Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=4)[N:25]=3)[CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reactant: Cc1nc(C)c(Cl)c(NCc2cccc(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C)c(Cl)c(NCc2cccc(Oc3ccc4ncc([N+](=O)[O-])n4n3)c2)n1

Procedure:
In analogy to the method described in example 1, 7.9 g (30 mmol) of 3-[(5-chloro-2,6-dimethylpyrimidin-4-ylamino)methyl]phenol (from example B2), 6.08 g (30 mmol) of 6-chloro-3-nitroimidazo-[1,2-b]pyridazine and 20.9 g (150 mmol) of potassium carbonate are reacted in 125 ml of dimethylformamide. After chromatography on silica gel (mobile phase: gradient toluene/dioxane 5:1 to 2:1) and crystallization from methylene chloride/methanol and extraction with stirring from diisopropyl ether, 10.95 g (85%) of the title compound are isolated as a pale beige solid. m.p.: 222-223° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:5][C:6]([NH2:24])([C:20]([F:23])([F:22])[F:21])[CH2:7][C:8]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18]C)([CH3:10])[CH3:9].B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:24][C:6]([CH2:5][C:4]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:2]([CH3:1])[CH:3]=1)([C:20]([F:23])([F:21])[F:22])[CH2:7][C:8]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18])([CH3:10])[CH3:9]
Reactant: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1cc(C)cc(C)c1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)cc(CC(N)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a room temperature solution of 23 mg (0.058 mmol) of 1-(3,5-dimethylbenzyl)-3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-trifluoromethylbutylamine (Example 2) in 0.5 mL of CH2Cl2 was added 0.5 mL (0.5 mmol) of a 1 M solution of BBr3 in CH2Cl2. After 1 h, the reaction was cooled to 0° C. and MeOH was added. The reaction was concentrated in vacuo and partitioned between aqueous sodium bicarbonate and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to afford an oil. The crude material was purified on a short silica gel column eluting with hexanes-EtOAc (95:5) to afford 7 mg (33%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH3:28][NH:29][CH:30]1[CH2:32][CH2:31]1.C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH:30]1([N:29]([CH3:28])[C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:26])[CH2:32][CH2:31]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CNC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1)C1CC1
Temperature: 70 °C
Reaction time: 22 h
Yield: 86.9 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (140 mg, 0.377 mmole), N-methyl cyclopropylamine (161 mg, 2.26 mmole), N-ethyldiisopropylamine (527 ul, 3.02 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 566 ul, 0.943 mmole) in tetrahydrofurane (5 ml) was stirred for 22 hours at 70° C. The solution is loaded on silicagel (1.5 g) and purified by chromatography on a 10 g Silicycle cartridge with ethyl acetate as eluent affording N4-cyclopropyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (139 mg, 86.9%) as a white solid. mp.: 172-5° C., MS: m/z=415.4 (M+H+)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].O=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(C)C=CC=CC=1.Cl.O1CCOCC1>O1CCOCC1.C1(C)C=CC=CC=1.[Pd]>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:1][CH:2]=1
Reactant: NCC(c1ccccc1F)c1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Reactant: CCOC(=O)C=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a yellow, homogeneous solution of (3-(2-amino-1-(2-fluorophenyl)ethyl)-1H-indol-6-yl)(morpholino)methanone (0.270 g, 0.736 mmol) and 50% ethyl 2-oxoacetate/toluene (0.321 mL, 1.619 mmol) in 1,4-dioxane (30 mL) was added 4 N HCl/dioxane (0.368 mL, 1.472 mmol) under nitrogen, and the reaction was stirred overnight. The reaction was concentrated in vacuo, diluted with water and basified to pH ˜10 (by litmus paper) with NaHCO3. This was extracted with EtOAc (3×), and the organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude product which was used in the subsequent step. This was combined with 10% Pd/C (0.710 g, 0.668 mmol) in toluene (10 mL), and the solution was refluxed. After 45 min, the reaction was cooled to room temperature and filtered through a pad of CELITE®, rinsing with EtOAc. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 24 g column eluting with 0-100% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0592 g, 0.132 mmol, 19.8% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:13])[C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Br:16]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:16][CH2:11][C:10](=[O:12])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=1)=[O:13]
Reactant: CC(=O)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a chloroform (6.0 mL) solution of 1-[4-(trifluoromethyl)phenyl]propane-1,2-dione (0.65 g), bromine (0.62 mL) was added, and the resultant was stirred at 70° C. for 6 hours. After standing to cool to room temperature, a 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure to obtain the title compound (1.1 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].O>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C@H:3]([CH3:4])[O:5][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccccc1F
Reactant: C[C@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Oc1ccccc1C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
36.0 g (316 mmol) of (S)-1,1,1-trifluoro-propan-2-ol (CAS: 3539-97-7) was added to a cold (0 to 5° C.) suspension of 17.0 g (425 mmol) of NaH (pract., 60%) in 200 ml of dioxane. The suspension was stirred at room temperature during 0.5 h then cooled (0 to 5° C.) and a solution of 20.0 g (143 mmol) of 2-fluoro-benzoic acid in 100 ml of dioxane was added. The mixture was stirred during 0.5 h at room temperature and during 140 h under reflux. The mixture was poured into 800 ml of water, washed with 300 ml of MTBE, then acidified to pH 2 with hydrochloric acid and the product was extracted with MTBE. The solvent was concentrated in vacuo and the residue was crystallized from ethanol/water to provide 27.3 g (82%) of the title compound as a white solid. MS (m/e): 234.1 [M]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)[CH3:6])=[O:4].[CH2:16]([OH:21])[CH2:17][CH2:18][C:19]#[CH:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]([F:15])([F:14])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][OH:21])=[CH:9][CH:8]=1)[CH3:6])=[O:4]
Reactant: C#CCCCO
Reactant: CN(C(=O)C(F)(F)F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C(=O)C(F)(F)F)c1ccc(C#CCCCO)cc1

