Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=O)[NH:8][C:5]2=[N:6][CH:7]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[N:6][CH:7]=1)[NH:8][CH:9]=[CH:10]2
Reactant: O=C1Cc2cc(Br)cnc2N1
Solvent: C1CCOC1
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Under an argon atmosphere and in an anhydrous medium, 37.6 ml (37.6 mmol) of a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran are added at 0° C. and dropwise to a suspension of 2 g (9.4 mmol) of the compound obtained in Step B in 50 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 35 minutes at room temperature and then evaporated to dryness. The residue is taken up in an aqueous 6M hydrochloric acid solution and heated until the solid has completely dissolved. After cooling, the solution is rendered alkaline with an aqueous 6M sodium hydroxide solution and extracted with ethyl acetate. After drying over magnesium sulphate and evaporation, an equimolar mixture of 5-bromo-7-azaindoline and 5-bromo-7-azaindole is obtained. The preceding residue, which is dissolved in 20 ml of acetic acid, is added at room temperature to a suspension of 4.10 g (15.3 mmol) manganese(III)acetate dihydrate in 20 ml of acetic acid. After 45 minutes' stirring at 75° C., the solution is evaporated to dryness and coevaporated with toluene. The residue, which is taken up in water, is rendered alkaline with an aqueous saturated sodium hydrogen carbonate solution. After extraction with ethyl acetate, the organic phases are dried over magnesium sulphate and evaporated. The resulting residue is purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate) to yield the title compound in the form of a yellow solid.
Reaction SMILES: C([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[N:17]=[CH:16][N:15]([CH3:19])[C:14]=2[C:13](=[O:20])[N:12]([CH3:21])[C:11]1=[O:22])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[N:17]=[CH:16][N:15]([CH3:19])[C:14]=2[C:13](=[O:20])[N:12]([CH3:21])[C:11]1=[O:22]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)n(C)c(=O)c2c1ncn2C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](O)CCCCn1c(=O)n(C)c(=O)c2c1ncn2C
Yield: 82 %

Procedure:
To a stirring solution of (R)-3-(5-acetoxyhexyl)-1,7-dimethylxanthine (0.28 g, 0.87 mmol) in methanol (20 ml) was added an anhydrous solution of hydrogen chloride in ethyl ether (1 M, 2.6 ml, 2.6 mmol). After refluxing for 4 hours, the mixture was concentrated under reduced pressure. The residue was treated with saturated aqueous solution of sodium bicarbonate solution (30 ml) and extracted with dichloromethane (3×20 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over sodium sulfate and concentrated under reduced pressure to give (R)-3-(5-hydroxyhexyl)-1,7-dimethylxanthine (0.20 g, 85% yield) as a colorless oil that solidified on standing.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Fc1ccc2c(c1F)CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c2ccc(F)c3F)nc(N2CCOCC2)cc1=O
Yield: 39.7 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 287 mg of 4,5-difluoroindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 241 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 155 mg of 2-[2-(4,5-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a brick-red coloured powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].[CH3:25][C:26]([CH3:28])=O>>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][N:1]=[C:26]([CH3:28])[CH3:25])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3c(c2n1CCCCON)CCCC3
Reactant: CC(C)=O
Product: CCOCc1nc2c(N)nc3c(c2n1CCCCON=C(C)C)CCCC3

Procedure:
The method described in Example 3 can be used to treat 1-[4-(aminooxy)butyl]-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine with acetone to provide acetone O-{4-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]butyl}oxime.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH:2]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCC1>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1ccc(C=O)cc1-c1cccnc1
Solvent: CCO
Solvent: C1CCNC1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1-c1cccnc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 3-(3-pyridyl)-4-methoxybenzaldehyde (0.25 g), 5-chloro-2-oxindole (0.2 g) and pyrrolidine (0.5 ml) in ethanol (2 ml) was placed in a sealed tube and heated to 100° C. A precipitate formed within 10 minutes so the reaction was diluted with another 10 ml of ethanol and heating resumed. After 4 hours, the reaction was cooled and the solid was removed by filtration and washed with ethanol and then hexanes to afford 0.27 g (61%) of 5-chloro-3-(3-(3-pyridyl)-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.Br[CH2:11][C:12](=O)[CH3:13].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:5]([CH:4]=1)=[CH:9][C:12]([CH3:13])=[CH:11]2
Reactant: COc1ccnc(C)c1
Reactant: CC(=O)CBr
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccn2cc(C)cc2c1
Temperature: 0 °C
Yield: 31 %

