Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:12])=[CH:8][CH:7]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(C(C)c2ccccc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)c3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
2-methyl-4-(1-phenylethyl)benzoic acid (150 mg, 0.6 mmol) was dissolved in 20 mL dichloromethane, and then N-hydroxybenzotriazole (0.9 mmol, 100 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol, 200 mg), triethylamine (10.48 mmol, 3 mL) was added to the mixture. After the mixture was stirred at room temperature for 10 minute, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.6 mmol, 90 mg) was added. The mixture was stirred at room temperature for 18 hours. Then washed with water (30 mL), extracted with dichloromethane (40 mL). The organic layer were concentrated and subjected to column chromatography (silica gel, dichloromethane/menthol=15/1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenylethyl)benzamide (150 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1

Procedure:
U.S. Pat. No. 5,786,473 describes a reaction of 5-bromoindole with N-methyl-4-piperidone to obtain 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole which is condensed with N-methylvinylsulfonamide to afford N-methyl-2-[3-(1,2,3,6-tertahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulfonamide which is reduced under heterogeneous hydrogenation conditions to obtain naratritpan.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:13])[NH:4][C:3]1=O.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([CH2:23][N+:24]#[C-:25])[N:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[N:24]=[CH:25][N:4]4[C:5]5[C:10](=[C:9]([Cl:13])[CH:8]=[CH:7][CH:6]=5)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=34)[N:19]=2)[CH2:17][CH2:16]1
Reactant: Cn1c(=O)[nH]c2cccc(Cl)c2c1=O
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Product: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
M.p. 230°-240° C. (decomp.) by reaction between 3-methyl-5-chloro-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[CH3:15][NH:16][CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)C(C)C)(C)C>O>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][OH:20]
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: CNCCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCO)c1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Yield: 100.2 %

Procedure:
2-Bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.2 g, 0.806 mmol), 3-(methylamino)propan-1-ol (0.072 g, 0.806 mmol) and N,N-Diisopropylethylamine (0.141 ml, 0.806 mmol) were heated to 100° C. for 10 minutes in a microwave. Let the reaction cool to room temperature. Diluted reaction with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated to afford crude 3-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl(methyl)amino)propan-1-ol (0.207 g, 0.808 mmol, 100% yield).
Reaction SMILES: [NH:1]1[C:9]2[N:4]3[C:5](=[N:10][CH:11]=[C:3]3[C:2]1=[O:12])[CH:6]=[CH:7][CH:8]=2.[ClH:13]>CO>[ClH:13].[ClH:13].[NH2:1][CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[C:9]2[N:4]3[C:5](=[N:10][CH:11]=[C:3]3[C:2]1=[O:12])[CH:6]=[CH:7][CH:8]=2
Reactant: O=c1[nH]c2cccc3ncc1n32
Agent: Cl
Solvent: CO
Product: NCCCCn1c(=O)c2cnc3cccc1n32
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of 548 mg (1.66 mmol) of 1-[4-tert-butoxycarbonylamino)butan-1-yl]-1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one in 10 ml of methanol was added dropwise 10 ml of conc. HCl. The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue was added acetone. The resulting solid was collected by filtration and washed with acetone to give 400 mg of the desired compound (79.5%, grayish white solid).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O.CCOC(C)=O>[CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCC(OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a stirred solution of 8-(benzyloxy)-1,4-dioxaspiro[4.5]decane (12 g, 48.3 mmol) in acetone was added HCl (2 M, 50 mL, 100 mmol). The reaction mixture was heated to 50° C. overnight, cooled to room temperature, diluted with EtOAc, and washed with water and sodium bicarbonate solution. The organic layer was dried, and concentrated to give the title compound. 1H NMR (600 MHz, CDCl3) δ 7.25-7.36 (m, 5H); 4.58 (s, 2H); 3.81 (m, 1H); 2.60 (m, 2H); 2.25 (m, 2H); 2.13 (m, 2H); 1.94 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:19]([NH:21][CH:22]1[CH2:24][CH2:23]1)=[O:20].[C:25]([N:44]1[CH:48]=[CH:47][N:46]=[C:45]1[CH:49]=O)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH:22]1([NH:21][C:19]([C:4]2[N:5]=[N:6][N:7]([C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=3)[C:3]=2[CH2:2][NH:1][CH2:49][C:45]2[N:44]([C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:48]=[CH:47][N:46]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CNCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of 5-(aminomethyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (164 mg, 0.5 mmol) obtained in Example 1197 in dichloroethane (10 ml) were successively added 1-trityl-1H-imidazole-2-carbaldehyde (169 mg, 0.5 mmol), acetic acid (30 mg, 0.5 mmol) and sodium triacetoxyborohydride (138 mg, 0.65 mmol) at 0° C., and the mixture was stirred at room temperature for 48 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution (5 ml) and, after partitioning, the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (130 mg, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:16]1[CH:15]=[CH:14][N:13]2[C:12]=1[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:18]2
Reactant: COC(=O)c1ccc(-c2ncc[nH]2)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCCn1ccnc1-2
Temperature: 90 °C
Yield: 81.9 %

