Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH3:19])[C:10](=[O:20])[C:9]([C:21]([OH:23])=O)=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:26])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH3:19])[C:10](=[O:20])[C:9]([C:21]([Cl:26])=[O:23])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)n(C)c2cc1OC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)n(C)c2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-1-methyl-1,2-dihydro-2-oxoquinoline-3-carboxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in 40 mL of benzene, and the solvent was distilled off. Benzene (30 mL) was added to the residue and the benzene was distilled off again, followed by vacuum drying, to yield 6,7-diacetoxy-1-methyl-1,2-dihydro-2-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](I)[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:7][CH2:2][CH2:3][CH3:4])[N:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCI
Reactant: CCOC(=O)c1c(O)cc(O)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cc(OCCCC)c(C(=O)OCC)c(C(F)(F)F)n1
Yield: 198.8 %

Procedure:
A mechanically stirred mixture of 22.6 g (0.09 mol) of product of Example 1, 99 g of butyl iodide, 24.84 g of potassium carbonate and 250 ml of acetone was held at reflux for 26 hours and filtered. The acetone filtrate was concentrated and the residue was dissolved in ether. The ether solution was washed with water, dried, and concentrated. The residue was kugelrohr distilled at 0.3 torr to give 32.5 g (99%) of product, nD25 1.4543.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=O)=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1.F[B-](F)(F)F.C([O+](CC)CC)C.[CH2:26](N)[CH2:27][NH2:28]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[NH:28][CH2:27][CH2:26][N:9]=2)=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1
Reactant: NCCN
Reactant: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nn(C)c(C2=NCCN2)c1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 6 h
Yield: 28.7 %

Procedure:
1,3-Dimethyl-4-nitro-5-pyrazolecarboxamide (28 g, 0.15 mol) is added to a solution of 38 g (0.2 mol) of triethyloxonium fluoroborate in 250 ml of methylenedichloride. The mixture is stirred at 20° C. for six hours and evaporated in vacuo. The residue is dissolved in 200 ml of absolute ethanol and 18 g (0.3 mol) of ethylenediamine is added. The yellow solution is stirred overnight at 20° C. and the solvent is evaporated in vacuo. The residue is stirred in 300 ml of 2N hydrochloric acid and filtered from 11.5 g (41%) of recovered starting amide. The filtrate is made basic with sodium carbonate and extracted with methylenedichloride. Evaporation of the methylenedichloride gives 9 g of 2-(1,3-dimethyl-4-nitro-5-pyrazolyl)imidazoline, mp 143°-145° C. from ethyl acetate-pet ether.
Reaction SMILES: C(C[C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:10][C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)#N.[C:22]([OH:25])(=[O:24])[CH3:23].S(=O)(=O)(O)O>O>[O:21]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:23][C:22]([OH:25])=[O:24])[C:13]=2[O:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10]1
Reactant: CC(=O)O
Reactant: N#CCc1cccc2c(=O)cc(-c3cccc(F)c3)oc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cccc2c(=O)cc(-c3cccc(F)c3)oc12

Procedure:
A mixture of 4.6 g of 8-cyanomethyl-2-(3-fluorophenyl)-4H-benzopyran-4-one; 18 ml of glacial acetic acid and 18 ml of sulfuric acid in 418 ml of water was stirred 12 hours at room temperature and diluted with 200 ml of water. The resulting suspension was filtered and the solids washed with water, then dissolved in 170 ml of 5% aqueous sodium bicarbonate, filtered to removed insoluble solids and acidified by addition of 11 ml of concentrated sulfuric acid. The resulting precipitate was filtered and the solids washed with water and dried to give 4.4 g of 4-oxo-2-(3-fluorophenyl)-4H-1-benzopyran-8-acetic acid as a white solid: IR 1645 and 1700 cm-1 ; m.p. 208°-211° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:17][C:18]1[CH:22]=[C:21]([CH:23]2[CH2:25][CH2:24]2)[NH:20][N:19]=1>>[CH:23]1([C:21]2[NH:20][N:19]=[C:18]([NH:17][C:1]3[NH:2][C:6](=[O:7])[C:5]4[C:4]([CH:3]=3)=[CH:12][C:11]([O:13][CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=4)[CH:22]=2)[CH2:25][CH2:24]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1OC
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)[nH]c(=O)c2cc1OC

