Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]34[CH2:37][CH:32]5[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]5)[CH2:29]3)[CH2:35]4)[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]34[CH2:37][CH:32]5[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]5)[CH2:29]3)[CH2:35]4)[CH:19]=2)[CH2:13][O:12][C:11]([CH3:14])([CH3:15])[O:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)Oc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 16 h
Yield: 94.7 %

Procedure:
A mixture of the product of Step B (0.035 g, 0.07 mmol), and 10% Pd/C (0.025 g) in EtOH (5 ml) was stirred for 16 h under H2. The catalyst was removed by filtration through Celite pad and the filtrate was evaporated to dryness to give the title product (0.035 g; 100%); as colourless paste. 1H-NMR (CDCl3) 1.35 (d, 6H, J=5.99 Hz); 1.4 (s, 3H); 1.42 (s, 3H); 1.46 (s, 9H); 1.91-1.97 (m, 2H); 2.03 (s, 3H); 2.09 (s, 6H); 2.45-2.5 (m, 2H); 3.67 (d, 2H, J=11.73 Hz); 3.89 (d, 2H, J=11.67 Hz); 4.54-4.62 (m, 1H); 4.93 (s, 1H); 6.72 (d, 1H, J=8.27 Hz); 6.92 (broad d, 1H, J=9.98 Hz); 6.99 (broad s, 1H).
Reaction SMILES: C(B1O[C:9]([CH3:11])([CH3:10])[C:6]([CH3:8])([CH3:7])O1)(C)=C.C(=O)([O-])[O-].[K+].[K+].ClC1C=[C:22]([C:35]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]([N:42]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[N:36]=2)[C:23]([NH:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[N:24]C=1>O1CCOCC1.O>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][N:42]([CH2:52][C:53]2[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=2)[C:37]2[N:36]=[C:35]([C:22]3[C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[N:24][CH:11]=[C:9]([C:6]([CH3:7])=[CH2:8])[CH:10]=3)[N:40]=[C:39]([CH3:41])[N:38]=2)=[CH:49][CH:48]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Yield: 91.5 %

Procedure:
A mixture of isopropenylboronic acid pinacol ester (0.119 mL, 0.633 mmol, Aldrich, St. Louis, Mo.), potassium carbonate (0.175 g, 1.267 mmol), (Amphos)2PdCl2 (0.022 g, 0.032 mmol) and 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 155, 0.185 g, 0.317 mmol) in 4:1 dioxane/water (2.5 mL) was heated in a sealed tube for 24 h. The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (25 g column) using 0-30% EtOAc/hexane. The product-containing fractions were concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(prop-1-en-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.171 g, 0.290 mmol, 92% yield) as an orange solid. m/z (ESI, +ve ion) 590 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.71 (br. s., 1H); 8.94 (s, 1H); 8.44 (d, J=2.5 Hz, 1H); 8.27 (d, J=2.3 Hz, 1H); 7.91 (br. s., 1H); 7.22 range (m, 4H); 6.86 range (m, 4H); 6.73 (d, J=9.0 Hz, 1H); 5.33 (s, 1H); 5.01 (s, 1H); 4.89 (s, 2H); 4.82 (s, 2H); 3.94 (s, 3H); 3.82 (s, 3H); 3.79 (s, 3H); 2.59 (s, 3H); 2.13 (s, 3H).
Reaction SMILES: [OH2:1].O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[CH2:29])[CH2:24][CH2:23][CH2:22]2.C(Cl)(Cl)Cl>CO>[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][C:29](=[O:1])[CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=1
Reactant: O
Reactant: C=C1CCCc2cc(OC)ccc21
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)CCCC(=O)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1977, 21, 1827. To a suspension of methyltriphenylphosphonium bromide (11.5 g) in tetrahydrofuran (50 ml) was added dropwise potassium tert-butoxide (1.0 M solution in tetrahydrofuran) (40 ml) on an ice bath under a nitrogen atmosphere, the solution was stirred for 1 hour, then a solution of 6-methoxy-1-tetralone (4.74 g) in tetrahydrofuran (26 ml) was added dropwise thereto followed by stirring for 2.5 hours at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene (4.4 g). To a solution of thallium(III) nitrate trihydrate (4.5 g) in methanol (40 ml) was added dropwise a solution of 6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene (1.7 g) in methanol (13 ml) on an ice bath, and the solution was stirred for 10 minutes at room temperature. Chloroform was added thereto, the solution was stirred, then filtered through celite pad, extracted with diethyl ether, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.7 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([I:18])=[C:7]([C:9]2[CH:14]=[C:13]([O:15]C)[CH:12]=[CH:11][C:10]=2[I:17])[CH:8]=1.B(Br)(Br)Br.C(Cl)Cl>C(=O)=O.CC(C)=O>[OH:15][C:13]1[CH:12]=[CH:11][C:10]([I:17])=[C:9]([C:7]2[CH:8]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=2[I:18])[CH:14]=1
Reactant: COc1ccc(I)c(-c2cc(OC)ccc2I)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1ccc(I)c(-c2cc(O)ccc2I)c1
Reaction time: 18 h
Yield: 85 %