Procedure:
4-Methoxy-2-methylpyridine (0.123 g, 1 mmol) and bromoacetone (0.16 mL, 1 mmol) were heated at 95° C. under N2 for 2 h. 1,8-Diazabicyclo-[5.4.0]-undec-7-ene (0.34 mL, 2.2 mmol) in benzene (10 mL) was added. The mixture was then refluxed under N2 for 1 h, poured into ice water, and then extracted with EtOAc. The combined organic layers were washed with water and dried. After the solvent was removed in vacuo, the residue was purified on a silica gel column eluting with EtOAc:Hexane (1:9) and EtOAc to give 7-methoxy-2-methylindolizine (0.050 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: C1COCCN1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCOCC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 79 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with morpholine (1 mL) in MeOH (3 mL) under reflux to give the desired product (61 mg, 79%, Z/E=1/2) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.13 & 7.09 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.83 & 6.80 (d, J=8.6 Hz, 2H), 6.72 & 6.69 (d, J=8.6 Hz, 2H), 6.45 (s, 1H), 6.43 (d, J=8.8 Hz, 2H), 4.12 & 3.94 (t, J=5.6 Hz, 2H), 3.76 & 3.71 (t, J=4.8 Hz, 4H), 2.83 & 2.71 (t, J=5.6 Hz, 2H), 2.61 & 2.52 (t, J=4.4 Hz, 4H), 2.49 (q, J=7.2 Hz, 2H), 0.91 (t, J=7.2 Hz, 3H); m/z=504[M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:23]2[O:24][C:25]([CH3:28])=[CH:26][CH:27]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:25]1[O:24][C:23]([C:2]2[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)=[CH:27][CH:26]=1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1cc(-c2ccc(C)o2)cc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (5 g, 19.23 mmol) in 1,2-dimethoxyethane (200 ml) were added 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (5.9 g, 28.85 mmol), sodium carbonate (8.15 g, 76.92 mmol) and water (20 ml) and the mixture was degassed by N2 bubbling 15 min. Pd(dppf)Cl2 (3.2 g, 3.846 mmol) was added and the mixture was heated at 100° C. for 2 h. The mixture was brought to RT and quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by flash column chromatography (40% ethyl acetate in hexanes) to afford the product in 80% yield (4.0 g). 1H NMR (300 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.4 (s, 1H), 8.2 (d, 2H), 7.1 (s, 1H), 6.2 (s, 1H), 2.4 (s, 3H), 2.15 (s, 3H), Calculated mass: 260.25; Observed mass: 259.1 [M+H]+ (rt: 1.578 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([F:39])=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C(O)C.C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([F:39])=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1ccc(F)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1ccc(F)c2ccccc12
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(4-fluoro-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (160 mg, 0.293 mmol) in ethanol (2 mL) and THF (2 mL) was added LiOH (2.0 N in water, 2.93 mL, 5.86 mmol), then the mixture was stirred for one hour. The mixture was diluted with DCM, then acidified with 2.0 N HCl (aq). The layers were separated, then the organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to obtain the title compound as a white solid. 1H NMR (499 MHz, CD3OD): δ 8.40 (d, J=8.8 Hz, 1H); 7.92 (d, J=8.3 Hz, 1H); 7.70 (dd, J=8.2, 5.3 Hz, 1H); 7.60 (d, J=8.3 Hz, 2H); 7.55 (t, J=7.6 Hz, 1H); 7.50 (d, J=8.1 Hz, 2H); 7.45 (t, J=7.6 Hz, 1H); 7.39 (d, J=8.1 Hz, 2H); 7.30 (d, J=8.3 Hz, 2H); 7.00 (dd, J=10.4, 8.2 Hz, 1H); 5.19 (d, J=11.5 Hz, 1H); 3.52 (t, J=6.9 Hz, 2H); 3.36-330 (m, 1H); 2.53 (t, J=7.0 Hz, 2H); 1.62 (d, J=10.4 Hz, 2H); 1.11-1.05 (m, 2H); 0.78 (t, J=7.3 Hz, 3H). LC3 4.01 min. [M+H]+ 518.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[OH:2][CH:3]1[CH2:6][N:5]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:4]1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1CC(O)C1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a stirred mixture of 3-hydroxyazetidine hydrochloride (10.0 g, 91.3 mmol), benzoyl chloride (12.8 g, 91.3 mmol) in 3:2 water/ethyl acetate (500 mL) was added potassium carbonate (63.1 g, 456.5 mmol) at room temperature. After 16 h the organic layer was separated and concentrated under reduced pressure. The resulting residue was dissolved in 2:1 THF/methanol (150 mL) and stirred with 1.0 N sodium hydroxide (50.0 mL) at room temperature. After 1 h the reaction mixture was concentrated under reduced pressure, the resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to provide (3-hydroxyazetidin-1-yl)(phenyl)methanone (13.5 g, 83%) as a colorless gum-like substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:42])[O:10][CH2:11][CH:12]([O:36][C:37]1[CH:41]=[CH:40][O:39][N:38]=1)[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:17][N:16]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[C:43]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:42])[O:10][CH2:11][CH:12]([O:36][C:37]1[CH:41]=[CH:40][O:39][N:38]=1)[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:17][N:16]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCc1cc(OCC(COC(=O)NCc2ccccn2)Oc2ccon2)no1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCc1cc(OCC(COC(=O)N(Cc2ccccn2)C(C)=O)Oc2ccon2)no1
Reaction time: 48 h

