Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](=[O:47])([O:44][CH2:45][CH3:46])[O:40][CH:41](Cl)[CH3:42].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[CH2:41]([O:40][C:39]([O:44][CH2:45][CH2:46][O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])=[O:47])[CH3:42]
Reactant: CCOC(=O)OC(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)OCCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 78 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were added into the reaction tube, and then 1-chloroethyl ethyl carbonate (0.092 g, 0.6 mmol), potassium iodide (0.0415 g, 0.25 mmol) and potassium carbonate (0.083 g, 0.6 mmol) were added successively under stirring. Then the reaction tube was sealed up. The reaction mixture was reacted at 65° C. in an oil bath for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. After cooling to room temperature, 40 mL of water was added to the reaction tube. The reaction mixture was extracted with ethyl acetate (25 mL×3), and the combined organic phase was washed with water (20 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound, (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-ethoxycarbonyloxy)-ethyl ester 34a (0.26 g, yield 78.1%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([NH2:32])[N:23]=1.Cl.C(O)C>O>[NH2:32][C:24]1[N:23]=[C:22]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:25]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
19.0 mg (0.071 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 19.6 mg (0.099 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 5 ml of water. 0.1 ml (0.1 mmol) of 1N hydrochloric acid is added, and the mixture is heated at reflux overnight. 3 ml of ethanol and a further 19.6 mg (0.099 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added. The mixture is stirred at 100° C. for another 6 hours. The mixture is concentrated slightly and the pH is adjusted to 10 using 1N aqueous sodium hydroxide solution, resulting in the precipitation of crystals. The crystals are filtered off with suction, washed with water and purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 10:1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[O:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17]>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:14]2[CH2:15][CH2:16][O:12][C:13]2=[O:17])=[N:3][CH:4]=1
Reactant: O=C1NCCO1
Reactant: COC(=O)c1ccc(Br)nc1
Product: COC(=O)c1ccc(N2CCOC2=O)nc1
Yield: 78.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using methyl 6-bromonicotinate (1 g) and oxazolidin-2-one (474 mg), the title compound (810 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(Oc2cccc(CCl)c2)n1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(Oc2cccc(C)n2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-6-methylpyridine (4.0 g, 17 mmol) from Step 2 was treated neat with triethylphosphite (3.67 mL, 21.4 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-60%, EtOAc:CH2Cl2) to afford the title compound (4.7 g, 82% yield) as a thick oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].CC(=[O:13])C>>[CH3:7][CH:6]([CH:5]([CH3:8])[C:4](=[O:3])[CH3:9])[C:2](=[O:13])[CH3:1]
Reactant: Cc1oc(C)c(C)c1C
Reactant: CC(C)=O
Product: CC(=O)C(C)C(C)C(C)=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
Compound 219A was made in accordance with the procedures described in Hancock et al. J. Org. Chem. 42,1850–1856 (1977) & Amarnath et al. J. Org. Chem., 60, 301–307 (1995). 2-Propanone (100 mL, 1.1 mol) was refluxed over PbO2 (26.7 g, 0.112 mol) for 28 h. After cooling to rt, the reaction mixture was filtered and the residue was washed with acetone. The filtrate was concentrated under reduced pressure to remove the acetone and then distilled at 20 Torr. The fraction that came over between 100–120° C. was collected to give 6.75 g (42.5%) of 3,4-dimethylhexane-2,5-dione as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:26][CH2:25]1)(=[O:23])=[O:22]
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Product: COc1ccc(Nc2nc3c(N4CCN(S(C)(=O)=O)CC4)cccn3n2)cc1