Procedure:
A flask containing 5,5'-dimethoxy-2,2'-diiodobiphenyl (10.0 g, 21 mmol) was cooled to -76° C. in dry ice/acetone. A 1.0M solution of boron tribromide in methylene chloride (64 ml, 64 mmol) was added via syringe to the cold substrate. The ice bath was removed and the reaction allowed to reach room temperature. After 18 hours, the solution was added slowly to 1 L of water. The aqueous mixture was stirred for 2 hours, and the white solid which formed was filtered, washed with water, and dried to give I, which melted at 181°-182° C., in 85% yield.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])([O-:8])=[O:7].[CH3:19]COC(C)=O>CO>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])([O-:8])=[O:7]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Solvent: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]
Yield: 94.7 %

Procedure:
Add sulfonyl chloride (3 mL) dropwise to a solution of 2-nitrophenylacetic acid (7.0 g, 38.6 mmol) in methanol (20 mL) at 0° C., reflux the resulting mixture overnight. TLC (PE:EtOAc=3:1) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure, add water, extract with ethyl acetate twice, and wash the combined organic layers with brine, dry over anhydrous sodium sulfate. Concentrate under reduced pressure to yield the crude product (7.5 g, 94.7%) which is used directly without further purification. MS: (M+1): 196.1.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:29])=[CH2:28])[C:19]=4[S:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]>CO.[Pd]>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:19]=4[S:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C=C(C)c1cccc2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)sc12
Agent: [Pd]
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4c(C(C)C)cccc34)c(C)nc12
Yield: 37.5 %

Procedure:
A solution of 8-(1-ethyl-propyl)-3-(7-isopropenyl-2-methyl-benzo[b]thiophen-3-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (33 mg, 0.08 mmol) in CH3OH (25 mL) is hydrogenated at 30 psi/RT/1 h using 10% Pd—C (99 mg). The reaction mixture is filtered through celite, washed with EtOAc and concentrated to give the title compound (13.6 mg, 0.03 mmol, 41%). 1H NMR (CDCl3): δ 0.92 (t, J=7.5 Hz, 6H), 1.42 (d, J=2.6 Hz, 3H), 1.44 (d, J=2.6 Hz, 3H), 1.75-1.95 (m, 4H), 2.40 (s, 3H), 2.41 (s, 3H), 2.45 (s, 3H), 3.20-3.30 (m, 1H), 3.35-3.50 (m, 1H), 6.69 (s, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.18 (d, J=7.0 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H) ppm. ES-MS (m/z): calcd for C25H31N3S (M+H)+: 406.6. found: 406.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:6]=[C:5]2[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1.C[N:39]([CH3:42])C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:33]1[CH:32]=[C:31]([C:5]2[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([C:42]#[N:39])[CH:3]=3)[NH:7][N:6]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(Br)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 1.5 g of 5-bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole in 15 ml dimethylformamide were added 0.64 g of zinc cyanide and 0.32 g of tetrakis(triphenylphosphine)palladium(0) at room temperature, and the mixture was stirred at 100° C. for one day. At the same temperature, 0.32 g of tetrakis(triphenylphosphine)palladium(0) was added and the mixture was stirred at 130° C. for one day. The reaction mixture was diluted with ethyl acetate, and the organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography. (ethyl acetate:n-hexane=1:10 to 1:1) and the resulting crystals were washed with diethyl ether, to give 431 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][O:17]C3CCCCO3)[CH2:11][CH2:12][C:5]=2[NH:4][C:3]1=[O:24].O.Cl>CO>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:5]2[NH:4][C:3](=[O:24])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH2:9]1
Reactant: Cn1c(=O)[nH]c2c(c1=O)CN(CCCCOC1CCCCO1)CC2
Agent: Cl
Solvent: CO
Solvent: O
Product: Cn1c(=O)[nH]c2c(c1=O)CN(CCCCO)CC2
Reaction time: 7 h

