Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)(CCCC)C=O.[CH3:10][C:11]([CH3:19])([CH2:15][CH2:16][CH2:17][CH3:18])[C:12](=[O:14])[CH3:13].C[Mg]Br.[Br-].[Mg+2].C#C.[Br-]>>[CH3:13][C:12]([OH:14])([C:11]([CH3:19])([CH3:10])[CH2:15][CH2:16][CH2:17][CH3:18])[C:1]#[CH:2]
Reactant: CCCCC(C)(C)C(C)=O
Reactant: CCCCC(C)(C)C=O
Agent: C#C
Agent: C[Mg]Br
Agent: [Br-]
Product: C#CC(C)(O)C(C)(C)CCCC

Procedure:
The acetylenic alcohol intermediates are produced by reaction of the appropriate carbonyl compounds with an organometallic acetylene reagent, e.g. acetylene magnesium bromide. Typically, 2,2-dimethyl-n-hexaldehyde is contacted with acetylene magnesium bromide and the adduct hydrolyzed to afford 4,4-dimethyl-1-octyn-3-ol. The acetylenic alcohols in which the alcohol group is tertiary are obtained from the appropriate ketones. 2,2-Dimethyl-n-hexaldehyde, for example, is converted to 3,3-dimethyl-2-heptanone by reaction with methyl magnesium bromide followed by hydrolysis of the adduct and oxidation of the secondary alcohol group with chrominum trioxide. That ketone is then contacted with acetylene magnesium bromide and the adduct hydrolyzed to afford 3,4,4-trimethyl-1-octyn-3-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([NH:8][CH:9]=[C:10]2[C:15](=[O:16])OC(C)(C)OC2=O)[CH:7]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]2[C:7]=1[C:15](=[O:16])[CH:10]=[CH:9][NH:8]2
Reactant: CCCOc1ccc(F)cc1NC=C1C(=O)OC(C)(C)OC1=O
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)cc[nH]c12
Temperature: 25 °C
Yield: 60.6 %

Procedure:
5-[(5-Fluoro-2-propoxyphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (7.6 g, 23.5 mmol) was added to diphenyl ether (15 ml), and the mixture was heated using a mantle heater, and then kept under reflux for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (5 ml) and n-hexane (10 ml) were added. The resulting mixture was stirred and the resultant insoluble matter was collected by filtration. The filtrate was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 3.15 g of powdery dark brown 5-fluoro-8-propoxy-1H-quinolin-4-one (yield: 61%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[CH:14]1([C:19](O)([C:30]#[CH:31])[CH2:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[O:24][C:23](=[O:29])[CH:22]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(NC(C)C)(C)C.CN(C=O)C.[NH4+].[Cl-].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>[CH:14]1([CH:19]([CH2:20][C:21]2[O:26][C:25]([CH3:27])([CH3:28])[O:24][C:23](=[O:29])[CH:22]=2)[C:30]#[C:31][C:2]2[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH2:12][CH3:13])[CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: CCc1cc(Br)ccc1OCC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCc1cc(C#CC(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1OCC#N
Temperature: 90 °C
Yield: 61.6 %

Procedure:
To a solution (4-bromo-2-ethylphenoxy)acetonitrile (1.99 g, 8.33 mmol) in diisopropylamine (9 mL) and DMF (3 mL) was added 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (2.00 g, 7.57 mmol), PdCl2(PPh3)2 (211 mg, 4 mol %), CuI (115 mg, 8 mol %). The mixture was heated to 90° C. for 30 min before it was cooled down to room temperature. The reaction was diluted with aqueous NH4Cl, extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (10-50% EtOAc in hexanes) to give the product (1.9 g). 1H NMR (300 MHz, CDCl3) δ: 1.23 (t, J=12.07 Hz, 3H) 1.35-1.80 (m, 14H), 2.30 (m, 1H), 3.50 (m, 5H), 4.62 (s, 2H), 4.87 (s, 1H), 6.90 (d, J=2.54 Hz, 1H), 7.14 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:47])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[CH:25][CH:26]=3)[N:21]([C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)[CH:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:8][N:9]([CH3:47])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[CH:25][CH:26]=3)[N:21]([C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)[CH:20]=2)=[CH:17][CH:18]=1
Reactant: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCNCC4)ccc23)cc1
Reaction time: 15 h

