Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Li+:2].[OH-].[N:4]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:8]([C:9]([O:11]C)=[O:10])[CH2:7][CH:6]=[N:5]1.Cl.O>CO>[C:16]([O:15][C:13]([N:4]1[C@H:8]([C:9]([O-:11])=[O:10])[CH2:7][CH2:6][NH:5]1)=[O:14])([CH3:19])([CH3:17])[CH3:18].[Li+:2]
Reactant: COC(=O)[C@@H]1CC=NN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1NCC[C@H]1C(=O)[O-]
Reaction time: 7 h

Procedure:
A water (5 mL) solution of LiOH (0.146 g, 6.09 mmol) was added to a methanol (5 mL) solution of (S)-1-tert-butyl 5-methyl 1H-pyrazole-1,5(4H,5H)-dicarboxylate (0.76 g, 3.11 mmol), and stirred at ambient conditions for ˜7 h. The reaction mixture was cooled with an ice-water bath, and HCl/H2O (3 mL of 1.00 N; 3.0 mmol) was added dropwise and stirred for a few minutes. Then, the volatile component was removed in vacuo and the resultant viscous oil was exposed to high vacuum to afford lithium (S)-2-(tert-butoxycarbonyl)pyrazolidine-3-carboxylate as a white foam, which was used without further purification. 1H NMR (DMSO-d6, δ=2.50 ppm, 400 MHz) for crude sample: 3.98 (dd, J=8.5, 6.3, 1H), 2.86-2.74 (m, 2H), 2.45 (s, 3H), 2.25-2.17 (m, 1H), 2.10-2.02 (m, 1H), 1.35 (s, 9H). LC-MS: Anal. Calcd. for [M+H]+ C10H19N2O4: 231.13. found 231.21.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:21]([Mg]Br)#[CH:22]>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:21]#[CH:22])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2C=O)cc1
Reactant: C#C[Mg]Br
Product: C#CC(O)c1c(-c2ccc(OC)cc2)nn2c(Cl)cccc12
Yield: 93.8 %

Procedure:
In a similar manner as described in Example 46 from 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (5.11 g, 17.8 mmol) and ethynylmagnesium bromide (89 mL, 0.5 M in tetrahydrofuran, 44.6 mmol) at 0° C. was obtained 1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (5.22 g, 94%) as an off-white solid. 1H NMR (CDCl3): δ 8.02 (d, 1 H), 7.73 (d, 2 H), 7.18 (t, 1 H), 7.02 (d, 2 H), 6.97 (d, 1 H), 5.79 (m, 1 H), 3.87 (s, 3 H), 2.68 (m, 1 H), 2.25 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][C:19](I)=[CH:18][C:17]=3[CH3:27])=[O:14])=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cu][C:33]#[N:34]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][C:19]([C:33]#[N:34])=[CH:18][C:17]=3[CH3:27])=[O:14])=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: CNC(=O)c1cc(I)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
To a solution of 1-(3-chloro-2-pyridinyl)-N-[4-iodo-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (i.e. the diamide product of Step A) (410 mg, 0.72 mmol) in tetrahydrofuran (8 mL) was added copper(I) iodide (24 mg, 0.126 mmol), tetrakis(triphenyphosphine)palladium(0) (70 mg, 0.060 mmol) and copper(I) cyanide (640 mg, 7.2 mmol) sequentially at room temperature. The reaction mixture was heated at reflux for 4.5 hours. Thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 114 mg of the title compound, a compound of the present invention, as a white solid, melting at 214-216° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1N)[NH:28][C:27](=[O:33])[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:33])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: Nc1cc2c(cc1Br)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 39.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-6-amino-1,3-dihydro-indol-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 39.8%) as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.NO.Cl.CC[N:22](CC)CC>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH2:22])[CH3:15])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)c1cc(F)cc(N2CCOCC2)c1
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC(N)c1cc(F)cc(N2CCOCC2)c1
Reaction time: 16 h

Procedure:
A mixture of 1-(3-fluoro-5-morpholin-4-yl-phenyl)ethanone (2.23 g), NH2OH.HCl (1.4 g), and Et3N (2.8 mL) in EtOH (20 mL) was refluxed for 3 hours. After concentration, the residue was extracted with CH2Cl2. The organic layer was washed with water, dried over MgSO4 and concentrated in vacuo. A suspension of the resulting residue (2.23 g) and Ra—Ni (1 mL) in a mixture of 3 mL of 30% ammonium hydroxide and 15 mL of MeOH was hydrogenated at 50 psi for 16 hours. The crude reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography (10% ammonium hydroxide in methanol) to give 1.665 g of the title compound as an oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([O:35][CH3:36])[C:27]=1[O:28][CH2:29][CH:30](OC)OC)[C:21](=[NH:24])[NH:22]O.[NH:37]1[CH2:40][CH:39]([C:41]([O:43]CC)=[O:42])[CH2:38]1>>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]2[N:22]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:24]=2)[CH:25]=[C:26]([O:35][CH3:36])[C:27]=1[O:28][CH2:29][CH2:30][N:37]1[CH2:40][CH:39]([C:41]([OH:43])=[O:42])[CH2:38]1
Reactant: COc1cc(C(=N)NO)cc(Cl)c1OCC(OC)OC
Reactant: CCOC(=O)C1CNC1
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Product: COc1cc(-c2nc(-c3cc(Cl)c(OCCN4CC(C(=O)O)C4)c(OC)c3)no2)cc(C2CCCC2)n1

