Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:4]([C:3]4[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:2]=4[Br:1])=[O:6])[CH2:25][CH2:26]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cc1Br
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2Br)CC1
Yield: 69.4 %

Procedure:
Using 2,4-dibromobenzoic acid (530 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (413 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (630 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: COc1cccc(Nc2nc3c(Br)cccn3n2)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1cccc(Nc2nc3c(-c4ccc(S(C)(=O)=O)cc4)cccn3n2)c1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-methoxy-phenyl)-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(3-methoxy-phenyl)-amine (200.0 mg, 0.6266 mmol) and (4-methylsulfonylphenyl)boronic acid (150.0 mg, 0.7499 mmol) with Pd(dppf)Cl2 (50.0 mg) as the catalyst in a manner analogous to Step 2c and was isolated as a yellow solid (0.097 g, 39%). MP=204-206° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.1 Hz, 1H), 8.24 (d, J=7.8 Hz, 2H), 8.08 (d, J=7.7 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.37 (s, 1H), 7.28-7.22 (m, 1H), 7.08-7.00 (m, 2H), 6.92 (s, 1H), 6.58 (d, J=7.6 Hz, 1H), 3.86 (s, 3H), 3.10 (s, 3H). MS=395 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=3[CH:20]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:24].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:16]([CH3:24])[C:15](=[O:17])[O:14][C:13]([CH3:18])([CH3:19])[C:12]=3[CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)OC(C)(C)c2cc(-c3cccc(Br)c3)ccc21
Reaction time: 0.33 h
Yield: 72 %

Procedure:
To a solution of 6-(3-bromophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1 g, 3.0 mmol) in anhydrous DMF was added, at rt under a blanket of nitrogen, sodium hydride (60% in mineral oil, 0.24 g, 6.0 mmol). After stirring for 20 minutes, the reaction solution was treated with iodomethane and stirred for 1.5 hours. The mixture was poured into a saturated aqueous ammonium sulfate solution (40 mL) and ethyl acetate (40 mL) was added. The organic layer was separated, dried (MgSO4), and evaporated to yield 6-(3-bromophenyl)-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as off-white solid (0.75 g, 72%): mp 142-143° C.; 1H-NMR (DMSO-d6) δ7.93 (s, 1H), 7.71 (m, 1H), 7.65 (s, 1H), 7.55 (d, 1H, J=8.0 Hz), 7.42 (t 1H, J=7.7 Hz), 7.18 (d, 1H, J=8.4 Hz), 3.35 (s, 3H), 1.67 (s, 6H). MS (ESI) m/z 368, 370 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.[CH2:19]([C@@H:21]1[NH:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)[CH3:20].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>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].C1(C)C=CC=CC=1>[CH2:19]([C@@H:21]1[N:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:22]1)[CH3:20]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 103.7 %

Procedure:
2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.50 g, 1.5 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), tert-butyl (3S)-3-ethyl-1-piperazinecarboxylate hydrochloride (0.40 g, 1.9 mmol, Acesys Pharmatech, North Brunswick, N.J.), sodium tert-butoxide (0.36 g, 3.7 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.11 g, 0.23 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.080 g, 0.077 mmol, Strem Chemical Inc, Newburyport, Mass.), and toluene (3.1 mL) were added to a high-pressure reaction vessel. This mixture was sealed and heated at 100° C. for 29 h. After that time, the reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc (25 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated, the organic material was washed sequentially with saturated aqueous sodium bicarbonate (15 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated to give tert-butyl (3S)-3-ethyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.71 g) as a brown solid. The material was used in the next step without purification.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:4])=[O:3].[NH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:25](O)=[O:26].[BH4-].[Na+].II>C1COCC1>[CH3:1][S:2]([O:5][CH2:6][CH:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:3])=[O:4].[NH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH2:25][OH:26]
Reactant: NC(C(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)c1ccc(Cl)cc1
Agent: II
Agent: [BH4-]
Solvent: C1CCOC1
Product: NC(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 11.88 %

