Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=2)[CH:4]=[N:3]1>CO.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=2)[NH2:17])[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cn1
Agent: [Pd]
Solvent: CO
Product: Cn1cc(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reaction time: 12 h
Yield: 90 %

Procedure:
To a suspension of 1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (300 mg, 1.106 mmol) in MeOH (10 mL) was added Pd/C (118 mg, 1.106 mmol). The mixture was hydrogenated at 40 psi at 28° C. for 12 h under a H2 atmosphere. Then the solution was filtered and concentrated to yield 3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (240 mg, 0.995 mmol, 90% yield). TLC (PE/EA=1:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.81 (s, 1H), 7.16 (d, J=7.3 Hz, 2H), 6.88 (s, 1H), 3.92 (s, 3H). ES-LCMS m/z 242 (M+H).
Reaction SMILES: [C:1]1([NH:7]/[C:8](/[CH3:13])=[CH:9]\[C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](#[N:17])[CH2:15][CH3:16]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:15]([C:14]1[C:9]([C:10](=[O:12])[CH3:11])=[C:8]([CH3:13])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:17]=1)[CH3:16]
Reactant: CCC#N
Reactant: CC(=O)/C=C(/C)Nc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccccc2)c(C)c1C(C)=O

Procedure:
According to AVV A, (Z-4-phenylaminopent-3-ene-2-one (175.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. After the brown oily raw product (157.3 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 94:6→0:100), the desired product was obtained in the form of a yellow oil (57.2 mg, 0.25 mmol, 25%).
Reaction SMILES: [NH:1]=[C:2]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:3]>C(Cl)(Cl)Cl>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:1]=[C:2]([CH3:3])[NH:4][N:5]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)NNC(C)=N)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2n[nH]c(C)n2)cc1

Procedure:
33.6 g (162 mmol) 4-methoxy-benzoic acid N′-(1-imino-ethyl)-hydrazide are heated to 180° C. for 30 minutes. After cooling the solidified melt is dissolved in 250 mL chloroform and repeatedly extracted with aqueous sodium hydroxide solution. The aqueous phases are combined, washed with chloroform, filtered and adjusted to an acid pH by the addition of glacial acetic acid. The precipitated solid is suction filtered, washed with water and dissolved by heating in chloroform. The solvent is evaporated down and the residue is filtered. The solid is washed with chloroform and diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[CH2:11][CH:12]=O.O>CC(O)C>[Br:9][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]2[N:3]([CH:11]=[CH:12][N:1]=2)[CH:4]=1
Reactant: O=CCCl
Reactant: Nc1cc(Br)cnc1N
Solvent: O
Solvent: CC(C)O
Product: Nc1cc(Br)cn2ccnc12
Yield: 93.6 %

Procedure:
2,3-diamino-5-bromopyridine (10.0 g, 45.86 mmol) was dissolved in 80 ml of IPA and then 50% wt chloroacetaldehyde/H2O (6.51 ml, 50.45 mmol) was added. The resulting mixture was heated at reflux for 24 hrs. The mixture was cooled down and then filtered. The cake was dried to afford 9.10 g of product.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:20]1[CH2:22][CH2:21]1)[O:5][C:6]1[C:7]([Cl:19])=[N:8][C:9]([Cl:18])=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH:20]1([CH:4]([O:5][C:6]2[C:7]([Cl:19])=[N:8][C:9]([Cl:18])=[N:10][C:11]=2[N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:3][OH:2])[CH2:22][CH2:21]1
Reactant: COC(=O)C(Oc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCC(Oc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of cyclopropyl-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid methyl ester (233 mg, 0.64 mmol) in THF (6.5 mL) at −78° C. under an atmosphere of nitrogen was added DIBAL-H (1.93 mL, 1.93 mmol, 1.0M in toluene) dropwise. The reaction mixture was warmed to RT and stirred for 20 hours before being quenched with Rochelle's salt (15 mL, 1M aqueous solution). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic phases were dried (Na2SO4) then concentrated in vacuo to give 2-Cyclopropyl-2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethanol as a colorless gum (215 mg, quantitative). 1H NMR (CDCl3): δ 3.94-3.88 (2H, m), 3.87-3.82 (4H, m), 3.79-3.73 (4H, m), 3.48-3.41 (1H, m), 1.11-0.99 (1H, m), 0.60-0.51 (1H, m), 0.51-0.42 (1H, m), 0.19-0.11 (1H, m), 0.03-−0.05 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]O)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:23])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][F:23])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1nc(CO)cs1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nc(CF)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of 1.0 g of the above-obtained 2-(tert-butoxycarbonylamino)methyl-4-hydroxymethylthiazole in 20 ml of dichloromethane was added 0.6 ml of diethylaminosulphur trifluoride with ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To this reaction solution was added 20 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (10 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 50:1 mixture of chloroform and methanol to give 0.535 g (yield 47%) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]([NH:26][NH:27][C:28](=O)[CH2:29][C:30]1([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]1)=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:28]([CH2:29][C:30]2([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:32][CH2:31]2)=[N:27][N:26]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 67.5 %

