Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCOc1ccc(C(=O)Nc2ccccc2)cc1N
Product: CCOc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 77 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-ethoxy-N-phenyl-benzamide from Example 10 (0.335 g, 1.30 mmol) and 3,5-dichlorophenyl isothiocyanate (0.266 g, 1.30 mmol) to give the product (0.4609 g); m.p. 201-202° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10]C(=O)C.CC(O)=O.[N:18](OCCC(C)C)=O>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3](=[C:4]([CH3:9])[CH:5]=1)[NH:10][N:18]=[CH:1]2
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1c(C)cc(C)cc1C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C)c2[nH]ncc2c1
Yield: 100.3 %

Procedure:
N-(2,4,6-trimethyl-phenyl)-acetamide (23.8 g, 133 mmol) (prepared as described in Example 12) was dissolved in a mixture of toluene (300 mL) and glacial AcOH (10.4 g, 173 mmol, 1.3 eq) and then treated slowly with isoamyl nitrite (20.3 g, 23.2 mL, 173 mmol, 1.3 eq). The mixture was heated at reflux overnight or until all the starting material was consumed as judged by TLC (30% EtOAc-hexanes). The solution was then poured into H2O (1.3 L) and extracted with EtOAc (2×300 mL). The combined organic extracts were then washed with saturated aq. NaHCO3 solution (2×200 mL) and brine (1×100 mL). The extracts were dried (MgSO4), filtered, and concentrated to provide 19.5 g of 5,7-dimethyl-1H-indazole 2 as a red waxy solid. This material was carried on without additional purification. RP-HPLC Method: 2-100% B in 2 minutes
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:41]3[CH2:46][CH2:45][C@@H:44]([N:47]4[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]4)[CH2:43][CH2:42]3)[N:21]=[C:22]([C:23]3[CH:40]=[CH:39][C:26]([NH:27][C:28]4[O:29][C:30]5[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:31]=5[N:32]=4)=[CH:25][CH:24]=3)[C:15]=12.[OH-].[Na+].O.OO>O1CCOCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:41]3[CH2:42][CH2:43][C@@H:44]([N:47]4[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]4)[CH2:45][CH2:46]3)[N:21]=[C:22]([C:23]3[CH:40]=[CH:39][C:26]([NH:27][C:28]4[O:29][C:30]5[CH:36]=[CH:35][C:34]([C:37]([NH2:38])=[O:3])=[CH:33][C:31]=5[N:32]=4)=[CH:25][CH:24]=3)[C:15]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cc(C#N)ccc6o5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cc(C(N)=O)ccc6o5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 120 %

Procedure:
To a mixture of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1,3-benzoxazole-5-carbonitrile triacetate (0.18 g, 0.00025 mol) in dioxane (2 mL) were added a 2N aqueous solution of sodium hydroxide (1.25 mL, 0.0025 mol) and water (0.75 mL). The mixture was stirred at room temperature for 2 minutes under the atmosphere of nitrogen before adding 30% hydrogen peroxide solution (0.2 mL). The mixture was refluxed for 5 hours, then stirred at room temperature for 18 hours. More 30% hydrogen peroxide solution (0.2 mL) was added to the mixture before refluxing for additional 6 hours, then stirred at room temperature for 2 days. The organic solvent was removed under reduced pressure, and 5% citric acid solution was added to maintain pH 7. The aqueous layer was removed under reduced pressure, and the crude was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 25 min with 0.1 M ammonium acetate, 21 mL/min) to give cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1,3-benzoxazole-5-carboxamide triacetate (0.11 g, 0.00015 mol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reactant: Cn1c(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccc(Cl)cc2)n1C
Yield: 66.01 %

