Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[CH2:7][CH2:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[C:10]=1[CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=O)(C)(C)C.[H-].[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH3:18][O:17][C:11]1[C:10]2[CH2:19][CH2:20][C:21](=[O:23])[CH2:7][CH2:8][C:9]=2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=1
Reactant: COc1ccc(OC)c(CCC(=O)OC(C)(C)C)c1CCC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: COc1ccc(OC)c2c1CCC(=O)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
3-[2-(2-tert-butoxycarbonylethyl)-3,6-dimethoxyphenyl]-propionic acid tert-butyl ester (6.33 g) was added dropwise to a refluxed solution of sodium hydride (578 mg) in dry toluene (60 ml) and dry tert-butyl alcohol (0.5 ml), and stirred for 3 hours. After cooling, to the reaction mixture glacial acetic acid was added dropwise followed by addition of ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. To the residue were added methanol (50 ml) and 6N hydrochloric acid (15 ml), and this mixture was refluxed for 3 hours, poured into ice and extracted with ethyl acetate. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 1,4-dimethoxy-5,6,8,9-tetrahydrobenzocyclohepten-7-one (2.99 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:49]=[C:48]([Cl:50])[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:47]=[CH:46][C:15]([CH2:16][CH:17]([C:27]([N:29]([CH2:33][C:34]3[CH:39]=[C:38]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:37]=[CH:36][C:35]=3[Cl:45])[CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[C:6]([Cl:51])[CH:5]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:61].[Na+].OO>CCOC(C)=O.C1COCC1>[Cl:45][C:35]1[CH:36]=[CH:37][C:38]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:39][C:34]=1[CH2:33][N:29]([CH:30]1[CH2:32][CH2:31]1)[C:27](=[O:28])[CH:17]([CH2:16][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][O:8][C:7]2[C:6]([Cl:51])=[CH:5][C:4]([CH2:1][CH2:2][CH2:3][OH:61])=[CH:49][C:48]=2[Cl:50])=[CH:47][CH:46]=1)[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: [OH-]
Reactant: C=CCc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cc(CCCOC)ccc3Cl)C3CC3)cc2)c(Cl)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCc1ccc(Cl)c(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(CCCO)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a THF solution (0.04 M) of tert-butyl {2-{4-[2-(4-allyl-2,6-dichlorophenoxy)ethoxy]benzyl}-3-[[2-chloro-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]-3-oxopropyl)carbamate from Example 122, Step 5 (1 eq.) was added 9-borabicyclo[3.3.1]nonane (0.5 M THF solution, 2.6 eq.) dropwise at 0° C. The resulting solution was warmed slowly to RT over 16 h. The reaction was quenched at 0° C. with the dropwise addition of ethanol. Then, NaOH (1 N aqueous solution, 4 eq.) and H2O2 (30% w/w aqueous solution, 12 eq.) were added. After 1 h of stirring at 0° C. and another 4 h of stirring at RT, the reaction mixture was diluted with EtOAc. The organic layer was separated, washed with water, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc→EtOAc), revealed the title compound.
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+]>>[N:10](=[C:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7])[OH:11]
Reactant: NO
Reactant: CC(=O)CCCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(CCCC#N)=NO

Procedure:
Chem. Ber. 1966, 3387 to 3389 discloses the preparation of 1,5-diaminohexane from 5-oxocapronitrile. In this process, 1,5-diaminohexane is only obtained via the oxime intermediate by first reacting 5-oxocapronitrile with hydroxylamine hydrochloride in the presence of anhydrous sodium carbonate to give 5-oximinocapronitrile, which is subsequently reacted with lithium aluminum hydride to give the diamine; the overall yield is 42%. According to the authors, direct reductive amination of 5-oxocapronitrile gives the cyclization product, 2-methylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([CH2:13][NH2:14])[CH2:8]1)=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC[C@H](CNC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@@H](CN)C1
Yield: 6.2 %