Procedure:
Pyridine (5.2 g, 65.6 mmol) was added to a 0° C. solution of tert-butyl 1-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclopropylcarbamate (4.0 g, 8.2 mmol) in DCM (40 mL). Tf2O (5.7 g, 20.5 mmol) was added slowly at 0° C. The reaction mixture was stirred at 0° C. for 3.5 hrs. Sat. NaHCO3 was added very slowly at 0° C. The organic layer was separated and washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (0˜70% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclopropylcarbamate (2.6 g, 65%) as a yellow solid. ESI-MS (EI+, m/z): 470 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13]([C:15]1[S:19][N:18]=[CH:17][CH:16]=1)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][OH:30])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[S:19]1[C:15]([C:13]23[CH2:12][N:4]([C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[CH2:1][CH:2]2[CH2:3][O:30][N:29]3[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:16][CH:17]=[N:18]1
Reactant: C=CCN(CC(=O)c1ccns1)C(=O)OC(C)(C)C
Reactant: COc1ccc(CNO)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN2OCC3CN(C(=O)OC(C)(C)C)CC32c2ccns2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (610.1 g, 2.16 mol) is dissolved in toluene (6.10 L) under an atmosphere of nitrogen. N-[(4-methoxyphenyl)methyl]hydroxylamine (532.68 g, 2.81 mol) is added followed by diisopropylethylamine (489.86 mL, 2.81 mol). Ti(OEt)4 (640.78 g, 2.81 mol) is added and the yellow reaction solution is heated to 100° C. with stirring for 2 hours. The reaction is cooled to room temperature and diluted with ethyl acetate (3.05 L). A solution of citric acid 50% w/w in water (5.49 L) is added. A solid precipitates which then re-dissolves on stirring. The biphasic mixture is separated and the aqueous layer is extracted with ethyl acetate (2×1 L). The combined organic layers are washed with water (2×2 L), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue is dissolved in ethyl acetate (3 L) and concentrated under reduced pressure again. The crude product is triturated in ethyl acetate (1.2 L) and isohexane (4.8 L) for 40 minutes. The suspension is filtered and washed with hexane (4 L). The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours to give the title product (741.51 g, 82.2%). ES/MS (m/e): 418 (M+H). The mother liquor from the trituration is concentrated under reduced pressure to give a brown solid, which is re-crystallized from methanol (150 mL) to obtain a second crop of product as a off-white solid, (26.02 g, 62.32 mmol, 2.9% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[I:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[S:16]>C(O)C>[I:11][C:12]1[CH:13]=[C:14]([C:15]2[S:16][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[N:17]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=S)c1cccc(I)c1
Solvent: CCO
Product: Ic1cccc(-c2nc(-c3ccccn3)cs2)c1
Yield: 41.5 %

Procedure:
A solution of 2-bromoacetylpyridine (400 mg, 2.0 mmol) in ethanol (5 mL) was treated with 3-iodothiobenzamide (1.2 g, 6 mmol) and the mixture heated at reflux for 16 hours. After cooling the mixture was concentrated in vacuo. Silica gel chromatography of the residue using a gradient of hexane to ethyl acetate afforded 302 mg (55%) of 2-(3-iodophenyl)-4-(pyridin-2-yl)-1,3-thiazole, as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1C(=O)c1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
To a solution of 5-acetamidoindane (1.0 g, 5.7 mmol) and benzoyl chloride (732 mL, 6.3 mmol) in 15 mL of CH2Cl2 at 0° C. was added AlCl3 (1.52 g, 11.4 mmol) as a solid. The mixture was stirred to rt overnight. A spatula full of AlCl3 was added and the mixture heated to reflux for 3 days. The solution was then poured into a mixture of concentrated HCl and ice, and stirred. The mixture was then diluted with water and extracted with 2×50 mL of CH2Cl2. The extract was washed with brine, then dried over MgSO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography eluting with EtOAc/hexane to give the title compound (200 mg, 13%). 1H NMR (CDCl3): 10.95 (s, 1H), 8.50 (s, 1H), 7.68 (d, 2H), 7.59 (t, 1H), 7.49 (t, 2H), 7.37 (s, 1H), 2.99 (t, 2H), 2.83 (t, 2H), 2.22 (s, 3H), 2.10 (p, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N>>[F:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:14][OH:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Agent: N
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CO

