Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Br)C=C.C[Si](C)(C)[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[CH:8]=[CH2:7]
Reactant: C[Si](C)(C)CCCn1c(-c2nc3ccccc3o2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(-c2nc3ccccc3o2)nc2ccccc21
Temperature: 70 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Allyl bromide (1.13 ml, 9.35 mmol) was added dropwise over 10 minutes to a heterogeneous mixture of 2-(1H-benzimidazol-2-yl)benzoxazole (second step of Example 1) (2 g, 8.5 mmol) and potassium carbonate (1.29 g) in 10 ml of DMF heated to 70° C. The heating was continued at 70° C. for 4 hours. The reaction mixture was cooled and poured into water. The precipitate obtained was filtered off, washed with water and dried. 2.3 g (yield: 96%) of 2-(1-allyl-1H-benzimidazol-2-yl)-benzoxazole were obtained in the form of a beige-colored powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].[CH3:21][NH:22][CH3:23]>>[NH2:1][C:2]1[N:10]=[C:9]([N:22]([CH3:23])[CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 87 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and aqueous dimethylamine (30 ml) were heated at 120° C. for 15 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (90 mg, yield 87%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.[CH3:12]C1C=CC(C(O)=O)=CC=1.[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=1>CO>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1.[C:27]([O:29][CH3:12])(=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([C:22]([O:33][CH3:34])=[O:32])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: COC(=O)c1ccc(C)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)OC)cc1

Procedure:
A process for the production of terephthalic acid from p-xylene and methanol by way of the dimethyl terephthalate obtained by oxidation, in the liquid phase with atmospheric oxygen in the presence of dissolved heavy metal compounds as the catalyst, of a mixture of p-xylene and a fraction containing predominantly methyl p-toluate, which fraction is recycled into the oxidation, to obtain an oxidation product containing primarily p-toluic acid and monomethyl terephthalate at a temperature of 140°-170° C. and under a pressure of 4-8 bar; by esterification of the oxidation product in a reactor with liquid and subsequently vaporized methanol brought to an elevated pressure, at a temperature of 220°-280° C. and under a pressure of 20-25 bar to obtain a raw ester containing primarily methyl p-toluate and dimethyl terephthalate; by withdrawing the raw ester fraction and a methanol-containing vapor fraction from the esterification reactor; by distillatory separation of the raw ester into a methyl p-toluate fraction and a fraction rich in terephthalic aldehyde methyl ester, which fractions are recycled into the oxidation, a raw dimethyl terephthalate fraction, and a residual fraction; and by hydrolysis of the raw dimethyl terephthalate fraction with water, obtaining the thus-formed terephthalic acid and separation of a methanol-water mixture. In this process, the methanol-containing vapor fraction and the methanol-water mixture are separated by rectification under elevated pressure and elevated temperature into a methanol-rich head fraction and an aqueous sump phase, the methanol formed at the head of the rectification stage is withdrawn in vapor phase under elevated pressure, and esterification of the oxidation product is conducted with the methanol-containing vapor brought by compression to esterification pressure and esterification temperature.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([O:21][CH3:22])=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH:28]=[CH:27]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:19][CH:18]([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:7]2[N:6]=[C:5]([O:21][CH3:22])[C:4]([CH2:3][O:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29](=[O:34])[CH:28]=[CH:27]4)=[CH:9][N:8]=2)=[CH:12][CH:13]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1COc1ccc2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.8 %

