Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:25])[C:21](Br)([CH3:23])[CH3:22])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:25])([CH3:23])[CH3:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A mixture of piperazine-1-carboxylic acid benzyl ester (8.8 g, 40 mmol), 2-bromo-2-methylpropionic acid ethyl ester and potassium carbonate was stirred at 150° C. for 24 h. On cooling, the resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure to give 4-(1-Ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid benzyl ester (10.2 g, 77%) as an oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])[CH3:13].O>C(OCC)C>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([OH:14])[CH3:13]
Reactant: CC(=O)c1cccs1
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(O)(c1cccs1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 13.4 ml) in dry diethyl ether (25 ml) was added dropwise to a stirred solution of 2-bromothiazole (5 g) in diethyl ether (50 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylthiophene (3.85 g) in diethyl ether (25 ml) was added dropwise. After a further 1 hour the mixture was allowed to warm to room temperature and was left stirring overnight. Water was added.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:26])[CH2:10][CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[N:27]([Si](C)(C)C)=[N+:28]=[N-:29].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:26])[CH2:10][CH2:11][CH:12]2[N:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[N:27]=[N:28][NH:29][N:25]=3)[C:14](=[O:17])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCCCCN1C(=O)CCC1CCC(O)Cc1cccc(F)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C1CCC(CCC(O)Cc2cccc(F)c2)N1CCCCCCc1nn[nH]n1