Procedure:
Trifluoroacetic acid (0.2 mL) was added to a mixture solution of tert-butyl 4-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (4.1 mg, 7.6 μmol) in methylene chloride (0.2 mL) at room temperature. After stirring for 15 hours, the reaction solution was concentrated under reduced pressure. After adding ethyl acetate and saturated sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](B(O)O)=[C:8]([CH2:17][CH3:18])[CH:7]=2)=[CH:4][CH:3]=1.[C:21]([O-:24])(=[O:23])[CH3:22].[C:25]([O-:28])(=[O:27])[CH3:26].[C:29]([O-:32])(=[O:31])[CH3:30].C([O-])(=O)C.[Pb+4:37].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:21]([O-:24])(=[O:23])[CH3:22].[C:25]([O-:28])(=[O:27])[CH3:26].[C:29]([O-:32])(=[O:31])[CH3:30].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([Pb+3:37])=[C:8]([CH2:17][CH3:18])[CH:7]=2)=[CH:4][CH:3]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1[Pb+3]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
4′-Chloro-3,5-diethylbiphen-4-ylboronic acid (2.1 g, 0.007 mol) is added to a mixture of lead tetraacetate (3.67 g, 0.008 mol) and mercuric acetate (0.12 g, 5 mol %) in chloroform (15 ml) and the reaction mixture is stirred for 15 minutes at room temperature under an atmosphere of nitrogen, then stirred and heated at 40° C. for 4 hours. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and concentrated under reduced pressure to give an orange solid. Trituration with hexane (20 ml) affords a yellow solid which is dried under high vacuum. The solid is dissolved in chloroform (50 ml) and anhydrous potassium carbonate (11.6 g, 0.084 mol) is added. The suspension is stirred rapidly for 10 minutes, then filtered through plug of diatomaceous earth. The filtrate is concentrated under reduced pressure to give 4′-chloro-3,5-diethylbiphen-4-yllead triacetate (2.0 g) as a cream solid.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:22]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Temperature: 90 °C
Yield: 66 %