Procedure:
A solution of 5-(chloromethyl)-N-(4-(difluoromethoxy)phenyl)-4-methoxypyrimidin-2-amine hydrochloride (0.14 g, 0.398 mmol) in DMF (1.5 mL) was added to a mixture of 6-hydroxyquinolin-2(1H)-one (0.08 g, 0.496 mmol) and Cs2CO3 (0.518 g, 1.590 mmol) in DMF (6.5 mL). The reaction mixture was stirred at room temperature for 18 h, then diluted with water and filtered. The filter cake was stirred in methanol/DCM (1:1) for 18 h, filtered, and dried to give 6-((2-((4-(difluoromethoxy)phenyl)amino)-4-methoxypyrimidin-5-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.082 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (s, 1H), 9.76 (s, 1H), 8.35 (s, 1H), 7.96-7.70 (m, 3H), 7.36-6.93 (m, 6H), 6.51 (d, J=9.5 Hz, 1H), 4.94 (s, 2H), 3.99 (s, 3H). LCMS: R.T.=0.82; [M+H]+=441.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[OH:16])/[C:8]([O:10][CH2:11][CH2:12][S:13][CH3:14])=[O:9])[N:6]=1.Br[CH:18]([CH2:26][CH2:27][CH3:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[O:16][CH:18]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:26][CH2:27][CH3:28])/[C:8]([O:10][CH2:11][CH2:12][S:13][CH3:14])=[O:9])[N:6]=1
Reactant: CSCCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: CCCC(Br)C(=O)OC(C)(C)C
Product: CCCC(O/N=C(\C(=O)OCCSC)c1csc(N)n1)C(=O)OC(C)(C)C

Procedure:
Starting from 2-methylthioethyl 2-(2-aminothiazol-4-yl)-2(Z)-hydroxyiminoacetate and tert-butyl 2-bromovalerate, the above-identified compound is obtained by the procedure of Reference Example 16.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH2:9]([NH2:12])[CH2:10]N.[C:13](#[N:15])C>>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH:15][CH2:13][CH2:10][CH2:9][NH2:12])[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: NCCN
Reactant: CC#N
Product: Cn1cc(CNCCCN)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At room temperature 11 g of 1-methyl-4-pyrazole carbaldehyde was slowly added to 37 g of ethylenediamine in 150 ml of dry acetonitrile. Molecular sieves 4A (a product of Wako Pure Chemicals, Co.) were added as a dehydrating agent to the solution. The mixture was stirred at room temperature for 2 hours, and filtered. Acetonitrile was distilled off under reduced pressure from the filtrate. To the residue was added 100 ml of ethanol, and then 4 g of sodium borohydride was added little by little at room temperature. The mixture was then stirred at room temperature for 2 hours, and ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The solvent was distilled off from the dichloromethane layer, and the residue was vacuum-distilled to give 10 g of N-(1-methyl-4-pyrazolylmethyl)trimethylenediamine as a colorless oil.
Reaction SMILES: [CH3:1][C:2](=[CH:10][CH:11]([CH3:24])[CH:12](OC)[C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][C:2](=[CH:10][CH:11]([CH3:24])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=1)[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C=CC(C)=CC(C)C(OC)c1ccc(N(C)C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C=CC(C)=CC(C)Cc1ccc(N(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a stirred solution of ester compound 31 (99 mg, 0.299 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylsilane (41.9 mg, 0.36 mmol) followed by BF3.Et2O (51 mg, 0.36 mmol) dropwise via microsyringe, and the mixture was stirred at 0° C. for 30 min. The reaction was quenched with saturated NaHCO3 solution (3 mL), diluted with CH2Cl2 (20 mL), and washed with water, and the organic phase was dried and concentrated. Purification by flash silica gel chromatography (10% ethyl acetate in hexane) afforded the title compound 36 (87 mg, 97% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, J=15.6, 0.6 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 6.64 (d, J=8.7 Hz, 2H), 5.74 (d, J=15.6 Hz, 1H), 5.73 (br d, J=10.2 Hz, 1H), 4.20 (q, J=6.9 Hz, 2H), 2.90 (s, 6H), 2.73 (m, 1H), 2.53 (d, J=7.2 Hz, 2H), 1.61 (d, J=0.6 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 12.1, 14.3, 20.0, 35.5, 40.8, 42.2, 60.1, 112.7, 115.5, 128.1, 129.7, 131.6, 147.5, 149.0, 149.8, 167.5.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH2:12]([I:14])[CH3:13]>CC(C)=O>[I-:14].[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[CH:8][N+:9]([CH2:12][CH3:13])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CC(=O)NCc1ccncc1
Solvent: CC(C)=O
Product: CC[n+]1ccc(CNC(C)=O)cc1
Product: [I-]