Procedure:
[8-(4-Methanesulfonyl-piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and 1-methanesulfonyl-piperazine (29.0 mg, 0.176 mmol) in a manner analogous to example 30. The title compound was isolated as an off-white solid (0.021 g, 33%). MP=240-241° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (dd, J=6.5, 1.1 Hz, 1H), 7.51-7.46 (m, 2H), 6.93-6.88 (m, 2H), 6.77 (dd, J=7.7, 6.6 Hz, 1H), 6.73 (s, 1H), 6.71 (dd, J=7.7, 1.0 Hz, 1H), 3.81 (s, 3H), 3.59-3.54 (m, 4H), 3.50-3.45 (m, 4H), 2.83 (s, 3H). MS=403 (MH)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH:8]1[CH2:12][C:11](=[O:13])[N:10]([CH:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][CH2:16][CH:15]2[CH:21]([CH3:23])[CH3:22])[CH2:9]1)=[O:7]>O1CCCC1>[CH:21]([CH:15]1[CH2:16][CH2:17][CH:18]([CH3:20])[CH2:19][CH:14]1[N:10]1[C:11](=[O:13])[CH2:12][CH:8]([C:6]([OH:7])=[O:5])[CH2:9]1)([CH3:22])[CH3:23]
Reactant: COC(=O)C1CC(=O)N(C2CC(C)CCC2C(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
Lithium hydroxide, monohydrate (LiOH, H2O) (13.22 g, 0.315 mol) was added to a solution of 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (obtained as in EXAMPLE I, 59 g, 0.21 mol,) in a mixture of tetrahydrofuran (THF:H2O:CH3OH) (1:1:1) (300 mL) at room temperature and was stirred for 1-2 hours. THF and CH3OH were then removed via evaporation. HCl was added and the reaction mixture was extracted three times with ethyl acetate. The organic fractions were combined, washed with brine, dried, and concentrated to provide 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (50 g), which was further evaporated with benzene twice to remove traces of water.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([CH2:17][C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:17][C:18]2=[O:19]
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Temperature: 130 °C

Procedure:
A mixture of p-toluidine (2.14 g, 0.02 mole), ethyl benzoylacetate (4.9 g, 0.025 mole), and polyphosphoric acid (PPA) was heated at 130° C. with stirring. After the reaction was complete, the mixture was cooled to room temperature and neutralized with 4 M NaOH. The yellow solid was filtered, washed with water, dried and recrystallized from ethanol to give compound I-8-a as white solid (2.9 g, 48.9%).
Reaction SMILES: [C:1](=[O:47])([O:16][C:17]1[C:18]([CH3:46])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22]([CH3:45])([CH2:29][CH2:30][CH2:31][CH:32]([CH3:44])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:43])[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:21][CH2:20]2)[O:2][CH2:3][CH:4]1[O:15][CH:5]1[CH2:6][O:7]CC1C=CC=CC=1.C(O)C.[H][H]>[C].[Pd].C(O)(=O)C>[C:1](=[O:47])([O:16][C:17]1[C:18]([CH3:46])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22]([CH3:45])([CH2:29][CH2:30][CH2:31][CH:32]([CH3:44])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:43])[CH2:37][CH2:38][CH2:39][CH:40]([CH3:41])[CH3:42])[CH2:21][CH2:20]2)[O:2][CH2:3][CH:4]1[O:15][CH:5]1[CH2:6][OH:7]
Reactant: [H][H]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCC1OC1COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC1OC1CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 80.2 %

Procedure:
A mixture comprising 6.5 g (0.01 mol) of 4-benzyloxy-2,3-epoxybutyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate, 1 g of 5% palladium carbon, 150 ml of ethanol and 5 ml of acetic acid was catalytically reduced with hydrogen at an initial pressure of 4 kg/cm2 until no hydrogen was absorbed any more (approximately 6 hours). After filtering off the catalyst, the filtrate was concentrated to thereby reduce the amount to 1/3, poured into water and extracted with ether. Then the extract was successively washed with an aqueous solution of sodium hydrogencarbonate and water, and dried. After distilling off the solvent, the obtained oily residue was purifed by column chromatography (silica gel, hexane/ethyl acetate) to thereby give 4.5 g of the title compound as a colorless oily product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1([CH2:17][S:24][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccnc1SCc1ccccc1
Temperature: 140 °C
Yield: 71.49 %

