Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]CC2C=CC=CC=2)[C:3]=1[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:18]1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:18]1
Reactant: O=C(Nc1ccn(Cc2c(Cl)cccc2OCc2ccccc2)n1)c1c(F)cccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(Cc2c(O)cccc2Cl)n1)c1c(F)cccc1F

Procedure:
A solution of N-[1-({2-chloro-6-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide (for a preparation see Intermediate 10)(0.148 g, 0.326 mmol) in ethyl acetate (20 ml) was hydrogenated using an H-cube (settings: 20° C., 1 bar, 1 ml/min flow rate) and 5% Pd/C CatCart 30 as the catalyst. The solution was hydrogenated again using an H-cube (settings: 20° C., 1 bar, 1 ml/min flow rate) and 10% Pd/C CatCart 30 as the catalyst. The solvent was removed in vacuo to give the title compound as a colourless gum (70 mg); LCMS: (System 1) MH+=364, tRET=3.14 min.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[C:15]2[C:10](=[C:11]([N+:16]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>[Pd].C(O)C>[CH2:22]([O:21][C:19]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:6]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[O:20])[CH3:23]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(N)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Ammonium formate was added to a vigorously stirred mixture of 4-chloro-3-ethoxycarbonyl-8-nitro-quinoline (5.6 g), ethanol (1000 ml) and 10% palladium on carbon catalyst (2 g). The mixture was stirred at ambient temperature for 1 hour, filtered through a pad of celite and the pad washed with dichloromethane. The combined filtrate and washings were evaporated to dryness. The residue so obtained was purified by flash chromatography on silica using chloroform as eluant to give 3-ethoxycarbonyl-8-amino-quinoline in 58% yield, mp 94-96° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][CH2:11][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.C(O[K])(C)(C)C>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:10]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CC#Cc1nc(Br)cnc1N
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2nc(Br)cnc2[nH]1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
To a solution of 5-bromo-3-(3-trimethylsilanyl-prop-1-ynyl)-pyrazin-2-ylamine (1.66 g, 66% purity, 5.84 mmol) in 25 mL of THF was added a solution of tBuOK in THF (1M, 11.7 mL, 11.7 mmol) slowly at RT. The reaction mixture was heated to reflux for 2 days, then cooled to RT, diluted with EtOAc, quenched with H2O, filtered through a pad of celite, and washed with H2O and EtOAc. The organic layer was separated, washed with H2O and brine, dried (MgSO4), and concentrated to give 598 mg of 2-bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine as a brown solid (48% yield).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:31])[CH:7]([CH:8]=C(C)C)[CH:6]1[C:12]([O:14][CH:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]>C(OCC)(=O)C>[CH3:4][C:5]1([CH3:31])[CH:7]([CH:8]=[O:1])[CH:6]1[C:12]([O:14][CH:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]
Reactant: CC(C)=CC1C(C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Product: CC1(C)C(C=O)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Yield: 72 %

Procedure:
Ozone gas was bubbled at -78° C. into a solution of 1.88 g (5.00 mmol) of cyano(3-phenoxyphenyl)methyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate obtained in Reference Example 3, in 10 ml of ethyl acetate. The subsequent operation was conducted in the same manner as in Reference Example 5, whereby 1.26 g of cyano(3-phenoxyphenyl)methyl 2,2-dimethyl-3-formylcyclopropanecarboxylate was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[CH2:21]1>C1(C)C=CC=CC=1>[CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1
Yield: 86.8 %

