Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([OH:12])[C:10]=1[OH:11])=[O:5])[CH3:2].[CH2:18](O)[CH2:19]O>O1CCCC1>[CH2:16]([O:15][C:13]([C:8]1[S:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]2[C:9]=1[O:12][CH2:19][CH2:18][O:11]2)=[O:14])[CH3:17]
Reactant: OCCO
Reactant: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(C(=O)OCC)c2c1OCCO2
Yield: 30 %

Procedure:
ADC01 (2.9 g, 16.9 mmol) was slowly added to a solution of 3,4-dihydroxythiophene-2,5-dicarboxylic acid diethyl ester (2.0 g, 7.7 mmol), ethylene glycol (0.5 g, 8.5 mmol), and PH02 (4.4 g, 16.9 mmol) in dry tetrahydrofuran (150 ml) at 25° C. At 25° C. the reaction was slow and 2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid diethyl ester was obtained in 30-40% yield after 3 days. It was found that the reaction could be highly facilitated by heating. Stirring of the reaction mixture for 3 h followed by refluxing for 9 h (66° C.) gave yields of 90%. After refluxing the reaction mixture was allowed to cool to 25° C. and was concentrated by rotary evaporator to remove the THF. The residue was then diluted with diethyl ether and allowed to stand overnight to enable the triphenylphosphine oxide to precipitate out. The triphenylphosphine oxide was then removed by filtration and the residue purified by chromatography on silica gel (eluant: ethyl acetate/ hexane=2/1) to give 2.0 g of 2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid diethyl ester as white crystals (90% yield) as characterized by 1H NMR, 13C NMR, HRMS, and elemental analysis.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[NH2:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[F:22])[O:23][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Temperature: 140 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (12 g, 39.7 mmol) in N,N-dimethylformamide (120 mL) were added 3-amino-4-fluorophenol (7.6 g, 59.6 mmol) and potassium carbonate (11.0 g, 79.5 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) to give the title compound (9.5 g, 79%) as a brown powder.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]=[O:14]>C(=O)([O-])[O-].[K+].[K+].O1CCCC1>[CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cc[nH]c2)cc1
Reactant: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1[nH]ccc1Cc1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
2.18 g (13.9 mmole) of 3-benzylpyrrole, 0.42 g (13.9 mmole) of paraformaldehyde and 0.07 g (0.5 mmole) of anhydrous potassium carbonate are mixed and stirred at 50° C. for 4 hours in an atmosphere of nitrogen. Dry tetrahydrofuran is added to the reaction solution and filtered. The filtrate is concentrated to obtain 2.53 g of 3-benzyl-1-pyrrolylmethanol as a pale yellow liquid. Yield 97.3%. nD31.5 1.5837.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[CH2:34]([CH2:36][NH2:37])[OH:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:35][CH2:34][CH2:36][NH:37][C:21]([C:5]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1)=[O:22]
Reactant: NCCO
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)NCCO)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with ethanolamine, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 505.2 (MH+).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:17](OC)(=[O:22])[C:18]([O:20][CH3:21])=[O:19].Cl>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=O)OC
Reactant: Brc1ccccc1/C=C/c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1/C=C/c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
A solution of the Grignard reagent prepared from E-1-phenyl-2-(2-bromophenyl)ethylene (8.56 g) and magnesium (0.96 g) in dry tetrahydrofuran (20 ml) was added dropwise over 30 minutes to a stirred solution of dimethyl oxalate (7.76 g) in dry tetrahydrofuran (70 ml) cooled to −15° C. The resulting mixture was stirred at about −15° C. for 30 minutes, then at room temperature for 1 hour, then poured into dilute hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated to give the crude product as a yellow oil (17.22 g). Purification by column chromatography using dichloromethane and petrol (1:1) as eluant then evaporative distillation (0.07 torr, oven temperature 170° C.) gave E-methyl 2-(2′-phenylethenyl)phenylglyoxalate (2.01 g, 23% yield) as a yellow oil, pure by GC, 1H nmr (CDCl3): delta 3.78 (3H, s), 6.88 (centre of 2 doublets, each 1H, J 16 Hz) p.p.m.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2,6-dihydroxyphenyl)-ethanone (304 mg, 2 mmol) and benzyl bromide (0.255 mL, 2.1 mmol) in DMF (10 mL) is added K2CO3 (552 mg; 4 mmol) and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f5) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:33](O)=[O:34]>C(OCC)(=O)C>[CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH:33]=[O:34])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CO
Reactant: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Solvent: CCOC(C)=O
Product: COc1cc(NC=O)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Yield: 89 %

