Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CCOCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16]
Reactant: OC1CCCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a solution of cycloheptanol (0.600 mL, 5.0 mmol) in dichloromethane (15 mL) is added rhodium (II) acetate dimer (21 mg) followed by ethyl diazoacetate (0.60 g, 5.7 mmol). The reaction mixture is stirred at RT for 10 min. The reaction mixture is rotary evaporated, and the residue dissolved in Et2O, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 0.960 g of the product 411. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.06 (s, 2H), 3.50 (m, 1H), 1.93 (m, 2H), 1.7-1.4 (m, 8H), 1.4-1.3 (m, 2H), 1.28 (t, 3H); MS: m/z 201 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([OH:28])[C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:12]=1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:28])[C:12]=1[F:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)c(C(O)c2c[nH]c3ncccc23)c1F)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(C(=O)c2c[nH]c3ncccc23)c1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
Into a round bottom flask was added {2,4-difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamic acid benzyl ester (615, 1.01 g, 2.28 mmol) in tetrahydrofuran (5.00 mL, 0.0616 mol). Dess-Martin periodinane (1.20 g, 2.89 mmol) was added in portions. The reaction mixture was stirred at ambient temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography to give compound 616 (914 mg, 91%). MS (ESI) [M+H+]+=442.
Reaction SMILES: [ClH:1].C(OC([N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[C:18]([N:20]1[CH2:37][CH2:36][CH2:35][C@H:21]1[C:22]([NH:24][C@H:25]([CH:33]=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:32])[NH2:31])=[O:23])=[O:19])=O)C1C=CC=CC=1.[H][H]>CN(C)C=O.[Pd]>[ClH:1].[NH:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[C:18]([N:20]1[CH2:37][CH2:36][CH2:35][C@H:21]1[C:22]([NH:24][C@H:25]([CH:33]=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:31])[NH2:32])=[O:23])=[O:19]
Reactant: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1
Yield: 46.3 %

Procedure:
After N-benzyloxycarbonyl-L-pyroglutamyl-L-prolyl-L-argininal hydrochloride (0.081 g, 0.15 mmol) was dissolved in dimethlformamide (10 ml), palladium black (1 g) was added to the solution followed by catalytic hydrogenation at room temperature for 30 minutes in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and ether was added to the residue. The precipitated crystals were filtered to give 0.028 g (46%) of L-pyroglutamyl-L-prolyl-L-argininal hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)N2CCOCC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[NH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)N>CN(C)C=O.O.C(OCC)(=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:8][N:3]1[CH2:4][C:5]2[C:7](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:6]1
Reactant: NNc1ccccn1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(NN2Cc3ccccc3C2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
Triethylamine (10.5 ml) was added to a solution of alpha, alpha'-dibromo-o-xylene (10 g) and 2-hydrazinopyridine (4.1 g) in dimethylformamide. The mixture was stirred, under nitrogen, at ambient temperature for about 20 mins and diluted with water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Trituration of the residue with ethyl acetate gave 3.8 g (48%) of product. Recrystallization of the product from ethyl acetate afforded the analytical sample, mp 130-131° C.