Procedure:
The title compound is prepared starting from 2-cyclopentyl-6-methoxy-isonicotinic acid, 3-chloro-4-(2,2-dimethoxyethoxy)-N-hydroxy-5-methoxybenzimidamide and ethyl azetid ine-3-carboxylate in analogy to Example 43 and 1 (saponification); LC-MS: tR=0.88 min, [M+H]+=528.92; 1H NMR (CDCl3): δ 7.79 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.45 (s, 1H), 7.24 (s, 1H), 5.96 (s br, 1H), 4.55-4.64 (m, 2H), 4.44-4.54 (m, 2H), 4.32-4.38 (m, 2H), 4.00 (s, 6H), 3.65-3.74 (m, 1H), 3.58-3.65 (m, 2H), 3.18-3.27 (m, 1H), 2.05-2.14 (m, 2H), 1.82-1.94 (m, 4H), 1.75 (m, 2H).
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]([O:11][CH2:12][CH3:13])(=O)[C:5]([O:7]CC)=O.Cl.[OH-].[Na+].[C:17]([O:21]C)(C)(C)C>>[CH3:1][CH:4]1[C:5](=[O:7])[C:17]([OH:21])=[C:12]([CH3:13])[O:11]1
Reactant: C[O-]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(O)C(=O)C(C)O1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a suspension of 113.4 g of sodium methylate in 750 g of methyl t-butyl ether was added at 5° C. in one hour 146 g of diethyl oxalate followed by a stirring period of one hour at 5° C. Then 204 g of diethyl 2-methyldiglycolate in two hours was added at 5° C. and the mixture was stirred for four hours at that temperature followed by a reflux period of three hours. The reaction mixture was added to 797 g of 8.9% hydrochloric acid solution at 20° C. and the pH of the resulting mixture was adjusted to 5 with 33% sodium hydroxide solution. To the separated upper layer was added with stirring 903 g of 17.8% sodium hydroxide solution at 20° C. The layers were allowed to settle and the separated lower layer was kept at 20° C. for 20 hours. Then, 200 g of water was added, 104 g of methyl bromide was introduced at 20° C. in one hour, and the mixture was stirred for another hour; and the pH of the solution was adjusted to 6.5 by the addition of concentrated hydrochloric acid solution. Extraction with methyl t-butyl ether yielded 95 g of 2,5-dimethyl-4-hydroxy-3[2H] furanone of 97.3% purity (molar overall yield 72.2%).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18]([CH2:25][CH3:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18]([CH2:25][CH3:26])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1CC#N
Solvent: CO
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1CC#N
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a solution of {4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-ethylphenyl}acetonitrile (200 mg, 0.57 mmol, example A(102)) in anhydrous MeOH (6 mL) at room temperature was added 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (120 mg, 0.68 mmol). The mixture was stirred for 5 min before borane-dimethylamine complex (37 mg, 0.62 mmol) was added. The reaction was stirred at that temperature for 15 hours before it was quenched by the addition of 1.0 N HCl. The solvent was removed and the residue was purified by HPLC to obtain the desired product (60 mg, 21% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.03 (t, J=7.5 Hz, 3H), 1.32-1.64 (m, 8H), 2.06 (m, 2H), 2.36-2.55 (m, 12H), 2.73 (d, J=17.9 Hz, 1H), 3.64 (d, J=16.1 Hz, 1H), 3.77 (d, J=16.4 Hz, 1H), 3.89 (s, 2H), 6.95 (s, 1H), 7.00 (s, 1H), 7.04 (d, J=7.7 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:15])[NH:11][CH2:12][CH2:13][F:14])(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][CH2:12][CH2:13][F:14])=[O:15].[F:17][C:18]([F:23])([F:22])[C:19]([O-:21])=[O:20]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCCF
Solvent: ClCCl
Product: NCCC(=O)NCCF
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of [2-(2-Fluoro-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.353 g, 1.51 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (1 ml) and the reaction stirred at ambient temperature for 4 hours. The solvent was evaporated to dryness to yield the titled product as a trifluoroacetate salt.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH2:8][S:7][C:6]([NH:9][NH2:10])=[N:5][N:4]=1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27](Cl)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(#N)C.C(OCC)(=O)C>[N+:18]([C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]([NH:10][NH:9][C:6]2[S:7][CH2:8][C:3]([CH3:2])=[N:4][N:5]=2)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reactant: CC1=NN=C(NN)SC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)NNC1=NN=C(C)CS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A mixture of 24.25 g (0.134 m) of (5-methyl-6H-1,3,4-thiadiazin-2-yl)-hydrazine hydrochloride (2b) and 25.9 g (0.256 m) of triethylamine in 170 ml of acetonitrile is cooled to 0° C. A solution of 46.8 g (0.122 m) of 2-(4-nitrophenoxy)tetradecanoyl chloride (3b) in 50 ml of ethyl acetate is added slowly to the mixture keeping the temperature at 0-5° C. over an hour. The resulting mixture is stirred at 0° C. for 30 min, then warmed up to room temperature and stirred for another hour. After the reaction is complete, 170 ml of ethyl acetate is added and the mixture is stirred for 15 min. The solid is collected, washed with ethyl acetate, dried, and reslurried in 300 ml of water to remove triethylamine hydrochloride. The product is collected, washed with water, and dried to give 33.0 g (55%) of 2-(2-[4-nitrophenoxy] tetradecanoyl)-1-(5-methyl 6H-1, 3,4 thiadiazin-2-yl)hydrazine (1b) with 93 area % by HPLC.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH2:15].[OH-].[Na+]>>[CH2:1]([O:8][CH:9]1[CH2:12][N:15]([CH3:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: ClCC(CCl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 47 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloro-propane and 77.5 parts of monomethylamine (40% aqueous solution) were added to an autoclave and they were heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and 120 parts of 2N-NaOH aqueous solution were added thereto. Then the mixture was heated to distill off excessive monomethylamine. The remaining liquor was extracted twice with 200 parts of ether, and the extract was washed with 100 parts of water, extracted with 100 parts of 2N-HCl aqueous solution and further extracted with 50 parts of 2N-HCl aqueous solution. The water layers were combined, washed with 50 parts of ether and made sufficiently alkaline with 2N-NaOH aqueous solution. The liquor was extracted twice with 100 parts of ether, and the ether extract was washed in 50 parts of water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to distillation to yield 8.3 parts of 3 -benzyloxy-1-methylazetidine boiling at 80° - 82° C. The yield was 47%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.N#N.[CH:26]#[C:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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>[C:26]([C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1)#[C:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C#CCCCC
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC#Cc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Reaction time: 0.05 h
Yield: 94.7 %

