Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.C[Si](C)(C)[O:32][C:33]1([C:39]([O:41]C)=[O:40])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1>CO>[OH:32][C:33]1([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][CH2:36][N:35]([CH2:3][CH:2]([OH:1])[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]=4[C:26]([F:27])([F:28])[F:29])[O:12][N:11]=3)=[CH:6][CH:5]=2)[CH2:34]1
Reactant: COC(=O)C1(O[Si](C)(C)C)CCCNC1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Solvent: CO
Product: O=C(O)C1(O)CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in MeOH (3 mL) was added methyl 3-(trimethylsilyloxy)piperidine-3-carboxylate (100 mg, 0.432 mmol). The reaction mixture was heated at 80° C. for 2 days. The reaction mixture was concentrated in vacuo. The residue was treated with 6N HCl/MeCN at 50° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 14 mg of 3-hydroxy-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.23 (2H, d, J=7.91 Hz), 7.69 (4H, t, J=7.91 Hz), 7.54-7.65 (3H, m), 5.21-5.32 (1H, m), 3.69-4.01 (1H, m), 3.51 (2H, d, J=12.30 Hz), 3.33-3.43 (1H, m), 3.07-3.27 (2H, m), 2.32 (1H, br. s.), 1.78-2.08 (3H, m). MS (m+1)=545. HPLC Peak RT=3.24 minutes (Analytical Method A). Purity=95%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: BrCCCCCBr
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: BrCCCCCOc1cccc2ncccc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a stirred suspension of 5-hydroxyquinoline (10.0 g, 69.0 mmol) and 1,5-dibromo-pentane (23.9 g, 103.5 mmol) in N-methylpyrrolidinone (100 mL) was added potassium carbonate (14.7 g, 103.5 mmol). The resulting mixture was stirred at 90° C. for 4 h and then quenched with water (30 mL) followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and then concentrated under vacuum. The residue was purified by silica gel chromatography to give 5-(5-bromo-pentyloxy)-quinoline (12.6 g, 42.8 mmol, 62%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH:39]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[CH:39]1([NH:45][C:16]2[C:17]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:21][CH2:20][C:18]=3[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:12][CH:11]=3)[N:15]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC4CCCCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Yield: 54.7 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol) was dissolved in DMF (2 mL). Cyclohexanamine (44.7 mg, 0.45 mmol) was added and the reaction mixture was heated at 85° C. overnight. The reaction mixture was allowed to reach room temperature, the solvent was evaporated under reduced pressure and the crude was purified by flash chromatography using dichloromethane and methanol as eluent yielding tert-butyl 4-(cyclohexylamino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (124 mg, 54.6%). MS (ES+) m/z 504.4 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][Cl:20])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:5])[CH3:2].Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(O)C>[ClH:20].[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][N:30]2[CH2:31][CH2:32][C:27](=[CH:26][C:25]3[CH:33]=[CH:34][CH:35]=[C:23]([F:22])[CH:24]=3)[CH2:28][CH2:29]2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: Fc1cccc(C=C2CCNCC2)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)c(CCCl)s1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1
Yield: 47.2 %

Procedure:
1.50 g of 2-ethoxycarbonyl-4-(4-fluorophenyl)-5-(2-chloroethyl)thiazole, 1.10 g of 4-(3-fluorobenzylidene)piperidine hydrochloride and 2.50 g of N,N-diisopropylethylamine were stirred in 3 ml of ethanol at 80° C. for 40 hours. The reaction solution was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aqueous sodium bicarbonate to effect separation of layers. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the drying agent was removed by filtration. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by a flash column chromatography (Wako Gel C200 (manufactured by Wako Pure Chemical Industries), eluant: hexane-ethyl acetate-5.1) and then Chromatolex NH NHDM1020 (manufactured by Fuji Division Chemical), eluant: hexane-ethyl acetate=10.1). This product was treated with 4 N hydrogen chloride/1.4-dioxane solution and then recrystallized from ethanol to obtain 1.14 g of 2-ethoxycarbonyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole hydrochloride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>C(#N)C>[CH:20]1([CH2:19][O:11][C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: COc1cccc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(OC)c1OCC1CC1
Temperature: 80 °C
Yield: 74.4 %

Procedure:
To a stirring solution of 2,6-dimethoxyphenol (2 g, 12.9 mmol) in acetonitrile (50 mL) was added potassium carbonate (3.5 g, 25.8 mmol) and (bromomethyl)cyclopropane (3.5 g, 25.8 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) to afford 2-(Cyclopropylmethoxy)-1,3-dimethoxybenzene as a solid (2 g, 74%).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH:6]3[CH:11]([CH:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:4][C:3]=1[O:24][CH3:25].C[O-].[Na+].[C:29](OCC)(=[O:31])C.Cl>>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:2]=1[O:31][CH3:29])[CH2:13][CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2Cc3cc(Br)c(OC)cc3C3CCCCC23)cc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(C2Cc3cc(OC)c(OC)cc3C3CCCCC23)cc1
Yield: 68.1 %

