Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Reactant: OB(O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1Oc2ccc(-c3cccs3)cc2NC1=O
Temperature: 100 °C
Yield: 33 %

Procedure:
315 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is mixed in 4 ml of DME with 0.2 g of 2-thiopheneboronic acid and 150 mg of tetrakis-triphenylphosphine-palladium (O) and 340 mg of sodium bicarbonate (dissolved in 4 ml of water). It is stirred for some time at 100° C. The product is diluted with ethyl acetate, extracted 3 times with water, and dried with magnesium sulfate. It is concentrated by evaporation. The crude product is purified by column chromatography with a hexane/ethyl acetate mixture and yields pure 33% product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9][C:10]([F:13])([F:12])[F:11].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:9][C:10]([F:11])([F:12])[F:13])[CH:4]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Cl)c(SC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)c(SC(F)(F)F)c2)CC1
Reaction time: 24 h
Yield: 47 %

Procedure:
4-Chloro-3-trifluoromethylsulfanyl-phenylamine (683 mg; 3.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (598 mg; 3.00 mmol) and sodium triacetoxyborohydride (1.9 g; 9.00 mmol) are suspended in dichloroethane (25 mL) and the resulting mixture is stirred for 1 day. Acetic acid is then added (0.18 mL) and the reaction mixture is stirred for additional 9 days. The suspension is then diluted with dichloromethane (10 mL) and is washed with water (20 mL). The organic phase is then washed with aq. sat. sodium carbonate (10 mL), water (10 mL) and is then dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification of the crude by column chromatography on silica gel (dichloromethane) affords the desired product (580 mg; 1.41 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCN1C(=O)c2ccccc2C1(O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2C1(Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
Distilled THF (20 mL) was added to 3-(4-fluorophenyl)-3-hydroxy-2-propyl-2,3-dihydroisoindol-1-one (200 mg, 0.7 mmol) followed by thionyl chloride (0.06 mL, 0.84 mmol) and a catalytic amount of DMF (3 drops). The mixture was stirred at room temperature under nitrogen for 4 h and monitored by TLC. Removal of the solvent under vacuum gave 3-chloro-3-(4-fluorophenyl)-2-propyl-2,3-dihydroisoindol-1-one as a colourless oil (212 mg, 0.69 mmol, 100%) which was used immediately without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].S(OCC)(O[CH2:39][CH3:40])(=O)=O>C(#N)C.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:39][CH3:40])[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: CCn1c(CCCOCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 70 °C
Yield: 99.4 %

Procedure:
In 25 ml of dry acetonitrile was dissolved 5.0 g (11.5 mmol) of imidazole (101e), followed by addition of 1.7 g (23 mmol) of lithium carbonate and 2.7 g (17.5 mmol) of diethyl sulfate. The mixture was stirred under heating at 70° C. for 23 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to provide 5.3 g (yield 98%) of 2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-ethyl-1H-imidazole (136b) as oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:16]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(O)C>[ClH:1].[O:16]([C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:2]2[C:3]3[C:10]([C:11]4[S:12][CH:13]=[CH:14][CH:15]=4)=[CH:9][S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1ncnc2scc(-c3cccs3)c12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CC(C)O
Product: Cl
Product: c1ccc(Oc2ccc(Nc3ncnc4scc(-c5cccs5)c34)cc2)cc1
Yield: 71 %