Procedure:
A mixture of methyl 3-hydroxy-4-(1H-imidazol-2-yl)benzoate (2.2 g, 10 mmol), 1,2-dibromoethane (3.12 mL, 36 mmol) and cesium carbonate (13.14 g, 40 mmol) in DMF (100 mL) was heated at 90° C. for 12 hours. The mixture was filtered, the mother liquor was concentrated in vacuo, and the residue was partitioned between water and ethyl acetate. The suspension was filtered and the solid was pure byproduct. The organic layer was washed with water, brine and dried over MgSO4 and concentrated to give crude methyl 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (2 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:19]([C:28]#[N:29])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][O:27][S:31]([CH3:30])(=[O:33])=[O:32])=[C:19]([C:28]#[N:29])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Nc2ccc(SCCCO)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2ccc(SCCCOS(C)(=O)=O)c(C#N)c2)cnn1-c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-N-[3-cyano-4-(3-hydroxypropylthio)phenyl]-5-methylpyrazole-4-carboxamide (1.8 g) and methanesulfonyl chloride (0.5 ml) in pyridine (20 ml) was stirred overnight. To the reaction mixture was added aqueous hydrochloric acid solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform:methanol=50:1) to give 1-(4-chlorophenyl)-N-[3-cyano-4-(3-methanesulfonyloxypropylthio)phenyl]-5-methylpyrazole-4-carboxamide (1.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30](=[O:35])[NH:31][CH2:32][CH2:33][OH:34]>>[F:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[O:10][C:3]=23)[CH:27]=[CH:28][C:29]=1[C:30]([NH:31][CH2:32][CH2:33][OH:34])=[O:35]
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Reactant: O=C(NCCO)c1ccc(B(O)O)cc1F
Product: COc1cc(-c2cc3nccc(-c4ccc(C(=O)NCCO)c(F)c4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 3-fluoro-4-[(2-hydroxyethyl)-carbamoyl]benzeneboronic acid (35.14 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a pale yellow solid (32 mg, 48%). (HPLC (method F): 99%, RT: 3.09 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.60 (dd, J=5.1, 1.8, 1H), 8.38 (s, 1H), 8.12-8.06 (m, 2H), 7.89 (t, J=7.9, 1H), 7.79 (d, J=1.8, 1H), 7.71 (dd, J=5.1, 1.8, 1H), 7.33 (d, J=1.7, 2H), 4.80-4.73 (m, 1H), 3.92 (d, J=1.7, 6H), 3.74 (d, J=1.8, 3H), 3.57-3.51 (m, 2H), 3.37 (dd, J=12.0, 6.1, 2H); MS (m/z) 467 [M+H]+, RT: 3.0 min.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1>[Cu]>[Cl:15][C:14]1[C:9]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:10][CH:11]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:13]=1
Reactant: Sc1ccccc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [Cu]
Product: FC(F)(F)c1cnc(Sc2ccccc2)c(Cl)c1
Reaction time: 1 h
Yield: 99 %

Procedure:
26 g (0.233 mol) of 98.7% pure thiophenol, 50 g (0.226 mol) of 97.8% pure 2,3-dichloro-5-trifluoromethylpyridine and 14.7 mg (0.23 mmol) of copper powder were reacted by the method of Example 1, except that the reaction time was only 1 h and the reaction temperature was 160-170° C. The yield was 99%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:14](=[O:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)cc1O
Temperature: 75 °C
Yield: 70 %