Procedure:
The title compound was prepared as described in Example 53A substituting (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid for (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid. MS (DCI/NH3) m/z 220 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)cc(F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 5.8 g (30.5 mmol) of 2,4,5-trifluoro- 6-methylbenzoic acid, 4.7 g (37.0 mmol) of oxalyl chloride, and 100 mL of dichloromethane was treated with three drops of DMF. The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give 6.3 g of the title compound as an oily solid. The product was used "as is" in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=2)([NH:14][C:15]([NH2:17])=[S:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.Cl[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([F:28])[CH:19]=2)([NH:14][C:15]2[S:16][C:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[N:17]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: O=C1CCCCC1Cl
Reactant: COC(=O)C[C@](NC(N)=S)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Solvent: CO
Product: COC(=O)C[C@](Nc1nc2c(s1)CCCC2)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Yield: 11 %

Procedure:
A solution of (S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-thioureidopropanoate (100 mg, 0.23 mmol) and 2-chloro cyclohexanone (36 mg, 0.28 mmol) in MeOH (5.0 mL) was heated at 70° C. for 18 h. The concentrated reaction mixture was purified by silica gel ISCO chromatography (12 g column) using hexanes/EtOAc (0-30% over 15 min). (S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylamino)propanoate was isolated as a clear oil, (13 mg, 11% yield). LCMS: 1.70 min [M+1] 514.3 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.65 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 96%; NMR: 400 MHz 1H (CDCl3) 8.43 ppm, 1H, d, J=2.20 Hz; 7.55 ppm, 1H, dd, J=8.57, 2.42 Hz; 7.49 ppm, 1H, s; 7.29 ppm, 2H, m; 7.14 ppm, 1H, d, J=7.91 Hz; 3.98 ppm, 1H, d, J=15.82 Hz; 3.70 ppm, 1H, d, J=15.82 Hz; 3.60 ppm, 1H, s; 3.47 ppm, 3H, s; 2.40 ppm, 4H, m; 1.68 ppm, 4H, m.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[NH:11][CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[N:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[CH:18]([N:14]([CH:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][NH:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][N:6]=1)=[O:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(C(=O)NCCN(C(C)C)C(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(CCNC(=O)c1ccc(C(=O)O)cn1)C(C)C
Yield: 88.9 %

Procedure:
To a solution of 1100 mg (3.6 mmol) 6-(2-diisopropylamino-ethylcarbamoyl)-nicotinic acid methyl ester in 10 ml THF and 3.0 ml MeOH was added 3.6 ml of an 2N aqueous NaOH solution. After 4 h at rt the solvent was evaporated. The residue was acidified with 1N HCl, filtered off and washed with water to give 936 mg (3.2 mmol) 6-(2-diisopropylamino-ethylcarbamoyl)-nicotinic acid; exact MW [M+H] calc'd: 294.18; MW .found [M+H]: 209.15.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:22][CH3:23])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[C:15]([CH3:21])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:36][CH2:37][C:38](=[O:41])[CH2:39][CH3:40]>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:11][CH3:12])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:38]([CH2:39][CH3:40])([OH:41])[CH2:37][CH3:36])=[C:15]([CH3:21])[CH:14]=2)[CH2:22][CH3:23])=[CH:6][C:5]=1[CH3:24]
Reactant: CCC(=O)CC
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C)CC
Yield: 70.7 %

Procedure:
4-[1-Ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-benzoic acid methyl ester (2.50 g, 7.47 mmol), lithium hexamethyldisilazide (8.22 ml, 8.22 mmol, 1.0 M in THF) and 3-pentanone (870 μL, 8.22 mmol) are reacted and purified analogous to Example 1H to give the title compound (2.22 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCOCC>[Cl:1][C:2]1[C:3]([O:13][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)Oc1nc(C(Cl)(Cl)Cl)nc(C)c1Cl
Yield: 80.8 %