Procedure:
4-Chloro-5-(2-thienyl)thieno[2,3-d]pyrimidine (commercially available from Maybridge Chemical Co. Ltd.) (0.126 g, 0.50 mmol) and 4-phenoxyaniline (0.116 g, 0.63 mmol) were reacted in 2-propanol (3 ml) for 6.5 hours according to Procedure A. The product was obtained as an off-white powder (0.150 g, 71%), m.p. 171-172° C. (effervescence); (Found: C, 62.60; H, 3.60, N, 9.85. C22H15N3OS2.0.67HCl requires: C, 62.06; H, 3.71; N, 9.87%); δH [2H6]-DMSO 8.58 (1H,s), 7.79-7.85 (2H,m), 7.29-7.56 (7H,m), 6.93-7.13 (5H,m); m/z 401 (M+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([N:35]1[CH2:43][CH2:42][CH:38]([C:39]([OH:41])=O)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCN(C(C)C)C(C)C.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([CH:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)=[CH:57][C:56]=1[C:67]1[N:68]=[C:69]([NH2:72])[S:70][CH:71]=1>C(#N)C>[CH:61]1([C:58]2[CH:59]=[CH:60][C:55]([O:54][CH3:53])=[C:56]([C:67]3[N:68]=[C:69]([NH:72][C:39]([CH:38]4[CH2:37][CH2:36][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:43][CH2:42]4)=[O:41])[S:70][CH:71]=3)[CH:57]=2)[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
1.68 g of BOP, 0.75 g of Boc-isonipecotic acid and then 1.41 mL of DIPEA are added, at a temperature of 0° C., to a solution of 1 g of 4-(2-methoxy-5-cyclohexylphenyl)-1,3-thiazol-2-amine, obtained in preparation I.3, in 6 mL of acetonitrile. The medium is stirred at room temperature for 24 hours and then filtered. The solid thus obtained is rinsed with acetonitrile and then dried. 1.13 g of a white solid are thus obtained.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:12]1[O:13][C:14](I)=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Sn:18](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22].[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:27]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[C:36]1[O:32][C:33]([C:14]2[O:13][C:12]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:16][CH:15]=2)=[CH:34][CH:35]=1)[CH2:28][CH2:29][CH3:30]
Reactant: C1CCOC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCCCCCc1ccc(I)o1
Agent: [Li]CCCC
Product: CCCCCCc1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)o2)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of n-BuLi (14.1 mL, 1.6 M in hexanes, 22.5 mmol, 1.3 equivalents) was added dropwise to a solution of 2-hexyl-5-iodofuran (3.8 g, 17.4 mmol) in dry tetrahydrofuran (THF, 100 mL) at −78° C. under N2. The reaction mixture was allowed to reach to room temperature and stirred for 1 h. The resulting mixture was cooled to −78° C., Bu3SnCl (6.1 mL, 22.5 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature and stirred for 2 h. The mixture was quenched with water, extracted with hexane, dried (MgSO4), and evaporated. Flash chromatography on a basified (NEt3) silica, using hexane as eluent gave Tributyl(5′-hexyl-[2,2′-bifuran]-5-yl)stannane) (1.9 g, 20% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3): ppm. 13C NMR (75 MHz, CDCl3): δ 106.1, 155.9, 151.4, 145.7, 122.9, 106.4, 105.4, 104.0, 31.6, 28.9, 28.8, 28.1, 28.0, 27.2 22.6, 14.7, 14.1, 10.2 ppm. FIRMS (FD): m/z calcd for C26H44O2Sn: 508.2368. found 508.2374.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][C:21]([NH:23][C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=2)=[O:22])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55](Cl)=[O:56]>C(Cl)Cl.CN(C=O)C>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:55](=[O:56])[CH2:54][O:53][CH2:52][CH2:51][O:50][CH3:49])=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COCCOCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccncc3N)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCC(=O)Nc1cnccc1COc1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(4-((3-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate C) (50 mg, 0.10 mmol) and DIPEA (33.5 μl, 0.19 mmol) in anhydrous DCM (1.0 mL) and anhydrous DMF (0.2 mL) was added 2-(2-methoxyethoxy)acetyl chloride (15 μl, 0.11 mmol). The reaction mixture was stirred for 12 hr at RT. LC-MS indicated 50% conversion to the desired product. 2-(2-methoxyethoxy) acetyl chloride (15 μl, 0.11 mmol) was added and the reaction mixture stirred at RT. After 6 hr, LC-MS indicated the reaction had gone to completion. MeOH (2.0 mL) and AcOH (5 drops) were added and the reaction mixture was subjected to SCX capture and release, eluting with 1% NH3 in MeOH. The solvent was removed in vacuo and the crude material purified by column chromatography (4 g, 0-10% MeOH in EtOAc, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-3-yl)-2-(2-methoxyethoxy) acetamide (Example 17) as a white solid (27 mg, 43%): m/z 637 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 3.18 (3H, s), 3.36 (2H, m), 3.61 (2H, m), 4.14 (2H, s), 5.33 (2H, s), 6.35 (1H, s), 6.97 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.67-7.55 (4H, m), 7.92 (1H, d), 8.27 (1H, d), 8.46 (1H, d), 8.58 (1H, s), 8.74 (1H, s), 8.80 (1H, s), 9.65 (1H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[N:8][OH:9])[CH2:3][CH2:2]1.ClN1C(=O)CCC1=O.[C:18]([O:23][CH2:24][CH3:25])(=[O:22])[C:19]#[C:20][CH3:21].C(N(CC)CC)C>CN(C=O)C.C(OC)(C)(C)C>[CH2:24]([O:23][C:18]([C:19]1[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][O:9][C:20]=1[CH3:21])=[O:22])[CH3:25]
Reactant: ON=CC1CCOCC1
Reactant: CC#CC(=O)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C2CCOCC2)noc1C
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a solution of tetrahydro-pyran-4-carbaldehyde oxime (6.5 g, 50 mmol) in DMF (47 mL) was added N-chlorosuccinimide (6.95 g, 50 mmol) at room temperature and the after 3 h the mixture was extracted with tert-butylmethylether (100 mL). The organic extract was then added dropwise over 2 h to a solution of ethyl 2-butynoate (61.2 mL, 52.5 mmol) and triethylamine (8.4 mL, 60 mmol) in tert-butylmethylether (47 mL) heated under reflux and the resulting mixture heated overnight. The reaction mixture was then cooled to room temperature and extracted with tert-butylmethylether and washed with aqueous hydrochloric acid solution (1 N). The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (4.2 g, 35%) as a light yellow solid. MS: m/e=240.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:5][CH2:4][O:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:14]=[C:12]([NH2:13])[C:11]([NH2:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1
Reactant: [H][H]
Reactant: CC1CN(c2ccc([N+](=O)[O-])c(N)c2)CCO1
Agent: [Pd]
Solvent: CCO
Product: CC1CN(c2ccc(N)c(N)c2)CCO1
Yield: 85.8 %

