Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:32])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=1.[CH3:33][I:34]>>[I-:34].[CH3:33][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:32])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)NCc2ccccn2)cc1
Reactant: CI
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)NCc2cccc[n+]2C)cc1
Product: [I-]
Yield: 87.6 %

Procedure:
The title compound is prepared by the procedure of Example 28 using 1.0 g of product from Example 54 and 16.18 g of methyl iodide. The residue is recrystallized from methyl alcohol to give 1.16 g of the desired product as cream prisms.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]2[C:11]([CH3:12])=[C:10]([N:13]3[CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)[N:9]=[C:8]([CH:23]3[CH2:25][CH2:24]3)[N:7]=2)[CH2:4][CH2:3]1>O1CCCC1.ClCCl>[OH2:17].[CH:23]1([C:8]2[N:9]=[C:10]([N:13]3[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]3)[C:11]([CH3:12])=[C:6]([NH:5][CH:2]3[CH2:3][CH2:4]3)[N:7]=2)[CH2:25][CH2:24]1
Reactant: Cc1c(NC2CC2)nc(C2CC2)nc1N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(NC2CC2)nc(C2CC2)nc1N1CCC(=O)CC1
Product: O
Temperature: 25 °C
Reaction time: 18 h
Yield: 122.2 %

Procedure:
A solution of 1 N HCl (15 ml) is added to a solution of N,2-dicyclopropyl-6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-5-methyl-4-pyrimidinamine 149 (285 mg, 0.86 mmol) in tetrahydrofuran (15 ml). The mixture is stirred at room temperature for 18 h, then diluted with dichloromethane and washed three times with sodium bicarbonate. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford a white paste. The compound is dried under vacuum to give pure 1-[2-cyclopropyl-6-(cyclopropylamino)-5-methyl-4-pyrimidinyl]-4-piperidinone hydrate 107 (160 mg, 61%) as a white paste.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1F>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Br:20])[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Reactant: Fc1ccccc1Br
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2ccccc2Br)c1

Procedure:
In analogy to example 4.6, Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine and 1-bromo-2-fluoro-benzene were converted to yield Allyl-{5-[1-(2-bromo-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine as yellow oil, MS: 411 (MH+, 1Br).
Reaction SMILES: C(OC([P:9]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](Cl)(C)C>ClCCl>[CH2:11]([O:10][P:9]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[OH:13])[CH3:12]
Reactant: CCOC(C)(OCC)P(=O)(OCC)C1CCCO1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOP(O)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g of ethyl 1,1-diethoxyethyl(tetrahydrofuran-2-yl)-phosphinate in 10 ml of dichloromethane containing 1% (b.v.) of ethanol is treated with 0.71 g of trimethylsilylchloride. The faintly cloudy solution is stirred overnight at room temperature after which time thin layer chromatography indicates complete reaction. Removal of the solvent in vacuo affords a colourless oil which after distillation yields P-tetrahydrofuran-2-yl-phosphonous acid ethyl ester, b.p. 90°/8×10-2 mbar.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:41]=[CH:40][C:32]([CH2:33][C:34]3[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCCC1>[N:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:33][C:34]3[CH:35]=[C:36]([NH:39][CH:8]=[C:9]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[NH:37][N:38]=3)=[CH:40][CH:41]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1cc(Cc2ccc(OCCCN3CCOCC3)cc2)n[nH]1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc(Cc2ccc(OCCCN3CCOCC3)cc2)n[nH]1

Procedure:
The named compound is prepared by substituting 5-[4-(3-morpholin-4-yl-propoxy)-benzyl]-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.017 gms.) is reacted with 0.048 gms. of 5-[4-(3-morpholin-4-yl-propoxy)-benzyl]-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (1.0 mL). Recrystallization from a mixture of ethyl acetate and hexanes affords the named compound.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH-].[Na+].C[N:22]1[N:26]=[C:25]([SH:27])[S:24][CH2:23]1.Cl.[CH3:29]C(C)=O>O>[CH3:29][C:23]1[S:24][C:25]([S:27][CH2:5][C:6]2[CH2:15][S:14][CH:9]3[N:8]([C:11](=[O:12])[CH:10]3[NH2:13])[C:7]=2[C:16]([OH:18])=[O:17])=[N:26][N:22]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CN1CSC(S)=N1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)s1