Procedure:
To a stirred solution of N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.20 g, 0.536 mmol, 1 eq.) in 2 ml dry THF “degassed” with N2, was added hexyne (0.176 g, 2.14 mmol, 4 eq.) followed by N-ethyldiisopropylamine (0.361 g, 2.79 mmol, 4 eq.), Copper Iodide (0.031 g, 0.161 mmol, 0.3 eq.) and Tetrakis(triphenylphosphine)palladium (0.186 g, 0.161 mmol, 0.3 eq.). The reaction was microwaved 120° C./normal/fixed hold/pre stir 100 s for 180 s. The reaction was diluted with EtOAc and filtered through a “celite” plug. The solvent was evaporated and the residue purified by chromatography on silica gel to give N-{[6-(hex-1-yn-1-yl)pyridin-2-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.19 g, 85% yield) as a yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:15][C:16]([OH:18])=[O:17])[C:8]2=[O:19].S(=O)(=O)(O)O.[CH3:30]O>O>[CH3:30][O:17][C:16](=[O:18])[CH2:15][N:9]1[C:8](=[O:19])[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][C:3]3[C:2]([CH3:1])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:24])[CH:6]=2)[C:10]1=[O:14]
Reactant: Cc1cccc(C)c1Oc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CN1C(=O)c2ccc(Oc3c(C)cccc3C)cc2C1=O
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of [5-(2,6-Dimethyl-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid in MeOH (1 mL/mmol) was added concentrated sulfuric acid (35 μl/mmol) and the mixture was refluxed with stirring for 16 h before it was diluted with water (6.5 mL/mmol) and extracted twice with EtOAc. The combined organic phases were washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated in vacuo to give the title compound as a tan solid (yield: 96%); MS-(+)-ion: M+1=340.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH3:15])=[CH:10][C:11]([O:13][CH3:14])=[O:12].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=O>O1CCCC1.C(O)(=O)C.C(OC(C)C)(C)C>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([CH3:15])=[C:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)C=C(C)Nc1ccccc1N
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)Nc2ccccc2NC1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 3-[(2-aminophenyl)amino]-2-butenoic acid, methyl ester (4.74 g., 230 mmole) in anhydrous tetrahydrofuran (20 ml.) and acetic acid (0.2 ml.) is treated with 2,6-dichlorobenzaldehyde (4.03 g., 23.0 mmole). The resulting reaction mixture is stirred at room temperature for 4 days. The solvent is stripped off to give a brown oil which is dissolved in isopropyl ether and allowed to stand at 0°-5° (refrigerator) for 24 hours. The solid that precipitates is filtered off and washed with additional isopropyl ether. This product is triturated with isopropyl ether and filtered off to give 2-(2,6-dichlorophenyl)-2,5-dihydro-4-methyl-1H-1,5-benzodiazepine-3-carboxylic acid, methyl ester; 119°-120° (with decomposition). TLC (silica gel; ethyl acetate:hexanes, 40:60) Rf =0.38.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10]Br.[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:14]=1[OH:21]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:14]=1[O:21][CH2:10][CH2:9][O:8][CH3:7]
Reactant: COCCBr
Reactant: CCc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(OCCOC)c(Br)c1
Reaction time: 20 h
Yield: 89.3 %