Procedure:
To a solution of pyrrolidine-1-carboxylic acid [4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]amide (775 mg) in ethanol (50 ml) were added electrolytic iron powder (505 mg), ammonium chloride (967 mg) and water (10 ml), followed by stirring to heat at 90° C. for 30 min. The reaction mixture was cooled down to room temperature, and filtered to remove an insoluble portion, which was then washed with water and N,N-dimethylformamide in this order. The filtrate was concentrated under a reduced pressure to give a residue, which was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which ethyl acetate (10 ml) was added, followed by allowing to stand at room temperature. After a solid precipitated, diethyl ether (30 ml) was added thereto, followed by stirring at room temperature for 2 hrs. The solid was filtered off, and dried under aeration to provide the titled compound (467 mg, 66.2%) as powder.
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)[CH2:3][CH2:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[O:21]=[C:22]1[NH:30][C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C@:23]21[CH2:44][C:33]1[CH:34]=[C:35]3[C:40](=[CH:41][C:32]=1[CH2:31]2)[N:39]=[CH:38][C:37]([CH:42]=O)=[CH:36]3.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[F:20][C:15]1[CH:14]=[C:13]([C@@H:2]([NH:1][CH2:42][C:37]2[CH:38]=[N:39][C:40]3[C:35]([CH:36]=2)=[CH:34][C:33]2[CH2:44][C@:23]4([CH2:31][C:32]=2[CH:41]=3)[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:30][C:22]4=[O:21])[CH2:3][CH2:4][C:5]([CH3:11])([CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: CCOC(=O)C(C)(C)CC[C@H](N)c1cc(F)cc(F)c1
Reactant: O=Cc1cnc2cc3c(cc2c1)C[C@@]1(C3)C(=O)Nc2ncccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)CC[C@H](NCc1cnc2cc3c(cc2c1)C[C@@]1(C3)C(=O)Nc2ncccc21)c1cc(F)cc(F)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of ethyl (5S)-5-amino-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate from Step A (˜82.0 mg, 0.289 mmol) and (7S)-2′-oxo-1′, 2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-3-carbaldehyde (91.0 mg, Intermediate 1) in dry chloroform (3 mL) was added HOAc (35 μL, 0.606 mmol). After 10 minutes, sodium triacetoxyborohydride (129 mg, 0.606 mmol) was added. After 80 minutes of stifling, the reaction mixture was diluted with DCM (30 mL) and saturated sodium bicarbonate (20 mL). The layers were separated and the aqueous layer was extracted once with DCM (20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue. This residue was applied to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—99:1 to 93:7. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound, which still contained about 30% of the methyl ester. MS: m/z=585 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7](N)[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N([O-])=O.[Na+].[K+].[CH2:23]([O:25][C:26]([S-:28])=[S:27])[CH3:24]>CO.O.Cl.CCOC(C)=O>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([S:28][C:26](=[S:27])[O:25][CH2:23][CH3:24])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(-c2ccccc2)c(C(F)(F)F)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=S)Sc1ccc(-c2ccccc2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-trifluoromethyl-biphenyl-4-ylamine (175 mg, 0.7377 mmol, 1 eq.) is dissolved in a mixture of CH3OH (0.75 mL), H2O (0.75 mL), and concentrated aqueous HCl (0.4 mL). This solution is cooled to 0° C. and a solution of NaNO2 (71 mg, 1.033 mmol, 1.4 eq.) dissolved in H2O (0.30 mL) is added slowly over 1 h, keeping the reaction temperature at 0° C. After this addition is complete, the reaction mixture is quickly added to a solution of O-ethyl-xanthic acid potassium salt (237 mg, 1.475 mmol, 2 eq.) in H2O (0.70 mL) which has been pre-heated to 65° C. This reaction mixture is stirred at 65° C. for 15 min. After cooling to room temperature, the reaction is diluted with EtOAc and washed with H2O followed by saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (9:1 hexanes/EtOAc) to give dithiocarbonic acid O-ethyl ester S-(2-trifluoromethyl-biphenyl-4-yl) ester.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=O.[NH2:5][C:6]([CH2:13][CH2:14][CH3:15])=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[S].C(OCC)C>N1CCCCC1.C(O)C.O>[CH2:13]([C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=[CH:1][N:5]=1)[CH2:14][CH3:15]
Reactant: CCCC(N)=CC(=O)OCC
Reactant: C=CC=O
Agent: [S]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCCc1ncccc1C(=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 64685.6 %

