Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:43][C:44]1[CH:45]=[C:46]([CH:51]=[C:52]([NH:54][C:55]2[N:60]=[C:59]([O:61][CH2:62][C:63]#[CH:64])[C:58]([Br:65])=[CH:57][N:56]=2)[CH:53]=1)[C:47]([O:49][CH3:50])=[O:48]>CN(C=O)C.C(OCC)(=O)C>[Br:65][C:58]1[C:59]([O:61][CH2:62][C:63]#[CH:64])=[N:60][C:55]([NH:54][C:52]2[CH:53]=[C:44]([NH:43][C:17](=[O:19])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:45]=[C:46]([CH:51]=2)[C:47]([O:49][CH3:50])=[O:48])=[N:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: C#CCOc1nc(Nc2cc(N)cc(C(=O)OC)c2)ncc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1nc(Nc2cc(NC(=O)[C@@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc(C(=O)OC)c2)ncc1Br
Yield: 83.4 %

Procedure:
N-BOC-D-phenylalanine (3.3 g), 1-hydroxy-1H-benzotriazole hydrate(1.9 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimid hydrochloride (2.37 g) were stirred in DMF (30 ml) for 30 minutes Then methyl 3-amino-5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]benzoate (3.88 g) were added and the mixture stirred over night. Then ethyl acetate (500 ml) was added and the reaction mixture washed subsequently with hydrochloric acid (0.1 n), saturated NaHCO3-solution, water and brine. After drying (Na2SO4) the organic phase was evaporated and the residue subjected to column chromatography (ethyl acetate/dichloromethane) to yield 5.36 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)([CH3:20])[CH3:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH:18]([CH3:19])[CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(C)C)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.3 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.140 g, 0.0025 mol) and allowed to stir for 10 min at RT. 2-Isopropyl-5-vinyl-pyridine (0.185 g, 0.00125 mol) was added and stirred for further 4 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.027 g, 15% yield). 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.027 g, 0.00007 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.009 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.027 g, 81% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1/[CH:17]=[C:18](/[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])\[C:19]([O:21][CH3:22])=[O:20])C1C=CC=CC=1>CO.[Pd]>[C:27]([O:26][C:24]([NH:23][CH:18]([CH2:17][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[OH:8])[C:19]([O:21][CH3:22])=[O:20])=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: COC(=O)/C(=C\c1ccc(OC)cc1OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OC)cc1O)NC(=O)OC(C)(C)C
Yield: 74.6 %

Procedure:
350 mg of palladium-on-charcoal at 10% are added to a solution containing 1.5 g (3.5 mmol) of methyl (E)-3-(2-benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbonyl-amino)acrylate in 15 ml of methanol. After stirring for hours under a hydrogen atmosphere, the reaction medium is filtered through celite and the filtrate is evaporated off. 850 mg of methyl 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoate are obtained in the form of a grey powder with a yield of 74%.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)CCC.N1C=CC=C(B(O)O)C=1.ClC1C(=O)[C:40](C#N)=[C:41](C#N)[C:42](=[O:45])[C:43]=1Cl.N1C2C(=CC=CC=2)C=CC=1>>[OH:45][C:42]1[CH:43]=[C:19]2[C:14](=[CH:40][CH:41]=1)[N:15]=[CH:16][CH:17]=[CH:18]2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: OB(O)c1cccnc1
Solvent: c1ccc2ncccc2c1
Product: Oc1ccc2ncccc2c1