Procedure:
A mixture of 13.6 g. (0.05 M) of 7-aminocephalosporanic acid in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring. 9.8 g. (0.57 M) of 3-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80° for 4 hours. After cooling to 5°, this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes. The precipitated solid is filtered under suction and washed with acetone. This 3[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:11][CH:12]([F:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:13](=[O:14])[CH:12]([Cl:11])[F:16])=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1N
Reactant: O=C(Cl)C(F)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cscc1NC(=O)C(F)Cl
Temperature: -15 °C

Procedure:
To a suspension of 4-amino-thiophene-3-carboxylic acid methyl ester (2 g) in dichloromethane (25 mL) was added chlorofluoroacetyl chloride (1.16 mL) and the reaction mixture was stirred to −15° C. Then a solution of triethylamine (3.2 mL) in dichloromethane (5 mL) was added slowly to the cold reaction mixture which was then allowed to warm up and stirred at room temperature for one hour. The reaction mixture was then diluted with further methylene chloride and washed several times with water, dried with sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a light yellow solid. MS (EI): 251.1; mp=51-54° C.
Reaction SMILES: C(O)C.[N+:4]([C:7]1[C:8](=[O:25])[N:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:12]=1)([O-])=O>[H][H].[C].[Pd]>[NH2:4][C:7]1[C:8](=[O:25])[N:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:12]=1
Reactant: [H][H]
Reactant: O=c1c([N+](=O)[O-])cc(-c2ccccn2)cn1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Yield: 83.8 %

Procedure:
100 mg of 10% palladium-carbon was added to 20 ml of an ethanol solution containing 546 mg of 3-nitro-1-phenyl-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one, followed by stirring overnight in hydrogen atmosphere. The reaction mixture was filtered through silica gel and concentrated, to give 411 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C@@H:16](O)[CH2:15][N:14]3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:39])CCOC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C@H:16]([F:39])[CH2:15][N:14]3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@@H](F)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
(2S,4R)-benzyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (1.5 g, 3.4 mmol) was added as a solid to a solution of bis(2-methoxyethyl)aminosulfur trifluoride (0.98 mL, 5.1 mmol) in 15 mL CH2Cl2 cooled to −78° C. Reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. Reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. Layers were separated and aqueous layer washed one time with CH2Cl2. Combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give a yellow oil. The oil was triturated with CH2Cl2 and pentane to yield (2S,4S)-benzyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate JG-20 as a yellow solid (0.96 g, 62%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1.Br[CH2:27][C:28](=[CH2:33])[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:32][O:31][C:29](=[O:30])[C:28]([CH2:33][S:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:23])[CH3:24])([CH3:14])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)=[CH2:27]
Reactant: C=C(CBr)C(=O)OC
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(SCCCS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C(CSCCCSc1ccc(C(=O)C(C)(Cc2ccccc2)N(C)C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.5 g (4.0 mmol) of 1-[4-(3-mercaptopropylthio)phenyl]-2-dimethylamino-2-benzyl-propan-1-one are dissolved in 100 ml of methanol. To the solution are successively added 0.86 g (4.8 mmol) of methyl 2-(bromomethyl)acrylate and 0.55 g (4.0 mmol) of potassium carbonate, and the resulting reaction mixture is stirred at room temperature for 10 min. The reaction mixture is added to water and extracted with ethyl acetate. The organic phase is washed with water, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:7) as an eluent, and an oily product is obtained.
Reaction SMILES: [Na].[CH:2]([OH:5])([CH3:4])[CH3:3].Br[CH2:7][C:8]1[C:15]([F:16])=[C:14]([F:17])[C:11]([CH2:12][OH:13])=[C:10]([F:18])[C:9]=1[F:19].Cl>O>[F:17][C:14]1[C:15]([F:16])=[C:8]([CH2:7][O:5][CH:2]([CH3:4])[CH3:3])[C:9]([F:19])=[C:10]([F:18])[C:11]=1[CH2:12][OH:13]
Reactant: OCc1c(F)c(F)c(CBr)c(F)c1F
Reactant: CC(C)O
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(C)OCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Sodium (1.0 g) was added to dry isopropanol (200 cm3), maintained at 40° C. under an atmosphere of dry nitrogen. After dissolution was complete, 4-(bromomethyl)-2,3,5,6-tetrafluorobenzyl alcohol (10.9 g) was added and the reaction was stirred for 16 hours, at the ambient temperature. The reaction mixture was poured into water, acidified with dilute aqueous hydrochloric acid, and extracted into ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The residue was combined with the product of a similar reaction and distilled under reduced pressure to give 2,3,5,6-tetrafluoro-4-[(1-methylethoxy)methyl]-benzyl alcohol (0.8 g).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[N:8][C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]([OH:18])=[O:17])=[O:10])[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[N:4]=1)[CH3:2].[OH-].[K+:38]>C(O)C>[K+:38].[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]([O-:18])=[O:17])=[O:10])[N:5]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:33][N:34]=[N:35][N:36]=3)=[CH:24][CH:25]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)[O-])CCC2)s1