Procedure:
Combine 7-Bromo-6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (chiral) (0.025 g, 0.06 mmol), NaOMe 5N (1.4 ml, 7 mmol), CuIBr (0.005 g, 0.034 mmol) and ethyl acetate (0.005 ml, 0.05 mmol) and heat at 115° C. for 1.5 hours. Cool, and add 1N HCl and extract with ethyl acetate. Wash organic layer with water, dry over anhydrous sodium sulfate and remove solvent in vacuo. Chromatograph on silica gel with 9% ethyl acetate/hexanes to yield the titled compound (0.012 g, 55%). 1H NMR (CDCl3). MS m/z 352.9 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.[CH2:12]([Li])[CH2:13][CH2:14][CH3:15]>O1CCCC1>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)c1cc(C=O)co1
Solvent: C1CCOC1
Product: CCCCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-trimethylsilyl-3-furaldehyde (0.134 g., 0.796 mmol) in 15 ml tetrahydrofuran at -78° under argon was added n-butyllithium (0.836 mmol in hexane). The reaction mixture was allowed to warm to room temperature, stirred for 30 minutes and quenched with a 5% ammonium chloride solution. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate solution. The organic portion was washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol. This material was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH2:22](O)[CH3:23]>>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:22][CH3:23])=[O:5]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cccnc1N
Temperature: 120 °C
Yield: 60 %

Procedure:
Absolute ethanol (10 mL) was added to 2-aminonicotinic acid (120, commercially available) (3.9 g, 28 mmol). To the resulting stirred mixture was added H2SO4 (96%, 5 mL). The mixture was heated and refluxed at 120° C. for ~4 h. The suspension was cooled to room temperature, poured over ice (30 g), and neutralized to pH 5 using solid Na2CO3. The aqueous suspension was extracted with EtOAc (3×25 mL). These combined organic extracts were washed with water (3×30 mL), dried (Na2SO4), and rota-evaporated to dryness, leaving the title compound as off-white crystals (2.8 g, 60%); mp 90.5°-92.5° C. (Lit., 94°-95° C., Hirai, E., Chem. Pharm. Bull. 14:861 (1966)). 1H NMR (CDCl3): δ1.38 (t, J=7.2, 3, CH3CH2), 4.34 (q, J=7.2, 2, CH3CH2O), 6.40 (bm, 2, NH2), 6.62 (dd, J1 =4.9, J2 =7.8, 1, H-4), 8.14 (dd, J1 =1.0, J2 =8.4, 1, H-5), 8.21 (dd, J1 =1.2, J2 =3.8, 1, H-6).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[CH:36]([NH:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:16]([C@@H:10]3[CH:11]4[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]4)[CH2:9]3)=[O:17])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33])([CH3:38])[CH3:37]
Reactant: CC(C)NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
64.3 mg (0.46 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 65.1 mg (0.31 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 45.0 mg (0.15 mmol) of 4′-amino-N-isopropylbiphenyl-4-sulfonamide (Example 12A) in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., the reaction mixture is concentrated in vacuo. The residue is dissolved in water and acetonitrile and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 21 mg (29.2% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:18][CH3:19])[CH:11]=3)[C:6](=[O:20])[C:5]=2[CH:4]=1.[BH4-].[Na+].Cl>COCCOC>[CH3:19][O:18][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:13]([OH:17])[C:14]3[C:5]([C:6]=2[OH:20])=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)[CH:11]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccc(OC)cc1C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2c(O)c3cc(OC)ccc3c(O)c2c1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A dispersion of 268 g of 2,6-dimethoxyanthraquinone in 1800 ml of ethyleneglycol dimethylether was mixed with 75 g of sodium borohydride under stirring under a nitrogen atmosphere for one hour. The solution was then added dropwise to 6000 ml of a cold aqueous 1N hydrochloric acid, and the precipitates formed were filtered off, washed with water and dried to give 220 g of green 2,6-dimethoxyanthracene-9,10-diol.
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].Cl[C:8]1[CH:13]=[C:12](Cl)[C:11](Cl)=[CH:10][C:9]=1Cl>CN(C=O)C>[C:3]([S:6][C:8]1[CH:13]=[C:12]([S:6][C:3]([CH3:5])([CH3:4])[CH3:2])[C:11]([S:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[CH:10][C:9]=1[S:6][C:3]([CH3:5])([CH3:4])[CH3:2])([CH3:5])([CH3:4])[CH3:2]
Reactant: Clc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)(C)S
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1cc(SC(C)(C)C)c(SC(C)(C)C)cc1SC(C)(C)C
Temperature: 0 °C
Yield: 69 %

Procedure:
Sodium (9.3 g, 0.18 mol) was added to a degassed solution of 2-methyl-2-propanethiol (20.9 mL, 0.18 mol) in dry DMF (105 mL), under stirring at 0° C. in nitrogen atmosphere. The mixture was allowed to reach room temperature (RT, 20-25° C.) and stirred overnight. 1,2,4,5-Tetrachlorobenzene (8.0 g, 0.037 mol) was then added and the resulting mixture was stirred at RT for 2 h and then gently refluxed for 18 h. After cooling at RT, the reaction mixture was poured over ice (100 g), the precipitate was removed by filtration, washed with water, and dried to give 11.0 g of the title compound as an off-white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-fluoro-benzenesulfonyl chloride (1.65 g, 0.00848 mol), (R)-2-amino-4-methyl-pentanoic acid (1.233 g, 0.009398 mol), and sodium carbonate (1.91 g, 0.0180 mol) in water (15 mL) was stirred at room temperature for 5 days. The solution was filtered, and the filtrate was acidified with concentrated hydrochloric acid to pH=4. The mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried (MgSO4), and rotary evaporated to a yellow oil. The oil was chromatographed on silica gel (320 g, 230-400 mesh) eluting with dichloromethane-methanol (10:1, 10×300 mL). Fractions containing product were combined and rotary evaporated to give a pale yellow oil. The oil was dried in vacuo; yield 1.44 g (59%). 1H-NMR (DMSO-d6): δ8.1 (br s, 1H), 7.80 (m, 2H), 7.38 (m, 2H), 3.55 (t, 1H), 3.33 (br s, H2O),1.56 (m, 1H), 1.36 (dd, 2H), 0.75 (dd, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:23][N:22]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4cnc(N5CCCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 11.3 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyrimidin-2-yl)piperidin-3-ylcarbamate (150 mg, 0.26 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (111 mg, 0.39 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (16 mg, 11% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.35 (br s, 1H), 8.45 (s, 2H), 8.29 (dd, J=8.8, 1.9 Hz, 1H), 8.26-8.15 (br s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.07 (br s, 1H), 6.96 (br s, 1H), 4.76 (d, J=12.9 Hz, 1H), 4.45 (br s, 1H), 3.37-3.31 (m, 1H), 2.82 (br s, 1H), 2.23-2.16 (m, 1H), 1.96-1.85 (m, 1H), 1.78-1.68 (m, 1H), 1.68-1.56 (m, 1H), 1.22-1.16 (m, 4H); ESI MS m/z 545 [C29H29ClN6O3+H]+; HPLC 98.5% (AUC), tR=10.69 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)([O-])=O>CCOC(C)=O.[Pd]>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:9]1[C:8]2[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinazoline (400 mg, 1.19 mmol) in EtOAc (5 mL) was added 10% Pd on C (200 mg) and the suspension was hydrogenated in a Parr apparatus for 1 h at 20 psi. Then the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography using 5% EtOAc in CHCl3 to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.60 (s, 1H), 7.79 (s, 1H), 7.75-7.71 (m, 3H), 7.47-7.44 (m, 2H), 7.11 (d, J=6.3 Hz, 1H), 6.07 (s, 2H); MS (m/z): 305.19 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCCN1CCCC1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCN3CCCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 3-pyrrolidin-1-yl-propylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.05 mmol). 8-Cyclohexyl-5-oxo-2-(3-pyrrolidin-1-yl-propylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (18 mg, 85%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H33N5O3: 428.26 (M+H). Found: 428.3.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH:19]3[CH:24]([CH3:25])[CH2:23][CH2:22][CH2:21][CH:20]3[CH3:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH:19]3[CH:24]([CH3:25])[CH2:23][CH2:22][CH2:21][CH:20]3[CH3:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1CCCC(C)C1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1CCCC(C)C1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)c(=O)c1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,6-dimethyl-cyclohexyloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 69) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-2-[4-(2,6-dimethyl-cyclohexyloxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as an orange solid as a mixture of diastereomers (1.14 g, 76%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10]>CC(O)(C)C>[C:9]([CH:8]([C:7]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)(=[O:10])[CH3:11]
Reactant: COC(=O)CC(C)=O
Reactant: O=C1C=CCC1
Solvent: CC(C)(C)O
Product: COC(=O)C(C(C)=O)C1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
Under an atmosphere of argon, 12.6 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Tsdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 108 μL (1.0 mmol) of methyl acetoacetate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 196 mg (99% yield) of the title compound. The percentage diastereomeric excess and the percentage enantiomeric excess were measured by 1H NMR and HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.0 mL/min, detection at 210 nm), it was found that the product was a 1:1 diastereomeric mixture and each diastereomer was present in 70% ee.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[N:30]=[CH:29]1>>[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:37][CH:36]=2)[N:30]=[CH:29]1
Reactant: Nc1ccc(CCc2c[nH]cn2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CCc2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(2-(imidazol-4-yl)-ethyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=5:1) C28H24N4O3