Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([N+:20]([O-:22])=[O:21])[C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)=[C:4]([N+:20]([O-:22])=[O:21])[C:3]=1[C:23]#[N:24]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
To a biphasic solution of methyl 5-chloro-4-cyano-3-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (3.60 g, 9.26 mmol) and (3-fluorophenyl)boronic acid (1.42 g, 10.2 mmol) in toluene (80 mL) was added saturated NaHCO3 (80 mL) and then the reaction was bubbled with N2 to degas. Tetrakis(triphenylphosphine)palladium(0) (0.535 g, 0.463 mmol) was added. The resulting mixture was bubbled with N2 for 5 minutes and then heated at 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel column, eluting with ethyl acetate/hexane, 0-30%, to give the desired product (1.23 g, 40%). LCMS calculated for C15H9ClFN2O4 (M+H)+: m/z=335.0; Found: 335.1. 1H NMR (CDCl3, 400 MHz) δ 8.14 (1H, s), 7.40 (1H, m), 7.20 (1H, m), 6.97 (1H, m), 6.93 (1H, m), 3.66 (3H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[C:17]([O:23][C:24]([C:27]([O:29]C)=[O:28])([CH3:26])[CH3:25])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[C:17]([O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)cnc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 102.9 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-pyridin-3-yl]-2′-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol), LiOH.H2O (280 mg, 6.6 mmol), H2O (5 mL) and methanol (15 mL) was heated at 80° C. for 40 min. After cooled to room temperature, the solution was acidified to “pH” 1 by addition of 1N HCl solution. The aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (200 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH:14][C:15](=O)[CH:16]([CH3:18])[CH3:17])[CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C[Si]([N:39]=[N+:40]=[N-:41])(C)C>C(#N)C>[CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[N:14]2[C:15]([CH:16]([CH3:18])[CH3:17])=[N:41][N:40]=[N:39]2)[CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CC(C)c1nnnn1-c1cc([N+](=O)[O-])c(F)cc1C1CC1
Temperature: -5 °C
Reaction time: 0.03 h
Yield: 81.3 %

Procedure:
N-(2-Cyclopropyl-4-fluoro-5-nitrophenyl)isobutyramide (1.90 g, 7.14 mmol, 1 equiv) was dissolved in acetonitrile (40 mL) under argon and cooled to −5° C. (external temperature). While maintaining the temperature at −5° C., trifluoromethanesulfonic anhydride (2.40 mL, 4.03 g, 14.27 mmol, 2 equiv) was added slowly dropwise and stirred for 1-2 minutes. Then trimethylsilyl azide (3.75 mL, 28.54 mmol, 4 equiv) was added slowly dropwise while maintaining the temperature at −5° C. TLC, LCMS indicated the reaction was complete in less than 1 minute. While maintaining the temperature at −5° C., the reaction was slowly quenched with ice-cold saturated NaHCO3 and diluted with EtOAc. The layers were separated, and the organic layer was washed with brine 1×, dried over Na2SO4, and concentrated to dryness. The crude product was absorbed onto silica gel and purified by flash chromatography and eluted with hex:EtOAc=100:0 to 25%-30% EtOAc using 5% EtOAc increments to afford 1-(2-cyclopropyl-4-fluoro-5-nitrophenyl)-5-isopropyl-1H-tetrazole (1.69 g, 78%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][O:16]C(=O)C)[C:10]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][OH:16])[C:10]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCOc1ccnc(CO)c1C
Yield: 92.9 %

Procedure:
19.0 g (0.068 mol, 1.0 eq.) of 4-heptyloxy-2-acetoxymethyl-3-methylpyridine was added dropwise to a 25% aqueous solution of sodium hydroxide at 13 to 25° C., and the mixture was allowed to react for one hour at room temperature, and then extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 15.0 g of 4-heptyloxy-2-hydroxymethyl-3-methylpyridine as a brown oily matter (yield 92.9%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].Cl.[CH:31]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32]1>>[CH:31]1([CH2:34][CH2:35][NH:36][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:12][C:10]4[CH2:11][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:29])([F:28])[F:1])[CH2:8][C:9]=4[CH2:14]3)=[N:16][CH:17]=2)[CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: NCCC1CC1
Agent: Cl
Product: O=C(NCCC1CC1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 37 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (50 mg, 0.124 mmol) was reacted with 2-cyclopropylethylamine hydrochloride analogously to 3d. Yield: 37%, M+H+: 471.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[N:34]1([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:37]3[CH2:36][CH2:35][N:34]([CH2:40][CH2:41][N:42]4[CH2:43][CH2:44][CH:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)[CH2:39][CH2:38]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)C1CCN(CCN2CCNCC2)CC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added ethyl 1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride (199 mg, 0.65 mmol), DIEA (126 mg, 0.97 mmol), HATU (148 mg, 0.39 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 3% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (18.0% MeCN up to 27.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 18.0% in 2 min); Detector, UV 254/220 nm. This resulted in 66.1 mg (27%) of the formic acid salt of ethyl 1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate. LCMS (Method 24) [M+H]+=714.2, RT=2.42 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (m, 2H), 4.03 (q, 2H, J=6.8 Hz), 3.50-3.47 (m, 4H), 2.88-2.85 (m, 2H), 2.52-2.51 (m, 6H), 2.47-2.26 (m, 3H), 2.12-2.07 (m, 2H), 1.80-1.78 (m, 2H), 1.60-1.55 (m, 2H), 1.16 (t, 3H, J=7.2 Hz).
Reaction SMILES: [I-].OC1C=CC=CC=1C=[N:6][C@@H:7]1[C:40](=[O:41])[N:9]2[C:10]([C:24]([O:26]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:25])=[C:11]([CH2:14][N+:15]3[N:16]([CH3:23])[C:17]([NH:20][CH:21]=[O:22])=[CH:18][CH:19]=3)[CH2:12][S:13][C@H:8]12.[ClH:46].CC(C)=O.C(OCC)(=O)C>C(Cl)Cl.C(O)=O>[ClH:46].[NH2:6][C@@H:7]1[C:40](=[O:41])[N:9]2[C:10]([C:24]([O-:26])=[O:25])=[C:11]([CH2:14][N+:15]3[N:16]([CH3:23])[C:17]([NH:20][CH:21]=[O:22])=[CH:18][CH:19]=3)[CH2:12][S:13][C@H:8]12
Reactant: Cn1c(NC=O)cc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N=Cc3ccccc3O)[C@H]2SC1
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cn1c(NC=O)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of benzhydryl 7β-(2-hydroxybenzylideneamino)-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (170 g) in methylene chloride and formic acid was added 35% hydrochloric acid (24.65 g). The mixture was stirred for 3 hours at 25~30° C. and added dropwise into the mixture of acetone (1700 ml) and ethyl acetate (3400 ml). The resulting precipitate was collected by filtration and dried in vacuo to give 7β-amino-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate hydrochloride (86.7 g).
Reaction SMILES: [CH:1]([Mg]Br)=[CH:2][CH2:3][CH3:4].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([CH2:14][CH2:15][CH:16]=[O:17])[CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH3:19][O:18][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][C:12]=1[CH2:14][CH2:15][CH:16]([OH:17])[CH2:1][CH:2]=[CH:3][CH3:4]
Reactant: COc1ccc(F)cc1CCC=O
Reactant: CCC=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=CCC(O)CCc1cc(F)ccc1OC
Yield: 172.5 %