Procedure:
Methyl 2-hydroxy-4-aminobenzoate (5.0 g, 30 mmole) was dissolved in acetic anhydride (30 ml) and heated to 75° C. for 5 minutes, after which it was cooled, water (50 ml) was added, and the reaction mixture was evaporated to dryness, in vacuo. The product was recrystallized from water to give the title compound (1.25 g, 70%), m.p. 148°-151° C. Found (Calc. for C10H11NO4) C 57.53 (57.01), H 5.33 (5.27), N 6.68 (6.70).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8](=[O:9])[NH:7][C:6]([C:10]([O:12]CC)=O)=[CH:5][CH:4]=1>>[Cl:2][C:3]1[C:8](=[O:9])[NH:7][C:6]([C:10]([NH2:1])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(Cl)c(=O)[nH]1
Reactant: N
Product: NC(=O)c1ccc(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Aqueous ammonia (15 mL, 30% solution) was added to ethyl 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (1, 0.65 g, 3.2 mmol) at 0° C. and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether, filtered and dried to afford 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2). Yield: 0.43 g, 75%; MS (ESI) m/z 173[M+1]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:27]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](C)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (S)-(±)-3-hydroxy-2-methylpropionate (1.06 g, 8.99 mmol) (Aldrich) was dissolved in dichloromethane (10 mL, dried over molecular sieves). Imidazole (0.85 g, 12.41 mmol) (Aldrich) and tert-butyldiphenylsilyl chloride (2.30 mL, 8.85 mmol) (Aldrich) were added and the mixture was stirred at ambient temperature for three hours. The reaction was diluted with additional dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to yield methyl (S)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionate as an oil. (Yield 3.17 g, 98.8%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:19](=[O:20])[C:15]3([CH2:18][CH2:17][CH2:16]3)[NH:14][C:13]2=[O:21])=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])([O-:5])=[O:4].CS(O[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46])(=O)=O.O>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:19](=[O:20])[C:15]3([CH2:16][CH2:17][CH2:18]3)[N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:46])([F:47])[F:48])[C:13]2=[O:21])=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])([O-:5])=[O:4]
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: O=C1NC2(CCC2)C(=O)N1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C2(CCC2)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 23 °C
Yield: 33 %

Procedure:
NaH (to 60%) (44 mg, 1.1 mmole) is added under argon to a solution of 7-[4-nitro-3-(trifluoromethyl)phenyl]-5,7-diazaspiro[3.4]octane-6,8-dione (329 mg, 1 mmole) in anhydrous DMF (9 ml). A release of gas accompanies the change in colour of the reaction medium which becomes orange. Stirring is maintained for 1 hour at 23° C. before adding 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate (prepared according to an experimental protocol described in WO 2005077968) (332 mg, 0.8 mmole). After reaction for 15 hours, the reaction medium is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on an RP18 silica column (eluent: ACN/H2O: 8/2 to 100). The expected compound is obtained in the form of a colourless oil with a yield of 33% (214 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[F:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2([C:39](O)=[O:40])[CH2:38][CH2:37]2)=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:39]([C:36]2([C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:35])[CH2:38][CH2:37]2)=[O:40])=[CH:20][C:19]=1[F:25]
Reactant: COc1cc2nc(SC)cc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a mixture of 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine (0.22 g, 0.61 mmol) and 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.16 g, 0.73 mmol) in DMF (5 mL) was added TEA (0.25 mL, 1.8 mmol) followed by HATU (0.57 g, 1.5 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water and extracted with DCM (2×). The combined extracts were washed with 5% LiCl(aq) (3×), water, (1×) and brine (1×), followed by drying over Na2SO4 and concentration in vacuo. The crude solids were purified by preparatory HPLC with ammonium acetate, affording N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.39 g, 11% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 9.94 (s, 1H), 7.83 (d, 1H), 7.59 (m, 2H), 7.56 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1H), 7.09 (t, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H), 1.40 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1Cl
Reactant: NCc1ccccc1
Product: CS(=O)(=O)c1cc(-c2ccncc2)ccc1NCc1ccccc1
Temperature: 160 °C

