Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=1.Cl.Cl[CH2:27][CH2:28][NH2:29].Cl[CH2:31][CH2:32]N>ClC1C=CC=CC=1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][CH:10]([C:4]2[CH:3]=[C:2]([N:1]3[CH2:32][CH2:31][NH:29][CH2:28][CH2:27]3)[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: NCCCl
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(N)cc(CC)c1
Agent: Cl
Solvent: Clc1ccccc1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(N2CCNCC2)c1
Yield: 63.3 %

Procedure:
A mixture of the ethyl (RS)-(3-amino-5-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (500 mg, 1.55 mmol) obtained in Example 223.4, bis-(2-chloroethylamine) hydrochloride (276 mg, 1.55 mmol) and chlorobenzene (5 ml) was heated under reflux for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2/MeOH 9:1). There were obtained 385 mg (63%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-piperazin-1-yl-phenyl)-acetate as a brownish solid; MS: 393 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([N:29]([CH3:33])[CH2:30][CH2:31][NH2:32])=[CH:24][C:23]=1[Cl:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:32][CH2:31][CH2:30][N:29]([CH3:33])[C:25]3[CH:24]=[C:23]([Cl:34])[C:22]([NH2:21])=[C:27]([Cl:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CN(CCN)c1cc(Cl)c(N)c(Cl)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCN(C)c1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, 2-[N-(4-amino-3,5-dichlorophenyl)-methylamino]-ethylamine and triethylamine analogously to Example 6.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[N:16][OH:17])[CH3:15])=[CH:4]1)[CH3:2].[Li][CH2:19]CCC.CN(C=O)C.O>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:15]=[CH:19][O:17][N:16]=2)=[CH:4]1)[CH3:2]
Reactant: [Li]CCCC
Reactant: CCn1cc(C(C)=NO)c2ccc(OC)cc21
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1cc(-c2ccon2)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
1-(1-Ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime (100 mg, 0.43 mmol) was dissolved in THF (900 μL) at 0° C. n-BuLi (450 μL, 2.5 M in hexanes, 1.12 mol) was added dropwise, resulting in instant precipitation of solids. DMF (70 μL, 0.9 mol) in 260 μL of was then added dropwise. This was stirred at 0° C. for 1 h, then at room temperature for 1 h. The reaction mixture was pipetted into a mixture containing 1 mL of H2O, 1 mL of THF, and 100 μL of concentrated H2 SO4. This mixture was heated at 75° C. for 1 h and then was partitioned between H2O and EtOAc. The organic phase was dried and concentrated. Purification by column chromatography (CH2Cl2) yielded 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole product as a white solid (13 mg, 12%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:14][CH2:15][CH2:16][CH2:17][CH:18]=O)=[N:7][C:8]=2[NH:9][C:10](=[O:13])[C:11]=1[CH3:12].Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.O>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:6]2[N:7]=[C:8]3[C:3]([C:2]([CH3:1])=[C:11]([CH3:12])[C:10](=[O:13])[NH:9]3)=[CH:4][CH:5]=2)[CH2:31][CH2:30]1
Reactant: Cc1c(C)c2ccc(OCCCC=O)nc2[nH]c1=O
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C)c2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]c1=O
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
The crude 4-(5,6-dimethyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (100 mg, 0.38 mmol) is dissolved in dichloroethane (7 mL) and 1-(2,3-dichlorophenyl)piperazine monohydrochloride (112 mg, 0.42 mmol) is added, followed by triethylamine (39 mg, 0.05 mL, 1.14 mmol). The mixture is stirred for 5 minutes and NaBH(OAc)3 (81 mg, 0.38 mmol) is added. The mixture is stirred at room temperature for 1 hour and water (5 mL) is added. The organic layer is separated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude solid is purified by column chromatography (1:9 methanol/ethyl acetate) to yield the title compound (123 mg, 68%) as a white solid. mp 161–163° C., 1H NMR (400 MHz, CDCl3) δ 8.98 (br s, 1H), 7.80 (d, 1H), 7.20–7.10 (m, 2H), 7.00–6.90 (m, 1H), 6.60 (d, 1H), 4.20 (t, 2H), 3.15–3.00 (m, 4H), 2.75–2.60 (m, 4H), 2.50 (t, 2H), 2.40 (s, 3H), 2.20 (s, 3H), 1.85–1.60 (m, 4H), MS ES+ 474.76 (M)+ (Exact Mass: 474.16).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:11]1=2.O>ClCCCl>[C:5]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH3:9])[C:11]1[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][C:12]2=1)(=[O:7])[CH3:6]
Reactant: COC(=O)c1cc2c3ccccc3n(C)c2s1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc2c3cc(C(C)=O)ccc3n(C)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of 870 mg AlCl3 in 50 ml dry 1,2-dichloroethane was added 465 μl acetyl chloride. The mixture was stirred for 30 min. at room temperature. 800 mg of (6) was added, and stirring continued overnight. Another 870 mg AlCl3 and 465 μl acetyl chloride was added, and stirring continued overnight. Water was added, and the organic phase dried and evaporated to dryness giving a brown powder, which was crystallized from acetic acid and petrol ether giving (64). Yield 210 mg. M.p. 196-8° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.[NH2:28][C:29](N)=[NH:30].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)[C:29]([NH2:30])=[NH:28]
Reactant: N=C(N)N
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=N)N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.43 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.87 μmol), 1,3-di-boc-2-trifluoromethylsulfonyl)guanidine (38.45 mg, 98.25 μmol) and triethylamine (22.82 μL, 163.7 μmol) in DCM was stirred at room temperature for 5 hours. Then to the mixture was added TFA (6.308 μL, 81.87 μmol) and the mixture was stirred overnight. The crude product was purified by column chromatography to afford the title compound as brown oil in 49.43% yield. LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 3.5 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9 (s, 3H) 4.1 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.1 (d, J=5.6 Hz, 1H) 7.2 (d, J=9.1 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.5 (d, J=2.0 Hz, 1H) 7.6 (d, J=3.0 Hz, 1H) 7.8 (dd, J=8.8, 2.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[ClH:14].[Cl:14][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=1
Reactant: CCOc1cccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1cccc(CCl)n1
Product: Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
(6-Ethoxypyridin-2-yl)methanol (3.00 g, 19.6 mmol) was dissolved in toluene (0.5M, 40 mL). Thionyl chloride (2.86 ml, 39.2 mmol) was added dropwise, during which a white solid began to precipitate out of solution. The mixture was heated to 65° C. with stirring for 1 hour. The mixture was concentrated and the residue shaken with ether and collected by filtration to afford 2-(chloromethyl)-6-ethoxypyridine hydrochloride (1.2 g, 29% yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[NH:14][CH2:13][CH2:12]2.C(N(CC)CC)C.CN(C)[CH:29]=[O:30]>C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(Cl)Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[N:14]([C:29]([C:2]1[C:10]3[C:5](=[CH:6][N:7]=[CH:8][CH:9]=3)[NH:4][N:3]=1)=[O:30])[CH2:13][CH2:12]2
Reactant: C1CN2CCC(CC2)N1
Reactant: CN(C)C=O
Reactant: Brc1n[nH]c2cnccc12
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1n[nH]c2cnccc12)N1CCN2CCC1CC2
Temperature: 110 °C