Procedure:
Following the procedure described for Example 6, Step C, 7-{2-[4-(3-fluoro-phenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (141.3 mg, 0.392 mmol) was reacted with azidotrimethylsilane (0.210 mL, 1.57 mmol) and dibutyltin oxide (29 mg, 0.116 mmol) in toluene (8 mL) heated under reflux for 72 h. Purification by medium pressure chromatography (CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2) provided the title compound of Example 5C. (101.5 mg). 1H NMR (CDCl3) δ7.26 (m, 1H), 6.94 (m, 3H), 3.87 (m, 1H), 3.70 (m, 1H), 3.52 (m, 1H), 2.98 (m, 3H), 2.78 (m, 2H), 2.48 (m, 2H), 2.20 (m, 1H), 1.89-1.24 (m, 1 4H); MS 404.2 (M+1), 401.9 (M−1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:25]([S:32](Cl)(=[O:34])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH:17][S:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(NS(=O)(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (303 mg, 949 μmol) was dissolved in pyridine (3 mL) and cooled to 0° C. To this was added benzylsulfonyl chloride (362 mg, 1.90 mmol) and the mixture was stirred for 30 min at the same temperature. To this was further added benzylsulfonyl chloride (89.7 mg, 470 μmol) and the mixture was stirred for 30 min at the same temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction and extracted 3 times with dichloromethane. The organic layer was washed once with water, once with 2 M hydrochloric acid and once with saturated aqueous solution of sodium sulfate, and then dried over anhydrous sodium sulfate. After removing anhydrous sodium saturation by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was filtered through a Kiriyama funnel and recrystallized from ethyl acetate/methanol (1/1) to give 5-(4-acetoxyphenyl)-3-benzyl-2-(benzylsulfonylamino)pyrazine (c-32) as a colorless solid (124 mg, 27.6%). Rf=0.56 (n-hexane/ethyl acetate=1/1). Mp. 240-241° C. UV (MeOH, 0.3% DMSO) λmax (log ε) 324 (4.06), 286.5 (4.13), 264 (4.19). UV (pH PB, 0.3% DMSO) λmax (log ε) 338.5 (4.01), 290 (4.01), 273.5 (4.02). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.25 (s, 2H), 4.92 (s, 2H), 7.14-7.21 (m, 1H), 7.23-7.28 (m, 6H), 7.35 (s, 5H), 8.03-8.12 (AA′BB′, 2H), 8.93 (s, 1H), 10.55 (s, 1H). IR (KBr, cm−1) 530, 700, 889, 920, 1157, 1179, 1204, 1223, 1325, 1420, 1454, 1748, 3267. HRMS (FAB+) m/z 474.1486 (M+H, C26H24N3O4S requires 474.1488).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([OH:33])[CH2:29][C:30](=[O:32])[CH3:31])[CH:23]=1)=[O:21])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:12].[BH4-].[Na+]>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:12])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([OH:33])[CH2:29][CH:30]([OH:32])[CH3:31])[CH:23]=1)=[O:21]
Reactant: CC(=O)CC(O)c1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CC(O)c1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
At −10° C., 10 ml of ethanol solution containing 184 mg of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(1-hydroxy-3-oxobutyl)phenyl]propane-1,3-dione was mixed with sodium borohydride and stirred for 30 minutes. This was appropriate amounts of saturated ammonium chloride aqueous solution and purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 110 mg (60%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,3-dihydroxybutyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione (Example 6-1) from a hexane-ethyl acetate (1:1-1:3) eluate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:13])=[CH:9][NH:10]2)=[CH:6][C:5]=1[F:14].[CH3:15][C@@H:16]1[CH2:18][O:17]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:13])=[CH:9][N:10]2[CH2:15][C@H:16]([OH:17])[CH3:18])=[CH:6][C:5]=1[F:14]
Reactant: Cc1c[nH]c2cc(Cl)c(F)cc12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1cn(C[C@@H](C)O)c2cc(Cl)c(F)cc12
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of 0.07 g of sodium hydride dispersion in 10 ml of tetrahydrofuran was treated with 0.33 g of 6-chloro-5-fluoro-3-methylindole at 0° and stirred as this temperature for 1 hour. After the addition of 0.19 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 17 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 20 g of silica gel with toluene-ethyl acetate (9:1). 0.22 g (50%) of (R)-1-(6-chloro-5-fluoro-3-methylindol-1-yl)-propan-2-ol was obtained as a yellow oil.
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].[OH-].[Na+].Cl>CO.O>[C:11]1([CH2:10][NH:6][C@@H:5]([C:4]([OH:3])=[O:9])[CH2:7][OH:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](N)CO
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
D-Serine methyl ester hydrochloride (10.0 g, 64.3 mmol) in MeOH (29 mL) was cooled in ice water bath. TEA (9.00 mL, 64.6 mmol) was added dropwise via syringe and reaction was warmed to rt. When the solution was homogenous, it was re-cooled with an ice water bath. Benzaldehyde (6.46 mL, 63.6 mmol) was added dropwise via syringe and the reaction was stirred for 30 min. NaBH4 (7.84 g, 64.3 mmol) was then added in portions over 40 min and the resultant mixture was stirred for 1 h. To a separate flask, cooled in an ice bath, containing MeOH (12 mL) and H2O (17 mL) was added NaOH (7.84 g, 195 mmol) in H2O (16 mL). To this solution was added the NaBH4 solution followed by H2O (17 mL). The reaction was warmed to rt and the pH was adjusted to 9.5 using 6N HCl. The reaction mixture was washed twice with EtOAc and the pH was adjusted to 6.5 with 6N HCl. The resultant suspension was cooled in a refrigerator for 1 h. The solid was filtered, washed twice with H2O (20 mL), twice with heptane (20 mL) and dried overnight at 45° C. in a vacuum oven to give the title compound of step A (4.91 g, 25.2 mmol, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.08-3.17 (m, 1H), 3.57-3.68 (m, 2H), 3.94 (q, J=13.2 Hz, 2H), 7.26-7.35 (m, 4H), 7.37-7.40 (m, 3H), 7.44-8.45 (br.s., 1H). [α]D20° C.=−5.3, I=100 mm, c=1.0 in 6N HCl.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH-].[Ca+2:6].[OH-]>O>[C:1]([O-:4])(=[O:3])[CH3:2].[Ca+2:6].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC(=O)[O-]

Procedure:
A calcium acetate salt dispersion was prepared by mixing 11.9 parts of acetic acid, 1316.3 parts of water, and 263.2 parts hydrated lime at 20° C. The resulting dispersion had a beige color and separated upon standing, i.e. without agitation.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:13]([O:20][CH3:21])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[C:13]=2[O:20][CH3:21])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C=O)cccc1Oc1cc(Br)ccc1C#N
Yield: 82.8 %