Procedure:
A trifluoromethanesulfonate derivative may be produced by reacting a 7-benzyloxy-4-chloroquinoline derivative with a suitable reducing agent, for example, hydrogen gas/palladium hydroxide to give an alcohol (step (i) above) and then reacting the alcohol with trifluoromethanesulfonic anhydride (step (ii) above) to give a trifluoromethanesulfonate derivative. A quinoline derivative may be produced by reacting the trifluoromethanesulfonate derivative with an alkyltin reagent, for example, tri-n-butyl-(2-pyridyl)-tin or an alkylboronic acid reagent, for example, 3-pyridylboronic acid in the presence of a suitable transition metal catalyst, for example, tetrakis triphenylphosphine palladium (step (iii) above) and reacting the resultant compound with a suitable oxidizing agent, for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, to give a quinoline derivative (step (iv) above). Next, a 6-hydroxyquinoline derivative may be produced by reacting the quinoline derivative with a suitable reagent, for example, boron tribromide (step (v) above). The contemplated compound may be produced by reacting the 6-hydroxyquinoline derivative with a 4-chloroquinoline derivative or a corresponding quinazolone derivative in a suitable solvent, for example, o-dichlorobenzene, or in the absence of a solvent, for example, at 120 to 180° C. (step (vi) above).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][N:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:37]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)[CH2:32][C:33]1[CH:34]=[N:35][N:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:37]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2cnn(-c3ccccc3)c2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2cnn(-c3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 72.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.85 g) and (4-isopropylphenyl)[(1-phenylpyrazol-4-yl)methyl]amine (0.87 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.21 g) was obtained.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:37])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:35])([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][OH:26])=[CH:27][CH:28]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:37])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(O)(c1ccc(C=O)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(CO)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
NaBH4 (0.00413 mol) was added portionwise at 0° C. to a mixture of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6 quinolinyl]hydroxy (1-methyl-1H-imidazol-5yl)methyl]benzaldehyde (described in Example B6).(0.00207 mol) in THF (10 ml). The mixture was stirred at 0° C. for 30 minutes, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 90/10/0.5; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.5 g (50%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(hydroxymethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, mp. 273° C.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccn2)CC1
Temperature: 150 °C

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (5.0 g, 25.0 mmol) (Aldrich) and 2-bromopyridine (1.98 g, 12.50 mmol) (Aldrich) were combined in a sealed tube and heated at 150° C. for 12 hours. The mixture was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.48(m, 9H), 1.88–2.02(m, 2H), 3.20–3.48(m, 2H), 3.52–3.70(m, 4H), 3.72–3.83(m, 2H), 6.45–6.59(m, 2H), 7.47(m, 2H), 8.11–8.18(m, 1H); MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:19]1[O:23][C:22](=[O:24])[CH2:21][CH2:20]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.CN1C(=O)N(C)CCC1>[C:1]([NH:8][C@H:9]([C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:20]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](Cc3ccccc3)C(=O)O2)cc1

Procedure:
In analogy with Example 5d), 4.17 g (12.44 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl]dihydrofuran-2-(3H)-one, dissolved in 22.4 ml of THF and 2.5 ml of DMPU, are deprotonated, at -70° C., with 24 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated (-75° C., 1 h) with 1.5 ml (12.44 mmol) of benzyl bromide. Protonation, at -75° C., with 4.6 ml of propionic acid and 4.6 ml of water, extraction and column chromatography (SiO2, methylene chloride/ether 25:1) yields the title compound: TLC Rf (C)=0,74; tRet (II)=16.6 min; FAB-MS (M+H)+ =426.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][C:3]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[N:6]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:13][CH2:14]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
20.2 g bromacetylbromide was dropped to 16.5 g 1-pyrimidin-2-yl-piperazin and 10.2 g triethylamine in 250 mL THF. The reaction mixture was stirred overnight at RT and evaporated. The residue was extracted with DCM and water. The organic layer was evaporated and the residue was crystallized with petrolether and then purified by chromatography on silica gel (DCM/MeOH:95/5) to yield 8.9 g of the desired compound.
Reaction SMILES: CS(NC1C=CC([CH2:10][N:11]([CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=3)[CH2:14]2)C)=CC=1)(=O)=O>C(O)C.[Pd]>[CH3:26][S:23]([NH:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([NH:11][CH3:10])[CH2:21]2)(=[O:25])=[O:24]
Reactant: CN(Cc1ccc(NS(C)(=O)=O)cc1)C1Cc2ccc(NS(C)(=O)=O)cc2C1
Agent: [Pd]
Solvent: CCO
Product: CNC1Cc2ccc(NS(C)(=O)=O)cc2C1
Reaction time: 2 h

Procedure:
2-[N-(4-Methanesulphonamidobenzyl)-N-methylamino]-5-methanesulphonamidoindane (0.175 g) in ethanol (20 ml) containing 5% Pd/C (0.02 g) was stirred under a hydrogen atmosphere [275.8 kPa (40 p.s.i.)] for 31/2 hours at 40°. The catalyst was then removed by filtration and the filtrate evaporated to dryness in vacuo to give the title compound as an oil, yield 0.09 g, which was used directly without further purification.
Reaction SMILES: [C:1]([CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[C:23]3[C:24]4[C:16](=[C:17]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)([C:3]([O:5]C)=[O:4])=[O:2].[O-]CCCC.[K+].Cl>C(O)C.O>[C:1]([CH:7]1[CH2:8][CH2:9][N:10]([CH:13]2[C:23]3[C:24]4[C:16](=[C:17]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[CH2:11][CH2:12]1)([C:3]([OH:5])=[O:4])=[O:2]
Reactant: COC(=O)C(=O)C1CCN(C2CCc3c(-c4ccccc4)[nH]c4cccc2c34)CC1
Agent: CCCC[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)C1CCN(C2CCc3c(-c4ccccc4)[nH]c4cccc2c34)CC1
Yield: 73.1 %