Reaction SMILES: N1C=CC=CC=1.Cl.[N+:8]([C:11]1[C:16]([OH:17])=[C:15]([O:18]C)[CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:12]=1[CH2:23][CH2:24][C:25]([OH:27])=[O:26])([O-:10])=[O:9]>O>[OH:17][C:16]1[C:11]([N+:8]([O-:10])=[O:9])=[C:12]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:13]([N+:20]([O-:22])=[O:21])=[CH:14][C:15]=1[OH:18]
Reactant: COc1cc([N+](=O)[O-])c(CCC(=O)O)c([N+](=O)[O-])c1O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CCc1c([N+](=O)[O-])cc(O)c(O)c1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
Pyridine (16 ml) and concentrated hydrochloride acid (16.6 ml) were heated at 150° C. until the evaporation of water was ceased. 3-(2,6-Dinitro-3-hydroxy-4-methoxyphenyl)propanoic acid (2.3 g) was added and the resulting mixture heated at reflux for two minutes. The product mixture was cooled to about 150° C. and poured to ice water. The mixture was extracted with ethyl acetate and the product finally recrystallized from acetic acid. Yield: 0.93 g, melting point 165-166° C. NMR-data identical to that of example 11.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:43])([F:42])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:42])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCOC(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 87 were used. Thus, ethyl 4-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]butyl]piperazin-1-yl]benzoate was prepared.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@@H:19]([CH3:21])[OH:20])=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].C(O)(C(F)(F)F)=O.[NH:46]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@H:47]([C:52]([OH:54])=O)[CH2:48][CH:49]([CH3:51])[CH3:50].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:46]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@H:47]([C:52]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@@H:19]([CH3:21])[OH:20])=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:54])[CH2:48][CH:49]([CH3:50])[CH3:51]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Boc-Nle-Asn-Thr-OBzl (3.50 g) was treated with TFA (30 ml) and the solvent was evaporated. The residue was triturated with ether to give powders, which were dissolved in DMF (30 ml) together with TEA (1.2 ml). To this was added Boc-Leu-ONB which was prepared from Boc-Leu-OH (1.66 g), HONB (1.41 g) and DCC (1.63 g). The mixture was stirred at room temperature for 15 hours and the solvent was evaporated. The residue was triturated with water (50 ml) to give powders, which were collected by filtration and washed with ethyl acetate. Yield 3.60 g (83.8%); m.p. 200°-201° C. [α]D21.5 -22.7° (c=0.8, DMF), Rf1 0.60
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Br:21].CN([CH:25]=[O:26])C.[Cl-].[NH4+]>C1COCC1>[Br:21][C:15]1[C:14]([CH3:13])=[CH:19][C:18]([F:20])=[C:17]([CH:16]=1)[CH:25]=[O:26]
Reactant: Cc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(F)c(C=O)cc1Br
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (2.5 mL, 19.1 mmol) was dissolved in THF (24 mL) and the solution was cooled to −70° C., then the solution was added with n-butyllithium (1.57 mol/L hexane solution, 12 mL, 19.1 mmol), followed by stirring for 10 minutes. After warmed to room temperature, the mixture was cooled to −70° C. again and a solution of 2-methyl-4-fluorobromobenzene (3.0 g, 15.9 mmol) in THF (4 mL) was added dropwise thereto. After stirring for 15 minutes, the mixture was added with DMF (1.9 mL, 23.8 mmol) and warmed to 0° C., followed by stirring for 20 minutes. The reaction mixture was added with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-bromo-2-fluoro-4-methylbenzaldehyde as a crude product. In a similar manner to Reference Example 2, 2-amino-6-bromo-7-methylquinazoline (2.0 g, 50%) was obtained using the above-obtained 5-bromo-2-fluoro-4-methylbenzaldehyde. In a similar manner to Reference Example 3 and Reference Example 4, Compound A11 was obtained using the above-obtained 2-amino-6-bromo-7-methylquinazoline.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([O:16]CC3C=CC(OC)=CC=3)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.I[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.O.[Cu]I>[OH:16][C:11]1[C:12](=[O:15])[N:13]([CH3:14])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:3]=2)=[N:9][CH:10]=1
Reactant: COc1ccc(COc2cnc(-c3cccc(O)c3)n(C)c2=O)cc1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2cccc(-c3ncc(O)c(=O)n3C)c2)cc1
Temperature: 180 °C
Yield: 26.1 %

Procedure:
To a solution of 40.0 mg (0.118 mmol) 2-(3-hydroxyphenyl)-5-[(4-methoxybenzyl)oxy]-3-methylpyrimidin-4(3H)-one in 1 ml NMP was added 27.6 mg (0.118 mmol) 4-iodoanisole, 46.2 mg (0.142 mmol) Cs2CO3, 2.18 μl (0.012 mmol) 2,2,6,6-tetramethyl-3,5-heptanedione, and 5.85 mg (0.059 mmol) copper(I) iodide. The reaction mixture was heated to 180° C. for 30 min in microwave, diluted with 2 ml water, extracted with 10 ml EtOAc, and concentrated in vacuo. The oil was dissolved in 1 ml CH2Cl2, 1 ml TFA was added, and then concentrated in vacuo. Purification by mass-guided high throughput purification gave 10.0 mg (26% yield) of 5-hydroxy-2-[3-(4-methoxyphenoxy)phenyl]-3-methylpyrimidin-4(3H)-one. 1H NMR δ (ppm)(DMSO-d6): 7.50 (1 H, s), 7.45 (1 H, t, J=7.93 Hz), 7.25 (1 H, d, J=7.66 Hz), 7.09-7.02 (4 H, m), 6.98 (2 H, d, J=8.74 Hz), 3.75 (3 H, s), 2.54 (3 H, s). HRMS (ESI positive) calc M+H=325.1181. Found 325.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(p-fluorophenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(p-fluorophenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.[OH-].[Li+]>C1COCC1.O>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:4]([C:3]([OH:30])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(N)cc3)C(=O)O)CCCC2)cc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
4-Amino-N-[[1[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (280 mg, 0.68 mmol) in THF (12 mL) was treated with a solution of lithium hydroxide hydrate (100 mg, 2.4 mmol) in water (2 mL) and the mixture was stirred for 3 hr. The mixture was concentrated and the residue was acidified with 6 H HCl to give a white sticky solid. Trituration with water and drying under high vacuum afforded crude 4-amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (200 mg) suitable for use in the next step.