Procedure:
Intermediate 33 (0.377 g, 1.147 mmol) in 10 mL of TEA was combined with PdCl2(PPh3)2 (0.02294 mmol, 0.016 g) the mixture was then degassed using N2 for 5 minutes. Then CuI (0.01147 mmol, 0.002 g) and Pent-4-yn-1-ol (1.147 mmol, 0.115 g) then reacted at 50° C. for 4 hours. The reaction was worked up quenching the reaction with 1× saturated NaHCO3, extracted 4×25 ml EtOAc then washed 1× water, 1× saturated NaCl, dried over Na2SO4, then concentrated. The product was purified 0-75% EtOAc in Hexanes over 20 min on silica. ES/MS calcd. for C14H14F3NO2 285.1. Found m/z=286 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28](C(F)(F)F)=[CH:27][N:26]=1.ClC1C=CC=C([C:42]([F:45])([F:44])[F:43])N=1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:42]([F:45])([F:44])[F:43])[N:26]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cccc(C(F)(F)F)n2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-chloro-6-(trifluoromethyl)pyridine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccccc1-c1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1
Temperature: 100 °C
Yield: 51.7 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (21.0 mg, 0.08 mmol) in DMF (1 mL) was added Pd(PPh3)2Cl2 (5 mg, 0.007 mmol), 2-chlorophenyl boronic acid (15 mg, 0.096 mmol), and Na2-CO3 (21.0 mg in 0.5 mL water). The reaction mixture was heated at an oil bath temperature of 100° C. for about 12 hours. The mixture was cooled to RT and water (20 mL) was added. The aqueous layer was washed with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (30% EtOAc/hexanes) to give the title compound as a brown solid (15 mg, 55%). 1H-NMR (300 MHz, CDCl3) δ 9.14 (d, 1H, J=9.2 Hz), 8.52 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 7.74-7.71 (m, 1H), 7.56-7.52 (m, 2H), 7.46-7.42 (m, 2H), 5.61 (bs, 1H), 2.88 (m, 1H), 0.89 (m, 2H), 0.66 (m, 2H); MS (ESI) (M+H)+ 363.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[F:17][C:15]([F:16])([F:18])[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][NH2:1]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: NCCc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-azidoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole (0.400 g; 1.09 mmol) and triphenyl phosphine (0.427 g; 1.63 mmol) in methanol (5 mL) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a solution of tetrabutylamonium fluoride (3.26 mL, 1M) in THF and stirred at room temperature for 36 hours and concentrated under reduced pressure to yield 2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine which was used without any further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br.O1CCOCC1>O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)C(=O)O
Temperature: 95 °C

