Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:3]([OH:10])[C:4](OC(C)C)=[O:5].[NH3:18]>CO>[NH2:1][C@@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:3]([OH:10])[C:4]([NH2:18])=[O:5]
Reactant: N
Reactant: CC(C)OC(=O)C(O)[C@@H](N)Cc1ccccc1
Solvent: CO
Product: NC(=O)C(O)[C@@H](N)Cc1ccccc1
Reaction time: 8 h

Procedure:
A solution of isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (200 mg, Reference compound No. 4-1) in methanol (3 ml) is saturated with an ammonia gas, and the solution is sealed and stirred overnight. The reaction solution is concentrated under reduced pressure to give the titled reference compound (162 mg).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C@@H:10]1[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C@@H:10]1[C:22]([F:25])([F:24])[F:23]
Reactant: O=C1Nc2cc(F)ccc2O[C@H](C(F)(F)F)[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1C(=O)Nc2cc(F)ccc2O[C@@H]1C(F)(F)F

Procedure:
The title compound was prepared by hydrogenation of (−)-(6S,7S)-7-dibenzylamino-2-fluoro-6-trifluoromethyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 265.2 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH:55]([C:58]1[O:62][N:61]=[CH:60][C:59]=1[C:63](O)=[O:64])([CH3:57])[CH3:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([C:59]2[CH:60]=[N:61][O:62][C:58]=2[CH:55]([CH3:57])[CH3:56])=[O:64])[CH2:49][CH2:48]1
Reactant: CC(C)c1oncc1C(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1oncc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 18 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-isopropylisoxazole-4-carboxylic acid as starting materials in 18% yield. LCMS for C31H34ClN8O3 (M+H)+: m/z=601.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:33])[CH2:21][S:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:40]>>[ClH:40].[N:11]1([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:33])[CH2:21][S:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)CSc3ccnc4ccccc34)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CSc1ccnc2ccccc12)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
4-[2-[4-(4-tert-Butoxycarbonyl-1-piperazinyl)phenyl]-2-oxoethylthio]quinoline (Compound 49; 2.8 g, 6.0 mmol) was gradually added to an ice-cooled solution of 4N hydrochloride dioxane solution (40 ml). The reaction mixture was stirred at room temperature for one hour. The resulting precipitates were collected by filtration and washed well with dry dioxane and dry ether to obtain 2.8 g of the titled compound (99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([O:27][CH3:28])=[C:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)[CH:6]=[C:7]([NH:9]C(=O)C(F)(F)F)[CH:8]=1.O>CO>[NH2:9][C:7]1[CH:6]=[C:5]([C:16]([O:27][CH3:28])=[C:17]2[CH:18]3[CH2:26][CH:22]4[CH2:21][CH:20]([CH2:25][CH:24]2[CH2:23]4)[CH2:19]3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COC(=C1C2CC3CC(C2)CC1C3)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Solvent: O
Solvent: CO
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(N)cc(OC)c1

Procedure:
Trifluoroacetamide enol ether 31 is hydrolyzed at 60° C. with finely ground K2CO2 (3 eq) in MeOH containing trace water. Workup by partitioning the mixture with EtOAc/H2O, followed by silica gel chromatography provides enol ether aniline 32.
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.[NH2:10][CH:11]([CH2:15][CH3:16])C(O)=O>C(#N)C>[C:7]([C:3]1[NH:1][C:11]([CH2:15][CH3:16])=[N:10][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CCC(N)C(=O)O
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CCc1nc(C)c(C(C)=O)[nH]1