Reaction SMILES: [OH:1][CH:2]([C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)S(O)(=O)=O.[Na].Cl.CC(C)=[O:25]>>[OH:1][CH:2]([OH:25])[C:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)=[O:20]
Reactant: CC(C)=O
Reactant: CC(C)CCOc1ccc(C(=O)C(O)S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na]
Product: CC(C)CCOc1ccc(C(=O)C(O)O)cc1

Procedure:
A 6.0 g. portion of hydroxy [p-(isopentyloxy)benzoyl]methanesulfonic acid, sodium salt was dissolved in a mixture of 100 ml. of 0.5N hydrochloric acid and 15 ml. of acetone. The solid was collected, giving the desired product, m.p. 80°-85° C.
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[K+].[F:7][C:8]([F:22])([F:21])[O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][C:13]2=[O:20]>C(O)(=O)C>[NH:5]=[C:4]1[N:16]2[C:17]3[C:12]([C:13](=[O:20])[CH2:14][CH2:15]2)=[CH:11][C:10]([O:9][C:8]([F:21])([F:7])[F:22])=[CH:19][C:18]=3[S:3]1
Reactant: O=C1CCNc2ccc(OC(F)(F)F)cc21
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N=c1sc2cc(OC(F)(F)F)cc3c2n1CCC3=O
Yield: 6.3 %

Procedure:
The procedure is carried out as in Example 1, but starting with 2.2 g of bromine in 10 ml of acetic acid, 3.09 g of potassium thiocyanate and 3.2 g of 6-trifluoromethoxy-2,3-dihydro-(1H)-quinolin-4-one in 35 ml of acetic acid. The organic phase is extracted with 170 ml of an approximately 0.1 N aqueous hydrochloric acid solution. The aqueous hydrochloric phase is alkalinized with 4 ml of a 10 N sodium hydroxide solution and extracted with three times 100 ml of ethyl acetate. The organic extracts are combined, washed with 100 ml of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa) at 40° C. The crude product obtained is chromatographed on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (80-20 by volume). The yellow solid isolated (0.3 g) is washed with a cold solution of petroleum ether and of isopropyl ether (60-40 by volume), and is then dried under reduced pressure (70 Pa) at 40° C. 0.25 g of 2-imino-8-trifluoromethoxy-2H,4H-thiazolo-[5,4,3-ij]quinolin-6-one is thus obtained in the form of a yellow powder melting at 192° C. [Analysis C11H7F3N2O2S, % calculated C: 45.84, H: 2.45, F: 19.77, N: 9.72, O: 11.1, S: 11.12, % found C: 45.5, H: 2.1, F: 19.4, N: 9.3, S: 11.1].