Procedure:
Following the procedures as described in Example 113, (R)-tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 131 as a white solid (12 mg, 6.2%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.74 (d, J=4.0, 1H), 7.60-7.42 (m, 4H), 7.28 (t, J=8.8, 2H), 3.63 (d, J=3.3, 3H), 3.24-2.81 (m, 4H), 2.77-2.61 (m, 2H), 1.84-1.42 (m, 4H), 1.03 (d, J=10.6, 1H). ESIMS m/z=448.1 (M+1)
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1>CC(C)=O>[O:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccncc2)cc1
Agent: BrCc1ccccc1
Solvent: CC(C)=O
Product: c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-phenoxypyridine and benzylbromide in acetone was stirred overnight at room temperature. After removal of the solvent, the residue was dissolved in methanol, cooled to -20° C. and treated portionwise with sodium borohydride, and warmed to 0° C. After a standard workup and purification, the resulting tetrahydropyridine adduct was dissolved in methanol and hydrogenated using 20% Pd-C as a catalyst to provide 4-phenoxypiperidine. A mixture of 4-phenoxypiperidine and 1-bromo-3-(4-fluorophenoxy)propane in acetone with excess potassium carbonate was heated at reflux for 12 hours to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[F:19]C1C=CC(C#N)=CC=1.C(N(CC)C(C)C)(C)C.[CH3:37][N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=O>CO>[F:19][C:40]1[C:39]([N:15]2[CH2:16][CH2:17][C:10]3([C:9](=[O:18])[N:8]([C@H:5]4[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]4)[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[N:38][CH:37]=[CH:42][CH:41]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCNCC2
Reactant: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCN(c1ncccc1F)CC2

Procedure:
A mixture of 2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (20 mg, 0.08 mmol), 4-fluorobenzonitrile (12.3 mg, 0.102 mmol) and N,N-diisopropylethylamine (44 μL, 0.25 mmol) in N-methylpyrrolidinone (0.5 mL) was irradiated under microwave at 200° C. for 15 min. The mixture was diluted with methanol (1.3 mL), and purified by Prep-HPLC to give 8-(3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+H)+=348.2.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:17]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 0 °C

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.0 g, 19.15 mmol) in tetrahydrofuran (100 mL) was treated with tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate (5.38 g, 28.73 mmol) and triphenylphosphine (7.53 g, 28.73 mmol). The reaction mixture was cooled to 0° C. on an ice bath. Diethylazodicarboxyate (5.0 g, 28.73 mmol) was slowly added to the reaction mixture. The solvent was removed under reduced pressure after 6 days. The crude oil was used directly in the subsequent reaction without further analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:19]([O:28][CH3:29])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([S:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[C:19]([O:28][CH3:29])=[O:27])[CH:3]=3)[N:8]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Fc1ccc(-c2ccc3cc(Br)ccc3n2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1Sc1ccc2nc(-c3ccc(F)cc3)ccc2c1
Yield: 90 %

Procedure:
A mixture of 6-bromo-2-(4-fluorophenyl)quinoline (Example 19 Step 1; 758 mg, 2.51 mmol), methyl thiosalicylate (0.35 mL, 2.54 mmol), N,N-diisopropylethylamine (0.87 mL, 4.99 mmol), tris(dibenzylideneacetone)dipalladium(0) (58 mg, 0.063 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (74 mg, 0.128 mmol) in 1,4-dioxane (15 mL) was degassed then heated at reflux under nitrogen for 15 hours. The reaction mixture was allowed to cool, concentrated in vacuo and the residue purified by flash chromatography, eluting with 15-25% ethyl acetate/isohexane, to afford methyl 2-{[2-(4-fluorophenyl)quinolin-6-yl]thio}benzoate (0.876, 90%). 1H NMR (400 MHz, CDCl3) δ 8.20-8.14 (4H, m), 8.08 (1H, d, J 1.9 Hz), 8.01 (1H, dd, J 1.6, 7.8 Hz), 7.88 (1H, d, J 8.6 Hz), 7.76 (1H, dd, J 2.0, 8.7 Hz), 7.23-7.15 (4H, m), 6.91 (1H, dd, J 0.9, 8.0 Hz), 3.97 (3H, s); m/z (ES+) 390 [MH+].
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)=[O:10])C1C=CC=CC=1>O1CCCC1.[Pd]>[C:9]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)([OH:10])=[O:8]
Reactant: CCOC(=O)CN1CCC(CCC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(CCC(=O)O)CC1

