Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[F:15][C:16]([F:32])([F:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([NH:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 67.1 %

Procedure:
A mixture of methyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A3) (14.28 g, 1 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (19.6 g, 0.85 equiv), DCE (300 ml), acetic acid (3.8 ml, 0.90 equiv) and sodium triacetoxyborohydride (20.7 g, 1.25 equiv) was stirred at room temperature under nitrogen for 17.5 h. Aqueous sodium carbonate (2M solution, excess) was added and stirred for 4 h, then the mixture was extracted with a mixture of diethyl ether and THF. The organic extracts were backwashed with water and brine, dried over sodium sulfate and filterered through a pad of silica gel which was rinsed with 2.5% methanol in DCM. After evaporation in vacuo, the crude product was crystallised from ether/hexane, finally at ice bath temperature, which after drying yielded a white solid (20.9 g).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]#[N:4].S(=O)(=O)(O)[OH:10]>C1COCC1>[NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]([NH2:4])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(N)C#N
Solvent: C1CCOC1
Product: CC(C)C(C)(N)C(N)=O

Procedure:
In a similar way, hydrolysis of the (+)-2-amino-2,3-dimethylbutyronitrile with sulfuric acid yields the (-)-2-amino-2,3-dimethylbutyramide, mp 81°-82° C., [α]D25 =-57.14° (c=0.0654 g/ml THF).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(OCC(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from [4-chloro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M182) (272 mg, 0.482 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (150 mg, 70%).
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)[S:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:17]>CO>[NH2:17][CH:6]([C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)c1cccs1
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)CC(N)c1cccs1
Temperature: 80 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
Ru(OCOCH3)2((S)-segphos)(45.0 mg, 0.543 mmol), methyl 2-(2-thenoyl)acetate (1.00 g, 5.428 mmol), ammonium acetate (0.418 g, 5.428 mmol) and methanol (5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled down to room temperature and further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo and the residue was purified by silica gel chromatography (eluent hexane ethyl acetate/triethylamine=50/50/5) to give methyl (+)-3-amino-3-thiophen-2-yl-propionate (270 mg) as a colorless oil in 26.8% yield. The resulting methyl (+)-3-amino-3-thiophen-2-yl-propionate was converted into methyl 3-(4-nitrobenzoylamino)-3-thiophen-2-yl-propionate, and the enantiomeric excess of the product was found to be 95.7% ee by HPLC analysis using a SUMICHIRAL OA-4100 column (available from SUMIKA CHEMICAL ANALYSIS SERVICE LTD.).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:24])[CH2:19][CH2:18][C:17](OC)([O:20]C)[CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[NH:29][C:30]([C:33]#[N:34])=[CH:31][N:32]=2)=[O:27])=[CH:4][CH2:3]1>CC#N>[CH3:1][C:2]1([CH3:35])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:24])[CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH2:19]3)[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[NH:29][C:30]([C:33]#[N:34])=[CH:31][N:32]=2)=[O:27])=[CH:4][CH2:3]1
Reactant: COC1(OC)CCC(O)(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Solvent: CC#N
Product: CC1(C)CC=C(c2cc(C3(O)CCC(=O)CC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-4,4-dimethoxy-cyclohexyl)-phenyl]-amide (as prepared in Example 19) by treatment with LiBF4 in wet CH3CN using the procedure of Lipshutz, B. and Harvey, D., Synth. Commun., 12, 267 (1982).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:4][NH:5][CH:6]=1.[CH2:11]=[O:12]>C(N(CC)CC)C.CC(C)=O>[Br:1][C:2]1[C:3]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:4][N:5]([CH2:11][OH:12])[CH:6]=1
Reactant: CC(C)(C)c1n[nH]cc1Br
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)c1nn(CO)cc1Br
Temperature: 130 °C
Reaction time: 7 h
Yield: 105.2 %

Procedure:
The mixture of 3.14 g of 4-bromo-3-t-butyl-1H-pyrazole, 0.93 g of paraformaldehyde and 0.11 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 3.79 g of 4-bromo-3-t-butyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(=O)O[CH2:16][CH2:15][O:14]1.O(C(C)(C)C)[K]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:16][CH2:15][OH:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1OCCO1
Reactant: Nc1ccc2cccc(O)c2n1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2cccc(OCCO)c2n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 27.7 %