Procedure:
A solution of 0.140 g of the compound of Example 6 and 0.4 mL of formic acid in 8 mL of ethyl acetate was stirred at room temperature for 8 h. Afterwards, the reaction mixture was diluted with 40 mL of ethyl acetate, washed with 1 N sodium hydroxide and water, dried on sodium sulphate and evaporated to dryness in vacuo. The crude was purified by flash chromatography (ethyl acetate—3N ammonia in methanol 95:5) to afford 0. 130 g (89%) of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=O)=O)=[CH:7][CH:6]=1)=[O:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26]>O1CCCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[S:26][C:9]([C:8]3[CH:23]=[CH:24][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[N:11][CH:12]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C(=O)NCC(=O)c2ccc(OC)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ncc(-c3ccc(OC)cc3)s2)cc1
Reaction time: 1 h
Yield: 126.2 %

Procedure:
To a solution of 2-(4-methoxycarbonylbenzamido)-4′-methoxyacetophenone (4.0 g) in tetrahydrofuran (80 ml) was added phosphorus pentasulfide (3.53 g), and refluxed for 2.5 hours. The reaction mixture was additionally added phosphorus pentasulfide (1.0 g), and refluxed for 1 hour. The reaction mixture was filtered, and the filtrate was cooled, and poured into water (1200 ml), and stirred for 1 hour. The resulting precipitate was collected by filtration. The solids were slurried in acetonitrile, and collected by filtration to give methyl 4-[5-(4-methoxyphenyl)thiazol-2-yl]benzoate (3.26 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][OH:14])=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:6]([C:15]([F:16])([F:17])[F:18])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C#CCCO)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCCCO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 157.2 %

Procedure:
4-(4-Nitro-2-(trifluoromethyl)phenyl)but-3-yn-1-ol (156 mg, 0.60 mmol) was dissolved in methanol (2 mL), and palladium carbon (10%, 30 mg) was added thereto. The resulting mixture was stirred under hydrogen atmosphere at room temperature for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-(4-amino-2-(trifluoromethyl)phenyl)butan-1-ol (220 mg, quantitative) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.C(NC(C)C)(C)C.[OH:48][NH:49][C:50](=[NH:59])[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1>CN(C)C=O>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[C:14](=[O:16])[NH:59][C:50](=[N:49][OH:48])[C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: COc1ccc(C(=N)NO)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=NO)NC(=O)[C@H]2CCCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
23 mg (0.1 mmol) of Boc-D-Pipecolic Acid were treated with 0.1 mmol [Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate (HATU) and Diisopropylamine (DIPEA) in 1 ml Dimethylforamide (DMF) for 10 min. 17 mg (0.1 mmol) of N-Hydroxy-4-methoxy-benzamidine were added and the reaction stirred at room temperature for 20 min. The product was not further characterized.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17](N[C@H](C2C=CC=CC=2)CO)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:33]>O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17]([OH:18])=[O:33])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
3-(4-Benzyloxyphenyl)-(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoic amide (8.9 g; 21.22 mmole) was hydrolyzed with concentrated sulfuric acid (27 ml) in water (104 ml) and dioxane (104 ml) at 90° C. for 5 hours. The reaction mixture was poured onto water (220 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate) and the solvent was evaporated in vacuo to give 6.85 g of a mixture of 3-(4-benzyloxyphenyl)-2-(S)-ethoxypropanoic acid and (S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoic acid, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:30][CH3:31].[CH3:32][Si](Cl)(C)C>CO>[CH3:32][O:14][C:13](=[O:15])[CH2:12][NH:11][C:8]1[O:9][C:10]2[C:2]([OH:1])=[C:3]([O:30][CH3:31])[CH:4]=[CH:5][C:6]=2[C:7]=1[C:16](=[O:29])[C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1cc(C(=O)c2c(NCC(=O)O)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Solvent: CO
Product: COC(=O)CNc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
[7-hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-ylamino]acetic acid (30 mg, 0.07 mmol) was dissolved in dry methanol (5 mL) and trimethylsilyl chloride (100 μL) was added to it. The reaction was stirred at room temperature for 6 hours (monitored by tlc). Solvent was distilled under vacuum and the crude was purified over silica gel plate to afford the title compound as yellow solid (23 mg, 79%); 1H NMR (300 MHz, CDCl3) δ 9.11 (b, 1H, NH), 6.97 (s, 2H, benzoyl Hs), 6.62 (d, 1H, J=8.56 Hz), 6.51 (d, 1H, J=8.49 Hz), 4.42 (d, 1H, J=6.09 Hz), 3.91 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe), 3.81 (s, 3H, OMe).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:21][CH2:20][CH2:19][N:14]([CH2:15][CH2:16][CH2:17][OH:18])[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: OCCCN(CCO)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCCCN(CCO)C1CCNCC1

Procedure:
13.3 g of 1-benzyl-4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidine are combined with 1.5 g of 10% palladium/charcoal in 150 ml of methanol and hydrogenated at ambient temperature for 18 hours under 5 bars of hydrogen. The catalyst is renewed after 8 and 15 hours. Then the catalyst is filtered off and the filtrate, the solvent, is eliminated in vacuo. 4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidine is obtained as an oil, which is used without further purification for the next reaction.
Reaction SMILES: [CH:1]1([C:7]2[NH:8][C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]([C:12]([O:14]C)=[O:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].O>C(O)C>[CH:1]1([C:7]2[NH:8][C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1nc(C2CCCCC2)[nH]c1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2[nH]c(C3CCCCC3)nc2C(=O)O)cc1
Yield: 45.5 %