Procedure:
1 g (5 mmol) of 3-bromo-1H-pyrazolo[3,4-c]-pyridine, 0.53 g (0.75 mmol) of bis(triphenylphosphino)dichloropalladium, 1.9 g (15.1 mmol) of 1,4-diazabicyclo[3.2.2]nonane and 3.5 ml (25 mmol) of triethylamine dissolved in 15 ml of N,N-dimethylformamide are successively introduced into a 50 ml reactor. The mixture is then purged with carbon monoxide and heated at 110° C. for 20 hours. The reaction medium is poured into 100 ml of water and the aqueous phase is extracted with chloroform. After drying the organic phases, they are dried, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 90/10/1 proportions.
Reaction SMILES: [CH2:1]([N:3]1[CH2:20][CH2:19][C:5]2([CH2:9][N:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].C(NC(C)C)(C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]=1[N+:38]([O-:40])=[O:39]>ClCCl>[CH2:1]([N:3]1[CH2:20][CH2:19][C:5]2([CH2:9][N:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[C:30]([N+:38]([O-:40])=[O:39])[CH:31]=4)=[CH:16][CH:17]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCC2(CCN(CCc3ccc(N)cc3)C2)C1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(F)c([N+](=O)[O-])c4)cc3)C2)C1
Reaction time: 1 h

Procedure:
4-[2-(7-Ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenylamine from above was dissolved in dichloromethane to which was added diisopropylamine (1 ml) and the reaction was cooled in an ice bath. A solution of 4-Fluoro-3-nitro-benzoyl chloride (0.5 N, 8 ml) was added and the reaction stirred for 1 h then evaporated under reduced pressure to a yellow foam which was used as is in the next step.
Reaction SMILES: [Na].C(O)C.[NH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1)=[O:9].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O.C(O)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[C:20](=[O:26])[NH:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1)=[O:9])[CH3:25]
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(=O)Nc1ccccc1C(=O)Nc1nnn[nH]1
Temperature: 50 °C