Procedure:
The tert-butyl 1-(4-chlorophenyl)-2-hydroxyethylcarbamate used in the above reaction was prepared as follows. 2-Amino-2-(4-chlorophenyl)acetic acid (12 g, 64.65 mmol) was stirred in THF (200 mL) and sodium borohydride (5.82 g, 153.87 mmol) was added in portions to the stirred mixture under nitrogen. A solution of iodine (16.41 g, 64.65 mmol) in THF (20 mL) was added dropwise maintaining the temperature below 15° C. using an ice bath. The resulting mixture was warmed to room temperature and stirred at reflux overnight. The reaction was quenched by the addition of methanol (40 mL). A portion of this solution was removed (50 mL) and partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The residue was purified by MPLC on silica using gradient elution (0 to 10% methanol/DCM). The desired product, 2-amino-2-(4-chlorophenyl)ethanol (1.318 g, 11.88%), was thus isolated as a colourless solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][C:11]([CH3:13])=[O:12])[CH:7]=[C:6]([O:14][C:15]([CH3:17])=[O:16])[CH:5]=1)=[O:3]>[Pd].CO>[OH:3][CH:2]([C:4]1[CH:9]=[C:8]([O:10][C:11](=[O:12])[CH3:13])[CH:7]=[C:6]([O:14][C:15](=[O:16])[CH3:17])[CH:5]=1)[CH3:1]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(C)=O)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(C)O)c1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A 500 ml autoclave was charged with 20 g (85 mmol) of 3,5-diacetoxyacetophenone, 2 g of palladium on charcoal (catalyst E101 CA/W 5%, Degussa, Germany) and 350 ml of methanol. The autoclave was flushed three times with hydrogen (3 bar), the mixture was stirred and hydrogenation was carried out at 30 bar hydrogen pressure for two hours. After flushing the solution twice with 3 bar nitrogen the catalyst was removed by filtration over Hyflo Super Cel®. Evaporation of the solvent left 19.2 g of a slightly brown oil, which was further purified by flash-chromatography on silica gel using n-hexane/ethyl acetate (5:2) as eluent mixture giving 18.4 g of 1-(1-hydroxyethyl)-3,5-diacetoxybenzene as a colorless oil (81 mmol, GC 98%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)CCC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=1
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: Nc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.66 g, 12.1 mmol) in toluene (20 mL) and n-butanol (7 mL), a solution of 2-bromopyridine (0.991 g, 6.27 mmol) and Cs2CO3 (6.10 g, 18.7 mmol) in H2O (20 mL) was added. The mixture was degassed three times with Ar/vacuum cycle before being charged with Pd(Ph3P)4 (540 mg, 0.46 mmol, 7% mol). It was then heated at reflux under Ar overnight. The reaction mixture was allowed to cool at room temperature, and then in an ice-bath. The precipitates were collected, dried on vacuum to give a solid (0.840 g)
Reaction SMILES: [OH:1]N1C2C=CC=CC=2N=N1.[CH:11]1([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O=O.C1C=C2C(O)=CNC2=CC=1.C(N(CC)CC)C>O.O1CCCC1>[CH:20]1([NH:19][C:18]([NH:17][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=O
Agent: Oc1c[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
For the reaction by the active ester process, 4.26 g. (0.02 mol) N-(furyl-(2')-methoxycarbonyl)-L-alanine and 5.4 g. (0.04 mol) N-hydroxybenzotriazole are dissolved in 50 ml. anhydrous tetrahydrofuran (THF), cooled to 0° C. and mixed with a solution of 4.4 g. (0.022 mol) dicyclohexylcarbodiimide (DCC) in 10 ml. anhydrous THF. For the formation of the active ester, the reaction mixture is stirred for 1.5 hours at 0° C. and then for 2 hours at ambient temperature. Thereafter, with the exclusion of oxygen and water, there are added thereto 2.66 g. (0.02 mol) indoxyl and 2.77 ml. (0.04 mol) anhydrous triethylamine. The reaction mixture is stirred for 18 hours at ambient temperature. The N,N'-dicyclohexylurea formed is filtered off with suction, the solvent is distilled off in a vacuum and the residue is worked up in the manner described in Example 7. The amorphous crude product obtained is then purified by column chromatography on a silica gel column with a mixture of toluene and ethyl acetate (5:1 v/v). After evaporation of the appropriate collected fractions and recrystallization of the residue from ethyl acetate-petroleum ether (1:1 v/v), there are obtained 3.0 g. (45.7% of theory) 3-[N-(furyl-(2')-methoxycarbonyl)-L-alanyloxy]-indole in the form of colorless crystals; m.p. 129° C.: [α]D20 =-51.9° (c=1% in methanol).
Reaction SMILES: ClCCl.Br[C:5]1[O:9][C:8]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:11])=[CH:7][CH:6]=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:5]1[O:9][C:8]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]2[CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:11])=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)o2)C(COc2cccnc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccc3Cl)o2)C(COc2cccnc2)C1
Temperature: 80 °C

