Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=2[C:19]=34)=[CH:8][CH:7]=1)[CH3:2].BrC1C=CC(CCN2CCCC2)=CC=1>>[N:3]1([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]5[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=3[C:19]=45)=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:27][CH2:26]1
Reactant: CCN(CC)CCc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Agent: Brc1ccc(CCN2CCCC2)cc1
Product: O=C1NCCc2c(-c3ccc(CCN4CCCC4)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for 2-[4-(2-diethylamino-ethyl)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (Example YY), the tricyclic bromide (198 mg, 0.75 mmol) and 1-[2-(4-bromo-phenyl)-ethyl]-pyrrolidine were coupled to yield 2-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 160 mg (59%) as a beige solid: m.p. 228-229° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 1.69 (m, 4H), 2.51 (m, 4H), 2.67 (m, 2H), 2.81 (m, 2H), 3.05 (m, 2H), 3.39 (m, 2H), 7.20 (t, J=7.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.56 (m, 3H), 7.68 (d, J=7.5 Hz, 1H), 8.08 (br t, 1H), 11.31 (br s, 1H). MS (FAB, MH+): 360. Anal. (C23H25N3O) C, H, N.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[CH2:17][S:18](Cl)(=[O:20])=[O:19])=[CH:12][CH:11]=1>O1CCCC1>[CH3:1][NH:2][S:18]([CH2:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[CH:11][CH:12]=1)[CH3:22])(=[O:20])=[O:19]
Reactant: CN
Reactant: CC(CS(=O)(=O)Cl)c1ccc(-c2ccccc2F)cc1
Solvent: C1CCOC1
Product: CNS(=O)(=O)CC(C)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To 10 mL of 40% aqueous methylamine was added 0.3 g (1.0 mmol) of 2-(4-(2-fluorophenyl)phenyl)propanesulfonyl chloride above in 3 mL of tetrahydrofuran and the mixture stirred at room temperature for 16 hours. The reaction mixture was extracted three times with 5 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (25 g of silica gel, 35% ethyl acetate/hexanes) of the residue afforded 0.1 g (42%) of the title compound.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][C:16](OC)=[O:17])[CH:11]=[CH:12][CH:13]=1>O1CCOCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][C:16](=[O:17])[CH2:2][C:1]#[N:3])[CH:11]=[CH:12][CH:13]=1
Reactant: CC#N
Reactant: COC(=O)CCc1cccc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cccc(CCC(=O)CC#N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
Acetonitrile (3.36 ml, 64.25 mmol, 1 eq) was added to a slurry of sodium hydride (2.57 g dispersion in mineral oil, 64.25 mmol, 1 eq) in anhydrous 1,4-dioxane (50 ml) and the mixture was stirred at room temperature for 20 mins. Methyl 3-(3-methoxyphenyl)propanoate (10.4 g, 53.54 mmol, 1 eq) in 1,4-dioxane (25 ml) was added and the reaction was refluxed for 2 h. The reaction mixture was cooled and quenched with water. The residue was dissolved in 2M HCl and extracted into ethyl acetate. The organic layer was separated, washed with 2M HCl, water and brine and dried over magnesium sulphate. Evaporation under reduced pressure gave yield to a yellow oil, which was purified by silica column chromatography, eluting with a mixture of 0-50% ethyl acetate in hexanes. Fractions containing the product were combined and evaporated to leave 5-(3-methoxyphenyl)-3-oxo-pentanenitrile (5.37 g, 49% yield).