Procedure:
A mixture of 2-amino-8-quinolinol (3.20 g, 20.0 mmol), ethylene carbonate (1.76 g, 20.0 mmol) and KO-t-Bu (2.24 g, 20.0 mmol) in DMF (20 mL) was stirred at 90° C. for 15 h The mixture was poured into brine, extracted with EtOAc, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using toluene/EtOAc/MeOH (50:50-2) as eluent to give 1.13 g (28%) of the title product as a solid HRMS m/z calcd for C11H12N2O2 (M)+ 204.0899. found 204.0906
Reaction SMILES: C([O:3][P:4]([CH2:9][NH:10][CH2:11][C:12]([CH3:35])=[CH:13][CH2:14][C:15]1[C:16]([O:28]CC[Si](C)(C)C)=[C:17]2[C:21](=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[CH2:20][O:19][C:18]2=[O:27])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>CN(C=O)C>[OH:28][C:16]1[C:15]([CH2:14][CH:13]=[C:12]([CH3:35])[CH2:11][NH:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[C:23]([O:24][CH3:25])[C:22]([CH3:26])=[C:21]2[C:17]=1[C:18](=[O:27])[O:19][CH2:20]2
Reactant: CCOP(=O)(CNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)CNCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of ({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-methyl)-phosphonic acid diethyl ester (20 mg, 0.038 mmol) in DMF (0.5 mL) was added TMSBr (49 μL, 0.38 mmol) and 2,6-lutidine (44 μL, 0.38 mmol). The solution was stirred at room temperature for 1 hour when it was quenched by addition of methanol. The product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.6 mg of the product as a white solid. 1H NMR (300 MHz, CD3OD and CDCl3) δ 1.93 (s, 3H), 2.13 (s, 3H), 2.94 (br d, 2H, J=11 Hz), 3.42-3.53 (m, 2H), 3.60 (s, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 5.71 (br s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 8.5 ppm; MS (m/z) 372.2 [M+H]+, 743.2 [2M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[C:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]1=[O:23]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN1C(=O)C(=C(O)c2ccccc2)c2ccccc21
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
4.15 g (41 mmol) of diisopropylamine are placed in 50 ml of THF, cooled to −70° C. and combined with a solution of 14.4 ml of (36 mmol) of n-butyl lithium solution (2.5 mol in toluene) and stirred for 10 minutes. Then a solution of 5.0 g (34 mmol) of 1-methyl-2-indolinone in 30 ml of THF is added dropwise and stirred for 45 minutes at −70° C. Then 5.8 g (0.041 mol) of benzoylchloride are added dropwise. The reaction solution is left to heat up slowly within 14 hours. It is then poured onto sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel (dichloromethane/methanol/ammonia=200:8:1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27]O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:31])=O.C(=O)([O-])O.[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][Cl:31])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1csc(-c2cc3cc(CSc4ccccc4CO)ccc3o2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1csc(-c2cc3cc(CSc4ccccc4CCl)ccc3o2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 136.2 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-hydroxymethylphenylthiomethyl)benzofuran-2-yl]thiazole (0.42 g), thionyl chloride (0.1 g) and N,N-dimethylformamide (3 drops) in chloroform (5 ml) was stirred for 3 hours at ambient temperature. The resulting mixture was poured into aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-tert-butyl-2-[5-(2-chloromethylphenylthiomethyl)benzofuran-2-yl]thiazole (0.49 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]=[C:20]=[O:21])=[CH:14][C:13]=1[Cl:22].CCCCCC>C1COCC1>[Cl:22][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[Cl:11])[CH2:18][NH:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)=[O:21]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: Nc1cccc2[nH]ccc12
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1cccc2[nH]ccc12