Procedure:
In a stirred suspension of 96.37 g potassium carbonate in 700 gm dimethyl formamide, 100 gm 2-chloro nicotinic acid was charged. A solution of 82.38 g benzyl mercaptan in 300 gm dimethyl formamide was added in a period of two hours maintaining reaction temperature 80-90° C. The temperature of the reaction was raised up to 140° C. and then maintained for another three hours. 500 g water was added after completion of the reaction and solvent recovery. Product precipitation achieved by lowering the pH of the reaction mass by using dilute HCl. Product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid precipitated completely till pH 4.5. After filtration and washing, cake was dried to get 110 g white to off white solid product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid with 71.49% yield (Assay by HPLC 99.23%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[O:22])[CH2:11]1)=[O:7])(C)(C)C.[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37](C(O)=O)=[C:36]([O:44][CH3:45])[CH:35]=1>>[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH3:32])[CH:24]=3)=[O:22])[CH2:11]2)=[O:7])=[C:36]([O:44][CH3:45])[CH:35]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1cc(C(=O)NCCCCCN2CC[C@@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@@H]1CCN(CCCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(5-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-pentyl)-1-methyl-1 H-indole-3-carboxamide (1.48 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.68 g) to give N-(5-((3S)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]2[CH:11]=[C:10]([CH3:12])[CH2:9][C@@:8]\1([NH2:13])[C:7]1[CH:14]=[CH:15][C:16]([NH:18][C:6]=1[CH2:5]2)=[O:17].[CH:19](=O)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C.C1COCC1>[C:22]1([CH:21]=[CH:20][CH:19]=[N:13][C@@:8]23[C:7]4[CH:14]=[CH:15][C:16](=[O:17])[NH:18][C:6]=4[CH2:5][C@@H:4](/[C:3]/2=[CH:2]\[CH3:1])[CH:11]=[C:10]([CH3:12])[CH2:9]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C/C=C1\[C@H]2C=C(C)C[C@@]1(N)c1ccc(=O)[nH]c1C2
Reactant: O=CC=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C/C=C1\[C@H]2C=C(C)C[C@]1(N=CC=Cc1ccccc1)c1ccc(=O)[nH]c1C2
Yield: 95.2 %

Procedure:
20 mg Huperzine A, and 77 mg cinnamaldehyde were refluxed in 2 mL isopropanol for 3 hours. Solvent was removed under vacuum. The crude reaction mixture was dissolved in 3 mL anhydrous THF and purified with prep. TLC (CHCl3: methanol=9:1) to give 28 mg of title product. MS: 357 (M+H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[CH2:20][S:21][CH3:22].C(=O)([O-])O.[Na+]>CO.O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[CH2:20][S:21][CH3:22]
Reactant: COc1ccc([N+](=O)[O-])cc1CSC
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(N)cc1CSC
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
Sodium dithionite (3.264 g) was added to a solution of 1-methoxy-2-methylsulfanylmethyl-4-nitro-benzene (0.8 g), and sodium hydrogen carbonate (1.57 g) in methanol:water (1:1, 200 ml) and stirred at room temperature for 16 h. Solvent was removed at reduced pressure, the residue partitioned between water and ethyl acetate, the organic phase separated, washed with brine dried (Na2SO4) and solvent removed at reduced pressure to give the title compound (0.23 g) as a brown oil. m/z (API+): 184 (MH+).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1COCC1>[CH2:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
At 0° C., 1.32 g (33 mmol) of 60% NaH was added to a solution containing 5.2 g (30 mmol) of 1,4-dioxaspiro[4,5]decan-8-ylmethanol dissolved in 75 ml of THF. After stirring for 10 minutes, benzyl bromide (50 mmol) was added and the mixture was stirred for 18 hours at room temperature. Then, the reaction solution was neutralized with 1N aqueous hydrochloric acid solution, and concentrated under reduced pressure. The residue was dissolved in ether, washed twice with water and once with brine, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography to obtain 8-(benzyloxymethyl)-1,4-dioxaspiro[4,5]decane (6.0 g, 77%) as a colorless clear oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[CH:10]=[CH:9]1.[C:21]1(I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:21]1([C:9]2[CH2:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1=Cc2ccc3ccccc3c2C1
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C1=C(c2ccccc2)Cc2c1ccc1ccccc21
Temperature: 25 °C
Yield: 49.5 %

Procedure:
20 ml of triethylamine, 3.32 g (20 mmole) of benzindene, 4.08 g (20 mmole) of phenyl-iodide and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with ethanol and dried under vacuum to obtain 2.4 g (50%) of the mixture of two isomers.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=1)=[O:8].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH3:17])[CH:10]=1)=[O:8]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCOC(=O)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1c(C)cc(C=O)cc1C
Temperature: 110 °C