Procedure:
12 g of 3-methyl-6-[4-(tetrahydropyran-2-yloxy)butyl]-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione were dissolved in 150 ml of methanol and 150 ml of water and the pH was adjusted to i with conc. hydrochloric acid at 20°-25° C., with stirring. After 7 h at room temperature, the mixture was concentrated to dryness under reduced pressure, the residue was taken up with water and the solution was adjusted to pH 7.8. It was concentrated under vacuum and the residue was extracted exhaustively with hot ethanol. The ethanolic extract was evaporated under reduced pressure and the crude 6-(4-hydroxybutyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrido-[4,3-d]pyrimidine-2,4-dione was purified by column chromatography on silica gel with dichloromethane/methanol (volume ratio 90:10) and by recrystallization from isopropanol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl.Cl>[CH:18]([C:12]1[CH:17]=[CH:16][C:15]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:14][CH:13]=1)([CH3:20])[CH3:19]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)c1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a suspension of aluminum (III) chloride (6.7 g, 50.1 mmol) and succinic anhydride (2 g, 20 mmol) in 1,2-dichloroethane was added Cumene (2 g, 16.7 mmol) at 0-5° C. The reaction mixture was stirred at ambient temperature for 16 hours, diluted with 20 mL of aqueous HCl solution (1 M) and extracted with ethyl acetate (3×80 mL). The combined organic phases were washed with saturated sodium chloride (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica-gel (4×20 cm, petroleum ether:ethyl acetate=8:1 elution) to give 3.1 g of compound 76. 1H NMR (CDCl3, 300 MHz) δ 1.27-1.29 (d, 6H), 2.80-2.84 (t, 2H), 2.95-3.00 (m, 1H), 3.29-3.33 (t, 2H), 7.32-7.34 (d, 2H), 7.92-7.94 (d, 2H). MS m/z 221 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:4][O:3]1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl.[O-]S([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1([CH3:32])[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[CH:27][C:26]([S:29]([CH3:31])(=[O:41])=[O:30])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:4][O:3]1
Reactant: CS(=O)c1cnc(Nc2ccc(CC[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ncc(S(C)(=O)=O)cn3)cc2)COC1(C)C
Reaction time: 0.67 h
Yield: 114.5 %

Procedure:
To a stirred solution of (4S)-tert-butyl 2,2-dimethyl-4-(4-(5-(methylsulfinyl)pyrimidin-2-ylamino)phenethyl)oxazolidine-3-carboxylate (227 mg) in dichloromethane (5 ml) was added m-CPBA (155 mg) and stirring was continued at RT for 40 min. The reaction mixture was then diluted with aq. Na2SO3 solution and extracted with dichloromethane. The organic layers were dried over MgSO4 and concentrated in vacuo to give (S)-tert-butyl 2,2-dimethyl-4-(4-(5-(methylsulfonyl)pyrimidin-2-ylamino)phenethyl)oxazolidine-3-carboxylate (269 mg, 70% purity, 94% yield) as a brown oil. MS (ISP): 477.4 ([M+H]+), 421.3 ([M+H—C4H8—CO2]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]([C:13]2C(C3C=CC=C([N+]([O-])=O)C3=C=O)C(OCCOC)=C(C)[NH:17][C:18]=2[CH3:19])=[O:12])[CH3:9])=[CH:4][CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:10][C:11](=[O:12])/[CH:13]=[C:18](\[NH2:17])/[CH3:19])[CH3:9])=[CH:6][CH:7]=1
Reactant: COCCOC1=C(C)NC(C)=C(C(=O)OC(C)c2ccc(Cl)cc2)C1C1C=CC=C([N+](=O)[O-])C1=C=O
Solvent: CCO
Product: C/C(N)=C/C(=O)OC(C)c1ccc(Cl)cc1
Yield: 72 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid 2-methoxyethyl ester and 75 mmols of β-aminocrotonic acid 1-(4-chlorophenyl)-ethyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-(2-methoxyethyloxy)-carbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 1-(4-chlorophenyl)-ethyl ester of melting point 106° C (from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[N:9]2[CH3:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl.[Al]>[Br:16][C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]([CH3:15])[C:10]=1[CH3:14]
Reactant: Cc1cc(=O)n(-c2ccc(F)cc2)n1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: ClCCl
Product: Cc1c(Br)c(=O)n(-c2ccc(F)cc2)n1C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 2-(4-fluoro-phenyl)-1,5-dimethyl-1,2-dihydro-pyrazol-3-one (0.5 g) in methylene chloride (10 mL) was added N-bromosuccinimide (0.43 g). The reaction vessel was wrapped in aluminium foil and stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with more EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to give a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 4-bromo-2-(4-fluoro-phenyl)-1,5-dimethyl-1,2-dihydro-pyrazol-3-one (0.43 g) as an off-white solid. MS (ESI+): 287.0 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[C:3]2[C:10]([C:21]3[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)n1cc(I)c2c(Cl)ncnc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)n1cc(-c2ccc([N+](=O)[O-])cc2)c2c(Cl)ncnc21