Procedure:
Similar procedure as described in example 2c was used, starting from 2-cyanomethyl-4,5-dimethoxy-benzoic acid and 3-amino-5-cyclopropylpyrazol to give 3-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dimethoxy-2H-isoquinolin-1-one. LC-MS: m/e 327 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-:12].[NH2:13][C@@H:14]([CH2:17][CH3:18])[CH2:15][OH:16]>C(O)C>[OH:16][CH2:15][C@@H:14]([NH:13][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-:12])[CH2:17][CH3:18]
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Reactant: CC[C@H](N)CO
Solvent: CCO
Product: CC[C@@H](CO)Nc1cc([N+](=O)[O-])c(C)c[n+]1[O-]
Yield: 57.5 %

Procedure:
2-Chloro-5-methyl-4-nitropyridine N-oxide (200 mg, 1.06 mmol, 1.0 equivalent) was dissolved in ethanol (1.5 mL). (S)-2-Aminobutanol (284 mg, 3.2 mmol, 3.0 equivalent) was then added and the resulting mixture was refluxed for 16 hours. The crude solution was then purified by reversed phase HPLC (acetonitrile/water/TFA) to afford the title compound as a brown solid (146 mg, 0.61 mmol, Rt(min) 3.787; FIA ES+ 241.8, ES− not observed).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([OH:25])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]#[N:44].O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:20]=[C:21]([F:33])[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[CH:23][C:24]=1[O:25][CH2:42][C:43]#[N:44])[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1cc(F)c(-c2cccc(F)c2)cc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Yield: 107 %

Procedure:
6-(Benzylthio)-1-(2,3′-difluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (528 mg, 1.120 mmol) was dissolved in DMF (2240 μl). Then potassium carbonate (155 mg, 1.120 mmol) was added followed by 2-bromoacetonitrile (86 μl, 1.232 mmol). The whole was stirred at rt for 1d. Water (1 mL) was added. White precipitate was collected with an aid of water, and dried to afford 2-((4-(6-(benzylthio)-2-oxoquinolin-1(2H)-yl)-3′,6-difluoro-[1,1′-biphenyl]-3-yl)oxy)acetonitrile (612 mg, 107% yield). m/z (ESI): [M+H]+=511.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.25 (s, 2 H) 5.14-5.31 (m, 2 H) 6.59 (d, J=8.80 Hz, 1 H) 6.71 (d, J=9.59 Hz, 1 H) 7.19-7.40 (m, 6 H) 7.44 (dd, J=8.80, 2.15 Hz, 1 H) 7.53-7.68 (m, 5 H) 7.81 (d, J=2.15 Hz, 1 H) 7.95 (br. s., 1 H) 7.99 (d, J=9.49 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[C:3]=1[N+:16]([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>O1CCCC1.Cl>[NH2:16][C:3]1[C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(C(=O)c2ccc(Cl)cc2)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(C(=O)c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of (5-methyl-4-nitroisoxazol-3-yl)-4-chlorophenylmethanone of Example Va (5.3 g, 20 moles) in tetrahydrofuran (THF) (100 ml) was added to a mixture of SnCl2 2H2O (27 g, 120 mmoles) in concentrated hydrochloric acid (35 ml) and THF (11 ml) over 1 hour. After warming to room temperature, the reaction mixture was poured into cold 10% sodium hydroxide (500 ml) with stirring and extracted with ethyl acetate. The extracts were washed with dilute sodium chloride and dried (sodium sulfate). Concentration gave 3.7 g (78%) of a solid, which was flash chromatographed (20% ethyl acetate:hexane) to yield 2.9 g (62%) of a solid, melting point 84°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([N:11]2[CH2:15][CH2:14][S:13][C:12]2=[S:16])=[O:10])=[CH:7][C:6]([C:17]([N:19]2CCS[C:20]2=S)=[O:18])=[CH:5][C:4]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29][C:28]1=[S:32])=[O:26].CN.C(O)(C)C.CO>ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:25]([N:27]2[CH2:31][CH2:30][S:29][C:28]2=[S:32])=[O:26])=[CH:5][C:6]([C:17]([NH:19][CH3:20])=[O:18])=[CH:7][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][S:13][C:12]1=[S:16])=[O:10]
Reactant: COc1c(C(=O)N2CCSC2=S)cc(C(=O)N2CCSC2=S)cc1C(=O)N1CCSC1=S
Agent: CN
Solvent: CC(C)O
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1cc(C(=O)N2CCSC2=S)c(OC)c(C(=O)N2CCSC2=S)c1

