1CCCCO1
Yield: 87.9 %

Procedure:
A solution of 2-(5-chloropentyloxy)tetrahydro-2H-pyrane (10) (20.67 g, 0.1 mol) in dry acetone (50 mL) was added in drops to a magnetically stirred solution of sodium iodide (16.49 g, 0.11 mol) in dry acetone (150 mL). The reaction mixture was refluxed in a nitrogen atmosphere over night. After cooling the precipitated sodium chloride was filtered out and acetone was distilled out on a rotary evaporator. The residue which still contained some sodium chloride was dissolved in dry pentane (200 mL). Sodium chloride was filtered out and pentane distilled out on a rotary evaporator, yielding 26.2 g (88%) of a yellowish brown oil. NMR indicated a pure product.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH3:20])[CH:14]=[C:13]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)=O>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH3:20])[CH2:14][CH:13]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Agent: [Pd]
Solvent: O=CO
Product: CCN1CC(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Temperature: 80 °C
Yield: 73.7 %

Procedure:
Palladium-on-carbon (10% w/w, 0.5 g.) was added to a mixture of methyl 4-[5-(2-cyclopentylacetamido)-1-ethylindol-3-ylmethyl]-3-methoxybenzoate (0.5 g., prepared as described in Example 80), and formic acid (99%, 20 ml.), under an atmosphere of nitrogen. The mixture was vigorously stirred and heated at 80° C. for one hour. The cooled mixture was filtered through a pad of diatomaceous earth, the filter cake washed with methanol, and the filtrate evaporated. The resulting oil was dissolved in ethyl acetate (30 ml.) washed with water, brine, then dried (MgSO4) and evaporated. The product was purified by flash chromatography on silica gel (4 cm. diameter column), eluting with 2:3 v/v ethyl acetate:hexane, to give the title compound (0.37 g., 80%) as a foam; NMR (250 MHz, DMSO-d6): 1.04 (t,3 H, --CH2C/e,uns/H/ 3); 1.15 (m,2 H, cyclopentyl ring); 1.4-1.8 (m,6 H, cyclopentyl ring); 2.2 (m,3 H); 2.7 (dd,1 H); 2.85-3.25 (m,5 H); 3.45 (m,1 H); 3.86 (s,3 H, OCH3); 3.87 (s,3 H, OCH3); 6.43 (d,1 H); 7.20 (m,2 H); 7.30 (d,1 H); 7.50 (m,2 H); 9.47 (s,1 H, NH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 62.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (1.12 g, 1.544 mmol) was deprotected in TFA/DCM (10/5 ml). This afforded 600 mg (64.8% yield) of the titled compound. MS: m/z=625.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>CN(C)C=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:13]([CH2:12][O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:7]=2)=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: Oc1cncc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1COc1cncc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of 3-fluoro-5-hydroxypyridine (34 mg, 0.30 mmol) in dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 12 mg, 0.30 mmol) at 0° C. and the mixture was stirred at room temperature for 15 minutes. To the mixture was added methyl 2-(bromomethyl)-5-chlorobenzoate (100 mg, 0.4 mmol) in dimethylformamide and the mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel to afford 47 mg (53%) of the title compound:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([C:16]2[S:20][C:19]([NH2:21])=[N:18][N:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:11]1([C:16]2[S:20][C:19]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:18][N:17]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Nc1nnc(C2CCCC2)s1
Reactant: O=C(O)c1ccccc1F
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1nnc(C2CCCC2)s1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a 20 ml scintillation vial was added 2-fluorobenzoic acid (845 mg, 5.0 mmol) and commercially available 5-cyclopentyl-1,3,4-thiadiazol-2-amine (intermediate 49) (700 mg, 5.0 mmol). To this was added EDC (960 mg, 5 0 mmol) and HOAt (675 mg, 5.0 mmol) followed by 25 ml DCM. The reaction mixture was stirred with a Teflon covered magnetic stir-bar at room temperature for overnight. The product was collected by ethyl acetate and 5% HCl solution work up, and then to purified by column (CH3OH/DCM, 1-10% gradient system), yielding N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide (0.61 g, 42%) as solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].CC[O-].[Na+].[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=O)[CH3:15]>CCO>[OH:8][C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=[C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:23])[N:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1sccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc(O)c2sccc2n1
Yield: 73.7 %