Procedure:
To 4.78 g (0.037 moles) of 3-oximino-2,4-pentanedione dissolved in 40 ml of acetonitrile was added 3.82 g (0.037 moles) of 2-aminobutyric acid. The mixture was brought to reflux, while stirring rapidly under nitrogen, with an oil bath. After 22.5 h the reaction mixture was cooled, suction filtered, and the residue washed with acetonitrile (50 ml). The combined filtrates were concentrated in vacuo, and the resulting oil dissolved in 1 M hydrochloric acid (30 ml). The acid solution was washed with methylene chloride (4×20 ml), then neutralized with solid potassium carbonate. Extraction with methylene chloride, followed by drying over anhydrous potassium carbonate and concentration in vacuo furnished 0.021 moles (67.8%) yield based on recovered d,l-norvaline) of 5-acetyl-2-ethyl-4-methylimidazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.[H-].[Na+].[I-].[K+].Br[CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][CH:20]([O:23][CH3:24])[CH2:19][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccn(CC(OC)OC)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a stirred solution of methyl 1H-indole-7-carboxylate (2.0 g, 11.4 mmol) in DMF (10 ml) was added sodium hydride (800 mg, 20 mmol) in portions. The mixture was stirred at room temperature for 1 h, then potassium iodide (160 mg, 0.9 mmol) and 2-bromo-1,1-dimethoxyethane (3.4 ml, 28.5 mmol) were added. The mixture was heated to 80° C. for 15 h. After cooling to room temperature, the reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 1-(2,2-dimethoxyethyl)-1H-indole-7-carboxylate (1.77 g, 59%) as a semitransparent liquid: 1H NMR (500 MHz, CDCl3) δ 7.77 (dd, J=4.5, 1.0 Hz, 1H), 7.66 (dd, J=4.3, 1.0 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.57 (d, J=1.8 Hz, 1H), 4.54-4.52 (dd, J=5.0, 4.5 Hz, 1H), 4.48 (d, J=2.5 Hz, 2H), 3.96 (s, 3H), 3.31 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[NH:8][C:9]1[CH:10]=[C:11]([C:12]2[NH:27][N:26]=[N:25][N:13]=2)[CH:14]=[CH:15][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cc(Nc2cccc(C#N)c2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2cccc(-c3nnn[nH]3)c2)cc(C(C)(C)C)c1O
Temperature: 110 °C
Yield: 65.3 %

Procedure:
Eight g (0.025 mole) of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzonitrile (from Example 27), 4.9 g (0.075 mole) of sodium azide, 4.0 g (0.075 mole) of ammonium chloride, 1.06 g (0.025 mole) of lithium chloride and 60 ml of N,N-dimethylformamide were combined under a nitrogen atmosphere and heated at 110° C. for 48 hours. The reaction mixture was poured into cold 6N hydrochloric acid and a gummy solid precipitated out. The supernatant was decanted off and the residue dissolved in ethanol. The ethanol solution was diluted with water and a pink solid was collected. This material was recrystallized from a mixture of ethanol and water to give 5.97 g of 5-[3-(3,5-di-t-butyl-4-hydroxyanilino)phenyl]tetrazole, m.p. 231°-233° C. Analysis: Calculated for C21H27N5O: %C, 69.0; %H, 7.4; %N, 19.2; Found: %C, 68.4; %H, 7.6; %N, 8.8.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[C:10]([S:21][CH3:22])=[CH:9]2)=[N:6][CH:7]=1.Br[C:24]1[CH:25]=[C:26]([CH:31]([OH:33])[CH3:32])[CH:27]=[CH:28][C:29]=1[F:30]>>[F:30][C:29]1[CH:28]=[CH:27][C:26]([CH:31]([OH:33])[CH3:32])=[CH:25][C:24]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[C:10]([S:21][CH3:22])=[CH:9]2)=[N:6][CH:7]=1
Reactant: CC(O)c1ccc(F)c(Br)c1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C(C)O)ccc4F)cn3)c2c1

Procedure:
Synthesized from methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate (1.0 g, 2.65 mmol) and 1-(3-bromo-4-fluorophenyl)ethanol (0.87 g, 3.98 mmol) analogously to the experimental procedure 289a). Yellow solid. Yield: 1.0 g (89% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cccc(N)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(C#N)c1
Temperature: 5 °C
Reaction time: 12 h