Procedure:
A solution of 2.7 g of (E)-3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]benzeneamine, 1.78 g of homophthalic anhydride and 40 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 3.75 g of (E)-2-[2-[3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 209°-210° C. from tetrahydrofuran.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC(O)C2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.5 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.52 g, 3.1 mmol), azetidin-3-ol hydrochloride (0.5 g, 4.6 mmol) and 4 Å molecular sieves (0.7 g) in DCE (8 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (1.3 g, 6.13 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 40:60) to give 3-Hydroxy-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester as yellow oil (0.69 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 4.45-4.35 (m, 1H); 3.96 (dd, J=9.3, 6.7 Hz, 2H); 3.74 (dd, J=9.3, 4.5 Hz, 2H); 3.66 (td, J=8.8, 6.7 Hz, 2H); 3.40-3.37 (m, 1H); 3.20 (td, J=8.8, 4.5 Hz, 2H); 1.43 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N:19]1[CH:23]=[N:22][N:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([CH3:34])=[CH2:33].O>CN(C)C=O.C(OCC)(=O)C>[CH3:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH:31]=[C:32]([CH3:34])[CH3:33])=[C:3]([N:19]3[CH:23]=[N:22][N:21]=[N:20]3)[CH:4]=2)[S:9][C:10]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=C(C)CBr
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(-n3cnnn3)c2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccc(OC=C(C)C)c(-n3cnnn3)c2)nc1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A solution was prepared by dissolving 33.1 mg of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 1.0 mL of dimethylformamide. A reaction mixture solution prepared by adding 20.7 mg of potassium carbonate and 16.2 mg of 3-bromo-2-methylpropene to the solution was heated under stirring at 100° C. for 4 hours. The reaction mixture solution was cooled to room temperature and then 3 mL of water and 4 mL of ethyl acetate were added under stirring, followed by concentrating the organic phase to obtain 34.1 mg of ethyl 4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (2) A reaction mixture solution prepared by adding 1.0 mL of 35% sulfuric acid aqueous solution to 34.1 mg of ethyl 4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate was heated under stirring at 80° C. for 4 hours. The reaction mixture solution was cooled to room temperature and then 3 mL of water and 4 mL of ethyl acetate were added under stirring, and the organic phase was concentrated and purified using a conventional method to obtain 9.9 mg of ethyl 2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([C:17]#[C:18][CH3:19])=[O:16].[C:20]([Mg]Br)#[C:21][CH3:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([C:20]#[C:21][CH3:22])([C:17]#[C:18][CH3:19])[OH:16]
Reactant: CC#C[Mg]Br
Reactant: CC#CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Product: CC#CC(O)(C#CC)c1cc(-c2cccc(Cl)c2)ccc1N

Procedure:
Following the procedure of Example 41, (4-amino-3′-chloro-biphenyl-3-yl)-propynyl-methanone (mp 112-114° C.; MS ((+) ESI) m/z 270/272 (M+H)+) was treated with propynylmagnesium bromide to give (4-amino-3′-chloro-biphenyl-3-yl)-dipropynyl-methanol which was reacted with 1,1′-carbonyldiimidazole to afford the title compound. Yellow solid: mp 151° C. (decomposed); 1H-NMR (DMSO-d6) δ 10.8 (s, 1H), 7.71 (dd, 1H, J=8.52, 1.94 Hz), 7.69 (m, 2H), 7.61 (d, 1H, J=7.64 Hz), 7.50 (t, 1H, J=7.85 Hz), 7.43 (d, 1H, J=7.99 Hz), 7.06 (d, 1H, J=8.23 Hz), 2.0 (s, 6H); MS (APCI) m/z 336 ([M+H]+, 20%).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.CN(C=O)C.[H-].[Na+].[C:21]([O:24][CH2:25][CH3:26])(=O)C>[NH4+].[Cl-]>[CH3:12][C:2]([O:13][CH2:26][C@H:25]1[CH2:21][O:24]1)([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CCOC(C)=O
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(Cn1ccc([N+](=O)[O-])n1)OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
A mixture of 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (1.31 g, 7.07 mmol), and DMF (60 mL) was stirred at 0° C. for 5 min, then NaH (60% dispersion in oil, 0.85 g, 21.2 mmol) was added and stirred 20 min at 0° C. R-(−)-glycidyl-3-nitrobenzenesulfonate (2.75 g, 10.6 mmol) was added and stirred at 0° C. for 1 h then warmed to rt for 14 h. The mixture was then diluted with NH4Cl(s), ethyl acetate, the organic phase was separated, washed with NaHCO3(satd) dried with Na2SO4, and filtered. The mixture was then concentrated and purified by column chromatography (40-240 g Analogix column, 70% EtoAc/heptane to yield the product 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole as a white solid (0.7 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:24][CH:25]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Product: CN(C)CCn1ncc(-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)c1-c1ccc(Cl)cc1