Procedure:
5-(2-Methylmorpholino)-2-nitroaniline (200 mg, 0.843 mmol) was added to the 10% Pd/C (25 mg) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for overnight at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (150 mg). 1H NMR: (400 MHz, DMSO-d6): δ 6.38 (d, 1H, J=8.0 Hz), 6.18 (d, 1H, J=2.4 Hz), 5.99 (dd, 1H, J=2.8 and 8.0 Hz), 4.34 (bs, 2H), 3.96 (bs, 2H), 3.82 (m, 1H), 3.57 (m, 2H), 3.19 (d, 1H, J=11.2 Hz), 3.11 (d, 1H, J=11.2 Hz), 2.44 (m, 1H), 2.13 (t, 1H, J=11.2 Hz), 1.08 (d, 3H, J=6.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([Cl:27])=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:27][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: N#Cc1cn[nH]c1N
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(c1cc(-c2ccnc3c(C#N)cnn23)ccc1Cl)S(C)(=O)=O
Yield: 70.2 %

Procedure:
A mixture of 0.042 g (0.39 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.124 g (0.39 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-methanesulfonamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 99 mg of N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 70%).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[Br:12]CC[CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].[C:25](#N)[CH3:26]>>[BrH:12].[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:25][CH2:26][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:18][C:16]([CH3:15])=[O:17])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: O=C(CCCBr)Nc1ccccc1
Reactant: CC#N
Reactant: Cc1[nH]c2ncccc2c1C
Product: Br
Product: CC(=O)Nc1ccccc1CCn1cccc2c(C)c(C)nc1-2
Yield: 7 %

Procedure:
A solution of 73 mg (0,5 mmol) 2,3 dimethylpyrrolo[2,3-b]pyridine and 122 mg (0,5 mmol) of (2-bromoethyl)acetanilide in 2 ml acetonitrile was refluxed for 10 h. The solvent was evaporated and the crude product was treated with 5 ml petroleum ether:ether 1:1 and the insoluble fraction was treated with ether. The etheral layer was separated from the oily residue, which crystallized from acetronitrile and gave 15 mg (7,7%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Nitrophenyl isocyanate (3.34 g) in 100 mL of toluene was added aniline (2 g). The mixture was stirred at 20° C. for 30 min. Hexane (300 mL) was added and the resulting solid was filtered and dried to yield N-(2-Nitrophenyl)-N′-phenyl-urea as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](OC(=O)C)[O:4][N:3]=1.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]([O:21]CC)[CH3:20]>>[CH3:1][C:2]1[CH:6]=[C:5]([C:19]([OH:21])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:20])[O:4][N:3]=1
Reactant: CCOCC
Reactant: CC(=O)Oc1cc(C)no1
Reactant: Br[Mg]c1ccccc1
Product: Cc1cc(C(C)(O)c2ccccc2)on1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 3-methyl-5-acetoxy-isoxazole (14 g, 112 mM) in diethyl ether (400 mL) at 0° C., was added a 3M solution of phenylmagnesium bromide in diethyl ether (44.7 mL, 134 mM) dropwise. After the addition was complete, the reaction mixture was stirred for 30 minutes. When pH 7 buffer (100 mL) was added, the layers were separated. The aqueous layer was extracted with diethyl ether (2×75 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 3-methyl-5-(1-hydroxy-1-phenylethyl)-isoxazole as an amber oil (20.2 g, 89%) that was used without further purification. 1H NMR (CDCl3, 100 MHz): δ 7.40 (m, 5H), 6.0 (s, 1H), 2.38 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:9]
Reactant: NCCCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Product: O=S(=O)(NCCCCO)c1ccc(Br)cc1C(F)(F)F