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25].O>C(Cl)Cl>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[N:3][N:2]([CH3:1])[C:24]([O:26][CH3:27])=[O:25])[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:10][CH:9]=1
Reactant: COC(=O)Cl
Reactant: CNN=C(c1ccc(Cl)cc1)C(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N(C)N=C(c1ccc(Cl)cc1)C(C)(C)C
Reaction time: 1 h

Procedure:
3 g (0.013 mol) of 4-chlorophenyl tert.-butyl ketone N-methylhydrazone was dissolved in 30 ml methylene chloride and treated with 1.5 g triethylamine (0.014 mol). Then, at 0° C., 1.33 g (0.014 mol) methyl chloroformate was added dropwise and the mixture stirred for one hour. The reaction mixture was then treated with water and methylene chloride and the organic phase dried and concentrated. After thin layer chromatography, there was obtained methyl 3-[1-(4-chlorophenyl)-2,2-dimethylpropylidene]-2-methylcarbazate, m.p. 58°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11](Cl)=[O:12])[N:10]=2)[N:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].C([O-])(O)=O.[Na+]>CC(C)=O>[N:14]([C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)=[O:12])=[N+:15]=[N-:16]
Reactant: O=C(Cl)c1cn2nc(Cl)ccc2n1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-carbonyl chloride from Step 1 (2.2 g, 10 mmol) in acetone (40 mL) was added sodium azide (0.43 g, 6.6 mmol, solution in 1.5 mL H2O). The mixture was stirred at 25° C. for 1 h then poured into aq. NaHCO3. The solid precipitate was collected by careful filtration. The filtercake was not allowed to go dry (solvent-free). The filtercake was washed with benzene (2×50 mL) and then transferred to a 150-mL, round-bottomed flask. To azeotropically remove residual water, the solid was suspended in benzene (75 mL) and then concentrated to one-third its volume. Then once again the material was suspended in benzene (75 mL) and concentrated to near dryness to provide the title compound, which was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:29])[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:18]=1.[CH2:30](OC[C@@H]1[C@@H](C=O)[C@@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1)C>>[CH2:1]([O:2][CH2:3][C@@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:29])[C:17]1[CH:18]=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:20]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:22]=1)[CH3:30]
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: CCOC[C@@H]1[C@@H](C=O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 73 %

Procedure:
Following a procedure similar to that for the preparation of Compound 24 but using Intermediate 48b as the starting material afforded the title compound (36 mg, 73% yield) as a white solid:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:2]=1.Br[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:21]1[C:22]2[C:17](=[CH:16][CH:15]=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[N:9]1[CH2:10][CH2:11][CH2:12][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:13]
Reactant: O=C1NCCCN1c1cccnc1
Reactant: Brc1ccc2ccccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cccnc2)CCCN1c1ccc2ccccc2c1
Yield: 34.1 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-tetrahydro-pyrimidin-2-one (I-10b: 118 mg, 0.724 mmol) was reacted with 2-bromo-naphthalene (150 mg, 0.724 mmol), 1,4-dioxane (5 mL), copper iodide (13.79 mg, 0.0724 mmol), trans-1,2-diamino cyclohexane (24.865 mg, 0.2172 mmol) and potassium carbonate (200 mg, 1.448 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 75 mg of the product (35.71% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14]C)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:21](=[O:22])[C:20]3[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Product: COC(=O)C1CCc2cc(C(=O)c3ccc(Cl)cc3)c(O)cc21

Procedure:
Analogously to the process described in Example 5, 19 g of 6-methoxy-indane-1-carboxylic acid methyl ester and 48 g of p-chlorobenzoyl chloride give 5-(p-chlorobenzoyl)-6-hydroxy-indane-1-carboxylic acid methyl ester of melting point 96°-98° C (from ether-petroleum ether.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:7][C:8]1[C:9]([CH2:18][CH3:19])=[N:10][N:11]([CH2:15][CH2:16][OH:17])[C:12]=1[CH2:13][CH3:14].Cl.Cl[CH2:26][CH2:27][NH2:28]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:7][C:8]1[C:9]([CH2:18][CH3:19])=[N:10][N:11]([CH2:15][CH2:16][O:17][CH2:26][CH2:27][NH2:28])[C:12]=1[CH2:13][CH3:14]
Reactant: CCc1nn(CCO)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: NCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CCOCCN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 24 mg, 0.600 mmol) was added to a stirred solution of the pyrazole of Example 2 (100 mg, 0.303 mmol) in dry N,N-dimethylformamide (4 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 minutes and 2-chloroethylamine hydrochloride (53 mg, 0.455 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for 30 minutes. The reaction was cooled to 0° C., further sodium hydride (60% dispersion in oil, 24 mg, 0.600 mmol) and 2-chloroethylamine hydrochloride (53 mg, 0.455 mmol) were added and the reaction was stirred for 1 hour. The reaction was quenched by the addition of water (5 ml) and extracted with ether (10 ml). The organic layer was washed with 2M aqueous hydrochloric acid (30 ml). The acid was neutralised with solid sodium carbonate and extracted with ether (3×20 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (21 mg) as a colourless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].CCOCC>C(N(CC)CC)C>[CH3:6][S:7]([O:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCBr
Reaction time: 1 h

Procedure:
A mixture containing 13.9 ml. of 3-bromo-1-propanol, 7.6 ml. of methane sulfonyl chloride and 100 ml. ether was formed. The mixture was mixed together and 14 ml. of triethylamine was added over a period of 45 minutes at 5°-10° C. and then stirred at 5°-10° C. for 1 hour. The mixture was allowed to come to room temperature and was stirred for an additional 15 minutes. To the mixture was added 100 ml. of water and the ether solution dried over magnesium sulfate and evaporated to yield 14.5 g. of a colorless oil. nD30 1.4749.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:47][CH3:48])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:35]=2)[CH:29]=[C:28]([CH2:49]Cl)[N:27]=1.[Na].[CH3:52][SH:53].O.C1(C)C=CC=CC=1>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:47][CH3:48])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:35]=2)[CH:29]=[C:28]([CH2:49][S:53][CH3:52])[N:27]=1
Reactant: CS
Reactant: CCC(Nc1cc(CCl)nc(Cl)n1)c1cccc(Oc2ccccc2)c1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCC(Nc1cc(CSC)nc(Cl)n1)c1cccc(Oc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 2.0 g of dl-5-chloro-6-chloromethyl-4-(α-ethyl-3-phenoxybenzyl)aminopyrimidine obtained in Example 4 dissolved in 50 ml of methanol was added 10 ml of a 15% aqueous methanthiol sodium salt solution, and the mixture was refluxed under stirring for 2 hours. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The oily product obtained was isolated by chromatography (Wako Gel C-200, trade name, eluted with toluene:ethyl acetate=5:1) to give 1.8 g of the desired product as pale yellow oily liquid.
Reaction SMILES: CS(O[C@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:10][O:9][C:8]([CH3:23])([CH3:22])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:24]([C@H:6]1[CH2:7][C:8]([CH3:23])([CH3:22])[O:9][CH2:10][C@H:11]1[NH:12][C:13](=[O:14])[O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C[C@H](N=[N+]=[N-])[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
To a solution of (4R,5R)-2,2-dimethyl-5-((2-(trimethylsilyl)ethoxy)carbonylamino)-tetrahydro-2H-pyran-4-yl methanesulfonate (550 mg, 1.25 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (812 mg, 12.5 mmol) and sodium acetate (1.05 mg, 12.5 mmol) at room temperature. The resultant mixture was stirred at 95° C. for 2 days. After that, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL×8) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound (510 mg, crude) as a yellow oil which was directly used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[N:2]1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1COCC1.CC#N.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:18](=[O:19])[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]nnc2c1)Oc1ccccc1