Procedure:
0.370 g of (2RS)-3-(5-hexadecyl-3-isoxazolyloxy)-2-(3-isoxazolyloxy)propyl N-(2-pyridylmethyl)carbamate (prepared as described in Example 30), 0.60 ml of acetic anhydride and 0.733 g of 4-(N,N-dimethylamino)pyridine were dissolved in 10 ml of toluene, and the mixture was stirred on an oil bath kept at 90° C. for 48 hours. The solvent was distilled off, and the residue was purified by column chromatography through 15 g of silica gel and by medium pressure liquid chromatography using a Lobar B column, 0.308 g of the title compound was obtained, as an oil, from the fractions eluted with methylene chloride.
Reaction SMILES: [C:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].CC(C)([O-])C.[K+].Br[CH2:20][C:21]([N:23]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])=[O:22]>CN(C=O)C>[C:1]([N:3]([CH2:20][C:21](=[O:22])[N:23]([CH2:33][CH:34]([CH3:35])[CH3:36])[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)#[N:2]
Reactant: CC(C)CN(CC(=O)N1CCOCC1)C(=O)CBr
Reactant: N#CNC(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN(CC(=O)N1CCOCC1)C(=O)CN(C#N)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
N-Cyano-2-phenylacetamide (160 mg, 1.00 mmol) was dissolved in 5 mL of dry DMF. Potassium t-butoxide (112 mg, 1.00 mmol) was added. This mixture was stirred at room temperature for 30 min. The 2-bromo-N-isobutyl-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide (321 mg, 1.00 mmol) from above was dissolved in 5 mL of dry DMF and added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h and then heated at 70° C. for 6 h. Solvent was removed in vacuo and residue was purified by HPLC to give the title compound (87 mg, 22%) as a clear oil.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[NH:14]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:16]=[CH:15]1>C(O)CC(C)C>[NH:14]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:21][CH2:20]2)[N:16]=[CH:15]1
Reactant: c1nc(C2CCNCC2)c[nH]1
Reactant: Clc1nc2cccc3c2n1CCC3
Solvent: CC(C)CCO
Product: c1cc2c3c(c1)nc(N1CCC(c4c[nH]cn4)CC1)n3CCC2
Yield: 62.6 %

Procedure:
1 g (0.0052 mol) of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline, 1.57 g (0.0104 mol) of 4-(1H-imidazol-4-yl)piperidine and 5 ml of isoamyl alcohol are heated at 120° C. for 1 day. The alcohol is then evaporated to dryness, the residue is taken up in a water/ether (50/50) mixture and the product sucked dry. The product is purified by chromatography on a column of silica gel, the eluent being a dichloromethane/methanol/aqueous ammonia (95/5/0.5) mixture, is then triturated in ether and dried under vacuum at 60° C. 1 g of product is obtained.
Reaction SMILES: C([N:14]1[CH2:17][C:16]2([C:21](=[O:22])[N:20]=[CH:19][N:18]2[CH3:23])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24]>CO.C(OCC)C.[OH-].[OH-].[Pd+2]>[ClH:24].[CH3:23][N:18]1[CH2:19][NH:20][C:21](=[O:22])[C:16]21[CH2:17][NH:14][CH2:15]2
Reactant: CN1C=NC(=O)C12CN(C(c1ccccc1)c1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CN1CNC(=O)C12CNC2

Procedure:
To a solution of 2-benzhydryl-5-methyl-2,5,7-triazaspiro[3.4]oct-6-en-8-one (I-3A-4a; 189 mg, 0.619 mmol) in methanol (30 ml) was added 1 M HCl in diethyl ether (1.3 ml). After the addition of 20% Pd(OH)2 on carbon (50% water; 95 mg), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 5 hours. The reaction was filtered through a 0.45 μM disk, and then concentrated, in vacuo, to give a solid. Trituration from diethyl ether afforded I-3A-4b (124 mg, 94%) as an off-white solid: +APcI MS (M+1) 142.0; 1H NMR (400 MHz, CD3OD) δ 4.38 (d, J=12.0 Hz, 2H), 4.17 (s, 2H), 4.13 (d, J=12.5 Hz, 2H), 2.71 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C@H:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]1.[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2Cl)=[CH:26][C:25]=1[O:35][CH3:36]>CS(C)=O>[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2[O:7][C@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]2)=[CH:26][C:25]=1[O:35][CH3:36]
Reactant: COc1cc2ccnc(Cl)c2cc1Br
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2ccnc(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)c2cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (14.1 g, 125 mmol) was added to a solution of trans 4-hydroxy L-BOC-proline (9.67 g, 41.8 mmol) in DMSO (180 mL) at RT. The reaction mixture was stirred at RT for 30 min and cooled to 15° C. The product from step 3 (11.4 g, 41.8 mmol) was added to the reaction mixture as a solution in DMSO (45 mL); the reaction mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was quenched with ice-cold 10% citric acid solution and partitioned with EtOAc. The organic layer was washed with aqueous citric acid solution, water and brine, and the aqueous phases were back-extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, and the solvent was evaporated. LRMS ESI+ (M+H-tBu)+411.2.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][O:20][N:21]1[C:29]2[C:24](=[N:25][C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=2)[CH:23]=[CH:22]1.[Cl:40]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:19][O:20][N:21]1[C:29]2[C:24](=[N:25][C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=2)[C:23]([Cl:40])=[CH:22]1
Reactant: CCOC(=O)c1cc2c(ccn2OC)nc1C(=O)OCC
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(nc1C(=O)OCC)c(Cl)cn2OC
Temperature: 60 °C
Yield: 51 %

Procedure:
Benzoyl peroxide (0.91 g, 0.037 mol) is added to diethyl 1-methoxypyrrolo[3,2-b]pyridine-5,6-dicarboxylate (1.0 g, 0.003 mol) dissolved in (40 mL) carbon tetrachloride under a nitrogen atmosphere and the suspension stirred for ten minutes. N-Chlorosuccinimide (0.84 g, 0.0063 mol) is then added and the reaction heated at 60° C. for four hours. The mixtue is cooled to room temperature and the inorganics are removed by filtration. The organic mother liquors are washed with water and sodium bisulfate and concentrated in vacuo to an orange oil. The oil is flash chromatographed using hexanes and then 4:1 hexanes/ethyl acetate, giving the title product as an off-white solid in 51% yield, having a melting point 146°-148° C.
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])[CH2:23][CH2:22]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:27]([N:24]5[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]5)[CH:28]=4)[N:19]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CNc2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccc(F)cc5)cccn4n3)c2)CC1

Procedure:
N(8)-(4-Fluoro-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-fluoro-benzyl)-amine (0.288 g, 1.04 mol) and ]3-(4-methylpiperazin-1-yl)aniline (223 mg, 1.17 mol) in a manner analogous to Example 2d. Product isolated as red foam (83.06 mg, 18.5%). 1H NMR (400 MHz, (D3C)2SO, δ, pap): 9.16 (s, 1H), 7.96 (d, J=6.3 Hz, 1H), 7.43 (t, J=12.8, 6.7 Hz, 2H), 7.26 (m, 2H), 7.18-7.06 (m, 3H), 6.72 (t, J=14.3, 7.2 Hz, 1H), 6.45 (m, 2H), 6.32 (d, J=8.4 Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 3.11 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=432 (MH)+.
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][C@H:38]([CH2:42][C:43]2[CH:48]=[CH:47][C:46](OS(C(F)(F)F)(=O)=O)=[C:45]([Cl:57])[CH:44]=2)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[F:58][C:59]1[CH:60]=[C:61](B(O)O)[CH:62]=[CH:63][C:64]=1[CH3:65]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][C@H:38]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:61]3[CH:62]=[CH:63][C:64]([CH3:65])=[C:59]([F:58])[CH:60]=3)=[C:45]([Cl:57])[CH:44]=2)[CH2:37]1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: Cc1ccc(-c2ccc(C[C@@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2Cl)cc1F

Procedure:
The title compound was synthesized in analogy to example 80, intermediate (a), from (R)-2-(3-chloro-4-trifluoromethanesulfonyloxy-benzyl)-morpholine-4-carboxylic acid tert-butyl ester and 3-fluoro-4-methylbenzeneboronic acid to give the compound as a colorless oil (97%).