Procedure:
A solution of 4-acetylaminomethylpyridine (22.40 g) and ethyl iodide (17.9 ml) in acetone (300 ml) was heated under reflux for 24 hours and then the solvent was evaporated in vacuo. The residue was washed with a mixture of n-hexane, ethyl acetate and ethanol to give very hygroscopic 4-acetylaminomethyl-1-ethylpyridinium iodide (42.18 g), which was used without further purification.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[C:4]([C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13](F)[C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].N[C@@H](C)[CH2:24][OH:25].[F-].[Ca+2].[F-].[CH:30](Cl)(Cl)Cl>C(O)C.CS(C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[C:10](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:2]3[C@@H:21]([CH3:30])[CH2:24][O:25][C:13]=1[C:12]=23
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(F)c(F)c1F
Reactant: ClC(Cl)Cl
Reactant: C[C@H](N)CO
Agent: [Ca+2]
Agent: [F-]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn2c3c(c(F)ccc3c1=O)OC[C@@H]2C
Yield: 39 %

Procedure:
Ethyl 3-dimethylamino-2-(2,3,4-trifluorobenzoyl)acrylate (15.0 g, 49.8 mmol) was dissolved in ethanol (30 ml), and to this solution, an ethanol (10 ml) solution of (S)-2-amino-1-propanol (4.50 g, 59.8 mmol) was added dropwise while stirring and cooling with ice. After completion of dripping, the reaction solution was stirred for 1 hour at room temperature and then concentrated under a reduced pressure. The residue obtained was dissolved in dimethyl sulfoxide (50 ml), and after adding spray-dried calcium fluoride (16 g) thereto, it was stirred at 120° C. for 26 hours. After letting the reaction suspension cool, the reaction suspension was concentrated under a reduced pressure, chloroform (200 ml) and water (200 ml) were added to the residue, and after performing a separation operation, the water layer was extracted using chloroform (200 ml). The combined organic layers were then washed with saturated saline solution (100 ml) and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the residue obtained was applied to a silica gel chromatography, and 5.60 g (39%) of the title compound was obtained as a white powder from a chloroform:methanol=50:1 eluate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25]([NH:31][CH3:30])=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)sc1C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1sc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)nc1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylic acid (Example 16) (0.15 g, 0.35 mmol), methylamine (96 μL, 2.46 mmol), HATU (0.268 g, 0.70 mmol) and DIPEA (80 μL, 0.46 mmol) in DMF was stirred at 40° C. overnight. The solvent was evaporated and the residue was washed with water and extracted with DCM (large volume). The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was twice purified by flash chromatography eluting with DCM/MeOH (95/5) to give after crystallisation from ether the title compound as a white solid (33 mg, 21%). HRMS calculated for C17H16Cl2N6O2S (M+H)+439.0511, found: 439.0548, Rt: 2.69 min. MP: 218.5° C.
Reaction SMILES: [CH3:1][Mg]Cl.[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1>>[Cl:4][C:5]1[N:6]=[C:7]([CH3:1])[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Reactant: C[Mg]Cl
Product: Cc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12

Procedure:
The experimental procedure of example 5 was repeated, except for the use of methylmagnesium chloride instead of ethylmagnesium bromide and 2,4-dichloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine instead of N-[4-chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:29]=[CH:28][C:20]3[C:21]([CH3:27])([CH3:26])[O:22][C:23](=[O:25])[NH:24][C:19]=3[CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:30]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:29]=[CH:28][C:20]3[C:21]([CH3:26])([CH3:27])[O:22][C:23](=[O:25])[NH:24][C:19]=3[CH:18]=2)=[O:30])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1
Reactant: OO
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 7-[4-(4-acetamido-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][Cl:10])=[N:6][N:7]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:13][N:14]([CH3:18])[C:15]([N:2]([CH3:1])[C:3]1[S:4][C:5]([C:8]([CH3:11])([CH3:12])[CH2:9][Cl:10])=[N:6][N:7]=1)=[O:16]
Reactant: CN(C)C(=O)Cl
Reactant: CNc1nnc(C(C)(C)CCl)s1
Solvent: c1ccncc1
Product: CN(C)C(=O)N(C)c1nnc(C(C)(C)CCl)s1
Yield: 89.2 %

