Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([NH2:12])=[O:11])[C:2]1=2.C(O)(=O)C.C1C(=O)N([Br:24])C(=O)C1>ClCCl>[Br:24][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([NH2:12])=[O:11])[C:2]=2[S:1][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)c1cccc2ccsc12
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1cccc2c(Br)csc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of benzo[b]thiophene-7-carboxylic acid amide (500 mg, 2.82 mmol) in dichloromethane (5 mL) is stirred at rt and acetic acid (5 mL) is added followed by NBS (750 mg, 4.23 mmol, 1.5 equiv.). The reaction is stirred at room temperature for 1 hour at which point LC-MS analysis shows full conversion of the starting material to the desired compound (79%) and dibrominated material (21%). The reaction is diluted with water (50 mL), neutralized with aqueous potassium disulfite, followed by sodium bicarbonate. The aqueous layer is then extracted with dichloromethane and the resulting organic layers are combined, washed with brine, dried over Na2SO4 and evaporated. The crude material is purified by LC using DCM as the eluent to afford the title compound as a white solid (300 mg, 41%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[S:3]1>[Pd].CN(C=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[S:3]1
Reactant: COC(=O)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CC2SC(=O)NC2=O)ccc1OC
Yield: 61.3 %

Procedure:
Methyl 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxy-benzoate (9.52 g) was suspended into DMF (250 ml) and hydrogenated with 10% palladium/carbon (10.0 g) at room temperature under a hydrogen pressure of 3.5 kg/cm2. After the reaction, the solution was filtered and concentrated and water was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent; methylene chloride:acetone=50:1) to obtain 5.88 g (61%) of aimed compound as an amorphous material.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:39])[CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=[O:39])[CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3cccc(Cl)c3)cc2)S1
Yield: 47.2 %

Procedure:
To a stirring solution of phosphorus pentoxide (0.38 g, 1.30 mmol) in DCM (8 ml) at 0° C. was added a solution of 5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.25 g, 0.66 mmol) in DCM (8 ml) followed by dimethyl sulfoxide (0.23 mL, 3.30 mml). After stirring for 15 minutes N,N-diisopropylethylamine (0.34 mL, 2.00 mmol) was added. After 45 minutes the reaction was poured into cold sat'd NaHCO3 and the mixture was extracted with EtOAc (x2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-15% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 117 mg (47%) of a white solid. MS (ESI−) for C18H14ClNO4S m/z 374.1 (M−H)−.
Reaction SMILES: [I-].Br[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]([CH:11]([NH:16][C:17](=[O:34])[C@H:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[O:10].Cl>C1COCC1.C1C=CC=CC=1.[Zn]>[OH:10][CH:9]([CH:11]([NH:16][C:17](=[O:34])[C@H:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [I-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(O)CC(=O)OCC

Procedure:
To 10 ml of anhydrous THF were added 360 mg of zinc powder and a small amount of iodide, and the mixture was heated at reflux. A solution of 0.54 ml of ethyl bromoacetate in 6.0 ml of anhydrous THF was added thereto dropwise, followed by heating at reflux for 5 minutes. A solution of 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide prepared in the same manner as in Example 4-(b) in 14 ml of anhydrous benzene was then added thereto dropwise, followed by heating at reflux for 30 minutes. After allowing the mixture to cool, 1N hydrochloric acid was added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 410 mg of the titled compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:61][O:62][CH2:63][CH2:64][NH2:65]>CN(C=O)C.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:65][CH2:64][CH2:63][O:62][CH3:61])=[O:26])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: COCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCNC(=O)[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1