Procedure:
To a solution of 2.3 g of sodium and 200 ml of ethanol was added 5.1 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide and 11.0 g of diethyl oxalate. The resulting solution was heated at 50° C. for 20 hours and then acidified with glacial acetic acid. The clear acid solution obtained was diluted with water and the solid which formed was separated by filtration, washed with water and air-dried to give 2-oxo-N-[2-((1H-tetrazol-5-yl)aminocarbonyl)phenyl]glycine ethyl ester melting at about 231°-232° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl)([O-:15])=[O:14].O.Cl>O1CCCC1>[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:1][CH2:2][CH2:3][CH2:4][OH:5])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: NCCCO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1CNCCCO
Yield: 33.2 %

Procedure:
3-Aminopropanol (3.94 g, 52.5 mmol) and triethylamine (1.77 g, 17.5 mmol) were dissolved in tetrahydrofuran (30 ml) and added with 2-nitrobenzyl chloride (3.00 g, 17.5 mmol) at room temperature. After heated to reflux for seven hours, the reaction mixture was allowed to cool and poured into 1N hydrochloric acid water and extracted with ether. The aqueous layer was adjusted to pH 9 with a saturated sodium hydrogen carbonate aqueous solution and then extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-(2-nitrobenzylamino)propanol (1.22 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][CH2:5][CH2:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CC(C)([O-])C.[K+].[H][H]>CO>[CH3:1][O:2][CH2:3][NH:4][CH2:5][CH2:6][C@@H:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[OH:8]
Reactant: [H][H]
Reactant: COCNCCC(=O)c1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COCNCC[C@H](O)c1cccs1
Reaction time: 12 h

Procedure:
A degassed methanol solution (4 mL) containing RuCl2((R)-3,5-xylylBINAP)((2R)-DAIPEN) (10 mg), 3-methoxymethylamino-1-(2-thienyl)-1-propanone (160 mg), potassium tert-butoxide (100 mg) and methanol (10 mL) was charged in a glass autoclave under an argon gas flow. After deaeration and replacement by argon, hydrogen was introduced to a predetermined pressure. The resulting solution was hydrogenated at 20° C. for 12 hours. Upon completion of hydrogenation, the reaction mixture was concentrated to give an oily product (161 mg, 95.8% measured by HPLC assay, 95% ee).
Reaction SMILES: C([Li])CCC.[Br-].[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:42][C:43]([F:53])([F:52])[C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=O>CCCCCC.O1CCCC1>[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH:22]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43]([F:52])([F:42])[F:53])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: c1ccc(Oc2cccc(CCC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FC(F)(F)C(=CCCc1cccc(Oc2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A solution of butyllithium in n-hexane (8.5 ml of 1.6 molar) was added, dropwise, at room temperature and under a nitrogen atmosphere over 10 minutes to [3-(3-phenoxyphenyl)propyl]-triphenylphophonium bromide (7.67 g; 13.75 mmol) in absolute tetrahydrofuran (40 ml). After stirring for 2 hours, α,α,α-trifluoroacetophenone (2.18 g; 12.5 mmol) dissolved in absolute tetrahydrofuran (10 ml) was added dropwise. After stirring for 3 hours at room temperature, the mixture was added to ice-water, extracted with ether and the extract dried over sodium sulphate and evaporated. After chromotography on silica gel using hexane-toluene, there was obtained 4-(3-phenoxyphenyl)-1-phenyl-1-trifluoromethyl-1-butene (3.31 g=71.9% of theory).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=2)=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cn1)c1ccc(NCc2ccccc2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccc(NCc2ccc(NCc3ccccc3)nc2)nc1
Temperature: 25 °C

