Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=[CH:3][C:2]=1[O:7]C(=S)OC1C=CC=CN=1.[Na].[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][CH2:26][CH:25]([N:29]([CH3:31])[CH3:30])[CH2:24]2.C(N(CCC)C1CC2C(=C(N)C=CC=2)NC1)CC>>[CH3:30][N:29]([CH3:31])[CH:25]1[CH2:26][N:27]2[C:2](=[O:7])[CH2:3][O:18][C:19]3[C:28]2=[C:23]([CH:22]=[CH:21][CH:20]=3)[CH2:24]1
Reactant: CN(C)C1CNc2c(O)cccc2C1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CCCN(CCC)C1CNc2c(N)cccc2C1
Agent: [Na]
Product: CN(C)C1Cc2cccc3c2N(C1)C(=O)CO3

Procedure:
This compound was prepared by following the procedure of Example 56 part B, but substituting ethyl bromoacetate for di (2-pyridyl)thiocarbonate and the sodium salt of 1,2,3,4-tetrahydro-8-hydroxy-N,N-dimethyl-3-quinolinamine for 1,2,3,4-tetrahydro-N3,N3 -dipropyl-3,8-quinolinediamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:30]([NH2:33])(=[O:32])[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[C:30]([NH:33][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)(=[O:32])[CH3:31]
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)N3CCN(C4CCOCC4)C3=O)nc2)ccn1
Temperature: 93 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of Example C1 (0.300 g, 0.718 mmol), acetamide (0.127 g, 2.154 mmol), Cs2CO3 (0.468 g, 1.436 mmol) and Xantphos (0.046 g, 0.079 mmol) in dioxane (7 mL) was sparged with Ar under sonication. Pd2(dba)3 0.053 g, 0.057 mmol) was added, and the mixture was sparged again with Ar and heated at 93° C. overnight. The mixture was cooled to RT, and partitioned with EtOAc and brine. The aqueous layer was extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM). The material was suspended in 4:1 MeCN/water, frozen and lyophilized overnight, and further dried in a drying oven to afford N-(5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (0.287 g, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1 H), 10.57 (s, 1 H), 8.23 (dd, J=2.9, 0.5 Hz, 1 H), 8.19 (d, J=5.7 Hz, 1 H), 8.08 (dd, J=9.0, 0.5 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.66 (d, J=2.3 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1 H), 3.94-3.79 (m, 5 H), 3.49-3.37 (m, 4 H), 2.04 (s, 3 H), 1.78-1.67 (m, 2 H), 1.64-1.58 (m, 2H); MS (ESI) m/z: 441.2 (M+H+).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].[BH4-].[Na+]>FC(F)C(O)=O>[F:20][CH:19]([F:21])[CH2:8][N:4]1[C:5]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[O:23][CH2:24][C@H:3]1[CH2:1][CH3:2]
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: O=C(O)C(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
Compound 112 was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (13 mg, 0.04 mmol) and NaBH4 pellets (large excess, >10 equiv) in 3 mL difluoroacetic acid (0.01 M) stirred at rt for 12 h, to afford 8 mg (53%) of (3R)-4-(2,2-difluoroethyl)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (8 mg, 0.02 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 1.5 mL acetic acid and 1.5 mL concentrated HCl and heated at 90° C. for 4 h to afford 4 mg (57%) of Compound 112, after purification by column chromatography (3:1 hexanes: EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) 12.19 (bs, 1H), 7.14 (s, 1H), 7.09 (d, 1H, J=8.8), 6.99 (d, 1H, J=9.3), 5.95 (m, 1H), 4.34 (dd, 1H, J=10.7, 1.5), 3.98 (dd, 1H, J=10.7, 2.4), 3.70 (m, 1H), 3.58 (m, 1H), 3.25 (m, 1H), 1.58 (m, 2H), 0.98 (t, 3H, J=7.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].O[C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16]>>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C@H:5]1[NH:17][C:15](=[O:16])[CH:14]([CH3:18])[O:6]1
Reactant: COc1cccc(OC)c1C=O
Reactant: C[C@H](O)C(N)=O
Product: COc1cccc(OC)c1[C@H]1NC(=O)C(C)O1