Procedure:
To a solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.0 g (0.02 mole) triethylamine, and 100 ml ether was added 2.2 g (0.02 mole) ethyl chloroformate. An immediate reaction ensued and a precipitate formed. After refluxing 2 hours longer the mixture was filtered, and the filtrate was washed with aqueous potassium carbonate and then with water. Rotary evaporation yielded 5.4 g residue which was recrystallized from ligroin to give 4.6 g (69% yield) of pure product (mp 43.5°-44.5° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](OC)=[O:25])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1.CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=[O:25])[CH2:20][CH2:19]2)=[CH:28][CH:29]=1
Reactant: COC(=O)C1CCN(Cc2ccc(OC)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(CN2CCC(C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1.5 M solution of diisobutylaluminium hydride in toluene (3.12 ml, 4.68 mmol) was added dropwise under argon at −78° C., in the course of 30 minutes, to a solution of methyl 1-(4-methoxybenzyl)piperidine-4-carboxylate (1.23 g, 4.68 mmol) in toluene (30 ml), and stirring was then carried out for 30 min at that temperature. Methanol (15 ml) was then added dropwise in such a manner that the internal temperature remained at −78° C., before the mixture was then slowly warmed to room temperature. Saturated sodium chloride solution (20 ml) was added to the reaction mixture, and the suspension was filtered through sea sand. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (1:3).
Reaction SMILES: [OH-].[K+].[Br:3][CH2:4][CH2:5]Br.[C:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:10])([CH3:9])[CH3:8].O>CO.C(Cl)(Cl)Cl>[C:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:5][CH2:4][Br:3])=[CH:16][CH:17]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)Oc1ccc(O)cc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)Oc1ccc(OCCBr)cc1
Yield: 29.3 %

Procedure:
A solution of KOH (0.224 g, 4 mmol) in MeOH (3 mL) was added, over the course of 30 min, to a warmed (70° C.) mixture of 1,2-dibromoethane (3 g, 0.016 mol) and 4-(tert-butoxy)phenol (0.66 g, 0.004 mol). The mixture was stirred at 70° C. for 15 h before water and CHCl3 were added. The layers were separated, the organic layer washed with 10% aqueous NaOH and then dried (Na2SO4) and concentrated in vacuo to give 0.32 g (28%) of the sub-title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7]O[C:5](=O)[CH:4]=1.[C:16]1(=[O:23])C=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1>ClC1C=CC=CC=1Cl.C(Cl)(Cl)Cl.O=[Mn]=O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:20](=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[C:19](=[O:22])[CH:18]=[CH:17][C:16]2=[O:23]
Reactant: O=c1cc(C(F)(F)F)c(C(F)(F)F)co1
Reactant: O=C1C=CC(=O)C=C1
Agent: O=[Mn]=O
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: O=C1C=CC(=O)c2cc(C(F)(F)F)c(C(F)(F)F)cc21

Procedure:
23.47 g (0.1011 mol) of 4,5-bis-trifluoromethyl-2-oxo-2H-pyran, 54.62 g (0.5053 mol) of 1,4-benzoquinone and 26.30 g (0.3026 mol) of MnO2 in 225 ml of 1,2-dichlorobenzene are heated at 180° C. for 12 hours. The reaction mixture is then diluted with 200 ml of CHCl3 and filtered through Hyflo®. After the chloroform has been removed by distillation, the distillation residue is chromatographed over a column packed with 1300 g of SiO2 (mobile phase: first cyclohexane and then CHCl3 ; 0.3 bar excess pressure). Yield 17.94 g (60.3%), melting point: 91°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]([CH2:14][C@H:15]([NH2:17])[CH3:16])[C:13]=3[C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][C@H:15]([NH:17][C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[CH3:16])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)N)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ccc3ccn(C[C@@H](C)NC(=O)C(F)(F)F)c3c2c1
Yield: 59.1 %

Procedure:
A solution of 1.2 g of (R)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethylamine, 0.52 g of triethylamine and 0.83 g of ethyl trifluoroacetate in 50 ml of anhydrous methanol was stirred at room temperature for 27 hours. After the solvent had been drawn off in a vacuum, the residue was taken up with 70 ml of anhydrous dioxane, 1.8 g of DDQ were added and the mixture was boiled under reflux for 1.5 hours, Subsequently, the reaction mixture was concentrated in a vacuum and the residue was purified by column chromatography on silica gel (dichloromethane/acetone 4:1). 0.97 g (59%) of (R)-N-[2-(8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethyl]-trifluoroacetamide was obtained as a pale brown solid which was used in the next reaction without additional recrystallization.