Procedure:
3-Benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-07) (340.0 mg, 66.01%) was synthesized as a light yellow solid from 3-benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-07) (500.0 mg, 1.08 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]2[C:14]3[CH2:15][CH2:16][CH2:17][C:13]=3[S:12][C:8]2=[N:9][C:10]=1[CH3:11].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:35]1[CH2:39]OC[CH2:36]1.ICCC>CN(C=O)C>[CH3:11][C:10]1[N:9]=[C:8]2[S:12][C:13]3[CH2:17][CH2:16][CH2:15][C:14]=3[C:7]2=[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]=1[CH:4]([CH2:36][CH2:35][CH3:39])[C:3]([O:2][CH3:1])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Yield: 85.8 %

Procedure:
This compound was prepared according to the procedure C from methyl[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.115 g; 0.341 mmol), LHMDS 1N in THF (0.375 mL; 0.375 mmol), 1-iodopropane (0.050 mL; 0.513 mmol) in DMF (5 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.111 g (86%) of the title compound as a yellow solid.
Reaction SMILES: [N+](C1C=CC(S(O[CH2:14][CH:15]2[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]2)(=O)=O)=CC=1)([O-])=O.[CH2:22]([O:24][C:25](=[O:38])[CH2:26][NH:27][S:28]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]=O)(=[O:30])=[O:29])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:21][C:17]1([CH3:20])[O:16][CH:15]([CH2:14][N:27]2[C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:38])=[CH:36][C:35]3[CH:34]=[CH:33][S:32][C:31]=3[S:28]2(=[O:30])=[O:29])[CH2:19][O:18]1
Reactant: CC1(C)OCC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reactant: CCOC(=O)CNS(=O)(=O)c1sccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CC1COC(C)(C)O1
Temperature: 55 °C
Reaction time: 12 h
Yield: 16.5 %

Procedure:
The product from Step A (46.5 g, 0.292 mol) was added in portions to a solution (room temperature) of (N-[[3-formyl-thien-2-yl]sulfonyl]glycine ethyl ester (27 g, 0.97 mol) in dimethylsulfoxide (200 mL) which contained potassium carbonate (40.45 g, 0.292 mol). This mixture was stirred at 55° C. for 12 h, cooled to 0° C, diluted with water, and extracted with ethyl acetate (3×200 mL). The combined extracts were dried (MgSO4) and evaporated to a crude oil which was purified by column chromatography (silica, 30% ethyl acetate in hexane) to give 18 g (50%) of the desired product as an oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][CH:8]=1)(C)C>O1CCCC1>[C:6]([C:7]1[N:12]=[C:11]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2ncccn2)n1
Solvent: C1CCOC1
Product: C#Cc1cccc(-c2ncccn2)n1
Reaction time: 2 h

Procedure:
Under argon, 500 mg (1.97 mmol) of 2-{6-[(trimethylsilyl)ethynyl]pyridin-2-yl}pyrimidine were initially charged in 20 ml of tetrahydrofuran at −5° C., 2.37 ml (2.37 mmol) of a 1 M solution of N,N,N-tributylbutane-1-ammonium fluoride in tetrahydrofuran were added and the mixture was stirred at this temperature for 2 hours. For work-up, the reaction mixture was filtered through silica gel (ethyl acetate), concentrated under reduced pressure and purified chromatographically. This gave 311 mg (87% of theory) of 2-(6-ethynylpyridin-2-yl)pyrimidine.
Reaction SMILES: [CH:1]1([CH2:6][S:7]([O-:10])(=O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].S(Cl)([Cl:14])=O>>[CH:1]1([CH2:6][S:7]([Cl:14])(=[O:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)([O-])CC1CCCC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Product: O=S(=O)(Cl)CC1CCCC1

Procedure:
The subtitle compound was prepared by the method of Preparation 58 from sodium cyclopentylmethanesulfonate [Preparation 64] and thionyl chloride, to afford cyclopentylmethanesulfonyl chloride as a solid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]>C(O)C>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: CCO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Yield: 10 %