Procedure:
4-Bromo-2-fluorobenzonitrile (0.41 g, 2.0 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.31 g, 2.0 mmol) and cesium carbonate (0.66 g, 2.0 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 18 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-bromo-2-(3-formyl-2-methoxyphenoxy)-benzonitrile (0.55 g, 81%) as a yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])[CH:21]=[CH2:20]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Hydroxyphthalimide (48.9 g) was dissolved in DMF (200 ml) and triethylamine (43.9 ml) was added followed by addition of allyl bromide. The reaction mixture was stirred at room temperature for 18 hours and the resulting precipitated material was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate, 4 M HCl aq. and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The remaining material was crystallised from hexane/EtOAc, affording 2-allyloxy-isoindole-1,3-dione (43.6 g). This allyl intermediate (2.03 g) was dissolved in toluene (5 ml) and nitroethane (825 mg), phenylisocyanate (2.4 ml) and triethylamine (0.02 eq.) was added. The reaction mixture was stirred at room temperature for 48 hours, and the precipitated material was removed by filtration. The filtrate was evaporated onto silica gel and chromatographed (0 to 50% EtOAc/heptane) and gave 2-(3-methyl-4,5-dihydro-isoxazol-5-ylmethoxy)-isoindole-1,3-dione (2.4 g). 13C-NMR (DMSO-d6) δ 162.9, 155.4, 134.7, 128.5, 123.2, 78.0, 76.9, 40.3, 12.4. This phthalimide intermediate (260 mg) was dissolved in methanol (1 ml) and dichloromethane (1 ml) and hydrazine monohydrate (1.0 eq.) was added. The mixture was stirred at room temperature for 20 hours. The formed solid material was removed by filtration. The filtrate was evaporated under reduced pressure and gave the title compound, which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([O:30][Si](C(C)(C)C)(C)C)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]2=[O:38])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([OH:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]2=[O:38])=[CH:5][CH:4]=1
Reactant: COc1cccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccccc3)C(=O)N2c2ccc(N)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(N)cc2)c1
Reaction time: 2 h
Yield: 61.4 %

Procedure:
15 ml of 2N aqueous hydrochloric acid are added to 2.3 g of product 5 in 20 ml of tetrahydrofuran and stirred for 2 h. An aqueous solution of sodium hydrogencarbonate is added to the reaction and extracted by ethylacetate. The organic phase is dried by magnesium sulfate, evaporated and purified by chromatography on silica gel (ethylacetate/heptane=1/1->1/0). 1.1 g of product 6 is obtained in form of a colorless compound in solid form: C25H26N2O3 (402.50) MS (ESI+) 403.2 (M+H+).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.CS(N)(=O)=O.[CH3:54][O:55][CH2:56][CH2:57][S:58]([NH2:61])(=[O:60])=[O:59]>>[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([NH:61][S:58]([CH2:57][CH2:56][O:55][CH3:54])(=[O:60])=[O:59])=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:27][CH:28]3[CH2:29][CH:30]([CH2:31][CH:32]([CH2:34]3)[CH2:33]1)[CH2:35]2
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid and methanesulfonamide with 2-methoxyethane-1-sulfonamide, the title compound was obtained as a colorless solid (0.05 g, 9%): 1H NMR (300 MHz, CDCl3) δ 8.68-8.54 (m, 1H), 8.13-8.03 (m, 1H), 6.74-6.62 (m, 1H), 3.91-3.74 (m, 4H), 3.59 (s, 2H), 3.31 (s, 3H), 2.05 (s, 3H), 1.85-1.64 (m, 12H); MS (ES−) m/z 458.3 (M−1), 460.3 (M−1).
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][NH:20][C:21]2(C(N)=O)[CH2:25][NH:24][CH:23]=[N:22]2)=[CH:11][CH:10]=1.CO>ClCCl>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][N:20]2[C:21]3[N:22]=[CH:23][NH:24][C:25]=3[C:4](=[O:5])[NH:6][C:7]2=[S:8])=[CH:11][CH:10]=1
Reactant: NC(=O)C1(NCc2ccnc3ccccc23)CNC=N1
Reactant: CCOC(=O)N=C=S
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2ccnc3ccccc23)c2nc[nH]c12
Temperature: 25 °C
Yield: 9 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.5 ml, 4.18 mmol) was added to a solution of 4-[(quinolin-4-ylmethyl)amino]-1H-imidazole-4-carboxamide (0.93 g, crude material from Example 24(a)) dissolved in anhydrous dichloromethane (10 mL) and methanol (5 mL) mixture. After o.n. (over night) at r.t., the solution was concentrated in vacuo and the residue was dissolved in 1N NaOH solution (30 mL) and refluxed for 3.5 h. After cooling to r.t., the pH was adjusted to ˜6.5 with 2 N HCl. The solid that formed was collected by filtration and dried generating 0.35 g of crude material. A portion of the solid (150 mg) was purified by preparative HPLC, and the solid obtained was washed with dichloromethane and ether, generating 25.9 mg (9% yield over two steps) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)=[C:4]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)=[O:22])[CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][C:4]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(NC(=O)Nc2cc(Cl)ccc2OCCCN)cn1
Yield: 6 %