Procedure:
Potassium tert-butoxide (2.1 g, mw 112.2, 18 mmol) was added to a solution of 4-formyl-2,6-dimethylphenol (2.5 g, mw 150.2, 17 mmol) in dry DMF (15 mL) and the resultant suspension stirred under N2 at 25° C. for 5 minutes. Ethyl 5-bromovalerate (2.8 mL, mw 209.1, ρ 1.32, 18 mmol) dissolved in dry DMF (15 mL) was added, and the reaction heated at 110° C. for 5 hours, following which DMF was removed at 60° C. and 2 mm Hg. The residue was taken up in ethyl acetate (125 mL), washed with water (25 mL), 1 N aqueous NaOH (25 mL), and brine (75 mL), dried over Na2SO4, filtered, and concentrated to yield 4.47 g (97%) of NMR and TLC (Rf 0.58, CHCl3 -methanol, 99:1) pure title product as an amber oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:22][CH3:23])[C:16](=[O:21])[CH:17]=[C:18](Cl)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]#[N:33].C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:22][CH3:23])[C:16](=[O:21])[CH:17]=[C:18]([C:28]3[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[C:26]([F:25])[CH:27]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)cc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)cc1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of [1-(4-chloro-1-ethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (210 mg, 0.59 mmol) in CH3CN (10 mL), 3-fluoro-4-cyanophenylboronic acid (126 mg, 0.77 mmol), Pd(PPh)4 (14 mg, 0.012 mmol) and 0.4 M Na2CO3 (4.5 mL, 1.77 mmol) was stirred at 90° C. overnight under N2 atmosphere. The organic was concentrated in vacuo, and the aqueous extracted with DCM (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica chromatography (1:2, EA:PE) to give 185 mg (64%) of the title compound as a yellow solid. [M+H] Calc'd for C23H28FN5O3, 442. Found, 442.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.[Cu]I>[N+:9]([C:5]1[CH:6]=[C:7]([C:26]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([NH2:1])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: C#Cc1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc([N+](=O)[O-])cc1C#Cc1ccccc1
Reaction time: 12 h

Procedure:
1.83 g 2-amino-3-bromo-5-nitropyridine 0.29 g PdCl2(PPh3)2 and 79 mg CuI were mixed in 36 ml dry tetrahydrofuran (THF) and 3.45 ml triethylamine and 1.12 g phenylacetylene were added. Stirring was continued at room temperature for 12 hrs, then the solvent was removed and the residue purified by flash chromatography on silica in ethyl acetate/heptane eluent. Yield 855 mg.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:11][CH:10]1[CH2:9][N:8]([CH3:12])[CH2:7]2)=[O:5])C.S(=O)(=O)(O)O>C(O)C.O>[CH3:12][N:8]1[CH2:9][CH:10]2[C:6]([C:4]([OH:5])=[O:3])([CH2:11]2)[CH2:7]1
Reactant: CCOC(=O)C12CC1CN(C)C2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CN1CC2CC2(C(=O)O)C1

Procedure:
A solution of 10 g of 3-methyl-3-azabicyclo[3.1.0]-hexane-1-carboxylic acid ethyl ester in 20 ml of ethanol is treated with a solution of 18.8 g of Ba(OH)2 ·8H2O in 500 ml of water. The resultant mixture is boiled under reflux for 15 hours. After cooling, the mixture is neutralized with 10% sulphuric acid. The resultant barium sulphate is filtered off. The filtrate is evaporated and taken up in methanol. After filtration through talc, the filtrate is concentrated to yield the title compound as crystals of M.Pt. 193°-195°.
Reaction SMILES: [C:1]([NH:6][C:7]1[O:8][CH:9]=[C:10]([CH3:12])[N:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.O>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:6]([C:7]1[O:8][CH:9]=[C:10]([CH3:12])[N:11]=1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1coc(NC(=O)C(C)C)n1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1coc(N(Cc2cccc(Cl)c2)C(=O)C(C)C)n1
Temperature: 70 °C

Procedure:
2-iso Butyramido-4-methyloxazole (11.1 g., 0.066 mol) prepared in a manner similar to that described in Example 20, was dissolved in dry dimethylformamide. Solid potassium carbonate (10.47 g., 0.076 mol) and 3-chlorobenzyl bromide (15.6 g., 0.076 mol) were added and the stirred mixture was heated at 70° C. for 2 hours, cooled and poured into cold water. The solution was extracted with ether and the extract was dried over magnesium sulphate and evaporated. The residue was distilled to give the product, 12.3 g., b.p. 115-120° C./0.08 mm.