Procedure:
Strain CD861 consumes essentially all the xylose in 30 hours, producing 16.1 g/L ethanol in that time. Ethanol yield for strain CD861 was 67%. The five XR+, XDH+ transformants all consumed xylose much more slowly, and produced average ethanol yields of about 16%. Strain CD861 produced a xylitol yield of 10%, but the five transformants averaged a xylitol yield of 56%. Xylose reductase activity for strain CD861 was about 2 mU/mg, whereas it ranged from 126-425 mU/mg in the transformants, after 73.5 hours cultivation. Xylitol dehydrogenase activity in strain CD861 was zero, but ranged from 21 to 98 mU/mg in the transformants after 73.5 hours cultivation. The increase in activities of these enzymes indicates that the reinserted KmXYL1 and KmXYL2 genes were functional in the five transformants. Xylose isomerase activity was higher in strain CD861 (˜131 mU/mg) than in the five transformants (˜26-45 mU/mg). However, xylitol that was present may have inhibited xylose isomerase activity in the five XR+, XDH+ transformants, resulting in an artificially low value.
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C1N=CN(C(N2C=NC=C2)=O)C=1.CCCCCCC.[C:43]([O:49][CH2:50][CH3:51])(=[O:48])[CH2:44]C(O)=O>C1COCC1>[Si:1]([O:18][C@H:19]([CH3:23])[C:20](=[O:22])[CH2:44][C:43]([O:49][CH2:50][CH3:51])=[O:48])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2R)-2-{[tert-Butyl(diphenyl)silyl]oxy}propanoic acid (the product from step i, 7.85 g) in THF (300 ml) was added CDI (4.26 g) and the reaction was stirred at room temperature for approximately 15 mins. In a separate flask (71.7 ml) of a 1M heptane solution was added to a solution of ethyl hydrogen malonate (9.47 g) in THF (300 ml) at 0° C. This solution was then allowed to warm to RT. The acyl imidazole solution was then transferred to the flask which contained the magnesium salt and the reaction was monitored for the next 2 d. When the reaction was complete it was quenched by the addition of 250 ml of sat. aq NH4Cl solution. The reaction mixture was then extracted with Et2O (3×200 ml). The combined organics were dried (MgSO4), filtered and reduced to yield a clear oil which was purified by column chromatography on silica gel 4% EtOAc/96% iso-hexane. This gave the subtitle compound as a colourless oil. Yield: 2.0 g
Reaction SMILES: [N:1]1([C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH:16]([C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C@H:30]3[CH2:32][C@H:31]3[CH2:33][CH2:34]O)[CH2:26][CH2:25]2)[O:21][N:20]=1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[N:1]1([C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C@@H:31]3[CH2:32][C@@H:30]3[CH:27]3[CH2:26][CH2:25][N:24]([C:22]4[O:21][N:20]=[C:19]([CH:16]([CH3:17])[CH3:18])[N:23]=4)[CH2:29][CH2:28]3)=[C:9]([F:14])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1ccc(O)c(F)c1)N1CCC1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cc3F)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(azetidin-1-yl)-2-(3-fluoro-4-hydroxyphenyl)ethanone (65.0 mg, 0.236 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethanol (59.0 mg, 0.283 mmol), triphenylphosphine, polymer-bound (186 mg, 0.534 mmol), and di-tert-butyl azodicarboxylate (109 mg, 0.472 mmol). The reaction mixture as stirred at RT for 3 hours. The mixture was filtered by Celite and concentrated. The residue The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-100% acetonitrile in 0.1% formic acid in water gradient), to give the title compound. LC/MS (m/z) 471.3 (M+H)+. Human EC50: 5.3 nM
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1>>[N:5]1([CH2:3][CH2:2][CH2:1][NH2:4])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: c1c[nH]cn1
Reactant: C=CC#N
Product: NCCCn1ccnc1
Reaction time: 6 h

