Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[I:11]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:11][C:10]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][NH:8][CH:9]=1
Reactant: c1csc(-c2cc[nH]n2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1c[nH]nc1-c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
3-(2-thienyl)-1H-pyrazole (2.9 mmol) was dissolved in 8 mL N,N-dimethylformamide under argon atmosphere. N-Iodosuccinimide (3.1 mmol) was added in small portions. The reaction mixture was stirred at room temperature overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed with little cold MTBE and dried in vacuum to afford 540 mg of 4-iodo-3-(2-thienyl)-1H-pyrazole (66% yield). The filtrate was extracted with ethyl acetate. The combined organic layers were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 303 mg of 4-iodo-3-(2-thienyl)-1H-pyrazole (34% yield) that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.Cl.[CH:31]1([N:34]([CH3:41])[CH2:35][CH:36]=[CH:37][C:38](O)=[O:39])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:22]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][N:13]([C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][N:34]([CH:31]2[CH2:33][CH2:32]2)[CH3:41])[CH2:12]1
Reactant: CN(CC=CC(=O)O)C1CC1
Reactant: Nc1ncnc2c1n(-c1ccc(Oc3ccccc3)cc1)c(=O)n2[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
A solution of (R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one (62) (95 mg, 0.24 mmol), 4-(cyclopropyl(methyl)amino)but-2-enoic acid hydrochloride (69 mg, 0.36 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mL dry DMF was cooled to 0° C. HBTU (190 mg, 0.49 mmol) was added in one portion. The reaction mixture was allowed to warm to rt, and stirred for 2 hrs under N2, then purified directly by Gilson using 10 to 95% acetonitrile in water (0.2% NH3.H2O) to give (R,E)-6-amino-9-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (63) (31 mg, 17.7%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 526. 1H NMR (400 MHz, DMSO) δ 8.14 (d, J=6.0 Hz, 1H), 7.55-7.34 (m, 4H), 7.30-7.08 (m, 5H), 6.76-6.59 (m, 1H), 6.36 (dd, J=37.4, 15.1 Hz, 1H), 5.82 (d, J=9.1 Hz, 2H), 5.20-4.99 (m, 1H), 4.11-3.40 (m, 4H), 3.26 (dd, J=17.7, 6.4 Hz, 2H), 2.78-2.59 (m, 1H), 2.24 (d, J=12.4 Hz, 3H), 1.80-1.63 (m, 1H), 0.51-0.37 (m, 2H), 0.37-0.24 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)[CH:3]=1)[CH3:38]
Reactant: CC(=O)CN1CCC(CCN2CCN(c3cccc(N)c3)CC2)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(N2CCN(CCC3CCN(CC(C)=O)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a cooled solution of 0.1 g (0.3 mmol) of 1-(4-{2-[4-(3-aminophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one in 5 mL of dichloromethane and 0.03 g (0.3 mmol) of triethylamine, is slowly added 0.032 g (0.3 mmol) of ethyl chloroformate. The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The product is dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 95/5) to give 0.025 g (20%) of [3-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)phenyl]carbamic acid ethyl ester as a solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:36])[C@@H:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:27]([Cl:35])[CH:26]=3)[CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:12]2)=[CH:6][CH:5]=1.Cl>O1CCOCC1.O>[Cl:35][C:27]1[CH:26]=[C:25]([C@@H:18]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:17]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)[N:12]=2)=[O:36])[CH:30]=[CH:29][C:28]=1[S:31]([CH3:34])(=[O:32])=[O:33]
Reactant: COC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
The 4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (prepared in example 44, 840 mg, 1.54 mmol) was dissolved in dioxane (20 mL) and 6.0 M aqueous hydrochloric acid (20 mL) was added. The reaction was heated to 80° C. in a sealed vial while stirring for 8 h. Upon cooling, the reaction was diluted with water (25 mL) and the product extracted into ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the desired product, 4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (328 mg, 40%) as a white powder: ESI-LRMS m/e calcd for C26H28ClN3O5S [M+] 529.1, found 530.2 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.13 (m, 2H, CH2), 1.33-1.80 (m, 8H, 4×CH2), 1.94-2.19 (m, 1H, CH), 3.32 (s, 3 H, SO2CH3), 3.83-3.93 (m, 1H, CH), 5.26 (s, 2H, NCH2), 6.47 (d, J=2.2 Hz, 1H, Ar), 7.26 (d, Jo=8.4 Hz, 2H, Ar), 7.55 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.65 (d, Jm=1.7 Hz, 1H, Ar), 7.74 (d, J=2.2 Hz, 1H, Ar), 7.87 (d, Jo=8.4 Hz, 2H, Ar), 7.97 (d, Jo=8.2 Hz, 1H, Ar), 10.78 (s, 1H, NH), 12.88 (br.s., 1H, CO2H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1.[C-:13]#[N:14].[Na+]>>[O:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:4]([CH:3]([CH3:2])[C:13]#[N:14])=[CH:5]1
Reactant: BrCCc1coc2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Product: CC(C#N)c1coc2ccccc12