Procedure:
3-Aminobenzonitrile (5.70 g) and N,N-dimethylaminopyridine (20 mg) were dissolved in pyridine (40 ml) and the mixture was cooled to 5° C. Acetic anhydride (5.8 ml) was added and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and 1N hydrochloric acid were added to the residue, and the organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried, concentrated and recrystallized from hexane-ethyl acetate to give the title compound (5.78 g) as pale-brown powder crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:34]([NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and phenyl isocyanate (0.013 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as an amorphous compound. 13C NMR (DMSO-d6) δ 195.1, 158.7 (dd), 155.7 (dd), 152.3, 148.9, 139.3, 139.1, 137.2, 133.4, 131.5, 129.6, 128.7, 127.0, 126.2 (dd), 124.2 (dd), 121.8, 120.3, 118.4, 118.2, 118.1, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 19.0
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]([O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([CH3:13])([CH3:12])[CH3:11].[H-].[Na+].O>CN(C)C=O.C(O)(=O)C>[C:10]([O:14][C:15](=[O:25])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C:7](=[O:9])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: COc1ccc(CC(=O)OC(C)(C)C)cc1
Reactant: O=C(O)c1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C(=O)OC(C)(C)C)C(=O)c2cnccn2)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
N,N-Carbonylimidazole (14.86 g) was added to a slurry of pyrazine-2-carboxylic acid in dry dimethylformamide (100 cm3). After stirring for one hour 4-methoxyphenylacetic acid t-butyl ester (10.8 g) was added. The reaction mixture was cooled to −30° C. then sodium hydride (4.62 g) was added. The reaction mixture was stirred at −30° C. for 1 h then allowed to warm to room temperature overnight. The reaction miLture was poured into water and acidified to pH 8 with acetic acid. The solution was extracted with ether (3×250 cm3). The ether extracts were combined, washed with brine, dried over magnesium sulphate filtered and evaporated under reduced pressure to give a solid. The solid was purified by chromatography using ethyl acetate/hexane (1:1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl propionic acid t-butyl ester as a solid (9.8 g 61%) δH (250 MHz; CDCl3) 1.39 (9 H, s, C(CH3)3), 3.70 (3 H, s, OCH3), 5.87(1 H, s, tBuO2CCH), 6.90 (2H, d, J 9 Hz, methoxyphenyl H-2) 7.32 (2H, d, J 9 Hz, methoxyphenyl H-3) 8.66 (1H, dd pyrazine H—) 8.74 (1H, d pyrazine H—) 9.25 (1H, d pyrazine H—)
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:16])[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O.O>[N:17]([CH2:2][C:3]1([CH3:16])[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCl)CN(c2ccc(Cl)cn2)C(=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CN=[N+]=[N-])CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 5-(chloromethyl)-3-(5-chloropyridin-2-yl)-5-methyl-1,3-oxazolidin-2-one (1.01 g, INTERMEDIATE 17) and sodium azide (503 mg) was heated to 140° C. in 40 ml of dimethylformamide for 40 h. The mixture was then cooled to room temperature, and diluted with 150 ml of water and extracted with 150 ml of ethyl acetate (3×). The combined organic layers were washed with water (100 ml) and brine (100 ml). Then they were dried over sodium sulfate and concentrated in vacuo (overnight to remove dimethylformamide) to provide 570 mg (55%) of the title compound. Mass spectrum (ESI) 268.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:21](OCC)=[O:22])[C:10]=1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:21][OH:22])[C:10]=1[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2c(OC)cccc2c(OCc2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c(OCc3ccccc3)c(C)c(CO)nc12
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a solution of ethyl 4-(benzyloxy)-8-methoxy-3-methylquinoline-2-carboxylate (1.95 g) in toluene (30 mL) was added dropwise a solution of diisobutylaluminum hydride in toluene (0.99M, 6.1 mL) at room temperature under nitrogen flow, followed by stirring. After 1 hour and 2 hours, a solution of diisobutylaluminum hydride in toluene (0.99M, each 6.1 mL) was added thereto, followed by stirring for 3 hours. Water was added to the reaction mixture to stop the reaction, and then anhydrous sodium sulfate was added thereto, followed by stirring. Insolubles were removed by filtration through Celite. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/50˜ethyl acetate, then chloroform˜chloroform/methanol=95/5) to obtain [4-(benzyloxy)-8-methoxy-3-methylquinolin-2-yl]methanol (551 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[CH:6][C:5]2=[O:15].C(N)CCC.[I:21]I.[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[C:6]([I:21])[C:5]2=[O:15]
Reactant: II
Reactant: COc1cc2[nH]c(C)cc(=O)c2cc1Cl
Agent: [I-]
Agent: [K+]
Solvent: CCCCN
Solvent: CN(C)C=O
Product: COc1cc2[nH]c(C)c(I)c(=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a stirred solution of 6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (6.43 g, 28.7 mmol) and n-butylamine (28 ml, 287 mmol) in dimethylformamide (57 ml) cooled by a room temperature water bath was added iodine (7.30 g, 28.7 mmol) in a saturated solution of aqueous potassium iodide (29 ml). The reaction mixture was stirred 12 hours at room temperature. Residual iodine was quenched with 0.1 M aqueous sodium thiosulfate, and the resulting solution was concentrated in vacuo. The residue was resuspended in water and filtered to give 8.93 g (89% yield) of 6-chloro-3-iodo-7-methoxy-2-methylquinolin-4(1H)-one as a light brown powder.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:15]=1[NH:16][C:17]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:18]=1[C:19]([NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20]>>[F:13][C:14]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:15]=1[N:16]1[C:17]2[C:18](=[CH:30][C:31]([F:35])=[C:32]([F:34])[CH:33]=2)[C:19](=[O:20])[N:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:1]1=[O:2]
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=c1c2cc(F)c(F)cc2n(-c2cc(F)c(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 5.3 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (4.9 g, 30.4 mmol) and crude 2-(2,4,5-trifluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example A-1, 6.22 g, 15.2 mmol) provided 0.35 g of the title compound as a solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].F[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([C:3]1([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Cc1ccnc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccnc(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (15.2 g, 72.3 mmol) and 2-fluoro-4-methylpyridine (9.64 g, 87.0 mmol) was dissolved in 361 mL of THF. The reaction was purged with a stream of nitrogen and cooled to −78° C. To this reaction was added 1.0 M sodium bis(trimethylsilyl)amide in THF (101 mL, 101 mmol), which was stirred for 1 hour. The reaction was warmed to ambient temperature, stirred for 36 hours, and quenched with a saturated ammonium chloride solution. The mixture was extracted with dichloromethane (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 0-25% EtOAc in hexanes to yield tert-butyl 4-cyano-4-(4-methylpyridin-2-yl)piperidine-1-carboxylate.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:9][CH:8]([N:10]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:17][C:16]3[C:11]2=[N:12][C:13]([CH3:34])=[N:14][C:15]=3[N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)[CH2:7]1.N1C=CC=CC=1>ClCCl>[CH3:5][O:4][C:2]([N:6]1[CH2:7][CH:8]([N:10]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:17][C:16]3[C:11]2=[N:12][C:13]([CH3:34])=[N:14][C:15]=3[N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH2:31]2)[CH2:9]1)=[O:3]
Reactant: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CNC2)CC1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CN(C(=O)OC)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add methyl chloroformate (0.0024 mol, 0.22 g, 2.5 equiv.) to a solution of 9-(azetidin-3-yl)-8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.0009 mol, 0.4 g) and pyridine (2 mL) in dry dichloromethane (2 mL) at 0° C. and stir for 2 hours at room temperature. Quench the reaction mixture with saturated sodium bicarbonate solution and then extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and concentrate under reduced pressure to give the residue. Purify the residue by silica gel chromatography eluting with dichloromethane:methanol 98:2 to give the title compound as the freebase (0.155 g). MS (m/z): 470.63 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([CH2:7][S:8][CH3:9])[CH2:5][NH:4][CH2:3]1.CO.Cl>>[OH:1][C@H:2]1[C@H:6]([CH2:7][S:8][CH3:9])[CH2:5][NH:4][CH2:3]1
Reactant: CSCC1CNCC1O
Agent: Cl
Solvent: CO
Product: CSC[C@@H]1CNC[C@H]1O
Yield: 88 %