Procedure:
To 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazolin-2-yliden]aminocarbonyl]-1-cyclopentenecarboxylic acid (206 mg) were added a 0.05N potassium hydroxide in ethanol solution (8.3 ml) and ethanol (50 ml) to dissolve the former in the latter. The solvent was then distilled off. To the residue was added ethanol. The solid so precipitated was collected by filtration and then dried, whereby 180 mg of the title compound was obtained. IR(KBr)cm1 : 1680(--COOH), 1570(=N--CO--)
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CC#N>[C:14]([N:3]1[C:4]2[CH:5]=[N:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:1]=[CH:2]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)ncc1nc[nH]c12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c4ccccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of 5.2 g of 1H-imidazo[4,5-c]quinoline (II-1) in 180 ml of MeCN were added 10.3 g of trityl chloride and 4.2 g of triethylamine, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed and the residue was chromatographed on a column of silica gel with ethyl acetate-n-hexane (1:1 v/v). Crystallization of the resulting oily substance from n-hexane gave 12.4 g (yield: 98%) of the titled compound (III-1). This was recrystallized from ethyl acetate-n-hexane to give colorless crystals melting at 190°~192° C.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH3:27])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[O:25][CH3:26])=[N+:11]([O-])[CH:12]=1)[CH2:4][CH3:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].O=P(Cl)(Cl)[Cl:36]>>[Cl:36][C:12]1[C:7]([O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:8][C:9]([CH3:27])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[O:25][CH3:26])[N:11]=1
Reactant: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1Cl
Temperature: 25 °C

Procedure:
A solution of compound 44 (340 mg, 0.88 mmol) in POCl3 (0.4 ml) is stirred at 65° C. for 1 hour, then cooled to room temperature and poured onto ice (10 g). The resulting solution is neutralized with Na2CO3, and extracted with 50% EtOAc in hexane. The combined extracts are washed with water, brine, dried, filtered and evaporated. The crude product is purified by chromatography (eluted with 6% EtOAc in hexane) to give the product as a white crystalline solid. 1H NMR (CDCl3) δ 1.01 (t, J=7.6 Hz, 6H), 1.76 (m, 4H), 2.12 (s, 3H), 3.78 (s, 3H), 4.19 (m, 1H), 6.78 (s, 1H), 6.89 (dd, 1H), 7.05 (s, 1H), 7.26 (s, 1H), 7.27 (d, J=8.4 Hz, 1H). LCMS 404.27 (M+1).
Reaction SMILES: COC(=O)[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1.[CH3:22][OH:23]>>[CH2:7]([N:6]1[CH2:5][CH2:4][C:22](=[O:23])[CH:18]([C:17](=[O:21])[CH3:16])[C:19]1=[O:20])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CCNCCc1ccccc1
Reactant: CO
Reactant: C=C1CC(=O)O1
Product: CC(=O)C1C(=O)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
N-Phenethyl-β-alanine methyl ester (80.2 g) is dissolved in methanol (150 ml), and thereto is added dropwise diketene (32 ml) under ice-cooling. The mixture is stirred at room temperature for 1 hour and then distilled to remove the solvent. The residue is dissolved in methanol (100 ml), and the solution is added dropwise to a solution of sodium methoxide [prepared from metal sodium (9.8 g) and methanol (150 ml)], and the mixture is stirred at room tempeature for 2 hours. After the reaction, the solvent is distilled off, and to the residue is added ice-water. The mixture is extracted with ethyl acetate, and the aqueous layer is acidified with conc. hydrochloric acid and then is extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and then distilled to remove the solvent to give 1-phenethyl-3-acetyl-2,4-dioxopiperidine (95.3 g, 95%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](Cl)=[CH:4][C:5]([F:8])([F:7])[F:6].[H][H].[OH-].[K+]>C(O)C.[Ni]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)CCC(F)(F)F
Yield: 47.8 %