Procedure:
(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarboxylic acid (HCl salt)(0.05 g, 0.12 mmol), HATU (0.09 g, 0.24 mmol), diisopropylethylamine (0.06 g, 0.47 mmol) and 2-methoxyethanamine (0.04 g, 0.47 mmol) were stirred together in 1 ml each of DMF and CH3CN at room temperature overnight. All volatiles were removed with a stream of nitrogen and heat. The residue was dissolved in methanol and purification with phase preparatory HPLC with 10-90% MeOH/water (HCl modifier) gave the desired product as the HCl salt.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:12]=[C:13]3[C:21](=[CH:22][CH:23]=2)[C:20]2[CH:19]=[CH:18][O:17][C:16]=2[CH:15]=[CH:14]3)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1>C(O)(=O)C.[C].[Rh]>[CH2:19]1[CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]3[C:21]([C:20]1=2)=[CH:22][CH:23]=[C:11]([C:6]([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)([OH:10])[CH:7]([CH3:9])[CH3:8])[CH:12]=3
Reactant: CC(C)C(O)(c1ccc2c(ccc3occc32)c1)c1c[nH]cn1
Agent: [Rh]
Solvent: CC(=O)O
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)OCC3)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 34.3 %

Procedure:
A mixture of 1-(1H-imidazol-4-yl)-1-(naphtho[2,1-b]furan-7-yl)-2-methyl-1-propanol (0.310 g) and 5% rhodium carbon (1.50 g) in acetic acid (50 mL) was stirred at room temperature for 7 h under hydrogen atmosphere at 4 atom pressure. Catalyst was filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried and concentrated. The residue was chromatographed on silica gel (eluent; dichloromethane:methanol=20:1) followed by crystallization from ethyl acetate to give the titled compound (0.107 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[C:13]([O:17]CC3C=CC=CC=3)=[CH:12][N:11]=2)=[O:9])[CH2:4][CH2:3]1>CO.[C].[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[C:13]([OH:17])=[CH:12][N:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)c2cc(O)c(OCc3ccccc3)cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2cc(O)c(O)cn2)CC1
Reaction time: 0.33 h
Yield: 38.7 %

Procedure:
To a solution of 1-methyl-4-(4-hydroxy-5-benzyloxy-2-pyridylcarbonyl)piperazine (4.71 g) in methanol (300 ml) was added 10% palladium-carbon(2.35 g) in a stream of nitrogen and the mixture was hydrogenated at atmospheric pressure for 20 minutes. After the catalyst was removed by filtration, the filtrate was evaporated to dryness. The residue was recrystallized from methanol to give 1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)piperazine (1.32 g).
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C[O-].[Na+].C(O[C:15](=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH2:16][CH3:17])C>C(O)C>[CH:2]1([N:7]2[C:21]([NH2:22])=[C:18]([C:19]#[N:20])[C:15]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NNC1CCCC1
Reactant: CCOC(CC)=C(C#N)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1nn(C2CCCC2)c(N)c1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
Cyclopentylhydrazine hydrochloride (20.9 g, 0.1 moles), 97% sodium methoxide (5.6 g, 0.1 moles) and ethanol (100 ml) were combined and stirred at room temperature under argon for 2.5 hours. (1-Ethoxypropylidene)malononitrile was added to the reaction mixture and the mixture was refluxed for 21 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was treated with water (150 ml) and the obtained precipitate was collected by filtration, washed with water and dried in a vacuum oven for 24 hours to afford 14.2 g (70%) of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carbonitrile as a brown powder, m.p. 171°-173° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7]
Reactant: Nc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1N
Yield: 37 %

Procedure:
Using 3-amino-4-methoxybenzoic acid and aniline as materials, compound 2621 is synthesized following a similar method as in Example 28. Yield: 37%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[C:23]([N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=O)=[N:28]1)([CH3:26])([CH3:25])[CH3:24]>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:35][C:34]4[CH:37]=[CH:38][CH:39]=[C:32]([C:29]5[N:30]=[N:31][N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:28]=5)[CH:33]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CC(C)(C)n1nnc(-c2cccc(C=O)c2)n1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)n1nnc(-c2cccc(C=Nc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)c2)n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 691 mg (3.0 mmol) of 3-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[{3-(2-tert-butyl-tetrazol-5-yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H, analogous working-up and digestion in methanol yield 4(3-chloro-phenylamino)-3-[3(2-tert-butyl-tetrazol-5-yl)-benzylamino]1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.60 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=10.3.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Oc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Yield: 85.7 %

Procedure:
A mixture of 2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (187 mg, 0.5 mmol), prepared in Example 78, p-chlorophenol (129 mg, 0.5 mmol) and NaH (60% oil suspension) (40 mg, 1 mmol) in THF (25 mL) was refluxed at 50° C. for 3 hours and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The acetate layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide 2-benzyl-4-(4-chlorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 200 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:19][C:20]1[S:21][C:22]2[C:23](=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=2)[N:24]=1>C(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[C:23](=[C:25]([S:30]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=2)[N:24]=1
Reactant: Nc1nc2c(S(=O)(=O)Cl)cc(F)cc2s1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2cc(F)cc3sc(N)nc23)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the ethyl 4-aminobenzoate (413 mg, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and 2-amino-6-fluorobenzo[d]thiazole-4-sulfonyl chloride (668 mg, 2.5 mmol). The resulting mixture was stirred at 50° C. overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HCl, water and brine, dried over Na2SO4 and concentrated to give crude product, which was purified by chromatography to give pure compound 26C. 1H NMR (CHLOROFORM-d) δ: 8.10 (s, 1H), 7.93-7.82 (m, 2H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.47 (dd, J=7.5, 2.6 Hz, 1H), 7.20-7.09 (m, 2H), 5.73 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H). LC-MS: m/z 396.5 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:17]=2[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:17]4[CH:16]=[CH:15][S:14][C:18]=4[CH2:19][CH2:20]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccsc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine. Yield: 56 mg (72% of theory). ESI-MS: m/z=377 (M+H)+; Rt(HPLC): 1.41 min (Method B).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][C:9]2=[O:15])=[N:4][N:5]([CH3:7])[CH:6]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH2:10][C:9]2=[O:15])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1cc(Br)c(N2CC(CO)CC2=O)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(Br)c(N2CC(CO[Si](C)(C)C(C)(C)C)CC2=O)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
To a solution of 1-(4-bromo-1-methyl-1H-pyrazol-3-yl)-4-(hydroxymethyl)pyrrolidin-2-one (84 mg) and 1H-imidazole (27 mg) in DMF (3.0 mL) was added tert-butyldimethylchlorosilane (54 mg). The reaction mixture was stirred at room temperature for 20 hr, and diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (44 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:17])([CH3:16])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][CH:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:16])([CH3:17])[N:7]([C:21](=[O:22])[CH2:20][CH:19]([CH3:18])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NNC(C)(C)C1c1ccccc1
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC1=NN(C(=O)CC(C)CC(C)(C)C)C(C)(C)C1c1ccccc1
Temperature: 30 °C
Reaction time: 21 h
Yield: 57 %

Procedure:
To a magnetically stirred solution of 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole (1 ml: 0.25 M in anhydrous tetrahydrofuran, 0.25 mmol) was successively added 3,5,5-trimethylhexanoyl chloride (1.1 ml: 0.25 M in anhydrous tetrahydrofuran; 0.275 mmol) and DIPEA (1.1 ml: 0.285 M in anhydrous tetrahydrofuran; 0.313 mmol) and the resulting mixture was stirred for 21 hours at 30° C. An aqueous 5% NaHCO3 solution and dichloromethane were added to the mixture. The organic layer was separated, successively washed with brine and water, dried over MgSO4, filtered and concentrated in vacuo to give [3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazol-1-yl]-3,5,5-trimethylhexan-1-one as a mixture of diastereomers (55 mg, 57% yield). 1H-NMR (400 MHz, CDCl3) δ 0.88 (t, J=7, 3H), 0.94 (s, 9H), 1.00 and 1.01 (2×d, J=7, 3H), 1.12-1.20 (m, 4H), 1.25-1.39 (m, 3H), 1.47-1.58 (m, 5H), 2.07-2.34 (m, 3H), 2.46-2.55 (m, 1H), 2.63-2.73 (m, 1H), 3.72 and 3.74 (2×s, 1H), 6.98 (br d, J=8 Hz, 2H), 7.28-7.37 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:9]=2)[NH:4][CH2:3]1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Cl:64][C:65]1[CH:66]=[C:67]([CH:69]=[CH:70][CH:71]=1)[NH2:68]>CN(C)C=O>[Cl:64][C:65]1[CH:66]=[C:67]([N:68]2[C:16](=[O:18])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]2([C:8]2[CH:9]=[C:10]3[C:5]([NH:4][CH2:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[OH:13])[CH:69]=[CH:70][CH:71]=1
Reactant: O=C1CNc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1CNc2ccc(C3(O)c4ccccc4C(=O)N3c3cccc(Cl)c3)cc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a solution of 2-[(3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)carbonyl]benzoic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (2.0 mL), HOAt (40 mg, 0.28 mmol), HATU (90 mg, 0.23 mmol) and NMM (0.1 mL, 0.80 mmol) was added and the reaction mixture was stirred for 20 minutes at room temperature, followed by the addition of 3-chloro-aniline (24 μL, 0.23 mmol). The reaction mixture was stirred for 15 hours at room temperature. The solvent was evaporated and the resulting crude was purified by reverse phase preparative HPLC (CH3CN/H2O with 0.1% TFA). The fractions were collected and the aqueous solution was lyophilized to give 7-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-3,4-dihydroquinoxalin-2(1H)-one (36 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6): 12.25 (s, 1H), 10.44 (s, 1H), 8.04 (d, 1H), 7.78 (t, 1H), 7.59 (d, 1H), 7.47 (m, 2H), 7.43 (dd, 1H), 7.33 (m, 3H), 7.08 (m, 3H), 4.22 (s, 2H); MS (EI) for C22H16ClN3O3: 406 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1
Agent: [Pt]
Product: NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1
Yield: 72 %

Procedure:
Treatment of (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (4.2 g, 9.34 mmol) with sodium azide (2.4 g, 37.38 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.32 g, 5 wt. %) generally according to the procedure described for Example 1 provided 2.16 g (72%) of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 198-200° C.; Anal. calcd. for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.5; H, 4.39; N, 4.16.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[O:12]([CH2:19][CH2:20][CH2:21]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>C(O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH2:21][CH2:20][CH2:19][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: BrCCCOc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(CCCOc2ccccc2)CC1

Procedure:
A mixture of ethyl isonipecotate (35.5 g 0.226 mole) 3-phenoxy-1-bromopropane (51.6 g, 0.24 mole) and sodium carbonate (25.4 g, 0.24 mole) in 500 ml of absolute ethanol was heated at reflux for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solution was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give a liquid. The liquid was dissolved in absolute ethanol, and a solution of oxalic acid (~0.23 mole) in absolute ethanol was added. The product 73.43 g (87.7%) precipitated as a white, crystalline solid, m.p. 180°-181° C.
Reaction SMILES: S(OCCCCC#C)([C:4]1[CH:10]=[CH:9][C:7](C)=[CH:6][CH:5]=1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+].CO>O>[N:18]([CH2:10][CH2:9][CH2:7][CH2:6][C:5]#[CH:4])=[N+:19]=[N-:20]
Reactant: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#CCCCCN=[N+]=[N-]

Procedure:
A mixture containing 0.397 mole of hex-5-yn-1-ol tosylate; 0.76 mole of sodium azide; and one liter of methanol and 200 ml. of water is stirred at 60° C for 4 hours. The mixture is then evaporated under vacuum to remove the majority of the methanol and the remaining concentrate then poured into 500 ml. of ethyl ether, and then extracted three times with water, and dried over anhydrous magnesium sulfate and filtered. The filtrate is then evaporated, under vacuum, affording 1-azidohex-5-yne as a residue.