Procedure:
A suspension of 4-(4-chloro-3-methanesulfonyl-phenyl)-pyridin (5.5 g) in benzylamine (23 ml) was heated to 160° C. for 4 h, concentrated under high vacuum. The residue was quenched with ice/water and extracted with ethyl acetate. The organic layers were washed, dried and concentrated; the residue was chromatographed on silica gel with heptane/ethyl acetate. The compound containing fractions were evaporated, and the residue crystallized from methanol/ether to obtain the desired compound (5.75 g) as an off-white solid. MS (ISP): 339.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:16])[CH3:15]>O1CCCC1>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:16][CH2:14][CH3:15])=[O:12]
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC(=O)c1cccc(F)c1N
Reaction time: 2 h
Yield: 90 %

Procedure:
8-Fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (10.0 g, 55.2 mmol) was dissolved in tetrahydrofuran (200 mL, 2000 mmol) at 0° C. 2.0 M Ethylamine in tetrahydrofuran (41 mL) was added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and azeotroped with toluene (50 mL). Ethyl ether (200 mL) was added and the precipitate (the acid byproduct formed by hydrolysis) was removed by filtration. The filtrate was concentrated under reduced pressure and the product was purified by silica gel chromatography using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain 2-amino-N-ethyl-3-fluoro-benzamide as a pale yellow solid (9.02 g, 90%). m.p.=60° C.; LCMS (m/e) 183 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.11 (d, 1H, J=8.0 Hz), 7.09-7.02 (m, 1H), 6.62-6.54 (m, 1H), 6.05 (bs, 1H), 5.61 (bs, 2H), 3.52-3.43 (m, 2H), 1.26 (t, 3H, J=6.6 Hz).
Reaction SMILES: [ClH:1].C([O:5][C:6]1[C:15]([O:16]C(=O)C)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:10]=[C:11]2[CH2:20][NH2:21])(=O)C>CO.Cl>[ClH:1].[NH2:21][CH2:20][C:11]1[C:12]2[C:7](=[C:6]([OH:5])[C:15]([OH:16])=[CH:14][CH:13]=2)[CH:8]=[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:10]=1
Reactant: CC(=O)Oc1ccc2c(CN)cc(-c3ccccc3)cc2c1OC(C)=O
Agent: Cl
Solvent: CO
Product: NCc1cc(-c2ccccc2)cc2c(O)c(O)ccc12
Yield: 75 %

Procedure:
5,6-Bis(acetoxy)-1-aminomethyl-3-phenylnaphthalene hydrochloride (130 mg, 0.34 mmol) from Step 3 was dissolved in 10 mL of methanol saturated with hydrogen chloride. The resultant solution was stirred at ambient temperature for 3 h and then concentrated in vacuo. The solid residue was dissolved in a minimal amount of ethanol. The ethanol solution was added slowly to 30 mL of dry diethyl ether and the precipitate was collected by filtration. The solid was dried at 60° C. in vacuo to give 77 mg (76% yield) of the title compound as a white solid, m.p. 205°-212° C. (dec); DCI MS M/Z: 266 (M+H)+, 283 (M+NH4)+ ; 1H NMR (d6 -DMSO) δ: 4.50 (d, 2H), 7.28 (d, 1H), 7.36-7.60 (m, 4H), 7.77 (s, 1H), 7.83 (d, 2H), 8.35 (s, 1H), 8.49 (br s, 3H), 9.22 (br s, 1H), 9.60 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:11]=[C:10]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CN1CCNCC1
Reactant: CNC(=O)c1ccc(F)cc1Cl
Product: CNC(=O)c1ccc(N2CCN(C)CC2)cc1Cl
Yield: 52.5 %

Procedure:
A mixture of 316 mg (1.68 mmol) 2-chloro-4-fluoro-N-methyl-benzamide and 0.94 ml (8.4 mmol) 1-methylpiperazine was heated at 140° for 7 h in a sealed glass tube. After cooling to room temperature excess 1-methylpiperazine was removed by distillation at 50°/0.5 mbar. The residue was partitioned between 25 ml CH2Cl2/2 N NaOH solution. The layers were separated and the aqueous layer was extracted with 3 15-ml portions of dichloromethane. The combined organic extracts were dried (Na2SO4) and evaporated. Chromatography (SiO2, CH2Cl2/methanol 19:1 yielded 236 mg (52%) 2-Chloro-N-methyl-4-(4-methyl-piperazin-1-yl)-benzamide as a light yellow solid, MS (EI): 2.67(M+).