Procedure:
This compound was prepared by the same method as for intermediate 27, using 1.98 g (8.8 mmol) of 3-(2-bromoethyl)benzofuran and 0.86 g (17.6 mmol) of NaCN, to afford 1.5 g (quant.) of the title compound: MS (ESI) m/z 171 [M]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[C:21]([CH:22]=[O:23])[C:20]([OH:25])=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([CH:24]=1)[CH:22]=[O:23]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-chloro-salicylaldehyde (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. for overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.O[CH2:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: OCC1CCNCC1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c1C(=O)N(CC1CCNCC1)C2=O)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
At room temperature, 0.43 ml (2.73 mmol) of diethyl azodicarboxylate (DEAD) is added dropwise to a suspension of 670 mg (2.18 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide, 314 mg (2.73 mmol) of 4-hydroxymethylpiperidine and 716 mg (2.73 mmol) of triphenylphosphine in 8.7 ml of absolute THF. After 2 h at room temperature, the mixture is concentrated and the residue is separated by chromatography on silica gel (gradient: from dichloromethane/methanol 95:5 to dichloromethane/methanol/triethylamine 9:1:0.1). Yield: 430 mg (41.5% of theory); MS (ESI): m/z (%)=404 (M+H, 60), 145 (100); LC-MS (Method 4): rt (%) =3.02 (84).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of crude (4-chloro-3-trifluoromethyl-phenyl)-methanol in DMF (anhydrous, 40 mL) at 0° C. is added NaH (600 mg, 15 mmol). After stirring for 30 min, 4-methoxy benzylbromide (2.21 g, 11 mmol) is added dropwise via syringe. After stirring at room temperature for 3 h, the reaction is quenched by pouring into a mixture of ice and saturated aqueous NH4Cl. The mixture is extracted with EtOAc (3×30 mL), and the combined organic layers are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the crude product is purified by silica gel chromatography (5% EtOAc in hexanes) to give 1-chloro-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene as a colorless oil.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.[OH:22][CH:23]([CH2:28][NH2:29])[CH2:24][C:25]([OH:27])=[O:26].N12CCN(CC1)CC2>O>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:29][CH2:28][CH:23]([OH:22])[CH2:24][C:25]([OH:27])=[O:26])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC(O)CC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(N2CCCCCC2)cc1
Agent: C1CN2CCN1CC2
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CC(O)CNS(=O)(=O)c1ccc(N2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 150.4 %

Procedure:
4.1 g of (4-hexahydro-azepin-1-yl-benzenesulphonyl) chloride then 12 cm3 of acetone are added to a solution of 1.4 g of 3-hydroxy-4-amino butanoic acid and 3.36 g of 1,4-diazabicyclo [2.2.2]octane (DABCO) in 18 cm3 of water. Agitation is carried out for 6 hours at ambient temperature, the acetone is evaporated off, the residue is cooled down to 0° C. and 7.5 cm3 of 2N hydrochloric acid is added. Extraction is carried out with chloroform, the extracts are dried and evaporated to dryness. 6.3 g of desired product is obtained, used as it is for the following stage.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O:3][CH3:4])=[O:2].S(Cl)(Cl)=O.[Br:16]N1C(=O)CCC1=O>>[Br:16][CH:8]([CH2:7][CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCCCC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCC(Br)C(=O)O