Procedure:
A mixture of methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]phenoxy]isobutyrate (50 mg), 48% w/v hydrobromic acid (0.74 ml), dioxane (1 ml) and water (3 ml) was heated at 95° C. for 4 hours. The solution was cooled, diluted with water and freeze-dried to give the title compound, 40 mg, as a pale yellow solid: m.p. 163°-167° C.; NMR (D2O) δ8.40 (2H, d), 8.16 (2H, d), 7.40 (2H, d), 7.21 (2H, d), 5.21 (2H, s), 4 32 (4H, b), 3 89 (4H, bt), 1.86 (6H s); m/e 384 (M+H)+ ; calculated for C21H25N3.2HBr.2H2O: C, 43.3; H, 5.3; N, 7.2. found: C, 43.6; H, 5.3; N, 7.3%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[O:21]1[C:25]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[CH:24][N:23]=[CH:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([C:25]4[O:21][CH:22]=[N:23][CH:24]=4)=[CH:34][CH:33]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(-c2cnco2)cc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-4-oxazol-5-yl-benzamide was prepared starting from intermediate D and 4-oxazol-5-yl-benzoic acid. MS calcd. for C26H18ClN3O3 [(M+H)+] 455.9, obsd. 456.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:6][C:5]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:6][C:5]2=[S:28]
Reactant: O=c1cc(-c2cccnc2)oc2ccc(F)cc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc2oc(-c3cccnc3)cc(=S)c2c1
Yield: 138.5 %

Procedure:
A stirred mixture of 6-fluoro-2-pyridin-3-yl-chromen-4-one (128 mg, 0.53 mmol), Lawesson's reagent (129 mg, 0.32 mmol) and anhydrous toluene (3.5 mL) was refluxed under N2 for 0.5 hr. The solvent was removed under vacuum and the residue was purified by silica gel chromatography (EtOAc/MeOH/NEt3, 40/2/1) to give 6-fluoro-2-pyridin-3-yl-chromene-4-thione (114.0 mg, 83.6% yield) as a brown yellow solid which was used in next step without further purification. LC/MS: 258.1 (M+H); LC/Method A/5.94 min, 96.6% purity by area %.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=C(O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoic acid (196 mg, 0.653 mmol) in CH2Cl2 (6.0 mL) was added oxalyl chloride (0.28 mL, 3.3 mmol) followed by DMF (2 drops). The mixture was stirred under nitrogen at rt for 15 hours. The reaction was concentrated to yield 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoyl chloride, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8].ClC1C=CC=C(C(OO)=[O:17])C=1>ClCCl>[CH2:7]([C@H:6]1[C@@H:5]([CH2:4][CH2:3][O:2][CH3:1])[O:17]1)[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC/C=C\CCOC
Solvent: ClCCl
Product: CC[C@@H]1O[C@@H]1CCOC
Yield: 79.7 %

Procedure:
27.4 g of (Z)-1-methoxy-3-hexene were dissolved in dichloromethane (850 ml) and cooled to 10°. 62 g of ca 70% m-chloroperbenzoic acid corresponding to 1.05 eq., were added in portions. The mixture was allowed to react during 15 hours and was then transferred into an extraction funnel wherein it was washed with an aqueous solution of NaOH and then with water to neutrality. After separation and drying of the organic layer on Na2SO4, the residue was distilled over a 5 cm long Vigreux type column at 51-52°/1.5×103Pa to give 24.9 g (80%) of the desired compound in the form of a colourless liquid which presented the following analytical data:
Reaction SMILES: I.C[O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[ClH:21]>>[ClH:21].[CH:17]([N:14]1[CH2:13][CH2:12][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:20])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH2:15]1)([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(C2CCN(C(C)C)CC2)cc1
Agent: Cl
Agent: I
Product: CC(C)N1CCC(c2ccc(C(=O)O)cc2)CC1