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-2-trifluoromethylphenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol. δC (CDCl3, 62.9 MHz): 26.5, 29.4, 43.3, 62.1, 127.3, 131.7, 131.7, 133.1, 135.4 and 137.9.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1.[Na].[CH:14]([OH:17])([CH3:16])[CH3:15]>>[CH:14]([O:17][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1)([CH3:16])[CH3:15]
Reactant: Clc1cc(-n2cccn2)ncn1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1cc(-n2cccn2)ncn1

Procedure:
Following the procedure of Example 15, 180 mg of 6-chloro-4-(1-pyrazolyl)pyrimidine was reacted with 23 mg of sodium metal and 3 ml of anhydrous isopropylalcohol to yield 127 mg of an oily substance, 6-isopropoxy-4-(1-pyrazolyl)pyrimidine,
Reaction SMILES: Br[C:2]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:19])[N:3]=1.[C-:20]#[N:21].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>C(#N)C.O>[C:20]([C:2]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:19])[N:3]=1)#[N:21]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc(NC(CC)CC)c(Br)nc1C
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(NC(CC)CC)c(C#N)nc1C
Temperature: 88 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of ethyl 6-bromo-2-methyl-5-(pentan-3-ylamino)nicotinate (1.202 g, 3.65 mmol) in acetonitrile (30 ml) was added sodium cyanide (0.357 g, 7.3 mmol), tributyltin chloride (1.306 g, 4.015 mmol) and Pd(dpppf)3 (0.298 g, 0.365 mmol). The reaction mixture was stirred at 88° C. overnight. The reaction mixture was diluted with water (100 ml), then extracted with ethyl acetate (3×100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and brine. After evaporation of solvent, ethyl 6-cyano-2-methyl-5-(pentan-3-ylamino)nicotinate (0.59 g, 59% yield) was obtained by column chromatography. 1H NMR (400 MHz, CDCl3): 7.56 (s, 1H), 4.50 (q, J=6.8 Hz, 2H), 4.35 (br, s, 1H), 3.40 a9m, 1H), 2.64 (s, 3H), 1.80-1.50 (m, 4H), 1.42 (t, J=6.8 Hz, 3H), 1.0 (t, 6H). MS (EI) for C15H21N3O2: 276.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(C1C=CC(OC)=C(C=1)[CH:31]=[O:32])C(F)(F)F>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:17])([F:18])[F:1])=[CH:10][C:11]=1[CH:31]=[O:32]
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Reactant: COc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Product: COc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 99 in the same manner of Compound 9.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.Br[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=1>O.CCOC(C)=O>[Cl:33][C:28]1[CH:27]=[C:26]([CH2:25][N:10]2[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]2)[CH:31]=[C:30]([Cl:32])[N:29]=1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Reactant: Clc1cc(CBr)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CSCCN(Cc2cc(Cl)nc(Cl)c2)C1=O
Yield: 23 %

Procedure:
121 mg of sodium hydride as a 60% suspension in oil (3.05 mmol) are introduced at room temperature into a 50 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of DMF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 489 mg (2.03 mmol) of 4-bromomethyl-2,6-dichloropyridine are then added. The medium is stirred for 3 hours, 50 ml of EtOAc and 50 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed once with 50 ml of water. The organic phase is dried, filtered and then evaporated to dryness. 1.5 g of crude product are recovered, which product is chromatographed on a silica cartridge (20 g) with an 80/20 heptane/EtOAc mixture. 190 mg of product 36 are recovered (yield=23%).