Procedure:
A portion (0.17 g) of the compound obtained in Example 157 was dissolved in ethanol/water (4:1) (80 ml) and to the solution was added potassium butoxide (t-BuOK; 48 mg). The mixture was heated to reflux for 30 minutes. The reaction mixture was adjusted to pH 5 by addition of 1N hydrochloric acid. Thereafter, the solvent was distilled off under reduced pressure. The residue was crystallized from ethanol and water to yield 0.12 g (73%) of the titled compound.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]([NH:8][C:9]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][C:17]=2[O:24][CH3:25])=[C:13]([CH3:26])[N:12]=[C:11]([NH2:27])[N:10]=1)[CH2:5][CH2:6][CH3:7]>CN(C=O)C.CS(C)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:27][C:11]1[N:10]=[C:9]([NH:8][CH2:4][CH2:5][CH2:6][CH3:7])[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:1]#[N:2])=[CH:18][C:17]=2[O:24][CH3:25])=[C:13]([CH3:26])[N:12]=1
Reactant: [C-]#N
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1OC
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
KCN (0.844 g) was added to a stirred solution of the product from step (iv) (2.78 g) in DMF (10 mL) and DMSO (10 mL). The mixture was stirred at rt for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and sat. NaHCO3 (100 mL). The organic phase was separated, dried and solvent removed to give the subtitle compound as a solid, 2.2 g.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH2:32]([O:34]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:33].Cl>C1(C)C=CC=CC=1>[CH3:26][C:21]1[CH:20]=[C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:31])([F:30])[F:1])=[CH:13][C:14]=2[CH2:27][CH2:28][CH3:29])[CH:24]=[CH:23][C:22]=1[C:32](=[O:34])[CH3:33]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(I)c(C)c1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C(C)=O)c(C)c1
Yield: 87 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(4-iodo-3-methylphenoxy)-2-propylbenzene (393 mg, 0.699 mmol) in toluene (7.0 mL), ethoxyvinyltributyl tin (473 μL, 1.40 mmol) and tetrakis triphenylphosphine palladium (162 mg, 0.140 mmol) were added sequentially, and the resultant mixture was heated to reflux for 1 hour. Then, ethoxyvinyltributyl tin (946 μL, 2.80 mmol) was added and heated to reflux for 1.5 hours. After completion of the reaction, 5% aqueous solution of hydrochloric acid was added under ice-cold conditions, and the resultant mixture was stirred overnight. The reaction solution was filtered using celite and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate), and 1-{2-methyl-4-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-phenyl}-ethanone (291 mg, yield 80%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[O:14])[CH:10](C)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C(=O)C(=O)C(C2C=CC=CC=2)N1)C1C=CC=CC=1.C(N1C(=O)C(=O)C(C2C=CC(C)=CC=2)N1)C1C=CC=CC=1.C(N1C(=O)C(=O)C(C2C=CC=C(OC)C=2)N1)C1C=CC=CC=1.C(N1C(=O)C(=O)C(C2C=CC(OC)=CC=2)N1)C1C=CC=CC=1.C(N1C(=O)C(=O)C(C2C=CC=C([N+]([O-])=O)C=2)N1)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[O:14])[CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1NN(Cc2ccccc2)C(=O)C1=O
Agent: COc1ccc(C2NN(Cc3ccccc3)C(=O)C2=O)cc1
Agent: COc1cccc(C2NN(Cc3ccccc3)C(=O)C2=O)c1
Agent: Cc1ccc(C2NN(Cc3ccccc3)C(=O)C2=O)cc1
Product: O=C1CNN(Cc2ccccc2)C1=O