Procedure:
Following the procedure of Schwan, J. Het. Chem. 4, 633 (1967), 25 ml. of acrylonitrile was heated to 70° C. A 13.6 g. portion of imidazole was added and the mixture was gradually heated to 90°-100° C. and maintained at that temperature for 3 hours. The mixture was then concentrated in vacuo to remove excess acrylonitrile, taken up in methanol and reconcentrated. The concentrate was added to 150 ml. of methanol, 100 ml. of concentrated ammonium hydroxide and 8 g. of Raney nickel catalyst in a Parr apparatus and subjected to hydrogenation at an initial pressure of 53 psi. After approximately 6 hours and the uptake of 32 psi. of hydrogen, the mixture was filtered. The filtrate was concentrated to remove the solvent, then concentrated once from ethanol, giving 1H-imidazole-1-propanamine as an oil. When this was added to 250 ml. of methanolic hydrogen chloride, concentrated to remove the solvent, boiled with 100 ml. of ethanol and then refrigerated, 20.3 g. of 1H-imidazole-1-propanamine dihydrochloride was obtained as a tan solid, m.p. 146°-150° C.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:3].CS(C)=[O:24]>C(O)CCC>[F:20][C:16]1[CH:15]=[C:14]([C:13]2[C:12](=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][C:4]=2[CH:2]([OH:24])[CH3:3])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(Br)c1oc2ccccc2c(=O)c1-c1cccc(F)c1
Reactant: CS(C)=O
Solvent: CCCCO
Product: CC(O)c1oc2ccccc2c(=O)c1-c1cccc(F)c1
Temperature: 120 °C
Yield: 64 %

Procedure:
To a solution of 2-(1-bromoethyl)-3-(3-fluorophenyl)-4H-chromen-4-one (30 g, 86.51 mmol) in DMSO (300 ml), n-butanol (15 ml) was added and heated to 120° C. for 3 h. The reaction mixture was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a off-white solid (16 g, 64%) which was used as such in next step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([OH:22])=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([NH:28][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.27 g of N-(tert-butoxycarbonyl)aspartic acid-4-benzyl ester and 1.31 mL of n-butyl amine were dissolved in 25 mL of DMF, and then 2.93 g of WSC hydrochloride and 1.93 g of HOBt were added thereto, and the reaction solution was stirred at room temperature overnight. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium hydrogen carbonate, dried with magnesium sulfate, and then distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 5.12 g of Compound 6.
Reaction SMILES: [CH:1]1C2NC3C(=CC=CC=3)SC=2C=[CH:3][C:2]=1[C:15](N[C@H](C(N[C@H](C(N[C@H](C(N[C@H]1CCOC1O)=O)CC(C)C)=O)CC(C)C)=O)CC(C)C)=O.[CH:48]1[C:61]2[NH:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[S:53][C:52]=2[CH:51]=[CH:50][C:49]=1[O:62][CH2:63][C:64]([NH:66][C@H:67]([C:72]([NH:74][C@H:75]([C:80]([NH:82][C@H:83]1[CH2:87][CH2:86][O:85][CH:84]1[O:88][CH3:89])=[O:81])CC(C)C)=[O:73])CC(C)C)=[O:65]>>[CH:48]1[C:61]2[NH:60][C:59]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[S:53][C:52]=2[CH:51]=[CH:50][C:49]=1[O:62][CH2:63][C:64]([NH:66][CH2:67][C:72]([N:74]([CH2:1][CH:2]([CH3:15])[CH3:3])[CH2:75][C:80]([NH:82][C@H:83]1[CH2:87][CH2:86][O:85][CH:84]1[O:88][CH3:89])=[O:81])=[O:73])=[O:65]
Reactant: CC(C)C[C@H](NC(=O)c1ccc2c(c1)Nc1ccccc1S2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CCOC1O
Reactant: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)COc1ccc2c(c1)Nc1ccccc1S2
Product: COC1OCC[C@@H]1NC(=O)CN(CC(C)C)C(=O)CNC(=O)COc1ccc2c(c1)Nc1ccccc1S2