Procedure:
In a stainless steel autoclave, 40 g of 1,1,1,4,4,4-hexafluoro-2-chloro-2-butene in 300 ml of ethanol were hydrogenated with hydrogen in the presence of 12 g of potassium hydroxide and 25 g of Raney nickel for 3 hours at 20° C. and another 1 hour at 100° C. at a pressure of from 30 to 40 bar. The solid components were then removed from the reaction mixture by filtration and the remaining liquid was distilled to give 16 g of 1,1,1,4,4,4-hexafluorobutane having a boiling point of 25-30° C. at 1013 mbar. The mass spectrum showed a molecular ion at m/e 166.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:25][CH:26]([F:28])Cl>O1CCCC1.O>[F:25][CH:26]([F:28])[C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Reactant: FC(F)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C(F)F)c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
16.8 g (0.07 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 300 mL of tetrahydrofuran and 9.1 g (0.077 mol) of potassium tert-butoxide are added batchwise while cooling. Then difluorochloromethane is piped in at 0° C. over a period of 1.5 hours. After all the gas has been piped in, the reaction mixture is left to stand for 72 hours at ambient temperature. The reaction mixture is then diluted with water to a total volume of about 2000 mL, extracted with ethyl acetate, the organic phase is separated off and washed with 5% aqueous sodium carbonate solution. After being extracted again with water, the organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product is purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate (98:2)) or by recrystallization from cyclohexane. Yield: 5.35 g of white crystals (26% of theoretical yield); melting point: 101° C.
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][OH:33]>CN1C(=O)CCC1.O>[OH:33][CH2:32][CH2:31][NH:30][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(F)cc1
Reactant: NCCO
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(NCCO)cc1
Yield: 31.3 %

Procedure:
A solution of 5-(4-fluorobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.10 g, 0.25 mmol) and 2-aminoethanol (0.15 g, 2.46 mmol) in NMP (1 mL) was treated using a microwave synthesizer for 1 hr (CEM Corp., 180° C.). The, reaction mixture was diluted with water (3 mL), and the resulting solids were collected by filtration. The solids were washed with water, and dried to give 0.035 g (31% yield) of the titled compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:12]([C:14]([C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])=[CH:18][CH:17]=1)=[O:15])[NH2:13]>CS(C)=O>[OH:27][NH:26][C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]1[CH:18]=[CH:17][C:16]([C:14]([NH:12]/[N:13]=[CH:4]/[C:3]2[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([OH:10])[C:2]=2[OH:1])=[O:15])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(O)c(O)c1O
Reactant: NNC(=O)c1ccc(/C=C/C(=O)NO)cc1
Solvent: CS(C)=O
Product: O=C(/C=C/c1ccc(C(=O)N/N=C/c2ccc(O)c(O)c2O)cc1)NO
Temperature: 70 °C
Yield: 23.3 %

Procedure:
Compound 6a was resynthesized and purified to be re-subjected to the biochemical assay to confirm the results from the initial library screen. To a 4 dram vial charged with 2,3,4-trihydroxybenzaldehyde (25.9 mg, 0.168 mmol) was added 420 μL of a 200 mM solution of hydrazine 5a (0.084 mmol) in DMSO. The solution was heated on a rotating heating block at 70° C. for 16 h. Reaction progress was monitored via LCMS. Following purification by reverse phase preparatory LCMS (44 mL/min, CH3CN/H2O with 1% formic acid, 5 min gradient), 6a (7 mg) was isolated as a yellow powder (98% pure, by analytical LCMS). 1H NMR (300 MHz, DMSO) δ 12.01 (s, 1H), 11.51 (s, 1H), 10.84 (s, 1H), 9.49 (s, 1H), 9.13 (s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 7.96 (d, J=8.3, 2H), 7.73 (d, J=8.2, 2H), 7.53 (d, J=16.2, 1H), 6.80 (d, J=8.6, 1H), 6.59 (d, J=15.9, 1H), 6.40 (d, J=8.4, 1H); m/z (ES−) 356 ([M-H]).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([C:34]2[CH:35]=[CH:36][C:37]3C=CS[C:38]=3[CH:42]=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:43]C1C=C(C=CC=1)C(O)=O>>[Cl:43][C:38]1[CH:42]=[C:34]([CH:35]=[CH:36][CH:37]=1)[C:32](/[N:31]=[C:14]1/[N:13]([C@H:10]2[CH2:11][CH2:12][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:9]2)[C:21]2[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:18]=[CH:17][C:16]=2[NH:15]/1)=[O:33]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(Cl)c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 37.4 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-chlorobenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-3-chloro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (37.4% yield). MS m/z=567.4 [M+H], calc 567.12 for C30H39ClN6O3.