Procedure:
N-Protected 3-hydroxy-4-(methylthiomethyl)-pyrrolidine (8.2 g, 33.2 mmol) was dissolved in methanol (40 mL, 33.2 mmol) and to this was added hydrochloric acid (10 mL, 326 mmol) and the resulting solution concentrated in vacuo. This step was repeated, whereupon TLC (10% v/v 7N NH3 in MeOH-dichloromethane) indicated complete deprotection. Column chromatography on silica eluted with 10-20% 7N NH3 in MeOH-dichloromethane afforded the title compound (4.3 g, 29.2 mmol, 88% yield).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4].[C:20](O)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[C:3]([N:2]([CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4])(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: CN(C(=O)c1nc2ccccc2[nH]1)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)n1c(C(=O)N(C)c2ccccn2)nc2ccccc21
Yield: 42.9 %

Procedure:
N-Methyl-N-(2-pyridyl)benzimidazole-2-carboxamide (1.5 g) prepared in Example 5 was suspended in dry pyridine (20 ml), anhydrous acetic acid (1.5 g) was added at room temperature while stirring and allowed to react overnight. Pyridine was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and dried over anhydrous Na2SO4, and the solvent was distilled off. Purification of the residue by column chromatography on silica gel gave the title compound (0.75 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH3:22])[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O)[CH:2]([CH3:4])[CH3:3].[H][H]>CCOC(C)=O.[Pd]>[NH2:17][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:6]=1[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:20][CH2:21][CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCN(CC(C)C)c1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN(CC(C)C)c1ccc(C(=O)OCC)cc1N
Yield: 92.6 %

Procedure:
A solution of ethyl 4-[isobutyl(propyl)amino]-3-nitrobenzoate (6 g, 0.0194 mol) in EtOAc (100 mL) was added Pd/C (600 mg). The reaction mixture was hydrogenated with hydrogen gas under 5 kg pressure for 3 h. The reaction mixture was filtered off Pd/C and filtrate was concentrated under reduced pressure to afford the title compound as yellow oil (5 g, 92%). 1H NMR (DMSO-d6, 400 MHz) δ 7.29 (s, 1H), 7.16 (d, 1H), 7.01 (d, 1H), 4.93 (s, 2H), 4.23 (q, 2H), 2.80 (t, 2H), 2.71 (t, 3H), 1.65 (m, 1H) 1.40 (m, 2H), 1.28 (t, 3H), 0.82 (m, 9H). LC/MS (Method A): 279.0 (M+H)+. HPLC (Method B) Rt 3.94 min (purity: 97.9%).