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (7 mg, 0.008 mmol) was added to a mixture of tert-butyl 4-(5-bromofuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (75 mg, 0.16 mmol), 2-chlorobenzeneboronic acid (50 mg, 0.32 mmol) and sodium carbonate (34 mg, 0.32 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water (1 mL). The reaction mixture was heated to 80° C. for 2 h. Upon cooling to room temperature, the reaction mixture was filtered, concentrated under reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 66.6 mg (68%, ˜85% pure) of the TFA salt of the desired product. LC-MS: RT=10.08 min, [M+H]+=498.2.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1>C(Cl)Cl>[C:7]1(=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCC(=O)c2ccccc21
Reaction time: 72 h
Yield: 90.6 %

Procedure:
According to the general procedure, a solution of naphthoquinone (50 mg, 0.31 mmol) and rac-32 (10.0 mg, 0.0063 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 72 h. Filtration of the reaction mixture and evaporation of the solvent gave the crude product, which was purified by column chromatography (30% EtOAc in hexane, silica gel) to give 47 (45 mg, 89%) as a 2:1 mixture of 2,3-dihydronaphthalene-1,4-dione and 1,4-dihydronaphthalene-1,4-diol. 1H NMR (300 MHz, acetone-d6, 2,3-dihydronaphthalene-1,4-dione33): δ 8.00-7.97 (m, 2H), 7.83-7.81 (m, 2H), 3.11 (s, 4H); 1,4-(dihydronaphthalene-1,4-diol34): δ 8.32 (bs, 2H), 8.18-8.15 (m, 2H), 7.47-7.43 (m, 2H), 6.73 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[F:13][C:14]([F:40])([F:39])[C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22][CH:21]=1>CS(C)=O.C(O)(=O)C.C(OCC)(=O)C>[F:13][C:14]([F:39])([F:40])[C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc12
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(NN=Cc1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc12)c1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 mL) was added 4-(3,5-bis-trifluoromethylbenzyloxy)-1-naphthaldehyde (440 mg, 1.1 mmol) and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. The organic volume was concentrated under vacuo to give the crude product. The product was purified by silica gel column chromatography using CH2Cl2/MeOH as the mobile phase.
Reaction SMILES: ClC1C2O[CH:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=O)OC=2C(Cl)=C(Cl)C=1Cl.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:11](=[N:28][NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:8]=[N:28][NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: O=C(c1cccs1)C1Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2O1
Solvent: CCO
Product: C(=NNc1ccccc1)C(=NNc1ccccc1)c1cccs1

Procedure:
A mixture of (4,5,6,7-tetrachlorobenzo[d][1,3]dioxol-2-yl)(thiophen-2-yl)methanone (1 g, 2.70 mmol) and phenyl hydrazine (880 mg, 8.13 mmol) in ethanol (14 mL) was heated under reflux for 30 minutes. The reaction mixture was then cooled in an ice bath. A solid precipitated, and the precipitate was collected by filtration and washed with hexane. Crude 2,2′-(1-(thiophen-2-yl)ethane-1,2-diylidene)bis(1-phenylhydrazine) was obtained as a brown solid (500 mg, 57.8% yield) and used in the next step without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][N:9]2[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:13]([O:12][C:11]1[C:10](=[O:20])[N:9]2[CH:21]=[C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:23]=[CH:24][C:8]2=[N:7][C:6]=1[CH:4]=[O:5])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.9 %