Procedure:
Methyl 2-cyclohexyl-5-(4-methylphenyl)imidazole-4-carboxylate (900 mg) was dissolved in ethyl alcohol (20 ml). Lithium hydroxide hydrate (1.1 g) and water (10 ml) were added, and the mixture was refluxed under heating for 2.5 hr and concentrated under reduced pressure. To the obtained residue were added water and ethyl acetate, and the mixture was partitioned. The aqueous layer was filtered, and aqueous citric acid was added to the filtrate. The precipitated crystals were collected by filtration to give 2-cyclohexyl-5-(4-methylphenyl)imidazole-4-carboxylic acid (390 mg), melting point 205-206° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1.[CH3:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[CH:11]12[O:16][CH:14]([CH2:13][CH2:12]1)[CH2:15][N:9]([C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19]([NH:18][CH3:17])=[O:20])=[CH:27][CH:26]=3)[N:3]=1)[CH2:10]2
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1nc(Cl)nc(N2CC3CCC(C2)O3)n1
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 29 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 4 using 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane and 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 5 g, 29% yield.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:15]([NH2:18])[CH2:16][OH:17]>C1COCC1>[OH:17][CH2:16][CH2:15][NH:18][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCO
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCO
Yield: 95 %

Procedure:
To a solution of 4.70 g (21.9 mmol) of methyl 2-chloro-3-nitrobenzoate in 300 mL of THF was added dropwise 300 mL of 2-ethanolamine (80 mmol) and the mixture was refluxed over night. The reaction was concentrated to dryness, dissolved in ethyl acetate, and washed aqueous sodium hydrogen carbonate and water. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5.00 g (20.8 mmol, 95%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH2:9][NH2:10])[CH:7]=1.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH2:9][N:10]=[CH:13][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1CCN
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCO
Product: COC(=O)c1ccc(C=NCCc2cc(F)ccc2OC)cc1

Procedure:
9.00 g (53 mmol) of 2-(5-fluoro-2-methoxyphenyl)ethylamine and 8.73 g (53 mmol) of methyl 4-formylbenzoate are dissolved in 450 ml of ethanol, the mixture is heated at reflux for 2 hours and the solvents are then evaporated under reduced pressure.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=2)=[O:19])[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CN(C=O)C.O>[CH2:29]([N:23]1[CH:24]=[CH:25][C:20]([C:18]([NH:17][C:8]2[S:9][C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=2)=[O:19])=[CH:21][C:22]1=[O:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1cc[nH]c(=O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
Compound 112 (146 mg, 0.400 mmol) was dissolved in DMF (2 mL), 60% sodium hydride (35.2 mg, 0.880 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Benzyl bromide (0.0523 mL, 0.440 mmol) was added dropwise to the reaction mixture, followed by stirring overnight at room temperature. The reaction mixture was poured into water, and 1 mol/L hydrochloric acid was added thereto to adjust the pH to 7, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=99:1) to afford the entitled Compound 113 (25.0 mg, 14%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[F:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:20][C:21]2[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=2[F:27])=[O:19])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: Nc1cc(O)ccc1F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)no1
Temperature: 50 °C
Yield: 68.2 %

Procedure:
To a stirred suspension of phenyl 5-tert-butylisoxazol-3-ylcarbamate (prepared as described in Example 270A) (260 mg, 1 mmol) and 3-amino-4-fluorophenol (127 mg, 1 mmol) in acetonitrile (15 mL) at rt, was added DBU (0.3 mL, 2 mmol). The mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue purified via silica gel column chromatography to afford 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (200 mg, 68%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (m, 2H), 8.41 (m, 1H), 7.68 (m, 1H), 6.56-6.65 (m, 2H), 6.45 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 294 (M+H)+.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[Cl:10][C:11]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([C:15]#[N:16])=O>S(=O)(=O)(O)O.C(#N)C>[Cl:10][C:11]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:12]=1/[C:13](=[N:5]/[NH:6][C:7]([NH2:9])=[NH:8])/[C:15]#[N:16]
Reactant: N=C(N)NN
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Agent: O=C(O)O
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: N#C/C(=N\NC(=N)N)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 45 h
Yield: 66 %

Procedure:
Aminoguanidine bicarbonate (1.75 moles) was dissolved in 9.3-10.0 M sulphuric acid solution. A solution of 2,3-dichlorobenzoyl cyanide (1 mole) in acetonitrile was added and the suspension stirred at 20-30° C. for 42-48 hours. The crude product was filtered and washed with water. The solid was added to sodium hydroxide solution below 35° C., then the product was filtered, washed with water and dried at 80-90° C. to obtain 1.5 as a yellow solid in 66% yield.