Procedure:
The title compound is prepared as described in Example 54, starting from {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and 2-dimethylamino-ethanol (Fluka).
Reaction SMILES: Cl.[Si]([O:9][C@H:10]1[C:19](=[O:20])[C:18]2[CH:17]=[CH:16][N:15]3[CH:21]=[C:22]([CH3:24])[N:23]=[C:14]3[C:13]=2[NH:12][C@@H:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.[OH-].[Na+]>CO>[OH:9][C@H:10]1[C:19](=[O:20])[C:18]2[CH:17]=[CH:16][N:15]3[CH:21]=[C:22]([CH3:24])[N:23]=[C:14]3[C:13]=2[NH:12][C@@H:11]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O[Si](C)(C)C(C)(C)C)C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)C3=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
30 ml of concentrated hydrochloric acid are added dropwise at room temperature in the course of 20 minutes to 29.8g (73.1 mmol) of (8R,9R)-8-(tert-butyldimethylsilanyloxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one, dissolved in 30 ml of methanol. The mixture is stirred for a further 30 minutes at room temperature. The methanol is stripped off and the pH of the remaining solution is adjusted to 10 using 2M sodium hydroxide solution. The mixture is extracted three times with 30 ml of dichloromethane each time, the combined dichloromethane phases are washed once with 30 ml of water and the organic phase is dried over magnesium sulfate. The drying agent is filtered off, the filtrate is concentrated and the residue is brought to crystallization using diethyl ether. The crystallizate is filtered off with suction and dried in vacuo at 50° C. 12.2 g (57% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.[CH3:32][O:33][C:34]([O:38][Si](C)(C)C)=[C:35]([CH3:37])[CH3:36].O>CN(C=O)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd].[F-].[F-].[Zn+2]>[CH3:32][O:33][C:34](=[O:38])[C:35]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1)([CH3:37])[CH3:36]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
A mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in Example 1, step (f), 100 mg, 0.200 mmol), (1-methoxy-2-methyl-propenyloxy)-trimethyl-silane (61 μL, 0.30 mmol), Pd(t-Bu3P)2 (10.2 mg, 0.0200 mmol) and ZnF2 (10.3 mg, 0.100 mmol) in 2 mL of DMF was stirred at 80° C. for 2 d under Ar. After cooling to RT, the mixture was treated with H2O (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (DCM) to afford the title compound (48 mg, 46%) as a colorless oil. LC-MS (ESI, m/z): Calcd. for C28H38N4O4Si, 523.3 (M+H). found 523.0.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[N:26]1[N:34]2[C:29]([CH2:30][O:31][CH2:32][CH2:33]2)=[CH:28][C:27]=1[NH:35][C:36]1[C:37](=[O:52])[N:38]([CH3:51])[CH:39]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:41]=1.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:40]3[CH:41]=[C:36]([NH:35][C:27]4[CH:28]=[C:29]5[CH2:30][O:31][CH2:32][CH2:33][N:34]5[N:26]=4)[C:37](=[O:52])[N:38]([CH3:51])[CH:39]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCOC3)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (216 mg, 1 eq., 0.60 mmol), 131d (446 mg, 2 eq., 1.2 mmol), Pd2(dba)3 (55 mg, 0.1 eq., 0.060 mmol), Cy3P (67 mg, 0.4 eq., 0.24 mmol), Cs2CO3 (395 mg, 2 eq., 1.2 mmol), water (0.5 mL), and dioxane (10 mL). After three cycles of vacuum/N2 flush, the reaction mixture was stirred at 100° C. for 2 hrs. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 131e (272 mg, 80%) as a brown solid. MS-ESI: [M+H]+ 569.8
Reaction SMILES: CO.Cl.O[NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1>[Fe].O>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 70 °C