Procedure:
BMS (400 μL) was added to a solution of 6-(benzylamino)-N-(5-fluoropyridin-2-yl)nicotinamide 4 in THF (20 mL). The reaction mixture was refluxed for 16 hrs. Then the reaction mixture was cooled to RT. MeOH (2 mL), followed by conc. HCl were added. The reaction mixture was refluxed for 8 hrs, concentrated and diluted with water (2 mL). The pH was adjusted to 14 and the reaction mixture was extracted with chloroform (50 mL×2). All organic phases were washed with brine and dried over Na2SO4. Evaporation of the solvent gave a crude product which was purified on silica gel (1:1, EtOAc: Pet-ether) to give N-benzyl-5-((5-fluoropyridin-2-ylamino)methyl)pyridin-2-amine 5. This was treated with HCl/MeOH to give the corresponding salt (50 mg 13%) as a white solid. Mp. 166-168° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[C:21]2[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N+:15]([O-:25])=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:3]([O:10][C:12]1[C:21]2[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N+:15]([O-:25])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc2c(Cl)cc[n+]([O-])c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3ccccc3)cc[n+]([O-])c2c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
NaH (973 mg, 60% in mineral oil, 24.3 mmol) was added at 0° C., under inert atmosphere, to benzylalcohol (2.96 mL, 28.6 mmol) in DMF (10 mL). After 5 min at 0° C., the solution was warmed up to room temperature. After 10 min at room temperature, 4-chloro-7-methoxy-8-methylquinoline N-oxide (61, 3.2 g, 14.3 mmol) was added in one portion. The resulting black solution was stirred at room temperature under inert atmosphere for another 30 min, then poured into ice-cooled water, and extracted 4 times with AcOEt. Combined organic layers were dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient AcOEt/CH2Cl2, 1:1 to 1:0, then AcOEt/MeOH 9:1) to give 2.5 g (59%) of the target product 62 as a yellow powder: m/z=296 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[CH2:10](I)[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:10]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:9])[CH:11]([CH3:13])[CH3:12]
Reactant: Cn1c(=O)cc[nH]c1=O
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-Methyluracil (3.0 g, 23.8 mmol), isobutyl iodide (7 mL, 60 mmol) and cesium carbonate (11.6 g, 35.7 mmol) in DMF (30 mL) is stirred at room temperature over a weekend. Solvent is removed under vacuum. The residue is treated with water, and then extracted with dichloromethane four times. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and then filtered through a short silica gel column. The filtrate is concentrated to dryness to give product as off white solids, which is used in the next step without further purification. MS (ESI) m/z 183.1 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Br)(Br)[Br:7].[CH2:10]1[O:22][C:21]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C:17](=O)[CH2:18]3)=[CH:13][C:12]=2[O:11]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:7][C:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][C:21]3[O:22][CH2:10][O:11][C:12]=3[CH:13]=2)[C:18]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: O=C1CCc2cc3c(cc2C1)OCO3
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=CC1=C(Br)CCc2cc3c(cc21)OCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Dimethylformamide (0.8 ml, 10 mmol) was added dropwise to a solution of phosphorus tribromide (0.8 ml, 8.5 mmol) in dry chloroform (20 ml) at 0° C. The mixture was stirred at 0° C. for 1 h to give pale yellow suspension. A solution of compound 6,7-methylenedioxy-2-tetralone (500 mg, 2.6 mmol) in dry chloroform(20 ml) was added to the yellow suspension and the mixture was heated at reflux for 1 h. The reaction mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution was added dropwise until no effervescence was obtained. The resulting mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed over 100 g of silica gel using 3:1 mixture respectively of hexanes and ethyl acetate to give the aldehyde in 60% yield; 1H NMR(CDCl3) δ2.80(2H, t, J=7.8), 2.98(2H, t, J=7.8), 5.93(2H, s), 6.64(1H, s), 7.57(1H, s), 10.28(1H, s); 13C NMR(CDCl3) δ29.3, 30.4, 101.6, 107.3,108.6, 124.0, 129.7, 132.7, 114.0, 146.7, 147.7, 193.2.
Reaction SMILES: [H-].[Na+].[CH:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[C:14]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:15][C:16](S(C)(=O)=O)=[N:17][CH:18]=1>CN(C=O)C.O>[F:12][C:13]1[C:14]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:15][C:16]([O:11][N:10]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:17][CH:18]=1
Reactant: ON=Cc1ccccc1
Reactant: CN(C)C=Nc1nc(S(C)(=O)=O)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=Nc1nc(ON=Cc2ccccc2)ncc1F
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a suspension of sodium hydride (NaH, 60% dispersion in mineral oil; 0.037 g, 0.91 mmol) in DMF (2 mL) was added a solution of benzaldehyde oxime (0.125 g, 1.04 mmol) in DMF (1 mL), and the resulting frothy mixture was stirred for 1 h. To the resulting pale yellow mixture was added a solution of N′-(5-fluoro-2-methanesulfonylpyrimidin-4-yl)-N,N-dimethylformamidine (0.15 g, 0.61 mmol) in DMF (1 mL), and the homogeneous, pale-yellow solution was stirred at 25° C. for 16 h. The reaction mixture was diluted with H2O (50 mL) and was extracted with CH2Cl2 (2×100 mL). The organic extracts were combined, washed with H2O (5×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to a colorless oil. Trituration with Et2O afforded N′-{5-fluoro-2-[1-phenylmethylideneaminooxy]pyrimidin-4-yl}-N,N-dimethylformamidine (0.054 g, 31%) as a white solid: mp 240-244° C. dec; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.53 (s, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.81-7.69 (m, 2H), 7.49-7.30 (m, 3H), 3.21 (s, 3H), 3.21 (s, 3H); ESIMS m/z 288 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25]>O1CCCC1.O>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(C(O)c2cc(C)c(C)o2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
2-Bromo-5-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6 M hexane solution (5.6 ml) of n-butyllithium was added dropwise to the solution at −78° C. The reaction solution was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raise to room temperature with stirring. Water was added to the reaction solution to stop the reaction. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(5-methyl-pyridin-2-yl)-methanol (855 mg, yield 44%).