Procedure:
To a slurry of the trithiazolide 5 (27.1 g, 0.05 mol) in dichloromethane (600 mL), a mixture of 2 mL methylamine solution (40% wt in water, d=0.902) and isopropanol (30 mL) was added dropwise over 48 h. The reaction mixture was applied directly onto a gradient flash silica column (1-5% methanol in methylene chloride). The desired product was obtained as a thick, yellow oil, yield 7.5 g (71% based on the methylamine). 12.8 g of unreacted starting trithiazolide was recovered during the separation.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][C:24]2[N:28]([CH2:29][CH2:30][CH2:31][N:32]([CH3:41])[CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:27]3[CH:42]=[CH:43][C:44]([C:46](O)=[O:47])=[CH:45][C:26]=3[N:25]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.[S:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[CH2:54][CH2:55]N.N.CN=C=S>C(Cl)(Cl)Cl.CN(C)C=O.O1CCCC1.ClCCl>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][C:24]2[N:28]([CH2:29][CH2:30][CH2:31][N:32]([CH3:41])[CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:27]3[CH:42]=[CH:43][C:44]([C:46](=[O:47])[CH2:55][CH2:54][C:50]4[S:49][CH:53]=[CH:52][CH:51]=4)=[CH:45][C:26]=3[N:25]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: NCCc1cccs1
Reactant: COc1cc(Nc2nc3cc(C(=O)O)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1
Agent: CN=C=S
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3cc(C(=O)CCc4cccs4)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
Carbonyldiimidazole (10.5 mg, 1.3 eq) in solution in chloroform (0.2 ml) is added to a solution of 2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylic acid (24 mg, 1 eq) in a mixture of dimethylformamide (0.2 ml) and tetrahydrofuran (0.4 ml). The mixture is stirred for 15 hours at approximately 20° C. then thiophene-2-ethylamine (13 mg, 2 eq) in solution in tetrahydrofuran (0.1 ml) is added. After stirring for 15 hours at approximately 20° C., aminomethyl polystyrene resin (2 eq), TBD-methyl polystyrene resin (2 eq) and methylisothiocyanate polystyrene resin (4 eq) are added to the mixture diluted in dichloromethane. After stirring for 6 hours at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (27 mg, 90% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:4]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1ccnc(-c2cccc(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)aniline (130 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (216 mg) and diisopropylethyl-amine (0.26 ml) in dichloromethane (6.5 ml) was added 1-methyl-2-chloropyridinium iodide (216 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=4:1) to give N,N′-bis (tert-butoxycarbonyl) -N″- (3- (4-methoxypyridin-2-yl) phenyl) guanidine (240 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[N:9]2[CH2:16][CH2:17][CH2:18][Cl:19]
Reactant: ClCCCBr
Reactant: O=C1CCc2c(Cl)cccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(Cl)cccc2N1CCCCl

Procedure:
In the same manner as in Reference Example 1, 60% sodium hydride in oil was added portionwise to a solution of 5-chloro-3,4-dihydrocarbostyril in DMF, the resultant mixture was stirred for 30 minutes, 1-bromo-3-chloropropane was then added, and the resultant mixture was further stirred at 80°-90° C. for 8 hours. The DMF was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and dried (anhydrous magnesium sulfate), the chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-chloro-1-(3-chloropropyl)-3,4-dihydrocarbostyril as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[C:6](I)[CH:7]=1)#[N:2].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=1>CN(C)C=O.C(OCC)(=O)C.[Cu]I>[Br:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:6]2[CH:7]=[C:3]([C:1]#[N:2])[NH:4][CH:5]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: C#Cc1cccc(Br)c1
Reactant: N#Cc1cc(I)c[nH]1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(C#Cc2cccc(Br)c2)c[nH]1
Yield: 99 %

Procedure:
The dimethylformamide was vigorously deoxygenated with nitrogen gas before use in this reaction. To a solution of 2-cyano-4-iodopyrrole (2.30 g, 10.52 mmol) in dimethylformamide was added dichloropalladium(II) bistriphenylphosphine (185 mg), copper(I) iodide (50 mg) and finally triethylamine (3.85 mL). After stirring ten minutes, 1-bromo-3-ethynyl-benzene (2.38 g, 13.15 mmol) was added. This mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with 2% aqueous lithium chloride and 5% aqueous sodium chloride. The organic phase was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate/hexane) to afford 4-(3-bromo-phenylethynyl)-1H-pyrrole-2-carbonitrile as a yellow solid, 2.84 g, 99% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[CH2:20])=[N:17][CH:18]=1>>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:22])([F:11])[F:21])=[CH:18][N:17]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc(C(F)(F)F)cn1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1

Procedure:
In analogy to the procedure described for the synthesis example 25 (step 1), the title compound (4-isopropyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 309.2 [M+H]+) was prepared from 4-isopropylaniline instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[CH:14]=O)([O-:3])=[O:2].[CH3:16][O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:19])/[CH:20]=[CH:14]/[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: O=Cc1cc2cccnc2cc1[N+](=O)[O-]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc2cccnc2cc1[N+](=O)[O-]