Procedure:
A mixture of 3-aminothiophene-2-carboxamide (1.23 g, 8.65 mmol) and EtOH (25 mL) was treated with NaOEt (1.2 g, 17.3 mmol) and diethyloxalate (2.3 mL, 17.3 mmol), refluxed for 18 h, cooled, concentrated in vacuo, treated with water, acidified with HOAc and filtered to give the title compound (1.43 g, 74%) as a cream solid: IR νmax Nujol)/cm−1 3180, 3119, 3078, 3006, 2955, 2924, 2854, 1737, 1667, 1651, 1300 and 1176; NMR δH (400 MHz, DMSO) 1.37 (3H, t, J 7.0 Hz), 4.40 (2H, q, J 7.0 Hz), 7.58 (1H, d, J 5.0 Hz), 8.30 (1H, d, J 5.1 Hz), and 12.92 (1H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH:11]([CH2:13][CH3:14])[CH3:12]>>[CH:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH2:13][CH3:14])[CH3:12]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCC(C)Br
Product: CCC(C)n1ccc2ccccc21

Procedure:
The title compound was prepared according to general procedure A described in Scheme 1 from indole and 2-bromobutane. The crude material was used directly without further purification.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].N1C=CC=CC=1.[S:23]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24]1>ClCCl>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][S:23][CH:24]=1
Reactant: O=C(Cl)Cc1ccsc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccsc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A mixture of the product of Example 11B (30.2 mg, 0.13 mmol), pyridine (0.14 mL, 0.17 mmol), and 2-(thiophen-3-yl)acetyl chloride (24.0 mg, 0.15 mmol) in dichloromethane (0.4 mL) was stirred for 3 hours, concentrated, and chromatographed (20% acetone/hexanes) to give the title compound (33.8 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.82-11.94 (m, 1H), 8.44 (dd, J=7.9, 1.5 Hz, 1H), 8.11-8.17 (m, 1H), 8.00-8.09 (m, 2H), 7.36-7.58 (m, 2H), 7.14 (dd, J=4.9, 1.3 Hz, 1H), 3.74 (s, 2H); MS (ESI−) M/Z 352 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]S(C)(=O)=O)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:50]=[CH:49][C:31]([CH2:32][N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]2[C:42]2([OH:48])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:30][CH:29]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:45]2[CH2:46][CH2:47][C:42]([C:34]3[N:33]([CH2:32][C:31]4[CH:49]=[CH:50][C:28]([F:27])=[CH:29][CH:30]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)([OH:48])[CH2:43][CH2:44]2)([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1=O
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Product: O=C1N(Cc2ccccc2)CCC1(CCN1CCC(O)(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1)Cc1ccccc1

Procedure:
Prepare by the method of Example 6.6.2 using 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.31 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH2:6])[CH3:2].[C:17]([O:21][C:22](=[O:26])[CH:23](Br)[CH3:24])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:24])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCCCCCCSC[C@H](N)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 20 ml of HMPA were dissolved 5.9 g of S-heptyl-L-cysteine ethyl ester and 5.5 g of 2-bromopropionic acid t-butyl ester. A 3.4 ml quantity of triethylamine was added to the solution. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was separated and purified by silica gel column chromatography (a 1:3 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound as a colorless oil from the first eluate. Yield 2.8 g.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].P([O-])(O)(O)=[O:14].[Na+].Cl([O-])=O.[Na+]>CS(C)=O.O>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]([OH:14])=[O:5])=[C:2]([CH3:1])[C:9]=1[CH3:10]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(C=O)c(C)c1C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
60.0 g of 2,3-dimethyl-4-methoxybenzaldehyde (DI) are dissolved in 1.20 l of dimethyl sulfoxide. A solution of 131.5 g of sodium dihydrogenphosphate and 132.2 g of sodium chlorite in 480 ml of water is subsequently added dropwise, during which the temperature of the reaction batch is kept below 40° C. The reaction mixture is then stirred at room temperature for a further 2 hours. For work-up, the suspension is diluted with 2.0 l of water and stirred for a further hour. The resultant precipitate is filtered, washed with water and dried at 100° C. in vacuo, giving 65.0 g of the title compound as colourless solid having a melting point of 214° C. (MS: 181.2 (MH+)).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:31])[C:28]#[C:29][CH3:30]>>[CH2:27]([O:31][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1)[C:28]#[C:29][CH3:30]
Reactant: CC#CCO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CC#CCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (150 mg; 0.395 mmol), intermediate 42.1, and 2-butin-1-ol (112 mg; 1.578 mmol), example 62 was prepared analogously to the procedure for the preparation of example 42.