Procedure:
Potassium carbonate (8.25 g, 60 mol) followed by 2-bromoethyl methyl ether (1.87 mL, 20 mmol) were added to a solution of 2-bromo-4-ethyl-phenol (4 g, 20 mmol, from step 1 of Example B(98)) in DMF (25 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (4.63 g, 90%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3 H), 2.57 (q, J=7.6 Hz, 2 H), 3.48 (s, 3 H), 3.79 (t, J=5.1 Hz, 2 H), 4.15 (t, J=4.8 Hz, 2 H), 6.85 (d, J=8.3 Hz, 1 H), 7.06 (dd, J=8.3, 2.3 Hz, 1 H), 7.37 (d, J=2.3 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:4]2[CH:3]=[C:2]([NH:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:13][CH2:12]1)(=[O:15])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(N2CCN(C(=O)c3ccccc3)CC2)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2cccc(Nc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A suspension of (4-(3-aminophenyl)piperazin-1-yl)(phenyl)methanone (0.5 g, 1.8 mmol), copper acetate (0.65 g, 3.6 mmol), triethylamine (1.7 ml, 12.4 mmol), 4 Å molecular sieves (0.5 g) and phenylboronic acid and pyridine complex (0.70 g, 1.8 mmol) in 30 ml dry dichloromethane was stirred at room temperature overnight. The reaction was quenched with 20 ml water extracted with dichloromethane (3×40 ml), followed by drying over anhydrous sodium sulfate. 3-(4-Benzoylpiperazin-1-yl)-N-phenylbenzenamine (0.42 g, 66%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.20 (d, br, 4H), 3.65 (d, br, 4H), 5.73 (s, 1H), 6.54 (dd, J=8.0, 1.6 Hz, 1H), 6.67 (m, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.11 (dd, J=8.6, 1.0 Hz, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.44 (m, 2H), 7.48 (m, 5H). 13C NMR (125 MHz, CDCl3): δ (ppm) 50.0, 50.1, 50.3, 106.5, 110.0, 110.7, 118.6, 121.6, 127.6, 129.0, 129.8, 130.3, 130.5, 136.1, 143.5, 144.7, 152.6, 170.9.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH:14](Cl)[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH3:11].CCN(CC)CC>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[S:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:15]=1[C:16]([F:17])([F:18])[F:19])=[O:22])[CH3:11]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=S)c1cccnc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(-c2cccnc2)nc1C(F)(F)F
Temperature: 150 °C

Procedure:
To a 20 mL microwave tube was added thionicotinamide (0.552 g, 4.0 mmol), ethanol (15 mL) and 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (1.75 g, 8 mmol). The tube was capped and heated in a microwave at 150° C. for 10 min. The reaction mixture was cooled to ambient temperature and Et3N (1.7 mL, 12 mmol) was added. The tube was capped and heated in a microwave at 130° C. for 1 min. After cooling to ambient temperature the solvent was evaporated and the crude reaction mixture was directly subjected to silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as an orange oil which subsequently solidified (0.885 g, 73%): IR (KBr) 2988, 1737, 1712 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.21 (dd, J=2.5, 0.8 Hz, 1H), 8.77 (dd, J=5.0, 1.7 Hz, 1H), 8.33 (dt, J=8.0, 2.2 Hz, 1H), 7.47 (ddd, J=11.8, 4.7, 0.8 Hz, 1H), 4.45 (q, J=14.3, 7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H); ESIMS m/z 303 (M+1).