Procedure:
5-Carbomethoxypentanoic acid (12), wherein alk is methyl, was reacted with thionyl chloride and then N-bromosuccinimide (NBS) followed by base hydrolysis to give 2-bromo-5-carbomethoxypentanoic acid (13). Compound (13) was reacted with methyl-3-mercaptopropionate (m=1, R1 '=H and R2 '=OCH3) to yield 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanoic acid (14). Compound (14) reacted first with diborane and then with dimethylsulfoxide and trifluoroacetic anhydride to afford 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanal (15). Compound (15) was reacted under Wittig conditions with tridecyltriphenylphosphonium ylid to yield methyl-5-[(2-carbomethoxyethyl)thio]-6(Z)-nonadecenoate (16) which was saponified to afford a compound of the formula (IV) wherein m is 1, R1 is hydrogen, and R2 is hydroxyl.
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH3:19][CH2:20][O:1][C:2]([C@@H:4]([NH2:5])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:12]([OH:13])[CH:14]=1)=[O:3]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)c(O)c1

Procedure:
reacting L-DOPA with ethanol in the presence of thionyl chloride or an acid catalyst to yield crude L-DOPA ethyl ester,
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>ClCCl>[C:1]([O:5][C:6]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:20](=[O:23])[CH:21]=[CH2:22])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 100.3 %

Procedure:
To a stirred solution of 5.0 g (29.2 mmol) D-Proline tert-butyl ester and 4.5 ml (32.1 mmol) triethylamine in 180 ml dichloromethane at 0° C. was added dropwise 3.6 ml (43.8 mmol) acryloyl chloride and stirring continued for 48 h at room temperature. The reaction mixture was then washed sequentially with water, saturated ammonium chloride solution, once more with water and then with saturated brine, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford 6.6 g (100%) of the title compound as a yellow oil. MS m/e (%): 243 (M+NH4+, 33), 226 (M+H+, 100).
Reaction SMILES: [O:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]>C(O)(=O)C.CCOC(C)=O.[Fe]>[O:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(N)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A 100 mL round-bottom flask was charged with the iron powder (5.6 g, 10 mmol) in acetic acid (30 mL) and heated to 80° C. (oil bath) under N2. To this mixture was added slowly the above 2-isopropoxyl-5-nitropyridine (4.6 g, 25.2 mmol) in acetic acid (30 mL) via dropping funnel and the reaction stirred at 80° C. for another 30 min after the addition. After cooling the reaction mixture, it was diluted with EtOAc, filtered through celite, and the solvent evaporated in vacuo. The residue was dissolved in EtOAc and washed with NaHCO3 (sat.), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography to afford 2-isopropoxyl-5-aminopyridine (3.8 g, 99%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, 1 H), 7.00 (dt, 1 H), 6.52 (d, 1 H), 5.10 (sep, 1 H), 1.30 (d, 6H); MS (ES) (M++H) expect 153.1, found 153.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:5][NH:6][C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)=[O:8].O1[CH2:35][CH2:34]OCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:5][NH:6][C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([N:10]2[CH2:35][CH2:34][N:6]([CH3:5])[CH2:7][CH2:9]2)[N:10]=1)=[O:8]
Reactant: Cc1ccccc1-c1cnc(S(C)(=O)=O)nc1C(=O)NCc1cc(Cl)cc(Cl)c1
Reactant: C1COCCO1
Product: Cc1ccccc1-c1cnc(N2CCN(C)CC2)nc1C(=O)NCc1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 175.9 %

Procedure:
To a solution of 0.19 g (0.435 mmol) 2-methanesulfonyl-5-o-tolyl-pyrimidine-4-carboxylic acid 3,5-dichloro-benzylamide in 5 ml dioxane 0.12 ml (1.08 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 5 ml CH2Cl2 and 25 ml H2O. The aqueous layer was extracted with 20 ml CH2Cl2, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 9:1) to give 0.18 g (88%) 2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid 3,5-dichloro-benzylamide as a colorless oil, MS (ISP): 470.2, 472.2 (M+H+).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](Br)=O)[CH:10]=[CH:11][C:12]=1[Cl:13]>O1CCOCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:5]=[C:3]([NH:2][NH2:1])[S:4][CH:15]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(Br)Cc1ccc(Cl)c(Cl)c1
Reactant: NNC(N)=S
Solvent: C1COCCO1
Product: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1