Procedure:
7-Nitroquinoline-6-carbaldehyde (370 mg; 1.83 mmol) in toluene (10 ml) was treated with (methoxycarbonylmethylen)triphenylphosphoran (672 mg; 2.0 mmol) for 1 h at reflux temperature. The pure title compound crystallised after cooling the reaction mixture and adding TBME (470 mg; 78%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH2:21])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.[Li+].[OH-]>N1C=CC=CC=1.C1COCC1>[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH:21][C:8](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
Picolinoyl chloride hydrochloride (501 mg, 2.82 mmol) was added to a solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (324 mg, 1.41 mmol, Example 1, Step H) in pyridine (5 mL). The reaction was stirred at room temperature for 10 minutes, and the pyridine was removed in vacuo. The residue obtained was dissolved in THF (5 mL), treated with 2N LiOH (3 mL), and stirred for 20 minutes. THF was then removed in vacuo, and water (20 mL) was added. The solid formed was collected by filtration and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (389 mg, 82% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.17 (br s, 1H), 10.39 (s, 1H), 8.76 (d, 1H), 8.40 (d, 1H), 8.17-8.15 (m, 1H), 8.09 (dt, 1H), 7.87 (d, 1H), 7.71-7.68 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]=[C:6]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][C:7]1[C:8](=[O:12])[C:9]2[C:5]([C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)C(c1ccccc1)=CC2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(c1ccccc1)=C(Br)C2=O
Temperature: 25 °C
Yield: 65.6 %

Procedure:
5-Methoxy-3-phenyl-1H-inden-1-one (2.8 g, 11.85 mmol) obtained in Step 3 was placed into a flask and dissolved in CCl4 (20 mL). To the resulting solution, NBS (2.53 g, 14.22 mmol, 1.2 eq) and AIBN (280 mg, 10%/w) were added. The resulting mixture was allowed to reflux for 2 h. After cooling to room temperature, the reaction mixture was quenched with sat. Na2S2O3 (20 mL) extracted with CH2Cl2(20 mL×3). The organic layers were washed H2O and brine, dried over MgSO4 and concentrated in vacuo to give the desired product (2.45 g, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(O)cc1
Yield: 79.9 %

Procedure:
To a solution of 3.58 g (0.011 mol) of 4-(4-Benzyloxy-phenoxy)-butyric acid ethyl ester in 200 mL of ethanol was added 0.81 g of 5% palladium on carbon and the resulting mixture was shaken under 35 psi of hydrogen for 4 h. The resulting mixture was filtered through Magnesol® and concentrated in vacuo to provide 1.97 g of the phenol as a grey solid. Electrospray Mass Spec: 225 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[N:18]=[C:17]([CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[O:31][C:30]([CH3:37])([CH3:36])[CH2:29]3)[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[CH:16][C:17]([CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[O:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)=[N:18]1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(O)cc1
Reaction time: 18 h
Yield: 99.8 %

Procedure:
Palladium on carbon catalyst (5%, 400 mg) and 5-(4-(benzyloxy)phenyl)-1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazole (257.8 mg, 0.52 mmol) were taken in MeOH (10 mL) and stirred under a H2 atmosphere (balloon) for 18 h. The catalyst was removed by filtration and the solvent was removed under vacuum to give 211 mg (100%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:25].[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]#[C:17][S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:16])=[O:15])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)C#Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(C#Cc1ccc(Cl)cc1)N1CCNCC1
Yield: 182.1 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[2-(4-chlorophenyl)ethynesulfonyl]piperazine (500 mg) was treated with 4N hydrochloric acid in ethyl acetate to give a colorless solid of the title compound (380 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>>[CH:4]([C:6]1[N:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:3]
Reactant: CCOC(=O)c1cccnc1C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOC(=O)c1cccnc1C=O
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
In flame-dried glassware under N2 atmosphere, to a solution of 2,3-pyridinedicarboxylic acid diethyl ester (0.254 g, 1.14 mmol) in anhydrous tolune (5 mL) at -78° C. was added diisobutylaluminum hydride (DiBal) (1.48 mL, 1.48 mmol, 1M in tolune). After 30 minutes, additional DiBal (0.4 mL, 0.4 mmol, 1M in toluene) was added. After 15 minutes, the reaction mixture was quenched with methanol (2 mL)/saturated Na/K tartrate (40 mL) and extracted into EtOAc (3×50 mL). The combined organic extracts were washed with saturated NaHCO3 (2×50 mL), saturated brine (1×75 mL), dried over MgSO4, filtered, concentrated, and flash chromatographed (5 to 10% EtOAc/CH2Cl2 gradient) to provide 0.075 g of the title compound as a colorless oil (36.8%).