Procedure:
The compounds of Examples 40 to 58 were prepared according to the experimental protocol described for the compound of Example 2 starting from the compounds of Examples 21 to 39 respectively.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(C(C)C)C(C)C.Cl.[CH3:46][N:47]([CH2:49][C:50](Cl)=[O:51])[CH3:48]>C(Cl)Cl>[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:50](=[O:51])[CH2:49][N:47]([CH3:48])[CH3:46])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 14, step (b), 655 mg, 1.30 mmol) in DCM (15 mL) was cooled to 0° C. and DIEA (0.92 mL, 5.2 mmol) was added. Dimethylaminoacetyl chloride hydrochloride (211 mg, 1.3 mol) was then added portion wise over 10 min. The reaction mixture was stirred at 0° C. for 30 min and allowed to warm to RT and stirred for 2 h. Solvent was removed in vacuo and the resulting residue was partitioned between brine and DCM. The organic layer was separated, dried (Na2SO4) and concentrated. The residue obtained was purified on silica (5% MeOH: DCM) to obtain 432 mg (70%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.49 (s, 1H), 8.24 (d, 1H, J=2.3 Hz), 7.70 (s, 1H), 7.12 (dd, 1H, J=8.4, 2.1 Hz), 7.01 (s, 1H), 5.82 (m, 1H), 4.75 (d, 1H, J=13.4 Hz), 4.13 (d, 1H, J=13.4 Hz), 3.57 (d, 1H, J=14.2 Hz), 3.18 (d, 1H, J=14.2 Hz), 3.12 (td, 1H, J=13.3, 2.4 Hz), 2.73 (dddd, 1H, J=11.9, 11.9, 3.8, 3.8 Hz), 2.65 (ddd, 1H, J=13.3, 13.3, 2.4 Hz), 2.40 (s, 6H), 2.18-2.32 (m, 4H), 1.60-1.98 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C26H32N6O2, 461.3 (M+H), found 461.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[N:9]=1)[CH3:4].[CH3:33]I.[Cl-].[NH4+]>CS(C)=O>[CH2:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([N:23]([CH3:33])[C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[N:9]=1)[CH3:4]
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)Cc3ccccc3)c2)s1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N(C)C(=O)Cc3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
Sodium hydride (60% paraffin dispersion, 58 mg, 1.5 mmol) was added to a solution of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (0.50 g, 1.2 mmol) in dimethyl sulfoxide (5 mL) and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.09 mL, 1.5 mmol) was added to this reaction solution and the mixture was stirred at room temperature for 1 hour. A 10% aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 7:1→4:1) and washed with hexane to obtain 0.18 g (yield 35%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12](O)=[O:13].[H-].C([Al+]C(C)C)(C)C.[Na+].[Cl-]>CO>[OH:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CC(C)[Al+]C(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Product: OCCc1c[nH]c2ccc(O)cc12
Temperature: -78 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
5-Hydroxyindol-3-acetic acid (1.91 g, 10 mmoles) was initially introduced into MC (40 ml) under argon, the mixture was cooled to −78° C. and diisopropylaluminium hydride (0.2 M in toluene, 40 ml, 48 mmoles) was added in the course of 20 min, while stirring. When the addition of the reducing agent had ended, the mixture was allowed to come to RT in the course of 5 hours and was then left at RT for a further hour. For working up, methanol (2 ml) was cautiously added to the reaction mixture. The previously continuously solid mass became liquid again during the addition. Saturated NaCl solution (10 ml) was now added in portions to the mixture. The resulting mixture was left to stand overnight and then filtered off with suction over kieselguhr. The filter cake was washed with a total of 400 ml MC. The filtrate was dried over sodium sulfate and concentrated. 730 mg 3-(2-hydroxy-ethyl)-1H-indol-5-ol were obtained (m.p. 98-102° C.).