Procedure:
prepared by reaction of 2,6-dimethoxybenzaldehyde with (S)-(−)-2-hydroxypropionamide; LC-MS: tR=0.45 min; [M+H]+=238.28.
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][C:6]=1[O:15][CH3:16].[C:17](Cl)(=O)[C:18](Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][C:6]=1[O:15][CH3:16])[CH2:11][C:12](=[O:14])[CH2:18][CH2:17]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(CC(=O)O)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)CCC(=O)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a DCM solution of (4-Bromo-3-methoxyphenyl)acetic acid (900 mg, 3.67 mmol) was added oxalyl chloride (0.64 ml, 7.3 mmol) and a drop of DMF. The solution was allowed to stir at RT for 3 hours, at which point bubbling stopped. The volatiles were removed under vacuum, and the residue was redissolved in DCM. The solution was cooled to 0° C. To this solution was added aluminum trichloride (1.2 g, 9.2 mmol). After stirring the mixture for 15 minutes, ethylene was bubbled into the reaction. The reaction was poured into ice, extracted with DCM, washed with brine, and purified by MPLC. LC-MS (IE, m/z): 255 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C)nc1
Yield: 91.1 %

Procedure:
17.8 g (0.092 mole) of 3-(6-methyl-3-pyridyl)-acrylic acid ethyl ester in 100 ml of ethanol are hydrogenated at 40° C./atmospheric pressure in the presence of 1.0 g of palladium/active carbon (10% Pd). On completion of the reaction, the reaction mixture is filtered and the solvent is concentrated in vacuo, leaving 16.2 g (90%) of a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1.CC[N:26]=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:26])=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC(CC)n1cc(-c2csc(C(=O)O)c2)c2c(=O)[nH]ccc21
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(CC)n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 4-(4-oxo-1-(pentan-3-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylic acid (23.0 mg) in DMA (2 mL) were added EDCI hydrochloride (16.0 mg) and HOBt ammonium salt (13.1 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (20.6 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[C:4](Cl)[CH:3]=1.C(N(CC)CC)C.Cl.[CH3:20][S:21]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].C(O)CO>C(OCC)(=O)C.O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[C:4]([N:27]2[CH2:28][CH2:29][CH:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]2)[CH:3]=1
Reactant: Clc1cc(Cl)c2sccc2n1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Solvent: OCCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)C1CCN(c2cc(Cl)nc3ccsc23)CC1
Temperature: 120 °C
Reaction time: 6 h
Yield: 13 %

Procedure:
A mixture of 5,7-dichlorothieno[3,2-b]pyridine (0.52 g), triethylamine (0.90 mL), 4-(methylsulfonyl)piperidine mono hydrochloride (0.62 g), and ethylene glycol (1.1 mL) was stirred at 120° C. for 6 h. Ethylene glycol (4.0 mL) and 1,4-dioxane (4.0 mL) were added, and the mixture was further stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, and then silica gel was added to the organic layer. Silica gel and the desiccant were removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting solids were washed with a mixture solution of ethyl acetate and diisopropyl ether. The resulting solids were purified by silica gel column chromatography (ethyl acetate/hexane=1:1-1:0) to obtain 5-chloro-7-(4-(methylsulfonyl)piperidin-1-yl)thieno[3,2-b]pyridine (0.11 g). (2) To a mixture of 5-chloro-7-(4-(methylsulfonyl)piperidin-1-yl)thieno[3,2-b]pyridine (0.11 g), Pd2(dba)3 (0.016 g), (±)-BINAP (0.032 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.13 g), and 1,4-dioxane (2.2 mL) was added sodium t-butoxide (0.099 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 20 h. The mixture was further stirred at 70° C. for 2 h and 30 min. The reaction mixture was diluted with ethyl acetate and water, and then the organic layer was washed with water. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=2:1−ethyl acetate/methanol=10:1, and silica gel, chloroform/methanol=50:1-10:1) to obtain colorless amorphous (S)-1-(3-(7-(4-methylsulfonylpiperidin-1-yl)thieno[3,2-b]pyridin-5-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.074 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([CH2:17][CH2:18][CH2:19][CH2:20][O:21]CC1C=CC=CC=1)[CH2:8][C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:41]([O:48][C:49]([C@H:51]1[CH2:56][CH2:55][C@@H:54]([NH2:57])[CH2:53][CH2:52]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[CH:7]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:8][C:9]1([C:14](=[O:16])[NH:57][C@H:54]2[CH2:55][CH2:56][C@@H:51]([C:49]([O:48][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:50])[CH2:52][CH2:53]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CCCCOCc1ccccc1)CC1(C(=O)O)CCCC1
Reactant: N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C(CCCCO)CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1
Reaction time: 72 h
Yield: 69.4 %

Procedure:
2-(4-Benzyloxybutyl)-3-(1-carboxycyclopentyl)propanoic acid t-butyl ester (1 g, 2.48 mmole) was dissolved in ethanol (35 ml) and stirred at room temperature with 5% palladium on carbon catalyst (250 mg) under hydrogen at 50 p.s.i. (3.45 bar). After 3 hours the catalyst was removed by filtration and the solvent evaporated. The residue was dissolved in dichloromethane (40 ml) and cis-4-amino-cyclohexanecarboxylic acid benzyl ester p-toluene sulphonate salt (1.5 g, 3.70 mmole), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride salt (1.22 g, 6.37 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 6.34 mmole) and triethylamine (1.28 g, 12.65 mmole) added. After 3 days at room temperature, the solvent was evaporated and the residue dissolved in ethyl acetate (50 ml). The solution was washed with water (50 ml), 1N hydrochloric acid (50 ml), water (50 ml) and saturated sodium hydrogen carbonate solution (50 ml), dried over magnesium sulphate and the solvent evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and pentane (1:1 by volume) and the appropriate fractions combined and evaporated to give the title product as a pale orange oil (912 mg, 61%). Found: C,70.29; H,8.94; N,2.64. C31H47NO6 requires C,70.05; H,9.08; N,2.59%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[N:9]=[N:10][C:5]3=[N:4][CH:3]=2)[CH:33]=[N:32]1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: c1cnc2ccc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a solution of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (845 mg, 2.48 mmol) in DME (16 mL) was added 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (800 mgs, 2.48 mmol) and Cs2CO3 (2.42 g, 7.43 mmol) in H2O (4 mL). The reaction mixture was degassed and charged with nitrogen for three times. The palladium catalyst Pd(dppf).CH2Cl2 (101 mg, 0.124 mmol) was added and the reaction mixture was degassed and charged with nitrogen for three times, and stirred for 16 hours at 80° C. under nitrogen. The reaction mixture was then filtered over a pad of Celite, and washed with EtOAc (50 mL) and water (25 mL). The filtrate was extracted with EtOAc (3×50 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified with a Biotage silica gel column chromatography (40+S, 0-50% EtOAc/Hexanes 5CV (column volume), 50-100% EtOAc/Hexanes 10 CV, 100% EtOAc 10 CV) to provide 6-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (910 mgs, 81% yield) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H) 8.82-8.95 (m, 1H) 8.67 (s, 1H) 8.28-8.45 (m, 2H) 7.92-8.08 (m, 2H) 7.77-7.90 (m, 1H) 7.53 (dd, J=8.29, 4.14 Hz, 1H) 6.15 (s, 2H) 4.49-4.62 (m, 2H) 4.30-4.47 (m, 2H) 3.91-4.00 (m, 1H) 3.67-3.87 (m, J=5.46 Hz, 1H) 3.47-3.60 (m, 1H) 3.35-3.42 (m, 1H) 1.48-1.66 (m, 2H) 1.32-1.45 (m, 3H).
Reaction SMILES: [C:1]([C:9]1([OH:53])[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC>>[OH:53][C:9]1([CH:1]([OH:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)=[O:17])[CH2:10]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(C(=O)c5ccccc5)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(O)(C(O)c5ccccc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-(3-Benzoyl-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide was stirred in neat TPA at room temperature for 10 minutes, and then Et3SiH (5 equiv.) was added. The reaction mixture was stirred at room temperature for 5 minutes, and then concentrated. The product was obtained after purification by reverse phase HPLC.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[CH3:26].N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[CH3:26])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C#N)cc(C)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C#N)cc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride was dropwise added, under ice-cooling, to a mixture of 4-hydroxy-3,5-dimethylbenzonitrile, pyridine and dichloromethane, followed by stirring at room temperature for 2 hours to obtain 4-cyano-2,6-dimethylphenyl trifluoromethanesulfonate. In an atmosphere of nitrogen, a mixture of 4-cyano-2,6-dimethylphenyl trifluoromethanesulfonate, (3-formylphenyl)boronic acid, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred at room temperature for 6 hours to obtain 3′-formyl-2,6-dimethylbiphenyl-4-carbonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]#[C:16][CH:17]([OH:19])[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]#[C:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(O)C#CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)C#CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 4-(1-phenyl-1-(3-hydroxy-1-butyn-1-yl)-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.197 g, 0.577 mmol) in CH2Cl2 (5 mL) was added activated MnO2 (1.125 g) at 0° C. The mixture was allowed to stir for 3 h, at which point no starting material remained. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give the title compound (0.190 g, 97%) as a colorless oil:
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]1.[CH3:27][O:28][C:29](=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:27][O:28][C:29](=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]1
Reactant: COC(=O)Cc1ccccc1O
Reactant: CC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OC1CCN(C(C)=O)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
Di-tert-butylazodicarboxylate (305 mg, 1.32 mmol) was dropped to a solution of 1-(4-hydroxy-piperidin-1-yl)-ethanone (259 mg, 1.8 mmol) in tetrahydrofuran (4 mL) under nitrogen atmosphere. Then (2-hydroxy-phenyl)-acetic acid methyl ester (200 mg, 1.2 mmol) and triphenylphosphine (347 mg, 1.3 mmol) were added. The yellow mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was purified on silica using hexane/ethyl acetate mixture of increasing polarity (from 70% to 100% ethyl acetate) as eluent to give 195 mg (55.6%) of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])[CH3:2].CN1C=CN=C1S.ClC[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([S:8]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1)(=[O:10])=[O:9])[CH2:6][C:36]1[CH:37]=[CH:38][C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:27]=2)=[CH:34][CH:35]=1)[CH3:2]
Reactant: ClCc1ccccc1-c1ccccc1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1nccn1C
Agent: Cn1ccnc1S
Product: CCOC(=O)C(C)(Cc1ccc(-c2ccccc2)cc1)S(=O)(=O)c1nccn1C

Procedure:
3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-methyl-(1-methyl-1H-imidazolesulfonyl)-propionic acid ethyl ester Prepared from (1-Methyl-2-mercapto imidazole and 2-bromo ethyl propionate) (3.0 g, 12.2 mmol) and 4 chloromethylbiphenyl (2.97 g,15 mmol). Yield 5.0 g (99 %); low melting solid; MS 413 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH2:19])[S:17][CH:18]=2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]=[C:22]=[O:23]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:22]([NH:21][CH3:20])=[O:23])[S:17][CH:18]=2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(NC(=O)Cc2csc(N)n2)s1
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CNC(=O)Nc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Yield: 70.5 %

Procedure:
A reaction mixture comprising 3.0 g (0.01 mole) of 4-(5-tert-butyl-1,3,4-thiadiazol-2-ylcarbamoylmethyl)-2-aminothiazole, 50 ml of pyridine and 0.8 g (0.014 mole) of methyl isocyanate was heated at 35°-37° for four hours. The reaction solution was allowed to stand over the weekend at ambient temperature. Most of the pyridine was removed by employing a rotary evaporator. The residue was mixed with hexane and the crude solid was collected. The filter cake was well washed with ethyl acetate. There was obtained 2.5 g of product, m.p. 190° (dec.). N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.4 [C(CH3)3 ], 2.6 (CH3, doublet), 3.7 (CH2), 6.7 (hetero-aromatic).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:11]=[N:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>ClCCl>[Cl:3][CH2:19][CH2:18][CH:15]1[CH2:16][CH2:17][N:12]([C:9]2[N:10]=[N:11][C:6]([CH3:5])=[CH:7][CH:8]=2)[CH2:13][CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(N2CCC(CCO)CC2)nn1
Solvent: ClCCl
Product: Cc1ccc(N2CCC(CCCl)CC2)nn1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice bath) solution of 7.1 parts of thionyl chloride in 65 parts of dichloromethane was added dropwise a solution of 6.6 parts of 1-(6-methyl-3-pyridazinyl)-4-piperidineethanol in 195 parts of dichloromethane. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was washed with alkaline water. The separated organic layer was dried, filtered and evaporated, yielding 7.2 parts (100%) of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine as a residue (int. 84).