Procedure:
10 g of 4-[2-(benzyloxycarbonyl)ethyl]-1-[(ethoxycarbonyl)methyl]-piperidine are hydrogenated in 150 ml of tetrahydrofuran for 4 hours at ambient temperature under a hydrogen pressure of 50 psi in the presence of 1.3 g of palladium on activated charcoal. The reaction mixture is concentrated by evaporation and crystallised with diethylether and a little acetone.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].Cl.[CH3:18][C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:29])[N:28]=1)[C:22]([NH:24][NH2:25])=O>>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:10][C:22]([C:21]3[CH:26]=[C:27]([CH3:29])[N:28]=[C:19]([CH3:18])[CH:20]=3)=[N:24][N:25]=2)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2]
Reactant: Cc1cc(C(=O)NN)cc(C)n1
Reactant: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Agent: Cl
Product: CCc1sc(-c2nnc(-c3cc(C)nc(C)c3)o2)c2c1CC(C)(C)CC2

Procedure:
4-[5-(3-Ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-pyridine is synthesized from 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid and 2,6-dimethyl-isonicotinic acid hydrazide hydrochloride in analogy to Example 9; LC-MS: tR=0.93 min, [M+1]=368.44; 1H NMR (CD3OD): δ 7.66 (s, 2H), 3.09 (t, J=6.7 Hz, 2H), 2.80 (q, J=7.6 Hz, 2H), 2.60 (s, 6H), 2.39 (s, 2H), 1.67 (t, J=6.7 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H), 1.03 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([Cl:17])([Cl:16])[Cl:15])=[N:12][C:11]([C:18]([O:20]C)=[O:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CO.O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([Cl:16])([Cl:17])[Cl:15])=[N:12][C:11]([C:18]([OH:20])=[O:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1nc(C(Cl)(Cl)Cl)n(-c2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(C(Cl)(Cl)Cl)n(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
210 g (0.54 mole) of 1-(3-trifluoromethylphenyl)-3-methoxycarbonyl-5-trichloromethyl-1,2,4-triazole in 540 ml of methanol were initially taken, and 0.57 mole (22.8 g) of NaOH in 100 ml of water was added. After being stirred at room temperature for 5 hours, the mixture was poured into 4,000 ml of water, the undissolved substance was filtered off and the clear filtrate was adjusted to pH 1 with hydrochloric acid. Colorless crystals were precipitated and were filtered off with suction and washed with water. The substance which remained undissolved in water--the sodium salt of the carboxylic acid--was dissolved in a mixture of 2,000 ml of methanol and 1,000 ml of water, the pH of the solution was adjusted to 1 with hydrochloric acid, and the colorless crystalline precipitate was filtered off with suction and washed with water.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH:16]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: FC(F)(F)c1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: FC(F)(F)c1ccc2c(Nc3ccccc3)ncnc2c1
Yield: 54.7 %

Procedure:
2.5 g of 4-chloro-7-trifluoromethylquinazoline were dissolved in 10 ml of ethanol, and 1.0 g of aniline was added to the solution. Reaction occurred violently and the reaction mixture solidified immediately. After cooling, the solidified product was collected and washed with ethanol. The resulting crystals were pulverized and added to a dilute aqueous solution of sodium hydroxide. Insolubles were filtered off and recrystallized from ethanol to give 1.7 g (yield 60%) of the desired Compound No. 17 in the form of colourless plates melting at 230°-232° C.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[O:15])[C:8]([CH3:11])=[CH:9][N:10]=1
Reactant: NCCc1ccncc1
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCCc1ccncc1

Procedure:
4-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 4-(2-aminoethyl)pyridine essentially according to the procedure of Example 1, Step K. It was characterized as the hydrochloride salt. Mass Spectrum: Found: (M+1) 429.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11](C(OCC)=O)(C(OCC)=O)[CH2:12][C:13]#[N:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[OH-].[Na+].Cl>CO>[N+:8]([C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([CH2:11][CH2:12][C:13]#[N:14])=[N:4][CH:5]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)C(CC#N)(C(=O)OCC)c1ncc([N+](=O)[O-])cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])cnc1CCC#N
Reaction time: 0.92 h
Yield: 61.4 %