Procedure:
To a solution of 50.0 g of 2-methylamino-5-(β-chloro-α,α-dimethylethyl)-1,3,4-thiadiazole in 300 ml of pyridine was added 46.0 g of dimethyl carbamyl chloride and the reaction heated at reflux temperature for 16 hrs. After cooling, the pyridine was removed on the rotary evaporator and water added to the residue. The reaction was extracted with ether which was shaken with water, saturated sodium chloride and dried over Na2SO4. The solvent was removed at reduced pressure giving 60 g of a viscous oil. Crystallization was effected using a mixture of ether-petroleum ether; wt. 34.5 g (52%), m.p. 80°-82°. Recrystallization from ether-petroleum ether gave the analytical sample, m.p. 82°-83°.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[CH2:29]([N:26]1[CH2:25][CH2:24][CH:23]([O:22][C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:6]([C:5]3[S:1][C:2]4[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=4[CH:4]=3)=[O:8])=[CH:21][C:18]=2[C:19]#[N:20])[CH2:28][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: N#Cc1cc(N)ccc1OC1CCN(Cc2ccccc2)CC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1OC1CCN(Cc2ccccc2)CC1
Yield: 32.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (0.7 g) and 5-amino-2-(1-benzylpiperidine-4-yloxy)benzonitrile (1.2 g), the title compound (0.6 g) was obtained. melting point: 206° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:5]=1)([O-])=O.O.C(Cl)Cl.[C:21](O)(=[O:23])[CH3:22]>[Fe]>[CH3:15][CH:14]([S:11]([CH2:10][C:6]1[CH:5]=[C:4]([NH:1][C:21](=[O:23])[CH3:22])[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12])[CH3:16]
Reactant: CC(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cccc(CS(=O)(=O)C(C)C)c1
Temperature: 110 °C

Procedure:
A suspension of crude 1-nitro-3-[(propan-2-ylsulfonyl)methyl]benzene (5.0 g) in acetic acid (58 mL) was treated with iron powder (4.7 g), heated for 22 hours at 110° C. bath temperature and cooled to room temperature. Then water (250 mL) and DCM (250 mL) were added, stirred, filtered, dried with sodium sulfate, filtered and concentrated. An analytical sample (200 mg) of the crude title compound (5.6 g) was recrystallized from diethyl ether/ethanol (121 mg). Lit.: [Grohmann and Hathaway, Molbank 2006, M502].
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH:3]1[CH2:4][CH:5]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:6]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH:5]1[CH2:4][CH:3]2[N:9]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH:7]([CH2:8][C:2]2=[O:1])[CH2:6]1
Reactant: COC(=O)CC1CC2CC(O)C(C1)N2C(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)CC1CC2CC(=O)C(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a solution of compound 109f (30 g, 0.09 mol, 1.0 eq) in DCM (800 mL) was added DMP (Dess-Martin Periodinane, 76.5 g, 0.18 mol, 2.0 eq) slowly at 0° C. The resulting mixture was stirred at room temperature for 16 h, and quenched with water. The solid was filtered off, the filtrate was washed with brine (500 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel (EA/PE=1:3) to give benzyl 3-(2-methoxy-2-oxo-ethyl)-6-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate 109g as a colorless oil (26.5 g, yield 88%). 1H NMR (400 MHz, DMSO-d6) δ: 7.46-7.30 (m, 5H), 5.15 (s, 2H), 4.61 (br, 1H), 4.00 (br, 1H), 3.58 (s, 3H), 2.77 (dd, J=7.2, 18.2 Hz, 1H), 2.41-2.30 (m, 3H), 2.28-2.10 (m, 3H), 1.49 (d, J=13.2 Hz, 1H), 1.38 (d, J=11.8 Hz, 1H); MS: calc'd (MH+) 332, measured (MH+) 332.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH2:14]O)=[C:4]([CH3:16])[CH:3]=1.CC(C)=[O:19]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH:9]2[C:10](=[O:11])[CH:14]=[CH:12][CH:13]2[OH:19])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1-c1ccoc1CO
Reactant: CC(C)=O
Solvent: O
Product: Cc1cc(Br)cc(C)c1C1C(=O)C=CC1O
Temperature: 55 °C