Procedure:
1-benzyl-3-methyl-4,5-pyrazolinedione; 1-benzyl-3-phenyl-4,5-pyrazolinedione; 1-benzyl-3-(4′-methylphenyl)-4,5-pyrazolinedione; 1-benzyl-3-(3′-methoxyphenyl)-4,5-pyrazolinedione; 1-benzyl-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-benzyl-3-(3′-nitrophenyl)-4,5-pyrazolinedione;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[I:8].C(O)=O>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: Fc1cc(C2CCC3(CC2)OCCO3)ccc1I
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: O=C1CCC(c2ccc(I)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
128.0 g of 8-(3-fluoro-4-iodophenyl)-1,4-dioxaspiro-[4.5]decane and 320 ml of formic acid were dissolved in 750 ml of toluene and stirred at 25° C. overnight, the HCOOH phase was run off, diluted with 2 1 of water and extracted twice with toluene, and the toluene phases were washed with water and sodium hydrogencarbonate solution until neutral, dried and evaporated. The crude product was recrystallized at -25° C. from 100 ml of hexane containing a few drops of ethyl acetate, giving 4-(3-fluoro-4-iodophenyl)cyclohexanone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH2:6]1.C(N(CC)CC)C.O1CCOCC1.Cl[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][C:27]=1[N+:36]([O-:38])=[O:37]>CN(C)C(=O)C>[N+:36]([C:27]1[CH:28]=[C:29]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:30]=[CH:31][C:26]=1[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH2:6]1)([O-:38])=[O:37]
Reactant: NCCCN1CCNC(=O)C1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(NCCCN2CCNC(=O)C2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
4-(3-Amino-propyl)-piperazin-2-one (3.45 g) and triethylamine (5.18 mL, 3.76 g) were added to 1,4-dioxane (100 mL) and N,N-dimethylacetamide (20 mL) and mixed until dissolved. 4-Chloro-3-nitrobenzenesulfonamide (4.00 g) was added, and the mixture was heated to 90° C. for 16 hours. The mixture was cooled and the solvent was removed under vacuum. The material purified by recrystallization from 20% methanol in dichloromethane with subsequent washing of the recrystallized solid with 10% methanol in dichloromethane followed by washing with 100% dichloromethane.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[OH:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]#[N:34]>CC(C)=O.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH2:32][C:33]#[N:34]
Reactant: N#CCBr
Reactant: Oc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: N#CCOc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a stirred solution of 6-(1-benzofuran-2-yl)-4-hydroxy-2-(trifluoromethyl)quinoline (0.770 g, 2.34 mmol) in acetone (40 mL) at room temperature was added Cs2CO3 (0.839 g, 2.57 mmol) followed by bromoacetonitrile (0.326 mL, 4.68 mmol) dropwise. The reaction was stirred at this temperature for 18 hours and then diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was recrystallized from EtOAc:Hexane to afford the product (0.711 g, 82%) as a off-white solid, mp 174-176° C. Mass spectrum (+APCI, [M+H]+) m/z 369. 1H NMR (500 MHz, DMSO-d6): δ 8.61 (d, 1H, J=2.0), 8.48 (dd, 1H, J=2.0, 8.8 Hz), 8.23 (d, 1H, J=8.8 Hz), 7.78 (s, 1H), 7.70-7.75 (m, 2H), 7.67 (s, 1H), 7.39 (t, 1H, J=7.2 Hz,), 7.30 (t, 1H, J=7.6 Hz), and 5.70 ppm (s, 2H), Elemental analysis for C20H11F3N2O2: Calculated: C, 65.22; H, 3.01; N, 7.61. Found: C, 65.02; H, 2.87; N, 7.51.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[Br:16]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:16][CH2:2][C:1]([C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:8]=1[CH3:9])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1nc(-c2ccccc2)oc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Temperature: 55 °C
Yield: 86.8 %

Procedure:
To a stirred solution of 4-acetyl-5-methyl-2-phenyloxazole (12.0 g) in chloroform (100 ml) was added at 50° C. a solution of bromine (10.5 g) in chloroform (10 ml). The mixture was further heated at 55° C. for 30 minutes and poured into saturated aqueous sodium bicarbonate solution (500 ml). The chloroform layer was separated and the aqueous layer was extracted with chloroform. The conbined chloroform layer was washed with water and dried (MgSO4). Evaporation of the solvent gave 4-bromoacetyl-5-methyl-2-phenyloxazole as crystals (14.5 g, 86.3%). Recrystallization from ethyl ether-hexane gave colorless rods, mp 88°-89° C.