Procedure:
To a mixture of 600 parts of methyl alcohol, 200 parts of water and 70 parts of a 35% aqueous hydrochloric acid there was added with stirring 50 parts of 1-hydroxylaminoanthraquinone and the resulting mixture was heated to 70°C. After addition of 17 parts of metallic iron in the form of ribbon little by little over 1 hour, the reaction mixture was maintained at 70°C for additional 4 hours, then cooled to 25°C and filtered. The residue was washed with water, then dissolved in 500 parts of dimethylformamide and filtered to remove residual metallic iron. Dimethylformamide in the filtrate was removed by distillation under reduced pressure to obtain 42.0 parts of 1-aminoanthraquinone of a purity of 92%.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[CH2:19]O)[CH:12]=[C:13]([Cl:15])[CH:14]=1)C1C=CC=CC=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Cl:15][C:13]1[CH:14]=[C:9]([OH:8])[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[CH3:19])[CH:12]=1
Reactant: OCc1cnn2cc(Cl)cc(OCc3ccccc3)c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn2cc(Cl)cc(O)c12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of (4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-3-yl)methanol (274 mg, 0.946 mmol) in TFA (3.0 mL) was added triethylsilane (0.604 mL, 3.78 mmol). The reaction was stirred at 60° C. overnight. Incomplete removal of the benzyl group was observed. The reaction was concentrated, dissolved in HBr (48%, 3.5 ml) and the reaction was heated at 100° C. overnight. The reaction was cooled and neutralized by the addition of 2N NaOH. The aqueous layer was extracted with EtOAc (3×) and the combined organics were washed with saturated NaHCO3 (aq), brine, dried (MgSO4), filtered and concentrated to provide 6-chloro-3-methylpyrazolo[1,5-a]pyridin-4-ol. LCMS-ES I+(m/z): [M+H]+ calcd for C8H7ClN2O: 183.0; found 183.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH3:12][C:13]1[S:17][CH:16]=[C:15]([C:18]([N:20]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][CH2:22][CH2:21]2)=[O:19])[CH:14]=1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][C:24]2([O:23][CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:14]=[C:13]([CH3:12])[S:17][CH:16]=3)=[O:19])[CH2:25]2)[CH2:26][CH2:27]1
Reactant: OCCCCCCCCCBr
Reactant: Cc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 9-bromo-1-nonanol (0.335 g) in acetonitrile (3 mL) was added to a solution of (5-methylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 104, step b) (0.28 g) and triethylamine (0.278 mL) in acetonitrile (7 mL). The resulting mixture was stirred at 60° C. overnight. The reaction mixture was evaporated in vacuo and the residue was taken up into DCM (30 mL), washed with brine (2×15 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a white solid. Yield 0.3 g.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:27])=[C:5]([CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([O:23]C)=[O:22])[C:6]=1[CH2:7][CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH3:1][C:2]1[S:3][C:4]([CH3:27])=[C:5]([CH2:17][CH2:18][C:19]([CH3:25])([CH3:26])[CH2:20][C:21]([OH:23])=[O:22])[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CC(C)(C)CCc1c(C)sc(C)c1CCC(=O)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: Cc1sc(C)c(CCC(C)(C)CC(=O)O)c1CCCc1ccccc1
Temperature: 210 °C
Yield: 75.6 %

Procedure:
6.4 g (0.0166 mol) of 2,5-dimethyl-3-(3-oxo-3-phenylpropyl)-4-(4-methoxycarbonyl-3,3-dimethylbutyl)thiophene and 100 ml of triethylene glycol are placed in a 250 ml three-necked flask fitted with a mechanical stirrer, a condenser and a thermometer. The temperature is brought to 60° C., 1.86 g (0.0580 mol) of 80% hydrazine hydrate are added to the reaction mixture and then, at 90° C., 2.84 g (0.050 mol) of potassium hydroxide are added. The reaction mixture is then brought to a vigorous reflux and, after the removal of water by distillation, the temperature is maintained at 210° C. for 45 minutes. After cooling, the mixture is hydrolysed with a mixture of water/ice/concentrated HCl (200 g/100 g/17 ml) and then extracted with ether. The combined organic phases are washed with dilute HCl, H2O, and then dried over MgSO4, rendered colourless with carbon black and concentrated to yield 4.5 g of 2,5-dimethyl-3-(3-phenylpropyl)-4-(4-carboxy-3,3-dimethylbutyl)thiophene in the form of a pale yellow oil, yield: 75%.