Procedure:
In a similar manner to Example 10 b), 4-chloro-5-iodo-7-isopropylpyrrolo-[2,3-d]pyrimidine (0.57 g), was reacted with 4-nitrophenylboronic acid (0.30 g) using bis(triphenylphosphine)palladium (II) chloride (0.126 g) to give 4-chloro-7-isopropyl-5-(4-nitrophenyl)pyrrolo[2,3-d]pyrimidine which was reduced using a mixture of ammonium chloride (22 mg),iron powder (0.45 g) in water (2 ml) and industrial methylated spirit (10 ml) to give 4-chloro-5-(4-aminophenyl)-7-isopropylpyrrolo[2,3-d]pyrimidine which was reacted with ammonia in 1,4-dioxen in a sealed vessel to give 4-amino-5-(4-aminophenyl)-7-isopropyl-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[C:24]([O:25][CH3:26])=[CH:23][C:9]([C:10]([C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[O:11])=[C:8]([CH3:27])[CH:7]=1.O>C1(C)C=CC=CC=1>[CH3:4][O:5][C:6]1[C:24]([O:25][CH3:26])=[CH:23][C:9]([C:10]([C:12]2[C:13]([O:2][CH3:1])=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[O:11])=[C:8]([CH3:27])[CH:7]=1
Reactant: C[O-]
Reactant: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2Cl)cc1OC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2OC)cc1OC
Yield: 100.5 %

Procedure:
0.9 g (16 mmol) of sodium methoxide was added to a solution having 1.5 g (4.2 mmol) of 3-(4,5-dimethoxy-2-methylbenzoyl)-2-chloro-4-trifluoromethylpyridine synthesized in accordance with a process in Synthesis Example 1 dissolved in 20 ml of toluene, followed by stirring under reflux by heating for 4 hours. The mixture was cooled, and then 20 ml of water was added thereto to terminate the reaction, the aqueous solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and subjected to filtration by using a silica gel cake. The solvent was distilled off under reduced pressure to obtain 1.5 g (yield 99%) of 3-(4,5-dimethoxy-2-methylbenzoyl)-2-methoxy-4-trifluoromethylpyridine (compound No. 32; m.p. 125-127° C.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:32][CH2:33][CH3:34])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:31]=[CH:30][C:18]([CH2:19][S:20]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])(=[O:22])=[O:21])=[CH:17][CH:16]=3)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.Cl>C1COCC1>[CH:1]1([CH2:4][N:5]([CH2:32][CH2:33][CH3:34])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:31]=[CH:30][C:18]([CH2:19][S:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:22])=[O:21])=[CH:17][CH:16]=3)=[O:13])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CS(=O)(=O)CCC(=O)OCC)cc2)ncn1
Agent: Cl
Solvent: C1CCOC1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CS(=O)(=O)CCC(=O)O)cc2)ncn1
Reaction time: 72 h
Yield: 78.2 %

Procedure:
A solution of ethyl 3-({4-[({6-[(cyclopropylmethyl)(propyl)amino]pyrimidin-4-yl}carbonyl)amino]benzyl}sulfonyl)propanoate (Example 119, 120 mg, 0.25 mmol) in THF (5 ml) was treated with concentrated HCl (2 ml). After stirring at RT for 48 hours a further portion of concentrated HCl (5 ml) was added. After stirring for a further 72 hours, the solvent was reduced in vacuo to half the volume and the mixture extracted with EtOAc. The combined organic extracts were washed with water, passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with DCM containing increasing amounts of methanol to give the title compound as a white solid (90 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22][O:23][C:24]1(OC)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:24]3([O:23][CH3:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC1(OC)CCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: COC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCC1
Yield: 33.5 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-dimethoxycycloheptane (1.58 g, 10 mmol) in the same manner as the example 20 to give the compound 25 (158 mg, 33.5%) as oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.C=O.[C:13]([BH3-])#N.[Na+]>CO>[OH:1][C@H:2]1[CH2:6][N:5]([CH3:13])[C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: [BH3-]C#N
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate 3a (5.53 g, 38 mmol) was dissolved in 80 mL of methanol in an ice-water bath, followed by addition of 40% formaldehyde solution (31 mL, 380 mmol) and sodium cyanoborohydride (12 g, 190 mmol) in batches. The reaction mixture was stirred for 0.5 hours, then warmed up to room temperature and stirred for 3 hours. The mixture was quenched with 40 mL of water, concentrated under reduced pressure and extracted with dichloromethane (80 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b crude product as a colourless oil, which was directly used in the next step.