Procedure:
Polyphosphoric acid (500 mg) is added to a warm (55° C.) solution of ([4-bromo-2,6-dimethylphenyl]furan-2-yl)methanol (843 mg, 3 mmol) in acetone (8 ml) and water (2 ml) and the mixture is heated at 55° C. for 24 hours. The mixture is cooled to room temperature and the acetone is removed under reduced pressure. The remaining mixture is partitioned between diethyl ether (20 ml) and water (20 ml). The aqueous phase is extracted with ether (2×50 ml), and then the organic phases are combined, washed with saturated aqueous sodium bicarbonate solution (20 ml), and brine (20 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-(4-bromo-2,6-dimethylphenyl)-4-hydroxycyclopent-2-enone (596 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O.[CH:29]([NH2:31])=O>C(O)=O>[CH2:17]([N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:20]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[NH:31][CH:29]=[N:1]2)=[CH:4][CH:5]=1)[CH3:16])[CH:18]=[CH2:19]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(N)c1
Reactant: NC=O
Solvent: O=CO
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)N=CNC2c1ccc(Br)cc1

Procedure:
A solution of 445 mg of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone in 1 ml of formic acid and 4 ml of formamide is boiled at 160° C. for 35 hrs., then concentrated and converted into the free amine (title compound) with sodium bicarbonate solution saturated with methylene chloride. The residue is dissolved in methylene chloride/ether and treated with 73 mg of fumaric acid. After stirring the mixture is decanted and the residue is triturated with ether and filtered off. There are obtained 30 mg of (RS)-allyl-[6-[4-(4-bromo-phenyl)-3,4-dihydro-quinazolin-7-yloxy]-hexyl]-methyl-amine.fumarate (1:1), m.p 120° C. (decomposition), MS: m/e 456 (M+H+, 1 Br).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH3:12][O:11][C:10]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: CCCCCBr
Reactant: COc1cccc(C(=O)O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1c(OC)cccc1C(=O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
2-Hydroxy-3-methoxybenzoic acid (15.66 g, 93 mmol), DMF (200 ml), potassium carbonate (51.4 g, 372 mmol) and pentyl bromide (29 ml, 233 mmol) were mixed, and this solution was stirred at 90° C. for 1 hour. DMF was evaporated under reduced pressure, and water (100 ml) was added. The aqueous layer was extracted 3 times with ethyl acetate (150 ml). The organic layers were combined, washed twice with saturated brine (70 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. To the obtained residue were added a 1N aqueous sodium hydroxide solution (70 ml) and ethanol (70 ml), and the mixture was refluxed under heating for 1 hour. A 1N aqueous sodium hydroxide solution (70 ml) and ethanol (70 ml) were further added, and the mixture was refluxed under heating for 2 hours. Ethanol was evaporated under reduced pressure, and conc. hydrochloric acid was added to make this solution acidic. The aqueous layer was extracted 3 times with ethyl acetate (100 ml). The organic layers were combined, washed twice with saturated brine (100 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1-1/1) to give 3-methoxy-2-pentyloxybenzoic acid (20.5 g, 97%) as a pale-yellow oil.