Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25].O>CN(C)C=O>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:30])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 59.3 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (234 mg, 1.00 mmol) prepared in Process 3 of Example 12 in N,N-dimethylformamide (2 mL) was added with potassium carbonate (277 mg, 2.00 mmol) and ethylbromoacetate (167 mg, 1.00 mmol) at room temperature, and the resultant was stirred at 80° C. for 20 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=2:1), and ethyl [4,4-dimethyl-3-oxo-2-(adamantan-2-yl)-1,2-diazetidin-1-yl]acetate (190 mg, 59.4%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[N:23]=[N:24][C:25]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:26][C:27]=4[C:28]([OH:30])=[O:29])=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH:39]1(N=C=NC2CCCCC2)CCCCC1.CN(C=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[N:23]=[N:24][C:25]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:26][C:27]=4[C:28]([O:30][CH3:39])=[O:29])=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)cc3C(=O)O)cc2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)nnc1Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A RBF was charged with 4-(dimethylamino)pyridine (5.4 mg, 44 μmol), 3-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)-6-phenylpyridazine-4-carboxylic acid (210 mg, 440 μmol), methanol (53 μl, 1319 μmol) and 1.3 mL DCM. The mixture was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (100 mg, 484 μmol) dissolved in 1.3 mL DCM was added. The heterogeneous mixture was allowed to warm to RT and stirred for 4 h. 1.3 mL of DMF was added and the reaction was stirred at RT for 72 h. The mixture was filtered through a pad of Celite, washing with DCM. The filtrate was concentrated twice from toluene to remove excess DMF. The crude material was purified by silica gel chromatography, 0-10% MeOH/dDCM. Further purification was done by reverse phase chromatography, Gilson, 5-75% acetonitrile/0.1% TFA over 14 min to provide methyl 3-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)-6-phenylpyridazine-4-carboxylate cleanly as a bright yellow solid. MS m/z=492 [M+H]+. Calc'd for C27H21N7O3: 491.50.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN.NN>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:21]([O:23][CH2:24][CH2:25][NH2:26])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1cccc([N+](=O)[O-])c1
Yield: 98.7 %

Procedure:
A solution of 2.32 g (4.59 mmol) of (±)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(2-phthalimidoethyloxycarbonyl)-1,4-dihydropyridine and 344 mg of hydrazine monohydrate in 100 ml of ethanol is heated at reflux for 2 hr. TLC indicates the reaction is incomplete so another 1.5 equivalents of hydrazine monhydrate is added and the mixture refluxed for an additional hr. After cooling, the precipitate is collected by filtration, washed with ethanol, and the filtrate evaporated under vacuum to leave a yellow solid. This solid is taken up in 125 ml of CH2Cl2, washed twice with 0.5N KOH, once with water, dried (MgSO4), filtered, and the solvent removed under vacuum to give 1.70 g of (±)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5 (2-aminoethoxycarbonyl)-1,4-dihydropyridine as a yellow solid. 1H-NMR (CDCl3); δ 1.85 (s, 2H); 2.40 (d, 6H); 3.40 (t, 2H); 3.68 (s, 3 H); 4.35 (s, 2H); 5.15 (s, 1H); 5.90 (s, 1H); 7.40 (t, 1H) 7.68 (d, 1H); 8.03 (d, 1H); 8.13 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:24][C@H:25]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:26]([N:28]1[CH2:33][CH2:32][C:31]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:40][C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29][N:28]([C:26]([C@H:25]([NH:24][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=2)=[O:14])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:27])[CH2:33][CH2:32]1
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A round-bottomed flask was charged with 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.12 g, 0.36 mmol), (R)-2-amino-1-(4-hydroxy-4-phenylpiperidin-1-yl)-3,3-dimethylbutan-1-one (191 mg, 0.49 mmol), HOBT (61 mg, 0.40 mmol) and EDC (76 mg, 0.40 mmol). Then added DMF (1.6 mL) followed by N,N-diisopropylethylamine (0.12 mL, 0.68 mmol). The reaction mixture was stirred at room temperature over the weekend the quenched with water and extracted with diethyl ether (2×). The organic layers were combined and washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 12 g SiO2 with 0-60% EtOAc/heptane to afford 0.21 g (94%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a light yellow oil.
Reaction SMILES: N[C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][C:3]=1[CH2:17][CH3:18].[B-](F)(F)(F)F.FC(F)(F)C([O-])=[O:27].[K+].FC(F)(F)C(O)=O>>[CH2:17]([C:3]1[S:4][C:5]2[N:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[OH:27])[CH3:18]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCOC(=O)c1nc2sc(CC)c(N)c2c(=O)[nH]1
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2sc(CC)c(O)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The diazonium fluoroborate salt is prepared as in Procedure 63 from the amino compound produced in Procedure 51 yielding 0.03 mole of the required idazonium fluoborate. The latter is added in one portion to a solution of 0.03 mole of potassium trifluoroacetate in 13 ml. of trifluoroacetic acid at 0° C. The mixture is stirred at 25° C. for 1 hour and then refluxed overnight. The trifluoroacetic acid is evaporated in vacuo to give a residue which is triturated with water and filtered to give the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([F:14])[CH:11]=[C:12]([F:13])[C:5]=2[N:4]=1.[CH3:15][Si:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19]>>[F:13][C:12]1[C:5]2[N:4]=[C:3]([CH2:2][CH2:19][C:18]#[C:17][Si:16]([CH3:21])([CH3:20])[CH3:15])[N:7]([CH3:8])[C:6]=2[CH:9]=[C:10]([F:14])[CH:11]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Cn1c(CCl)nc2c(F)cc(F)cc21
Product: Cn1c(CCC#C[Si](C)(C)C)nc2c(F)cc(F)cc21
Yield: 90.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from 2-(chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (440 mg, 2.03 mmol) and trimethyl(prop-1-ynyl)silane (274 mg, 2.44 mmol). 4,6-difluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (539 mg, Yield: 91%) was obtained as a brown oil which can be used in the next step without any purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:14]([C:17]1[CH:23]=[CH:22][C:20](N)=[CH:19][CH:18]=1)([O-:16])=[O:15].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:13])[NH:12][C:20]2[CH:22]=[CH:23][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Using the procedure described for the preparation of 4-{[4(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dioxo-1,2,3,4-tetrahyro-isoquinolin-6-yl)-carbamic acid 4-nitro-phenyl ester 5 g (26.0 mmol) of para-nitroanilin and 4-nitrophenyl chloroformate 14.6 g (72.4 mmol) were reacted to give (4-nitro-phenyl)-carbamic acid 4-nitro-phenyl ester, 11.0 g (100% yield) of yellow solid.
Reaction SMILES: CO[C:3](=[O:15])[NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=2[N:9]=1.[N:16]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN1CCCC1=O>[OH:14][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([NH:4][C:3]([NH:24][CH2:23][CH2:22][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[S:6][C:7]=2[CH:13]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)Nc1nc2ccc(O)cc2s1
Solvent: CN1CCCC1=O
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(O)cc2s1
Reaction time: 0.42 h
Yield: 93.9 %

Procedure:
In a 10 cm3 tube, 200 mg of methyl(6-hydroxy-1,3-benzothiazol-2-yl)carbamate are suspended in 6 cm3 of 1-methyl-pyrrolidin-2-one, and 580 mg of 2-morpholin-4-ylethylamine are added. After closing, the tube is placed in the microwave oven at a temperature in the region of 150° C. for about 25 minutes. After concentrating to dryness under reduced pressure, the residue obtained is purified by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)]. 270 mg of 1-(6-hydroxy-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea are thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[CH:9]([CH:11]=O)=O>O>[CH2:4]1[CH:3]2[CH:2]([NH:1][CH:3]3[NH:8][CH:9]4[CH:11]([CH2:4][CH2:5][CH2:6][CH2:7]4)[NH:1][CH:2]3[NH:8]2)[CH2:7][CH2:6][CH2:5]1
Reactant: O=CC=O
Reactant: NC1CCCCC1N
Solvent: O
Product: C1CCC2NC3NC4CCCCC4NC3NC2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
To an ice-cold solution of 11.4 grams (0.1 mole) of 1,2-diaminocyclohexane and 5 ml of water was added dropwise 8.3 grams of 40% aqueous glyoxal (2.9 grams, 0.05 mole). Within 5-10 minutes a precipitate formed, which was allowed to stand at room temperature for one hour, then heated at 65°-70° C. for 1.5 hours. The solid was recrystallized from acetonitrile to give 1.05 grams of tan crystals, m.p. 148°-155° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8](C(O)=O)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:25])C=CC=CC=1.C([N:37]([CH2:40]C)CC)C>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([O:16][CH3:17])=[CH:7][C:8]([N:37]=[C:40]=[O:25])=[CH:12][C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)O)cc(OC)c1OC(C)=O
Solvent: c1ccccc1
Product: COc1cc(N=C=O)cc(OC)c1OC(C)=O

Procedure:
To a mixture of 4-acetoxy-3,5-dimethoxybenzoic acid (672 mg), diphenylphosphoryl azide (990 mg) and benzene (15 ml) was dropwise added triethylamine (0.42 ml), while stirring. The mixture was stirred for 20 minutes at room temperature and further for 30 minutes under refluxing to obtain a solution of 4-acetoxy-3,5-dimethoxyphenyl isocyanate in benzene. 3-Amino-4-(2-chlorophenyl)-1,6,7-trimethyl-2(1H)-quinolone (624 mg) was added to the above solution and the mixture was refluxed for 2.5 hours. The mixture was washed with water, aqueous sodium hydrogen carbonate solution, water, diluted hydrochloric acid and then water in this order, dried (MgSO4) and concentrated.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1.O>[C:1]([C:3](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2]
Reactant: O=C1CCCCC1
Reactant: N#CCC(=O)NCCO
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: N#CC(C(=O)NCCO)=C1CCCCC1

Procedure:
2-Cyano-N-(2-hydroxyethyl)acetamide (4.62 g, 36.1 mmol), cyclohexanone (3.89 g, 4.10 mL, 39.7 mmol), acetic acid (0.433 g, 0.413 mL, 7.21 mmol) and ammonium acetate (2.78 g, 36.1 mmol) were suspended in toluene (150 mL) and the mixture heated to reflux under Dean-Stark conditions until no more water was collected (˜1.5 h). The mixture was concentrated to remove toluene before partitioning between EtOAc/Water. The organic phase was collected, dried and concentrated to a lower volume before addition of small quantities of heptane. The glass was etched until precipitation occurred and the solid collected by filtration. The desired product was isolated in 3 batches (4.2 g, 20.2 mmol, 56%). The sample was used directly in the next step without any further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[Cl:29][C:30]1[C:31]([C:40]([F:43])([F:42])[F:41])=[N:32][N:33]([CH2:36]C(O)=O)[C:34]=1[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.CCOC(C)=O.CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:36][N:33]4[C:34]([CH3:35])=[C:30]([Cl:29])[C:31]([C:40]([F:42])([F:43])[F:41])=[N:32]4)[CH2:27][CH2:26]3)[C:15]2=[O:16])=[CH:18][C:19]=1[O:24][CH3:25]
Reactant: COc1cc(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC3(CCN(C(=O)Cn4nc(C(F)(F)F)c(Cl)c4C)CC3)C2=O)ccc1Cl
Temperature: 25 °C

Procedure:
2-(4-Chloro-3-methoxy-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester ( 39.5 mg, 0.1 mmol, 1 equiv) was treated with 4 mL of 4N HCl in dioxane at rt for 1 h. The volatile was removed and to the residue were added 1 mL of DMF, (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (24.3 mg, 1 equiv), HATU (42 mg, 1.1 equiv), TEA (50 μL, 3 equiv). After stirring at rt over night, the mixture was taken up in EtOAc, washed with saturated sodium NaHCO3. Purification by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) gave 2-(4-Chloro-3-methoxy-phenyl)-8-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-2,8-diaza-spiro[4.5]decan-1-one. LCMS observed for (M+H)+: 519. Retention time: 4.75 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minutes gradient of 20% to 95% B with a 1.1 minutes wash at 95% B (A=0.1 % formic acid/5% acetonitrile/94.9% water, B=0.1 % formic acid/99.9% acetonitrile).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:13][CH2:14][Mg+].[Br-].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.CCOC(C)=O>C1COCC1>[CH2:13]([C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: CC[Mg+]
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: -15 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To a solution of 5-nitro-benzimidazole (2.8 g, 17 mmol) in THF was added 16 ml of EtMgBr solution (48 mmol) and reaction mixture was stirred for 2 h at −15° C. A solution of tetrachloro-1,4-benzoquinone (8.8 g, 36 mmol) in THF was added dropwise into reaction mixture, which was allowed to warm up to 25° C. over 1 h. Silica gel(20 g) was added into reaction mixture and solvent was removed in vacuo to provide a brown silica gel powder which was subjected to column chromatography (EtOAc, meat) to provide 1.7 g (8.9 mmol, 52%) of 4-ethyl-5-nitrobenzimidazole, which was subsequently subjected to hydrogenation (H2, Pd/c) to yield 1.32 g (8.2 mmol) of 4-ethyl-5-aminobenzimidazole.
Reaction SMILES: CON(C)[C:4](=[O:12])[CH2:5][CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=[O:9].[CH3:14][Li].Cl>C1COCC1>[CH3:11][CH:6]([CH2:5][C:4](=[O:12])[CH3:14])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: [Li]C
Reactant: CON(C)C(=O)CC(C)CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)CC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(methoxy(methyl)amino)-3-methyl-5-oxopentanoic acid (10 mmol) in THF (50 mL) and cooled to −78° C. and treated dropwise with methyllithium (1.4 M in diethyl ether, 2 equivalents). The resulting mixture was warmed to rt where it stirred overnight. After this time, the mixture was cooled to 0° C. and then treated with ice cold water. After stirring for 10 min at 0° C., the mixture was acidified with cold 1 M aqueous HCl. The acidified mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum to provide 3-methyl-5-oxohexanoic acid (quantitative yield). Mass spectrum m/z 143.22 (M−H−).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(CC)CC.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>CCOCC.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-benzodioxol-5-amine (10 g, 73 mmol) in 200 ml Et2O and 100 ml THF, NEt3 (12.3 ml, 87.6 mmol) is added. The reaction mixture is cooled to 0° C. and pivaloyl chloride (10.5 ml, 87.6 mmol) in THF is added. After stirring for 1 h at 25° C., ice water is added, the mixture extracted with EtOAc and washed with brine, followed by drying (Na2SO4), evaporation of volatiles, and crystallization (CH2Cl2/hexanes) which gives N-benzo[1,3]dioxol-5-yl-2,2-dimethyl-propionamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.[H][H].[CH2:18](O)[CH3:19]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Product: CCOC(=O)CCCc1ccc(N)cc1

Procedure:
A solution of 10.0 g. of 4-(4-nitrophenyl)butyric acid in 150 ml. of ethanol containing 50 mg. of a 10% palladium on carbon catalyst is hydrogenated until the uptake of hydrogen ceases. After the system is purged with nitrogen and the solution is filtered through a celite pad, 3 ml. of boron trifluoride etherate is added and the solution is heated to reflux for 10 hours. Upon cooling and evaporation of the ethanol, a colorless residue is obtained. This product is recrystallized from ethanol-hexane and affords ethyl 4-(4-aminophenyl)butyrate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].Cl>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: ClCCCCBr
Reactant: CC(=O)Nc1cc(C)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(CCCCCl)c1cc(C)cc(C)n1

Procedure:
To N-(4,6-dimethyl-2-pyridyl)acetamide (49.2 g, 0.3 mole) dissolved in dimethylformamide (550 ml) is added sodium hydride in mineral oil (50%) (13.45 g., 0.32 mole) in portions at room temperature. When reaction is complete, the mixture is warmed with stirring to 45° and 1-bromo-4-chlorobutane (52.5 g., 0.306 mole) is added in one portion and stirred one hour on the steam bath. The reaction mixture is then cooled, acidified with hydrochloric acid and concentrated under vacuum. The residue is dissolved in water and extracted with diethyl ether. The aqueous layer is made basic with sodium hydroxide and extracted with ether. The combined etheral extracts are washed with brine, treated with charcoal, dried (sodium sulfate) and concentrated to obtain the product oil, weight 56.6 g.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[N+](C1C=C(C=CC=1)C(Cl)=O)([O-])=O>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:6]1(=[O:11])[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][NH:5]1
Reactant: Nc1cccc2c1CNC2=O
Agent: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
The suspension of 2,3-dihydro-1H-isoindol-1-one 4 (0.100 gm, 0.61 mmol.) in ethyl acetate and aq. NaHCO3 solution, was added m-nitrobenzoyl chloride (0.15 mg, 0.81 mmol.) at room temperature. The reaction mixture was stirred at room temperature for 30 min, and solid separated was filtered and dried under vacuum to give 2,3-dihydro-1H-isoindol-1-one 25 (0.041 gm, 36%).
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(O)C.C(OC(C)C)(C)C>C(O)C.[Pd]>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: CC(C)O
Product: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reaction time: 72 h

Procedure:
A mixture of 35.8 g (0.1 mole) of α,α-diphenyl-1-(phenylmethyl)-4-piperidinemethanol and 1 tsp of 5% Pd/C in 500 ml of absolute ethanol was hydrogenated at 60° C. in a Parr apparatus for 3 days. The mixture was filtered through Celite® and the filtrate was concentrated to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to give 26.7 g (quantitative) of white solid. An analytical sample, mp 160°-161° C., was prepared from 2-propanol-isopropyl ether.