Procedure:
4-(1-Isopropyl-piperidin-4-yl)-benzoic acid methyl ester hydroiodide (1.7 mmol) is dissolved in 4N HCl (5 ml) and heated under reflux for 10 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum). A grey-brown powder with mp. >270° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C[O:13]C(OC)N(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-chloro-2-nitrotoluene (514.8 mg, 3.000 mmol) and dimethylformamide dimethylacetal (1.200 ml, 1074 mg, 9.000 mmol) in DMF (1.2 ml) was heated at 135° C. in a sealed tube for 15 h. The reaction mixture was cooled to rt and added dropwise to a 20° C. solution of NaIO4 (1926 mg, 9.000 mmol) in water (6.18 ml) and DMF (3.09 ml). After 3 h, the mixture was treated with water (20 ml) and extracted with EtOAc (3×15 ml). The extracts were washed with water (3×15 ml) and brine (15 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, a brown solid of 4-chloro-2-nitrobenzaldehyde was obtained (J. Org. Chem. 2003, 68, 4104-4107). NMR (CDCl3, 400 MHz) δ 7.74-7.78 (m, 1 H), 7.94-7.96 (m, 1 H), 8.11-8.12 (m, 1 H), 10.39 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[OH-].[K+]>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(=C(c1ccc(F)cc1)c1ccc(C=CC(=O)OC)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=C(c1ccc(F)cc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of ester (5) (300 mg, 0.78 mmol) in methanol (25 mL) and THF (8 mL) was added 1N KOH (12 mL, 12 mmol). After stirring overnight the solvent was partially removed under reduced pressure, the mixture was acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with brine and were dried (MgSO4). The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 5% methanol/CH2Cl2) to give the acid (6) as a white solid (270 mg, 93%): 1 H NMR (CDCl3) δ 7.60 (d, J=15.8 Hz, 1 H), 7.13 (m, 11 H), 6.87 (d, J=8.5 Hz, 2 H), 6.28 (d, J=15.8 Hz, 1 H), 2.47 (q, J=7.3 Hz, 2 H), 0.93 (t, J=7.3 Hz, 3 H); APcI m/z: 414 (M+H+CH3CN+, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-])=O)=[CH:11][CH:12]=3)[C:7](=[CH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[NH2:38])=[O:30])=[O:22])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:17][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=3)[C:7](=[CH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[NH2:38])=[O:30])=[O:22])[C:8]=2[CH:9]=1
Reactant: Nc1ccccc1NC(=O)CCCCCNC(=O)C=C1c2cc([N+](=O)[O-])ccc2-c2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=CC(=O)NCCCCCC(=O)Nc1ccccc1N)c1cc(N)ccc1-2
Yield: 95.9 %

Procedure:
To a solution of 6-(2-(2,7-dinitro-9H-fluoren-9-ylidene)acetamido)-N-(2-aminophenyl)-hexanamide (515 mg, 1 mmol) in methanol (20 ml) was added 5% palladium on charcoal (0.50 g). Then the mixture was stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution was filtered through celite, and the filtrate was evaporated under vacuum to give the title compound (437 mg, 96% yield) as a white solid. LC-MS (m/z) 456 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19]>O>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]([Br:19])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To 1-(3,5-bis(trifiuoromethyl)phenyl)-1-hydroxyethane (10 g) was added phosphorous tribromide (3.7 ml) to give a clear solution. After 30 minutes the solution was added to water (300 ml) and the solution stirred for a further 30 minutes. Petroleum ether bp=60°-80° C. was added and the organic solution washed with water (×3), saturated, NaHCO3, saturated brine and dried (MgSO4). The solution was evaporated in vacuo and the residue distilled b1-4 mm =69° C. to give 1-(3,5-bis(trifluoromethyl)phenyl)-1-bromoethane- 1H NMR (250 MHz; CDCl3) δ7.88 (2H; s; 2,6-arylH), 7.80 (1H; s; 4-arylH), 5.23 (2H,; q, J =6.9 Hz; CH3CH), 2.09 (3H; d, J =6.9 Hz; CH3).