Procedure:
4-Aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.25 g of the title compound as a tan solid. mp 201° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.23 (d, 2H), 6.36 (s, 1H), 6.54 (t, 1H), 7.0 (dd, 1H), 7.25 (m, 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31 (s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3Cl2O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94, H, 3.68; N, 11.97.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH:14]=O)[N:10]=2)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>N1C=CC=CC=1>[C:18](/[CH:17]=[CH:14]/[C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[O:13][N:12]=1)([OH:20])=[O:19]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1ccc(-c2nc(C=O)no2)cc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1ccc(-c2nc(/C=C/C(=O)O)no2)cc1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A mixture of 5-(4-cyanophenyl)-3-formyl-1,2,4-oxadiazole (2.0 g), malonic acid (4.18 g) and piperidine (0.50 ml) in pyridine (20 ml) was refluxed for 1 hour. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate, acidified to pH 2.0 with 4N hydrochloric acid washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethanol to give 3-{(E)-2-carboxyvinyl}-5-(4-cyanophenyl)-1,2,4-oxadiazole (1.2 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH2:4][CH2:3]1.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][C:13]1[CH:14]=[CH:15][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:9][C:10]=1[CH:11]=[O:12]
Reactant: CN1CCN(c2cccc(C=O)c2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN1CCN(c2ccc(Br)c(C=O)c2)CC1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A solution of 3-(4-Methyl-piperazin-1-yl)-benzaldehyde (49 mmol) in methylene chloride (150 ml) was slowly (30 min) added a solution of N-bromosuccinimide (98 mmol) in methylene chloride (450 ml). The mixture was stirred for 10 min, washed with 2M sodium hydroxide and the organic phase was removed under reduced pressure. The resulting oil was purified by column chromatography giving the title compound as 90% pure black oil in 95% yield (the impurity being 4-bromo-3-(4-methyl-piperazin-1-yl)-benzaldehyde).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.84 min; [M+H]+=412.07.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:40])([F:39])[C:13]([CH2:34][NH:35][CH2:36][CH2:37][CH3:38])([OH:33])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:34][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:12]([F:11])([F:40])[F:39])=[O:6]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:24])([F:25])[F:23])(=[O:21])=[O:20])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)sulfonyl]phenyl}propan-1-ol (260 mg, 0.69 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (131 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (218 mg, 58%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([Cl:12])=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:7]([C:6]2[C:9]([Cl:12])=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1Cl
Yield: 48 %

Procedure:
Upon boiling a solution of 9.3 g 3-nitro-6-chlorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 130° C (ethanol) is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[NH:18][C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=S.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(#N)C>[CH3:17][C:4]1[CH:5]=[C:6]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[N:18]=[C:19]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(Oc2ncc(Cl)cc2Cl)cc(C)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Oc2ncc(Cl)cc2Cl)cc(C)c1N=C=NC(C)(C)C

Procedure:
A reaction vessel is charged with 16.6 g of N-[2,6-dimethyl-4-(3,5-dichloro-2-pyridyloxy)phenyl]-N'-tert-butylthiourea and 12.8 g of 2-chloro-1-methylpyridinium iodide in 150 ml of acetonitrile. With stirring, a solution of 8.4 g of triethylamine in 80 ml of acetonitrile is added dropwise at room temperature. The reaction mixture is subsequently stirred for 2 hours at 80° C. and then concetrated by rotary evaporation at 50° C. 150 ml of hexane are added to the residue and the resultant solution is filtered. The hexane phase is washed with three 30 ml portions of cold water, dried over sodium sulfate and filtered. The filtrate is concentrated by evaporation, affording the title compound of the formula ##STR5## as a clear pale yellow oil which crystallises on standing and has a melting point of 69°-71° C. (compound 1).
Reaction SMILES: O[C:2]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3].O.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[CH:2]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3]
Reactant: COc1cccc(O)c1C(C)(C)O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(O)c1C(C)C
Yield: 92 %

Procedure:
To a solution of 2-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-phenol dissolved in acetic acid (50 mL) was added 10% palladium on charcoal (500 mg), water (6 mL), and ammonium formate (7.82 g, 124 mmol). After refluxing for 1 hour, the reaction was cooled and filtered through celite. The celite pad was washed with ethyl acetate (500 mL). Water (300 mL) was added to the filtrate, and the mixture was basified (pH=8) using solid sodium bicarbonate. The ethyl acetate layer was collected and washed with water, brine, dried using anhydrous sodium sulfate and concentrated to yield 2-Isopropyl-3-methoxy-phenol (3.68 g, 92%) as pale yellow solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)SC)#[N:2].[NH2:17][CH2:18][CH2:19]SCC1SC=CN=1.C(N)C>>[C:1]([NH:3][C:4]([NH:17][CH2:18][CH3:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)#[N:2]
Reactant: CSC(=NCCSCc1nccs1)NC#N
Reactant: NCCSCc1nccs1
Agent: CCN
Product: CCNC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of N-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea, prepared from 2-[(2-aminoethyl)thiomethyl]thiazole by the procedure of Example 3(c)(i), with ethylamine by the procedure of Example 4 gives N-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine.