Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:12][N:13](C(OCC3C=CC=CC=3)=O)[CH2:14][CH2:15][N:7]3[C:8]=2[C:3]=1[CH:4]1[CH2:28][CH2:27][CH2:26][CH:5]1[CH2:6]3.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1.[OH-].[Na+].C(Cl)[Cl:48]>>[ClH:48].[F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:12][NH:13][CH2:14][CH2:15][N:7]3[C:8]=2[C:3]=1[CH:4]1[CH2:28][CH2:27][CH2:26][CH:5]1[CH2:6]3
Reactant: ClCCl
Reactant: O=C(OCc1ccccc1)N1CCN2CC3CCCC3c3c(F)ccc(c32)C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Product: Cl
Product: Fc1ccc2c3c1C1CCCC1CN3CCNC2
Reaction time: 4.5 h
Yield: 67 %

Procedure:
The compound of Example 25 (0.350 g, 0.92 mmol) was dissolved in methylene chloride (1.41 mL). Trifluoromethane sulfonic acid (0.570 mL, 6.4 mmol) and anisole (0.300 mL, 2.7 mmol) were added at room temperature. After 4.5 hours, the pH of the reaction mixture was adjusted to a pH of 8 to 9 with 1N NaOH, and the solution was stirred for 20 minutes. The contents of the flask were transferred to a separatory funnel and extracted with methylene chloride (3×). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated. Further purification (15% ammonia in 2M solution ethanol/ethyl acetate) gave 0.1514 g of the desired free amine product as a yellow oil (67%). The free amine product (0.1514 g, 0.61 mmol) was dissolved in diethyl ether, and then HCl in 2M solution of diethyl ether was added. The mixture was stirred for 30 minutes and a pale yellow solid was filtered off.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(#N)C>[C:25]1([S:31]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:19]([C:17]([NH:16][C@H:13]3[CH2:12][CH2:11][C@H:10]([O:9][C:6]4[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[O:18])[CH2:20]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H](Oc2ccncc2)CC1)[C@H]1CCCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H](Oc2ccncc2)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3S)-N-[trans-4-(pyridin-4-yloxy)cyclohexyl]piperidine-3-carboxamide dihydrochloride (28 mg, purity: 40%, 0.03 mmol), benzenesulfonyl chloride (6.3 mg, 0.036 mmol), triethylamine (16 μL, 0.12 mmol) in acetonitrile (1 mL) was stirred at r.t. overnight. the mixture was purified with prep. HPLC. 5.9 mg (45%) of final product was obtained. LCMS: m/z 444.1 (M+H)+; 466.1 (M+Na)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH2:12]([O:5][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24]
Reactant: CC(C)CCCCCCCCCCO
Reactant: CC(CC(=O)O)CC(C)(C)C
Product: CC(C)CCCCCCCCCCOC(=O)CC(C)CC(C)(C)C

Procedure:
Preparation according to Example 3 from 3,5,5-trimethyl-hexanoic acid and isotridecyl alcohol (mixture of methyl branched primary tridecanols from Hoechst); colorless liquid of medium viscosity;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1.[H-].[Na+].[CH2:14](I)[CH2:15][CH3:16].O>CN(C)C=O.CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][N:9]([CH2:14][CH2:15][CH3:16])[N:8]=2)[S:5][CH:6]=1.[CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[N:8]([CH2:14][CH2:15][CH3:16])[N:9]=[CH:10][CH:11]=2)[S:5][CH:6]=1
Reactant: CCCI
Reactant: Cc1csc(-c2cc[nH]n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCn1ccc(-c2cc(C)cs2)n1
Product: CCCn1nccc1-c1cc(C)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %
Yield: 18 %

Procedure:
3-(4-methyl-2-thienyl)-1H-pyrazole (9.1 mmol) was dissolved in 20 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (13.7 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, propyl iodide (18.3 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:MTBE 100:0 to 90:10) to afford 1.39 g 3-(4-methyl-2-thienyl)-1-propyl-1H-pyrazole (74% yield) and 341 mg of 5-(4-methyl-2-thienyl)-1-propyl-1H-pyrazole (18% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:17]=1[CH2:16][CH2:15][NH:14][C:13]2=[O:12]
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C
Yield: 66 %

Procedure:
A mixture of 5-bromo-1,3-dihydro-indol-2-one (23 mg, 0.11 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-1-carbaldehyde (29.7 mg, 0.18 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 26 mg (67%) of the title compound.
Reaction SMILES: [C:1]([C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)(=[O:4])[CH:2]=[CH2:3].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[CH:16]1([SH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C.C(Cl)(Cl)Cl>[CH:16]1([S:22][CH2:3][CH2:2][C:1]([C-:5]2[CH:9]=[CH:8][CH:7]=[CH:6]2)=[O:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: SC1CCCCC1
Reactant: C=CC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(CCSC1CCCCC1)[c-]1cccc1

Procedure:
A solution of acryloyl ferrocene (2.16g) and cyclohexylmercaptan (1.16g) in ethanol (50 ml) was set aside at ambient temperature for 24 hours. Evaporation of the ethanol gave an oil which was dissolved in chloroform (100 ml). The chloroform solution was washed successively with aqueous sodium hydroxide and water, dried over sodium sulphate and evaporated affording crude product. This was chromatographed through a silica-gel column (66g) using initially 1% ethyl acetate/petroleum ether (60°-80°) then 3% ethyl acetate/petroleum ether as eluent. This afforded an oil which crystallised on cooling and trituration with petroleum ether. The solid was filtered off, washed well with petroleum ether and dried giving the title compound, m.p. 46.5°-48.5°to C.
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][CH:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][CH:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCC(O)C3)n1)CCN(CC(C)O)CC2
Yield: 61 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as a white solid (70 mg, 61%). mp: 199-202° C., MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.55 (m, 2H), 7.25 (m, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.89 (s, 4H), 3.43 (m, 3H), 2.89-2.52 (m, 9H), 2.26 (t, J=9 Hz, 1H), 1.96 (m, 1H), 1.87 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:7]([C:9]1[S:13][C:12]([NH:14][C:22](=[O:23])[C:21]([OH:20])([CH3:26])[CH3:25])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)C(=O)Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Compound 136 (150 mg, 0.555 mmol) was dissolved in DMF (2.5 mL), and 2-hydroxy-2-methylpropanoic acid (116 mg, 1.11 mmol), EDC hydrochloride (313 mg, 1.11 mmol) and 1-hydroxybenzotriazole monohydrate (170 mg, 1.11 mmol) were added thereto, followed by stirring at 50° C. for 3 hours. Water was added to the reaction mixture, 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 (hexane:ethyl acetate=1:1) to afford the entitled Compound 137 (158 mg, 80%).
Reaction SMILES: [C:1]([O:20]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14]CCCC.C([O:24]CC)=C>>[CH2:4]([OH:24])[CH:3]=[CH:2][CH2:1][OH:20].[CH3:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=COCC
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Product: CCCCCCCCCCCCCC
Product: OCC=CCO
Reaction time: 0.03 h

Procedure:
A) Route without additives: In a test tube the mixture of 1 ml (2.95 mmol) of methyl oleate, the corresponding amount of 2-butene-1,4-diol (0.24 ml or 0.73 ml) and 0.1 ml of tetradecane (internal standard) is prepared and mixed. If the reaction is being carried out without solvent, a blank sample is taken for GC measurement. In the case of the procedure with solvent, a blank sample for GC measurement is taken only after the addition of 1 ml of the corresponding solvents. After sampling has taken place, the reaction vessel is placed in the thermally conditioned oil bath. The mixture is stirred for about 2 minutes using a magnetic stirrer. When the desired temperature of the mixture has been reached, the catalyst (2 mol %) is added. The reaction mixture is further heated and stirred, and after 4 and 24 hours of reaction the next GC samples are taken for kinetic determinations. After 24 hours the reaction is halted by addition of 1 ml of ethyl vinyl ether.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:15]=2)=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
3-(Trifluoromethyl)aniline 10 g (62.1 mmol) was added to 500 ml of anhydrous dichloromethane in a 500 ml round bottomed flask. This stirred solution was cooled to 0° C. using an ice water bath. 3-(Trifluoromethyl)phenyl isocyanate 15 g (80.1 mmol) was added drop-wise over a period of 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred at ambient temperatures for 18 hours. During this time a heavy precipitate was formed. This solid was collected by filtration on a Buchner funnel, and was re-suspended in 250 ml of dichloromethane. After approximately 30 minutes of stirring, the solid was again filtered on a Buchner funnel and then placed under vacuum at 40° C. to dry for a period of 24 hours to give 20 g of a white solid (92.5% yield). 1H NMR (400 MHz DMSO) δ 9.20 (s 2H) 8.04 (s 2H) 7.61 (m 2H) 7.54 (t 2H) 7.34 (m 2H). MS: M+1 found 349.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.C[C:19]1C=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1N.CS(O)(=O)=O.O.C[N:36]1[CH2:40][CH2:39]N(C)C1=O>>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([N:6]2[C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[N:3]=[C:2]2[NH:36][C:40]2[CH:39]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=2[CH3:19])[CH:8]=1
Reactant: Nc1cc(-n2c(Cl)nc3ccccc32)ncn1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: CN1CCN(C)C1=O
Agent: CS(=O)(=O)O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-(2-chloro-benzoimidazol-1-yl)-pyrimidin-4-ylamine (110 mg, 0.45 mmol), 2-methyl-4-nitro-phenylamine (103 mg, 0.68 mmol), and MeSO3H (58.0 μL, 0.9 mmol) in 1,3-dimethyl-2-imidazolidinone (0.2 ml) is heated at 90° C. After stirring for 2 hours, the reaction mixture is cooled to room temperature and is treated with water (5 mL). Solid is collected via filtration and further purified by flash chromatography on silica gel (0% MeOH/Dichloromethane to 10% MeOH/Dichloromethane gradient). The title compound is obtained as white powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[O:14][CH2:13][CH2:12][O:11]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OCCO
Reactant: O=Cc1ccc2sccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2cc(C3OCCO3)ccc2s1
Reaction time: 7 h

Procedure:
16.5 g of 1-benzothiophene-5-carbaldehyde and 49.5 mL of ethylene glycol were dissolved in 165 mL of toluene, to which 0.30 g of para-toluenesulfonic acid monohydrate was added, and this solution was stirred for 7 hours while heating it under reflux. The reaction mixture was cooled to room temperature, to which an aqueous solution of sodium hydroxide was added, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to yield 15.8 g of 2-(1-benzothiophen-5-yl)-1,3-dioxolane as yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Br:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Br:28][C:29]1[CH:34]=[C:33]([C:8]2[CH:7]=[C:6]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: O=S(=O)(Oc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)n1)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C3CC3)c2)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.34) (1.0 g, 2.43 mmol) and commercially available 3-bromo-benzene-boronic acid (0.573 g, 2.85 mmol) according to the general procedure IVb. Obtained as a white solid (0.91 g, 89%). MS (ISP) 418.1 [(M+H)+] and 420.1 [(M+2+H)+].
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:3][C:4]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-n3cccn3)cc(Br)c2s1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-n3cccn3)cc(-c3cccnc3)c2s1
Temperature: 120 °C
Yield: 24.5 %

Procedure:
To a solution of 1-(7-bromo-5-pyrazol-1-yl-benzothiazol-2-yl)-3-ethyl-urea (0.27 g, 0.74 mmol) in DMF: H2O (2:1, 15 mL) was added 3-pyridyl boronic acid (0.11 g, 0.88 mmol) and K3PO4 (0.17 g, 0.81 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.077 g, 0.11 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 2 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (230-400 M) using EtOAc-Hexane (70:30) to provide the title compound (0.066 g, 22%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([NH:15][C:16](=[O:33])[CH:17]=[C:18]1[CH2:23][CH2:22][C:21]([N:30]([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[Cl:35][Si](C)(C)C>CC(CC)=O>[ClH:35].[CH3:1][O:2][C:3](=[O:34])[CH:4]([NH:15][C:16](=[O:33])[CH:17]=[C:18]1[CH2:19][CH2:20][C:21]([N:30]([CH3:31])[CH3:32])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1
Reactant: C[Si](C)(C)Cl
Agent: COC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)C=C1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 2 h

Procedure:
2-[2-(4-Dimethylamino-4-phenylcyclohexylidene)acetylamino]-3-(1H-indol-3-yl)propanoic acid methyl ester (142 mg, 0.3 mmol) was dissolved in ethyl methyl ketone (9 ml), and chlorotrimethylsilane (0.055 ml, 0.43 mmol) was added. After 2 h it was possible to obtain the product as a colourless compound in a yield of 50 mg (15%) with an m.p. of 164-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][C:18]4[CH:19]=[C:20]([CH2:25][C:26]#N)[CH:21]=[CH:22][C:23]=4[CH3:24])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[OH-:30].[Na+].[OH2:32]>C(O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][C:18]4[CH:19]=[C:20]([CH2:25][C:26]([OH:32])=[O:30])[CH:21]=[CH:22][C:23]=4[CH3:24])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(CC#N)cc1OCCC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CC(=O)O)cc1OCCC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of [3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}-4-methylphenyl]acetonitrile (1.14 g; 2.68 mmol), sodium hydroxide (0.54 g; 13.5 mmol), water (1.6 ml) and ethanol (21 ml) was stirred at 80° C. for 6 hours. The reaction solution was concentrated under reduced pressure and became pH=7 with 2N-aqueous hydrochloric acid. The precipitate was collected to give 3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}-4-methylphenyl acetic acid as colorless crystal (0.63 g; 53%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[N:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[N:18][N:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C#N)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nnc(NC2CCNCC2)s1
Temperature: 0 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a stirred solution of 4-(5-cyano-[1,3,4]thiadiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (D5) (0.973 g, 3.12 mmol) in dichloromethane (55 ml), at 0° C., was added trifluoroacetic acid (3 ml). The reaction mixture was stirred at 0° C. for 1 h. and at room temperature for 18 h. more. After this period, the reaction mixture was extracted with a saturated solution of sodium carbonate. The aqueous layer was extracted with ethyl acetate (2×25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo to yield D6 (0.60 g, 92%) as a solid. C8H11N3S requires 209. Found 210 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A solution of N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (61 mg, 0.14 mmol) in CH2Cl2 (3 mL) was treated with pyridine (0.058 mL, 0.72 mmol) and acetic anhydride (0.13 mL, 1.4 mmol). The resultant mixture was stirred at RT for 2 days. The reaction was quenched with saturated aqueous NaHCO3 and was further stirred for 2 h. The mixture was diluted with EtOAc (30 mL) and was washed with saturated aqueous NaHCO3 (20 mL), water (20 mL) and brine (20 mL). The mixture was concentrated in vacuo and purified by silica gel chromatography to provide N-(4-(2-acetamidopyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (46 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ10.56 (s, 1H), 10.54 (s, 1H), 9.96 (s, 1H), 8.18 (d, J=5.8 Hz, 1H), 7.92 (t, 1H), 7.65 (d, J=1.9 Hz, 1H) 7.59 (m, 2H), 7.24 (dd, J=11.2, 2.5 Hz, 1H), 7.15 (m, 2H), 7.01 (m, 1H), 6.68 (dd, J=5.7, 2.3 Hz, 1H), 2.02 (s, 3H), 1.60-1.52 (m, 4H); MS (ESI) m/z: 467.2 (M+H+).