Procedure:
3-Benzyloxy-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methoxy-methyl-amide (product of example 14, 112 mg, 0.264 mmol) was dissolved in THF (1 mL) and added to a stirred solution of LAH (14 mg, 0.369 mmol) in THF at −45° C. The reaction was warmed to room temperature and stirred for 2 days. After this time, the reaction was quenched by addition of water and the residue filtered through celite, washing with ether. The combined organic layers where extracted with 1M HCl. The aqueous layer was basified with saturated aqueous bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with water and brine, then dried and concentrated. Purification was achieved by column chromatography to afford the product (25 mg, 26% yield) as a yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1([C:34]([F:37])([F:36])[F:35])[CH:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]2[CH2:23][NH:24][CH:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][N:10]3[C:11]2=[C:7]1[CH:8]=[CH:9]3>N1C=CC=CC=1>[CH2:15]([C:14]1[C:6]([C:34]([F:37])([F:36])[F:35])=[C:7]2[C:11]3=[C:12]([CH2:23][NH:24][CH:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][N:10]3[CH:9]=[CH:8]2)[CH:13]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c2C(=CC(CCc2ccccc2)C3(O)C(F)(F)F)CN1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Thionyl chloride (0.7 g; 5.8 mmol) was added to a solution of tert-butyl 7-hydroxy-6-phenethyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate (2.7 g; 5.8 mmol) in pyridine (7 mL) at O° C. After 2 h at 0° C., the resulting mixture was concentrated and the residue purified by silica gel chromatography (heptane-ethyl acetate) to yield tert-butyl 6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate (1.4 g, 53%).
Reaction SMILES: [CH:1]([NH:4][NH2:5])([CH3:3])[CH3:2].CN([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>>[CH3:2][CH:1]([N:4]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:10]=2[CH:9]=[N:5]1)[CH3:3]
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CC(C)NN
Product: CC(C)n1ncc2c1CCCC2=O

Procedure:
Prepared analogously to Example 1 starting from isopropylhydrazine and 2-(dimethylaminomethylene)-cyclohexane-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Sn].Cl>O>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[C:8]([Cl:14])[CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Sn]
Solvent: O
Product: Nc1cc(Cl)cc(C(=O)O)c1Cl
Temperature: 95 °C

Procedure:
To a flask in which had been placed 47.20 grams (0.20 mole) of 2,5-dichloro-3-nitrobenzoic acid and 40.0 grams (0.326 mole) of granular tin were added, with good agitation, 200 mL of water and 200 mL of concentrated hydrochloric acid. The stirred reaction mixture was heated at 95° C. for 4.5 hours and at the conclusion of this period was poured over ice, causing a solid to form. This solid was removed by filtration and washed with water, then dissolved in ethyl acetate. This solution was washed three times with water and once with a saturated aqueous solution of sodium chloride. After being dried over anhydrous sodium sulfate and filtered, the solution was evaporated under reduced pressure to yield solid 3-amino-2,5-dichlorobenzoic acid, weighing 39.25 grams.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14](Cl)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1B(O)O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:22]1[C:21]([Cl:20])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:27])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc(OCc3ccccc3)ccc2n1
Reactant: OB(O)c1c(Cl)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1-c1ccc2cc(OCc3ccccc3)ccc2n1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 3 g of 6-(benzyloxy)-2-chloroquinoline 12 in toluene (294 ml) is added Pd(PPh3)4 (1 g). After 30 minutes, a solution of 2,6-dichlorophenylboronic acid (4.22 g) in methanol (186 ml) and 120 ml of a saturated aqueous solution of NaHCO3 is added. The reaction is heated under reflux for 4 h. After evaporation, the aqueous phase is extracted with AcOEt (3×20 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated to dryness. The residue is purified over silica gel using AcOEt/petroleum ether 5/95 then 10/90 as eluent to give 6-(benzyloxy)-2-(2,6-dichlorophenyl)quinoline 19 as an oil.