Procedure:
A solution of a thiosemicarbazide (10 mmol, 0.91 g) and 3,4-dichlorophenylacetyl bromide (10 mmol, 2.68 g) in dioxane (20 mL) was stirred at room temperature for 16 h. The precipitate of hydrobromide salt was filtered and washed with dioxane (3×10 mL) basified with 2N Na2CO3 (20 mL). The product was filtered, washed with water and dried (2.08 g, 80%). The product was generally satisfactory for further reaction. 1H NMR (400 MHz) δ 8.67 (s, 1H, NH), 8.00 (d, J=1.6 Hz, 1H), 7.76 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.31 (s), 1H MS+(APCI), 259.68, (M+1; calcd 258.97 (M+)
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[F:12][C:13]([F:43])([F:42])[C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][N:26]([CH3:41])[C:27](=[O:40])[CH:28](OS(C)(=O)=O)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(N(CC)CC)C>CC(C)=O>[F:12][C:13]([F:42])([F:43])[C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][N:26]([CH3:41])[C:27](=[O:40])[CH:28]([N:8]2[CH2:7][CH2:6][CH:5]([NH:4][C:3]([NH:2][CH3:1])=[O:11])[CH2:10][CH2:9]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(OS(C)(=O)=O)c1ccccc1
Reactant: CNC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)NC1CCN(C(C(=O)N(C)CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Yield: 32.8 %

Procedure:
6.8 g of 4-(3-methylureido)-piperidine are refluxed together with 19.2 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide (prepared analogously to the method described in WO 99/62893) and 6.8 ml of triethylamine in 400 ml of acetone for 8 hours. Then the solution is evaporated down, combined with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract is dried, the solvent is eliminated in vacuo and the residue is chromatographed with methylene chloride/methanol 9:1 over silica gel. The fractions found to be uniform by TLC are combined and the solvent is eliminated in vacuo. N-[2-(3,5-bis-tifluormethyl-phenyl)-ethyl]-N-methyl-2-[4-(3-methyl-ureido)-piperidin-1-yl]-2-phenyl-acetamide is crystallised from the residue with ethanolic hydrochloric acid and ether in the form of the hydrochloride, yielding 7.1 g of colourless crystals. 1H-NMR (250 MHz, CD3OD) δppm=7.93-7.33 (8H, m); 5.58; 5.38 (1H, 2s); 4.03-2.59 (5H, m); 3.05 (4H, m); 2.98; 2.90 (3H, 2s); 2.74; 2.70 (3H, 2s); NH in the solvent blind peak 4.89; 2.27-1.52 (4H, m). Most signals are split by amide rotation.
Reaction SMILES: [N:1]1[C:2]([CH2:10][O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[I:18]N1C(=O)CCC1=O>C(#N)C>[I:18][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[CH2:10][O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)COCc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCOC(=O)COCc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
0.45 g (1.921 mmol) of ethyl 2-(imidazo[1,2-a]pyridin-2-ylmethoxy)acetate were solubilised in 6 ml of acetonitrile with magnetic stirring, to this solution were added 0.475 g (2.113 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h. A solid was removed by filtration and the obtained filtrate was concentrated in vacuo. The residue was triturated with 10 ml of diisopropyl ether and a precipitate was isolated by filtration. 0.465 g (yield=67%) ethyl 2-((3-iodoimidazo[1,2-a]pyridin-2-yl)methoxy)acetate were obtained as a yellow solid. LC-MS: m/z=361 (MH+); UV purity at 254 nm=75%. 1H NMR (300 MHz, DMSO) δ 8.34 (d, J=6.9 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.47-7.28 (m, 1H), 7.07 (d, J=5.7 Hz, 1H), 4.67 (s, 2H), 4.14 (t, J=10.7 Hz, 4H), 1.22 (d, J=1.9 Hz, 3H)