Procedure:
Acrolein (30 g, 0.52 mmol) was added during a period of 2 hours to a stirred solution of ethyl 3-amino-hex-2-enoate (62 g, 0.4 mmol) dissolved in 2 g of piperidine and 300 ml of anhydrous ethanol. The mixture was refluxed for 3 hours and the ethanol was evaporated. The remaining oil was heated to 100° C. and solid sulfur (52 g, 1.6 mmol) was carefully added in portions. The temperature was elevated to 150° C. for 3 hours. The mixture was cooled to room temperature and 200 ml of diethyl ether and 800 ml of water was added. The organic material was extracted into diethyl ether (2×200 ml). The combined organic layer were dried overmagnesium sulfate, and evaporated to an oil. The crude product was purified by column chromatography over silica gel 60, using diethyl ether as the eluent to afford 50 g (65%) of ethyl 2-n-propylpyridine-3-carboxylate as an oil. 1H--NMR (CDCl3, 200 MHz) δ: 1.01 (t, 3 H); 1.40 (t, 3 H); 1.75 (sextet, 2 H); 3.12 (t, 2 H); 4.38 (q, 2 H); 7.19 (dd, 1 H); 8.13 (dd, 1 H); 8.63 (dd, 1 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCN(C(C)C)C(C)C.[C:35]([O:39][C:40]([N:42]1[CH2:56][CH2:55][C:46]2=C(Cl)[N:48]3[C:52]([N:53]=[C:45]2[CH2:44][CH2:43]1)=[CH:51][CH:50]=[N:49]3)=[O:41])([CH3:38])([CH3:37])[CH3:36].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.[Cl-].[Na+].O>[C:35]([O:39][C:40]([N:42]1[CH2:56][CH2:55][C:46]2=[C:6]([N:8]3[CH2:9][CH:10]([CH2:12][OH:13])[CH2:11]3)[N:48]3[C:52]([N:53]=[C:45]2[CH2:44][CH2:43]1)=[CH:51][CH:50]=[N:49]3)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(CO)C3)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.57 g (13.75 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester and 2.62 g (13.75 mmol) para-toluenesulfonic acid monohydrate in 14 mL DCM was stirred at room temperature for 16 hours. After evaporation of the solvent, the residue was dissolved in 28 mL EtOH, then 4.8 mL (27.5 mmol) DIPEA followed by 4.03 g (12.5 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester were added and the reaction mixture was heated under reflux for 24 hours. The mixture was allowed to cool to room temperature and the solvent was evaporated. 300 mL DCM was added to the mixture, the organic layer was washed sequentially with 100 mL saturated solution of NaHCO3, a mixture of 1.94 g (9.23 mmol) citric acid monohydrate in 100 mL H2O and 100 mL saturated brine, then was dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (Biotage silica 40+M, heptane/EtOAc 1:1 to EtOAc).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[CH:6][C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:4][N:3]=1>ClCCl.CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:5]2[CH:6]=[C:7]3[N:8]=[C:9]([CH2:10][CH2:11][C:12]4[N:13]=[C:14]([NH2:19])[CH:15]=[C:16]([CH3:18])[CH:17]=4)[NH:1][C:2]3=[N:3][CH:4]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(N)nc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(Cl)cc4)cnc3[nH]2)c1
Yield: 46.6 %

Procedure:
36 mg of N-[2-amino-5-(4-chloro-phenyl)-pyridin-3-yl]-3-(6-amino-4-methyl-pyridin-2-yl)-propionamide (compound A9) are treated with 2 g polyphosphoric acid at 125° C. for 24 h. Subsequent workup according to the procedure described herein for example A6 yields 16 mg of the title compound as a viscous oil after chromatography (dichloromethane/methanol 8:1). ESI-MS: 364.4/366.4 (MH+, 100%/36%). TLC: Rf=0.30 (dichloromethane/methanol 8:1).
Reaction SMILES: [C:1]1([CH:7]2[C:12]3=[N:13][C:14]([NH2:16])=[N:15][N:11]3[CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[S:20][N:19]=1>>[CH3:17][C:18]1[N:22]=[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([NH:16][C:14]3[N:13]=[C:12]4[CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[O:8][CH2:9][CH2:10][N:11]4[N:15]=3)[CH2:27][CH2:28]2)[S:20][N:19]=1
Reactant: Nc1nc2n(n1)CCOC2c1ccccc1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4n(n3)CCOC4c3ccccc3)CC2)n1

Procedure:
Prepared in analogy to example 261a employing 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine and 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (see example 1d). The title compound was obtained as an white foam.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2F)n1
Product: CSc1nc(Nc2ccccc2F)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-(2-fluoro-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: 8.61 (s, 3H), 7.11-7.23 (m, 4H), 7.26 (m, 1H), 7.45-7.62 (m, 2H), 8.38 (m, 1H), 9.80 (s, 1H), 11.33 (br s, 1H). LC MS (m/e)=358 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]OCl.[BH4-].[Na+].Cl>C1COCC1.O.CCOCC.CN1CCCN(C)C1=O>[I:12][C:9]1[CH:10]=[CH:11][C:4]([O:3][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:5]([CH:8]=1)[CH2:6][OH:7]
Reactant: O=Cc1cc(I)ccc1O
Reactant: COCCOCOCl
Agent: Cl
Agent: [BH4-]
Agent: [H-]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(I)cc1CO
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 80.4 %