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 1H-benzo[d][1,2,3]triazol-5-amine (1.85 g, 13.8 mmol, Alfa Aesar) in THF (10 mL) and CH3CN (8 mL) was added pyridine (1.34 mL, 16.6 mmol) followed by phenyl chloroformate (2.27 mL, 14.5 mmol) slowly. The reaction was stirred overnight. The reaction was concentrated to give an oil, which was partitioned between CH2Cl2 and water. The organic layer was dried using a SPE phase separator and concentrated to give a solid. This was taken up in CH2Cl2 and the precipitate was filtered to give the desired product (2.0 g, 57%) which was used without purification. MS M+1: 256.06.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4]>CO>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cccc1[N+](=O)[O-]
Solvent: CO
Product: Nc1cccc(F)c1N
Reaction time: 6 h

Procedure:
To a solution of 2-fluoro-6-nitroaniline (2 g, 12.8 mmol) in MeOH (15 mL) palladium 10 wt % on carbon (180 mg, 75 μmol) was added under N2. After flushing the flask with N2 for 2 min, the solution was stirred under a H2 balloon. After 6 h, the mixture was filtered through a celite pad rinsed with MeOH, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using EtOAc:DCM (1:1) as eluent to give 3-fluorobenzene-1,2-diamine: LC-MS (ESI) m/z 127.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1(C)C=CC=CC=1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.Cl>C1COCC1.O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: Clc1ccccn1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)cn1
Temperature: 27.5 °C
Reaction time: 8 h

Procedure:
1.09 kg=0.75 L (1.1 equiv., d=1.453 g/ml) of 5-bromo-2-methoxy pyridine and 3.60 L (6 V) of anhydrous toluene, previously degassed under a nitrogen flow, were loaded into a reactor A previously dried under nitrogen. The mixture was heated to 25-30° C. and added with 5.70 kg (1.485 equiv.) of a solution of Isopropyl magnesium chloride lithium chloride complex (20% wt/wt) in THF over about 1 h. It was stirred at 25-30° C. for at least 8 hours (the reaction may be conducted overnight). The conversion was monitored via HPLC. When the reaction was complete, a mixture of 9.67 g of Pd(dppf)C12 (0.25 mol %), 0.60 kg equal to 0.50 l (1 equiv., d=1.2 g/ml) of 2-chloropyridine and 3.60 l (6 V) of anhydrous toluene, previously degassed under a nitrogen flow, was loaded into a reactor B, previously dried and kept under a flow of nitrogen. The mixture was stirred at 45-50° C. for 30 min. The suspension of Grignard reagent from reactor A was transferred into reactor B over approximately 1 hr, while keeping the T at 45-50° C. Upon completion, stirring was prosecuted for at least 4 hr at 45-50° C. The conversion was monitored in HPLC (>99%; HPLC purity A/A % of the product >94%). When the reaction was complete, the mixture was cooled to 25-30° C., added with 3.60 L (6 V) of purified water carefully, keeping the temperature at 20-25° C., over about 30 min.-1 hr. Stirring was prosecuted for 15 min. The biphasic mixture was filtered on paper and the solid residue was washed with 0.60 L (1 V) of toluene. The filtrate was loaded into the reactor C. The organic phase (containing the reaction product) was separated. 3.60 L (6 V) of purified water were added to the organic phase. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The organic phase (containing the reaction product) was recovered. A solution of Hydrochloric acid 4 M, prepared by using 1.41 L (2.35 V) of concentrated hydrochloric acid and 2.06 L (3.44V) of purified water, was added to the organic phase. Stirring was continued for 15 min, the mixture was left to decant and the aqueous acid phase (the product was in aqueous phase) was separated. The acid aqueous phase (containing the product) was washed twice with 1.20 L (2×2V) of MTBE. The aqueous phase was separated and weighed. Determination of the yield in solution of 2-methoxy-5-(pyridine-2-yl)pyridine was made by external standard HPLC analysis (molar yield in solution: 90.3%):
Reaction SMILES: COC1C=C([N+]([O-])=O)C=C[C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12]O[CH2:10][CH2:9]1.[H-].[Na+].Cl[C:24]1C=CC([N+]([O-])=O)=C[C:25]=1[O:33]C>CN(C)C=O>[CH3:4][O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH:24]([CH:25]=[O:33])[CH2:12][CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-[2-(2-Methoxy-4-nitro-phenoxy)-ethyl]-morpholine To a solution of (1-(2-hydroxyethyl)-morpholine) (1.94 ml, 16 mmol) in dimethylformamide was added sodium hydride [60% dispersion in oil] (544 mg, 16 mmol). After stirring at room temperature for 10 min, a solution of (1-chloro-2-methoxy-4-nitro-benzene) (3 g, 16 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction mixture was left stirring at room temperature for 16 hours, concentrated, then the residue dissolved in ethyl acetate and washed with water. The organic phase was dried with magnesium sulphate, concentrated and the residue purified by column chromatography on silica gel to afford the title compound; MS(ES+) m/e 283 [M+H]+. Step 2. 3-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine To a solution of the product of Step 1 (2.3 g, 8.6 mmol) in ethanol (100 ml) was added 10% palladium on charcoal (50 mg). The mixture was then stirred at room temperature under an atmosphere of hydrogen for 16 hours, filtered through celite and concentrated to give the title compound; MS(ES+) m/e 252 [M+H]+.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:9]1[C:14]([CH:15]=O)=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]([CH:29]([CH3:31])[CH3:30])[N:10]=1)([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:6]([C:9]1[C:14]([CH:15]=[CH2:1])=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]([CH:29]([CH3:31])[CH3:30])[N:10]=1)([CH3:8])[CH3:7]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1c(C(C)C)nc(C(C)C)c(CCCCC)c1-c1ccc(F)cc1
Temperature: -78 °C
Yield: 66 %

Procedure:
Methyl triphenylphosphonium bromide was suspended in 15 mL of dry THF under argon and stirred at −78° C. Butyllithium (1.6M, 0.42 mL) was added dropwise over 2 min. and then the reaction mixture was allowed to stir at 0° C. for 1.5 hours. The solution was cooled again to −78° C., treated dropwise with a solution of 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) in 5 mL of dry THF, and then stirred at 0° C. for 2.5 hours. The reaction was quenched with water (10 mL) and the THF evaporated in vacuo. Diethyl ether was added and the mixture was washed with water (2×20 mL), brine (1×20 mL), and dried with MgSO4. Filtration, concentration and flash chromatography (30% CH2Cl2/hexanes) yielded a solid (0.132 g, 0.37 mmol, 66%). 1H NMR (300 MHz, CDCl3) δ 7.08 (m, J=1.1 Hz, 4 H), 6.34, 6.28 (d, J=11.4 Hz, J=11.4 Hz, 1 H), 5.19 (d, J=1.8 Hz, 1 H), 4.96 (d, J=1.8 Hz, 1 H), 3.39 (septet, J=6.6 Hz, 1 H), 3.24 (septet, J=6.6 Hz, 1 H), 2.30 (t, J=5.2 Hz, 2 H), 1.20 (m, J=2.2 Hz, 18 H), 0.979 (t, J=6.0 Hz, 3 H). FAB-MS: calcd for (C24H32FN) 353, found 354 (M+H). Anal. Calcd for C24H32FN: C, 81.54; H, 9.12; N, 3.96; F, 5.37. Found: C, 81.46; H, 9.06; N, 3.78; F, 5.59. mp 44-46° C. Rf=0.7 (30% CH2Cl2/hexanes).
Reaction SMILES: ClC1C=CC=CC=1N=C=O.CN.NC(N)=O.C(CC(O)=O)#N.N([O-])=O.[Na+].NC1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:32](=[O:41])[N:31](C)[C:30](=O)C=1.[H][H].ClC1C=CC=CC=1N1C(N)=C(N)C(=O)N(C)C1=O>>[CH3:30][NH:31][C:32]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40])=[O:41]
Reactant: Cn1c(=O)cc(N)n(-c2ccccc2Cl)c1=O
Reactant: [H][H]
Agent: CN
Agent: Cn1c(=O)c(N)c(N)n(-c2ccccc2Cl)c1=O
Agent: N#CCC(=O)O
Product: CNC(=O)Nc1ccccc1Cl

Procedure:
N-Methyl-N'-(2-chlorophenyl)urea was prepared preliminarily from 2-chlorophenyl isocyanate and methylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Using sodium nitrite a nitroso group was introduced into the 5-position of the uracil ring in the obtained 6-amino-1-(2-chlorophenyl)-3-methyluracil and then reduced with hydrogen gas to prepare 1-(2-chlorophenyl)-5,6-diamino-3-methyluracil.