Procedure:
3-(3-Methyl-5-nitropyrid-2-yl)-3,3-bis(carbethoxy)-propionitrile (29.8 g) was dissolved in methanol (1120 ml), molar sodium hydroxide solution (355 ml) was added, the reaction was cooled from 28° C. to room temperature and stirred for 55 minutes. The pH was lowered to 4 by the addition of concentrated hydrochloric acid, the reaction was stirred for 2.75 hr., the pH was then raised to 7 and the methanol was distilled off. The aqueous phase was extracted with chloroform, extracts were dried, filtered and concentrated. The residue was crystallised from chloroform/petroleum ether 40°-60° C. The crude product was treated with charcoal in ethanol and recrystallised from ethanol to give the title compound 10.44 g, m.p. 73°-74° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:20]1([C:19]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[CH2:37][O:38][C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])[CH2:32][O:1][C:2]2[C:3]([CH3:18])=[C:4]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(-c2cccc(O)c2C)cc1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2C)cc1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 1 g (4.1 mmol) of methyl 3′-hydroxy-2′-methylbiphenyl-4-carboxylate with 2 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 650 mg (4.7 mmol) of potassium carbonate, the desired product is obtained in the form of a colourless oil (m=2.4 9; Y=97%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.P(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7]
Reactant: c1ccccc1
Reactant: O=C(O)CCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClP(Cl)Cl
Product: O=C(CCCBr)c1ccccc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Into 23.7 g of the benzene solution of 4-bromobutyric acid obtained in Example 5, was added 4.5 g of phosphorus trichloride (33 mmol) dropwise at 20° C. After the temperature was raised to 60 to 70° C., the mixture was stirred for three hours. Then, after the mixture was cooled to 20° C., the reaction solution was dropwise added into a suspension solution containing 20 g of benzene (256 mmol) and 13.3 g of aluminum chloride (100 mmol) at 10° C. After stirring the mixture at that temperature for 30 minutes, the temperature was raised to 20° C. and the mixture was further stirred for one hour and added into a 10% aqueous solution of hydrochloric acid that had been cooled to 10° C. Then, the aqueous phase was extracted with benzene, and the organic phase was washed with diluted hydrochloric acid and brine, followed by partially removing benzene by distillation under reduced pressure to give 92.1 g of a benzene solution of 4-bromobutyrophenone.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:46][CH:47]([F:49])[F:48])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][N:37]([CH2:46][CH:47]([F:49])[F:48])[CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(CC(F)F)CC1
Yield: 4.6 %

Procedure:
The title compound was prepared as described in Example 103C, using 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea (0.213 g, 0.4 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.128 g. 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at room temperature for 4 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)piperidin-4-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea as a solid (0.011 g, 4%). 1H NMR (300 MHz, CDCl3) δ 9.45 (s, 1H), 8.61 (s, 1H), 7.66 (t, 1H), 7.55 (s, 1H), 7.31-7.44 (m, 4H), 7.01 (d, 1H), 5.90 (tt, 1H), 5.81 (s, 1H), 4.58 (m, 1H), 4.04 (s, 3H), 2.93 (m, 2H), 2.80 (td, 2H), 2.53 (m, 2H), 2.15 (m, 2H), 2.00 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 597 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10]C)[CH:5]=[N:6][C:7]=1[Cl:8].CCN(CC)CC.CC(O[C:23]([CH3:25])=[O:24])=O>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:23](=[O:24])[CH3:25])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CNCc1cnc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of the amine from step (c) above (1.77 g, 10 mmol) and Et3N (2.78 mL, 20 mmol, Aldrich) was added Ac2O dropwise with stirring at room temperature. The mixture was stirred for 30 min at room temperature, diluted with EtOAc (30 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 80% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 219 (M+1).
Reaction SMILES: [CH:1]([N:14]([CH3:34])[CH2:15][CH2:16][N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1C(=O)C2C(=CC=CC=2)C1=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O>C(O)C>[CH:1]([N:14]([CH3:34])[CH2:15][CH2:16][N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCCN1C(=O)c2ccccc2C1=O)CCN(C)C(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(CCCCN)CCN(C)C(c1ccccc1)c1ccccc1

Procedure:
Batch size: 20.8 g (45.6 mmol) 2-(4-{[2-(benzhydryl-methyl-amino)-ethyl]-methylamino}-butyl)-isoindol-1,3-dione and 4.6 g (91.9 mmol) hydrazine.hydrate in 200 ml ethanol.