Procedure:
To a solution of sodium hydride (1.2 g of a 60% mineral oil dispersion, 52 mmol) in 25 mL of THF at 0° C., is added 2-hydroxy-5-iodo-benzaldehyde (7.0 g, 28 mmol). To the resulting solution is added 2-methoxy-ethoxymethoxy chloride (3.4 mL, 30 mmol) and 4 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The solution is allowed to warm to ambient temperatures. After 45 minutes, the solution is cooled to -15° C. and 6 mL of a 2 M solution of sodium borohydride in THF is added. The solution is stirred for 10 minutes. After this time, 24 mL of a 2M HCl solution in water is added. The resulting solution is diluted with ether, washed with water and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude material is purified by column chromatography eluting with 40% EtOAc/hexanes to give the title compound (7.6 g, 22.5 mmol) as a white solid.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[N:6]1[C:15]2CCCC[C:10]=2[CH:9]=[CH:8][CH:7]=1.N1C2C(C(=S)N)CCCC=2C=CC=1>>[Li:5][CH:1]1[C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:4][CH2:3][CH2:2]1
Reactant: c1cnc2c(c1)CCCC2
Reactant: [Li]CCCC
Agent: NC(=S)C1CCCc2cccnc21
Product: [Li]C1CCCc2cccnc21

Procedure:
The title compound is prepared using n-butyl lithium (9% w/v in hexane) and 5,6,7,8-tetrahydroquinoline by the general procedure of Example 7. The product may be converted to 5,6,7,8-tetrahydroquinoline-8-thiocarboxamide by the procedures described in Example 2 above, and U.S. Ser. No. 460,265.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH2:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+].F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:4]1([C:5]([O:7][CH3:8])=[O:6])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: BrCCCCBr
Agent: CCCC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.3 %

Procedure:
To a solution of malonic acid dimethyl ester (5.28 g, 40 mmol) in DMF (100 ml), 1,4-dibromo-butane (5.26 ml, 44 mmol), K2CO3 (13.8 g, 100 mmol), 1-butyl-3-methylimidazolium tetrafluoroborate (0.904 g, 4.0 mmol) are added at room temperature. The mixture is stirred at room temperature for 15 hours. To the mixture, water is added and the solution is extracted with AcOEt. The organic layer is washed with H2O and brine, dried over MgSO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give cyclopentane-1,1-dicarboxylic acid dimethyl ester (6.13 g, 82%); TLC (hexane/AcOEt, 5:1) Rf 0.48, 1H NMR (400 MHz, chloroform-d) δ ppm 1.67-1.71 (m, 4H), 2.17-2.21 (m, 4H), 3.72 (s, 6H).
Reaction SMILES: C(=O)([O-])O.[K+].Br[C:7]1[CH:8]=[CH:9][C:10]([F:16])=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1.[CH3:17][C:18]1[N:19]=[CH:20][S:21][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(O)(=O)C(C)C.C(P(C(C)(C)C)C1CCCCC1)(C)(C)C>C1(C)C=CC=CC=1.Cl[Pd]Cl.[Cu](Br)Br>[F:16][C:10]1[CH:9]=[CH:8][C:7]([C:20]2[S:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:18]([CH3:17])[N:19]=2)=[CH:12][C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=O)c1scnc1C
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Br[Cu]Br
Agent: Cl[Pd]Cl
Agent: CC(C)(C)P(C1CCCCC1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(C)C(=O)O
Product: CCOC(=O)c1sc(-c2ccc(F)c([N+](=O)[O-])c2)nc1C
Temperature: 120 °C
Yield: 73.5 %

Procedure:
A mixture was prepared by adding 2.10 g of potassium hydrogen carbonate, 44 mg of palladium chloride (II) and 205 mg of a copper bromide (I) dimethylsulfide complex to 2.20 g of 5-bromo-2-fluoronitrobenzene and the resulting mixture was suspended in 20 mL of toluene. Subsequently, a reaction mixture solution prepared by adding 2.05 g of ethyl 4-methyl-1,3-thiazole-5-carboxylate, 92.5 μL of isobutyric acid and 228 mg of di-t-butylcyclohexylphosphine to the resulting suspension was heated at 120° C. for 14 hours under a nitrogen atmosphere. The reaction mixture solution was celite-filtered to remove insoluble matter and water was added to the filtrate, and extraction was performed using ethyl acetate. The organic layer was washed with saline and dried and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 2.28 g of ethyl 2-(4-fluoro-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate.