Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[C:15]([C:26]([O:28]C)=O)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:24][CH3:25])=[CH:19][CH:18]=2)C.C(O)(=O)C>O1CCCC1>[CH3:25][O:24][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]=[C:15]3[C:14](=[CH:23][C:22]=2[CH:21]=1)[NH:13][CH:12]=[C:7]([C:6]#[N:8])[C:26]3=[O:28]
Reactant: CC#N
Reactant: COC(=O)c1cc2ccc(OC)cc2cc1/N=C/N(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2cc3c(=O)c(C#N)c[nH]c3cc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.81 mL (7.03 mmol) of n-butyllithium (2.5M in hexane) in 2.0 mL of tetrahydrofuran at −78° C. is added dropwise a solution of 0.448 mL (8.44 mmol) of acetonitrile in 4.4 mL of tetrahydrofuran. After completion of addition, the suspension is stirred for 10 minutes. To this is added 804.5 mg (2.81 mmol) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate in 18 mL of tetrahydrofuran dropwise. The resulting reaction mixture is stirred at −78° C. for 1 hour and at −5° C. for 1 hour. The reaction mixture is again cooled to −78° C. and 4.0 mL (69.9 mmol) of acetic acid is added dropwise. The reaction mixture is warmed up to room temperature and stirred overnight. The precipitate is collected by filtration and washed sequentially with water, acetonitrile and methanol. After drying in vacuo, this yields 468.6 mg (67%) of 8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>265° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:67])[C@@H:15]([NH:37][C:38]([C:40]2[CH:44]=[C:43]([O:45][CH2:46][C:47]([N:49]3[CH2:53][CH2:52][CH2:51][C@H:50]3[C:54](=[O:60])[NH:55][CH:56]3[CH2:59][CH2:58][CH2:57]3)=[O:48])[N:42]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[N:41]=2)=[O:39])[CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:67])[C@@H:15]([NH:37][C:38]([C:40]2[CH:44]=[C:43]([O:45][CH2:46][C:47]([N:49]3[CH2:53][CH2:52][CH2:51][C@H:50]3[C:54](=[O:60])[NH:55][CH:56]3[CH2:59][CH2:58][CH2:57]3)=[O:48])[N:42]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[N:41]=2)=[O:39])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 400 mg 4-[(S)-5-(tert-Butyl-diphenyl-silanyloxy)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanoyl]-piperazine-1-carboxylic acid butyl ester in 40 ml THF were added 0.6 ml of TBAF (1 M in THF) and the mixture stirred at RT for 12 h. It was concentrated, the residue was dissolved in DCM and washed with water (3×). The solvent was removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[C:20]([NH:26][C@H:27]([C:30]([OH:32])=O)[CH2:28][OH:29])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].[CH:33]1[C:43]2[CH:42]=[CH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[C:38](=[C:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)[C:37]=2[CH:36]=[CH:35][CH:34]=1.Cl>ClCCl>[CH:33]1[C:43]2[CH:42]=[CH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[C:38](=[C:48]3[CH2:49][CH2:50][N:51]([C:30](=[O:32])[C@@H:27]([NH:26][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:28][OH:29])[CH2:52][CH2:53]3)[C:37]=2[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)N[C@@H](CO)C(=O)O
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N[C@@H](CO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
880 mg (4.59 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 0.63 ml (4.52 mmol) of triethylamine and 860 mg (4.55 mmol) of pivaloyl-L-serine were added to 1.231 g (4.50 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine in 20 ml of dichloromethane in the ice bath, and they were stirred at room temperature overnight. 1 N hydrochloric acid was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3 to 1:2) to obtain the title compound.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([N:14]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]([O:22]C)=[O:21])=[CH:15]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1>O1CCCC1.O>[C:20]([C:16]1[C:17]([CH3:19])=[CH:18][N:14]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][N:5]=2)[CH:15]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cn(-c2nccc3ccccc23)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(-c2nccc3ccccc23)cc1C(=O)O

Procedure:
0.63 g (15 mmol) of lithium hydroxide monohydrate is added at a temperature in the region of 20° C. to 1.35 g (5 mmol) of 1-(isoquinol-1-yl)-3-methoxycarbonyl-4-methyl-1H-pyrrole dissolved in 50 mL of tetrahydrofuran and 50 mL of water. After stirring at reflux for 25 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 mL of water and then triturated with 15 mL of 1N hydrochloric acid. After filtering off and drying the solid residue at ambient pressure at a temperature in the region of 50° C., 1.1 g of 3-carboxy-1-(isoquinol-1-yl)-4-methyl-1H-pyrrole are obtained in the form of a whitish solid melting at 245° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8]\[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+]>O1CCCC1>[C:1]1(/[C:7](/[C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8]\[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)/C=C(/C#Cc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C(/C#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
A mixture of 1.000 g of methyl (E)-3,5-diphenylpent-2-en-4-ynoate (prepared as described in Preparation 104), 15 ml of methanol, 7.5 ml of tetrahydrofuran and 15 ml of a 10% w/v aqueous solution of sodium hydroxide was stirred for 18 hours at room temperature. At the end of this time, the solvent was distilled off under reduced pressure. The resulting residue was diluted with water and extracted twice with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure, to give 0.912 g of the title compound, melting at 124°-126° C. (after recrystallisation from a mixture of methylene chloride and hexane).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:19])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:18]
Reactant: CCN(CC)C(=O)c1ccccc1NC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccccc1N(C)C(C)(C)C
Temperature: 40 °C
Yield: 72.2 %

Procedure:
A mixture of N,N-diethyl-2-(N-tert-butylamino)benzamide (4.2 g, 17 mmol), potassium carbonate (3.1 g, 22 mmol), and MeI (3.1 g, 22 mmol) in DMF (75 mL) was heated overnight at 40° C. The reaction was not complete, so additional MeI (3.1 g, 22 mmol) was added and the reaction heated at 40° C. for 1 d, then was partitioned between EtOAc and water. The EtOAc was dried (MgSO4), concentrated, and purified by HPLC with 1:4 ethyl acetate/cyclohexane to afford 3.22 g of N,N-diethyl-2-(N-methyl-N-tert-butylamino)benzamide as a yellow oil, a 72% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10][O:9]1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:8]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][O:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)COC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC2(CCN1)COC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 1,1-dimethylethyl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (Description 69, 80 mg, 0.625 mmol) in dichloromethane (15 mL) and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate (3 mL) and dichloromethane (5 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (3×3 mL) and the combined organic fractions were poured onto an SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (8 mg, 17%). m/z (ES+) 128 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[N:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[S:25][CH:26]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)cn12
Temperature: 100 °C
Yield: 15.6 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (80 mg), (2-(trifluoromethyl)-1,3-thiazol-4-yl)methanol (51.1 mg), potassium tert-butoxide (78 mg) and toluene (2 ml) was heated at 100° C. for 1 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (16.2 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-methoxy-5-pyrimidine-boronic acid in General Procedure A. Purification on silica and ether trituration gave 246. NMR (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 4.12 (3H, s), 7.32 (1H, br. s), 9.48 (2H, s). MS (ESI+): MH+506.2 (100%)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([NH2:16])(=[S:15])[CH2:13][CH3:14].O>C(O)C>[CH2:13]([C:12]1[S:15][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:16]=1)[CH3:14]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCC(N)=S
Solvent: CCO
Solvent: O
Product: CCc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C

Procedure:
A mixture of 2.40 g (11.0 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone and 1.00 g (11.0 mmol) of thiopropanamide in 50 ml of ethanol is stirred under reflux for 2 h and at room temperature for 16 h. The reaction mixture is stirred into 200 ml of water and extracted with ethyl acetate (3×100 ml). The combined organic phases are washed with 50 ml of water, dried over MgSO4 and freed from the solvent under reduced pressure. This gives 2.05 g (87%) of the desired product; 1H-NMR(DMSO-d6) δ: 7.99 (m, 2H), 7.92 (s, 1H), 7.26 (m, 2H), 3.04 (q, 2H), 1.34 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[O:29]=[C:30](C)[CH2:31][CH2:32][CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:30](=[O:29])[CH2:31][CH2:32][CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)CCCc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1CN(C(=O)CCCc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), 4-(4-oxo-pentyl)-benzoic acid (58.3 mg, 0.30 mmol), HATU (114.0 mg, 0.30 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-4-oxo-butyl}-benzoic acid (28.9 mg, 48.2%). HRMS (ES+) m/z Calcd for C33H30Cl2F2N2O3+H [(M+H): 599.1675; Found: 599.1674.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2Cl)[N:4]([CH3:13])[N:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([NH:21][C:9]1[N:8]=[C:7]([NH2:12])[N:6]=[C:5]2[N:4]([CH3:13])[N:3]=[C:2]([Br:1])[C:10]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: Cn1nc(Br)c2c(Cl)nc(N)nc21
Solvent: CN(C)C=O
Product: Cn1nc(Br)c2c(NCc3ccccc3)nc(N)nc21
Temperature: 40 °C

Procedure:
3-Bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 14) (160 mg, 0.61 mmol), benzylamine (0.2 ml, 1.83 mmol) and DMF (5 ml) are mixed together and heated at 40° C. overnight. After cooling to room temperature the solvent is removed in vacuo and the residue is dissolved in methanol (30 ml) and passed through an Isolute™ CBA column (silica based carboxylic acid sorbent). Silica gel is added to the filtrate, the solvent is removed in vacuo and the resulting residue is flash chromatographed eluting with EtOAc:iso-hexanes (4:6) and then increasing to EtOAc:iso-hexanes (1:1). The appropriate fractions are collected and concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)n1nnc(C(CO)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reaction time: 2 h

Procedure:
To a stired solution of ethyl 3,3-bis(4-fluorophenyl)-2-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2-propenoate (2.0 g, 4.8 mmoles) in dry methylene chloride (10 mL) under argon at -78° C. was added 10 mL of diisobutylaluminum hydride solution (1.0 Molar solution in methylene chloride) over a period of three minues. The reduction was llowed to proceed at -78° C. under argon for two hours. Analytical TLC eluted twice with 20% (v/v) ethyl acetate in hexanes showed no starting material at Rf =0.42 and a major spot at Rf =0.14 for desired product. The crude reaction misture (at -78° C.) was diluted with 10 mL of 2N HCl followed by extractions with ethyl acetate (40 mL×2). The organic layers were combined, dried over MgSO4, evaporated under reduced pressure and dried under high vacuum at room temperature overnight to give the title compound which was used without further purification in the next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH:48]([C:52](O)=[O:53])[CH2:47]3)=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:28][C:52]([CH:48]2[O:49][CH2:50][CH2:51][N:46]([C:44]([O:43][CH2:42][CH:40]3[C:39]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:33]4[C:41]3=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:45])[CH2:47]2)=[O:53])[CH2:27][CH2:26]1
Reactant: O=C(O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCO1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCO1
Reaction time: 2 h

Procedure:
HATU (1.17 g, 3.0 mmol) and cyclopropylamine (0.17 g, 3.0 mmol) were added to a solution of 4-[(9H-fluoren-9-ylmethoxy)carbonyl]morpholine-2-carboxylic acid (1.0 g, 2.9 mmol) and DIPEA (0.56 mL, 3.2 mmol) in DMF (50 mL). The reaction mixture was stirred for 2 hrs. at ambient temperature and the solvent was concentrated. The product was recovered in EtOAc and washed with water, saturated NaHCO3 solution, water and brine. The organic layer was dried over anhydrous MgSO4 and the solvent was concentrated to provide the title compound that was used for the next step without further purification. MS (ESI) (M+H)+=393.0.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[N:8]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Si:25]([O:1][CH2:2][CH:3]1[N:8]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO)C1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
(+/−) Tert-butyl 3-(hydroxymethyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (1 g, 3.67 mmol) was taken up in DMF (2 mL) and imidazole (0.500 g, 7.34 mmol) and TBS-Cl (0.609 g, 4.04 mmol) were added. The reaction was stirred at rt over the weekend. An additional 0.2 eq. of TBS-Cl and 0.5 eq. of imidazole was added, and the reaction mixture was heated at 40° C. overnight, then at 45° C. for 24 h. The reaction mixture was diluted with EtOAc and washed with water 4×. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-60% EtOAc/Hex). (+/−) Tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (665 mg) was obtained as a colorless oil.
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([N:8](CC)CC)[CH:5]=[CH:4][C:3]=1[N:13]=[C:14]1[CH:23]=[CH:22][C:21](=[O:24])[C:20]2N=CC=C[C:15]1=2>O.C(O)C>[CH:23]1[C:14](=[N:13][C:3]2[CH:2]=[CH:7][C:6]([NH2:8])=[CH:5][CH:4]=2)[CH:15]=[CH:20][C:21](=[O:24])[CH:22]=1
Reactant: CCN(CC)c1ccc(N=C2C=CC(=O)c3ncccc32)c(C)c1
Solvent: O
Solvent: CCO
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Then, a solution prepared by dissolving 285.3 mg of Ni(ClO4)2.6H2O in 50 ml of water, was added under a nitrogen atmosphere to a solution prepared by dissolving 100 mg of 5-(2'-methyl-4'-diethylaminophenylimino)quinoline-8-one obtained above in 50 ml of 99% ethanol, and the mixture was stirred at room temperature for about 30 minutes. Formed precipitates were subjected to suction filtration, washed with water and dried to obtain a metal-containing indoaniline compound having the formula: ##STR10##
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][O:4][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.4 %

Procedure:
To a mixture of Boc-Ser-OH (21.5 g, 0.105 mol) in DMF at 0° C. was added sodium hydride (8.4 g, 0.21 mol). The reaction mixture was stirred at 0° C. for 15 mins, and then allyl bromide (13.3 g, 0.105 mol) was added. The mixture was stirred at 40° C. overnight. After TLC showed the reaction was completed, the mixture was quenched with aqueous NH4Cl solution and concentrated in vacuum. The residue was diluted with water, and sequentially washed with hexane and ether. The organic layers were discarded, and the aqueous layer was carefully adjusted to pH=3 with 1 N HCl. The acidic aqueous solution was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuum to give Boc-Ser(O-allyl)-OH (14.0 g, 54.4%).
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[C:8]([N+:11]([O-:13])=[O:12])[C:7](Cl)=[C:6]([N+:15]([O-:17])=[O:16])[C:5]=1Cl)([O-:3])=[O:2].[CH2:19]([CH2:21][NH2:22])[OH:20]>CO>[N+:1]([C:4]1[C:9]([NH:22][CH2:21][CH2:19][OH:20])=[C:8]([N+:11]([O-:13])=[O:12])[C:7]([NH:22][CH2:21][CH2:19][OH:20])=[C:6]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:22][CH2:21][CH2:19][OH:20])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c(Cl)c([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Reactant: NCCO
Solvent: CO
Product: O=[N+]([O-])c1c(NCCO)c([N+](=O)[O-])c(NCCO)c([N+](=O)[O-])c1NCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 7.2 g (0.0227 mole) of 2,4,6-trinitro-1,3,5-trichlorobenzene and 70 ml of methanol was stirred in an ice bath while a solution of 9.9 g (0.162 mole) of ethanolamine in 70 ml of methanol was added over 10 min. Stirring at room temperature gave a solution from which yellow solid precipitated until the mixture became too thick to stir. After standing for 2 hr., the mixture was filtered to give 7.6 g (86%) of 2,4,6-trinitro-1,3,5-tris(2-hydroxyethylamino)benzene; 1H NMR (DMSO-d6): 3.48 (m, 6H), 3.72 (m, 6H).