Procedure:
A solution of Example 38A in trifluoroacetic acid (0.1 mL) and dichloromethane (0.9 mL) was stirred at room temperature for 3 hours and concentrated. The concentrate was purified by HPLC with acetonitrile/water containing 0.1% TFA to provide 2.8 mg (6%) of the desired product. MS (ESI(−)) m/z 347 (M−H)−; 1H NMR (500 MHz, DMSO-d6) δ 10.93 (br s, 1H), 10.09 (br s, 1H), 8.91 (s, 1H), 8.85 (s, 1H), 8.26 (d, J=2.5 Hz, 1H), 7.71 (br s, 2H), 7.12 (dd, J=8.7, 2.2 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.03 (br s, 2H), 2.10 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[N:28]=[N:27]1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([C:29]5[N:28]=[N:27][S:26][CH:30]=5)=[CH:36][CH:35]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Reactant: Nc1ccc(-c2csnn2)cc1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(-c5csnn5)cc4)nn23)cn1
Yield: 24 %

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.138 g, 0.369 mmol and 4-[1,2,3]Thiadiazol-4-yl-phenylamine (0.0817 g, 0.461 mmol) were reacted in an analogous manner to Example 908D at 50° overnight. The reaction mixture was filtered and the resulting solid was washed with acetone to give the title compound as a pale yellow solid (36 mg, 24%). HPLC rt=3.347, purity=99%. LCMS=401.9 (M+H). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.81 (s, 1H), 9.52 (s, 1H), 9.04 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.54 (dd, J=8.7 Hz, 2.3 Hz, 1H), 8.08 (d, J=7.9 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.21 (d, J=4.4 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 7.00 (d, J=4.3 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH2:22](I)[CH3:23]>>[CH2:22]([O:21][C:19]1[O:20][C:16]([C:13]2[O:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][O:4][CH3:3])[C:15]=3[CH:14]=2)=[N:17][N:18]=1)[CH3:23]
Reactant: COCOc1cccc2oc(-c3n[nH]c(=O)o3)cc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOc1nnc(-c2cc3c(OCOC)cccc3o2)o1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 117 using sodium hydride (0.37 g), 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (2.0 g) and ethyl iodide (0.73 ml), the title compound (1.9 g) was obtained as pale-yellow crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.Br[CH2:10][C:11]#[N:12]>C1COCC1>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([CH2:10][C:11]#[N:12])[CH2:2]1
Reactant: N#CCBr
Reactant: OCC1CCCNC1
Solvent: C1CCOC1
Product: N#CCN1CCCC(CO)C1
Yield: 91.6 %

Procedure:
The method follows that of S1 using 3-piperidinemethanol (4.79 g, 41.59 mmol), BrCH2CN (1.99 g, 16.64 mmol) and dry THF (25 mL). The title-compound was yielded as a straw-coloured oil (2.35 g, 92%) after flash chromatography using CH2Cl2/CH3OH (9:1) as eluent. dH (250 MHz; CDCl3); 1.05 (m, 1H, CHCH2OH), 1.5-1.9 (m, 5H, OH, CH2CH2CH2 and CH2CH2CH), 2.15 (t, 1H, J=10 Hz, 1×NCH2CH), 2.35 (3×d, 1H, J=4 Hz and J=10 Hz, 1×NCH2CH2), 2.7 (m, 1H, 1×NCH2CH2), 2.85 (2×d, 1H, J=4 Hz and J=12 Hz, 1×NCH2CH), 3.52 (s, 2H, NCH2CN) and 3.45-3.65 (m, 2H, CHCH2OH); dC (62.9 MHz; CDCl3); 24.43, 26.14, 38.55, 46.75, 52.83, 55.73, 65.88 and 114.74 (CN); FAB MS, m/z(M+H)+ 155.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6]C)=O.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>CO>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:4](=[O:6])[CH2:3][C:2](=[O:1])[CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCC(=O)CC(=O)OC
Reactant: CCCCNCCCC
Solvent: CO
Product: CCCCN(CCCC)C(=O)CC(=O)CC
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
0.16 mol (20 ml) of methyl 3-oxovalerate (3-oxo-pentanoic acid methyl ester) and 0.415 mol (70 ml) of dibutylamine were stirred for 3 h at 130° C., where methanol formed was removed via a distillation bridge. Thereafter, excess dibutylamine was distilled on a rotary evaporator, the crude product taken up in 40 ml water and 90 ml of ethanol, with 3 ml 20% HCl adjusted to pH 3 and stirred for 1 h at 50° C. The mixture was again evaporated to dryness, dissolved again in 200 ml ethyl acetate and washed 3 times with 100 ml of water. The organic phase was dried over Na2SO4 and after filtration evaporated in a rotary evaporator to dryness. After drying, 31.8 g of the title compound were obtained.