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.[CH3:15][CH2:16][O:17]C(C)=O.CCO>O.[CH]Cl.[Pd]>[CH:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[NH:1][C:16](=[O:17])[CH3:15]
Reactant: CCOC(C)=O
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: [CH]Cl
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCCC2
Temperature: 20 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 7-nitro-3,4-dihydro-1(2H)-naphthalenone (1.67 g, 8.7 mmol) in EtOAc/EtOH (1:1, 150 mL), water (15 mL) and cHCl (2 mL) with Pd/C (5%, 500 mg) was stirred vigorously under H2 (60 psi) for 16 h. The suspension was filtered through Celite, washed with EtOH (4×10 mL) and the organic solvent evaporated. The aqueous residue was partitioned between DCM and dilute aqueous NH3 solution and the organic fraction dried and the solvent evaporated. The residue was dissolved in dioxane (20 mL), and AcO (1.8 mL, 19.2 mmol) was added dropwise to the solution at 0° C. The solution was stirred at 20° C. for 16 h, diluted with water (50 mL), and partitioned between EtOAc and dilute aqueous NH3 solution. The organic fraction was washed with water (3×20 mL), dried and the solvent evaporated to give N-(5,6,7,8-tetrahydro-2-naphthalenyl)acetamide 166 (1.57 g, 95%) as a white solid: 1H NMR δ 7.18-7.25 (m, 2H, H-1, NH), 7.15 (dd, J=8.2, 2.1 Hz, 1H, H-3), 7.00 (d, J=8.2 Hz, 1H, H-4), 2.69-2.77 (m, 4H, 2×CH2), 2.15 (s, 3H, CH3), 1.74-1.80 (m, 4H, 2×CH2). The procedure was repeated a number of times to give N-(5,6,7,8-tetrahydro-2-naphthalenyl)acetamide 166 (10.21 g, 88% overall).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][CH2:6][C:7]([NH2:9])=[S:8])=[O:4].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=O>C(O)C>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][CH2:6][C:7]1[S:8][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[N:9]=1)=[O:4]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: CCO
Product: CC(C)(C)C(=O)OCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Yield: 103.7 %

Procedure:
A mixture of 2-amino-2-thioxoethyl 2,2-dimethylpropanoate (7.38 g), 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (7.50 g) and ethanol (150 ml) was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with diluted aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give crude {4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl 2,2-dimethylpropanoate (about 10 g) as a colorless solid. The solid was dissolved in ethanol (100 mL) and tetrahydrofuran (100 mL), 2N aqueous sodium hydroxide solution (80 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with diluted aqueous citric acid solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (4.90 g) as pale-yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)[CH2:6]O)C.Cl>[OH-].[K+]>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5](=[CH2:6])[C:4]([OH:17])=[O:3])=[CH:9][CH:10]=1)[CH3:16]
Reactant: CCOC(=O)C(CO)c1ccc(OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: C=C(C(=O)O)c1ccc(OCC)cc1

Procedure:
The ethyl-2-p-ethoxyphenyl-3-hydroxypropionate (0.7 g) was refluxed for 7 h in potassium hydroxide solution (20%, 2 ml). It was acidified with dilute HCl and the crude acid (0.46 g, m.p. 103°-107°) used for the next step without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=O)[CH2:18][CH3:19].C(=O)(O)[O-].[Na+]>ClC(Cl)Cl>[CH2:18]([C:19]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[C:9]([C:10](=[O:11])[N:12]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:17]
Reactant: NC(=O)c1ccccc1Nc1ccccc1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1nc(=O)c2ccccc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.0 g (9.42 mmol) 2-phenylamino-benzamide were dissolved in 30 ml trichloromethane the solution was cooled to 0° C., and 2.61 g (2.44 ml, 28.2 mmol) propionyl chloride was added slowly. The mixture was boiled for 90 minutes and afterwards neutralized with a saturated sodium bicarbonate solution. After evaporation the substance was crystallized from isopropanol.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].COCCOC>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:11]=[N:10][C:9]3[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:7](=[O:21])[N:6]4[N:22]=[CH:23][N:24]=[C:5]4[C:4]=3[CH:3]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(-c4ccc(OC)c(OC)c4)cnc32)cc1
Temperature: 120 °C
Yield: 7.1 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 1, 75 mg, 0.19 mmol), 3,4-dimethoxyphenylboronic acid (75 mg, 0.41 mmol), potassium phosphate (104 mg, 0.49 mmol) and DME (3 mL) were combined and nitrogen was bubbled through for 10 minutes. Pd2(dba)3 (13 mg, 0.01 mmol) was added and the mixture was heated for 2 h at 120° C. in the microwave. Purification (HPLC, 10-80% ACN-water) afforded the title compound (6 mg, 7%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 5.78 (s, 2H), 6.83-6.84 (m, 2H), 7.02 (d, J=6.7 Hz, 1H), 7.15 (d, J=1.6 Hz, 1H), 7.24 (dd, J=6.7, 1.5 Hz, 1H), 7.62-7.64 (m, 2H), 8.37 (s, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.99 (d, J=1.9 Hz, 1H). [M+H]=444.2.