Procedure:
To a solution of 1-butenylmagnesium bromide (0.5 M in THF, 18 mL, 9.0 mmol) at 0° C. was added a solution of 3-(5′-fluoro-2′-methoxyphenyl)propionaldehyde (3.0 g, 16.5 mmol) in THF (30 mL) dropwise for 15 min. The reaction mixture was poured into a solution of saturated ammonium chloride (80 mL) in a separatory funnel. The organic function was extracted with ethyl acetate (3×80 mL) and the combined organic layers were washed with brine (80 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by a flash column chromatography (15% EtOAc in hexane, Rf=0.20) to give the product as an oil (3.7 g, 94%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:20][N:19]=[N:18][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1nnn[nH]1
Temperature: 25 °C

Procedure:
A solution of (2-cyano-benzyl)-carbamic acid tert-butyl ester (35 mg, 0.15 mmol), sodium azide (49 mg, 0.75 mmol), ammonium chloride (40 mg, 0.75 mmol) in dimethylformamide (0.5 ml) was heated to 110° C. for 8 h. After cooling to room temperature, ethyl acetate was added and the resultant solid filtered. Concentration of the filtrate gave [2-(1H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester; 1H NMR (CD3OD, 400 MHz) δ 7.71(d, 1H, J=7.5 Hz), 7.58 (m, 2H), 7.48 (m, 1H), 4.44 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([C@H:5]1[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@@H:6]1[CH3:17])=O.[C:18]([C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:2]=[C:3]([C@H:5]3[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@@H:6]3[CH3:17])[N:28]=2)[CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(N)nc1
Reactant: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)CBr
Solvent: CC#N
Product: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1c1cn2cc(C(C)(C)C)ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(3R,4S)-4-(2-bromoacetyl)-1-(tert-butyldimethylsilyl)-3-methylazetidin-2-one (Preparation 72, 1144 mg, 3.57 mmol) and 5-(tert-butyl)pyridin-2-amine (537 mg, 3.57 mmol) were mixed in acetonitrile (10 mL) and the reaction mixture stirred for 18 hours at room temperature, then an additional 18 hours at 65° C. to complete the dehydration. The reaction solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the title compound which was immediately taken to the next step.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[CH2:18]([NH2:23])[CH2:19][CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:23][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CCN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CCNC(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
Phenyl chloroformate (14.8 ml, 0.117 mol) was dissolved in tetrahydrofuran (200 ml); triethylamine (18.0 ml, 0.129 mol) and isoamylamine (15.0 ml, 0.129 mol) were added thereto at room temperature while stirring; and the reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated and dried under reduced pressure to yield the title compound as crystals (14 g, 0.068 mol, 58%).
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.Cl>CN(C=O)C>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH:6]2[CH2:7][CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:36]2[C:35]2[CH:37]=[CH:38][C:32]([F:31])=[CH:33][CH:34]=2)=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Reactant: Nc1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc(Br)cc3)N2c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
Dissolved the product from Example 39C (5.25 g, 10.05 mmol) in DMF (31 mL) and then added 4-fluoroaniline (9.65 mL, 101 mmol) and heated solution at 50° C. for 18 h. Solution was cooled to room temperature and 1N aq. HCl added (100 mL) then extracted with ethyl acetate (2×200 mL), then combined organic extracts washed with brine, dried and concentrated to an amber oil to which methanol (10 mL) was added and after 3 h a yellow solid (1.05 g, 24%) resulted as the title compound as a 1/1 mixture of trans pyrrolidine isomers.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[CH2:28]([N:27]([CH2:30][CH3:31])[CH2:26][CH2:25][CH2:24][CH2:23][N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:21])[N:7]2[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)[CH3:29]
Reactant: CCN(CC)CCCCBr
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(C)c(C)cc13
Product: CCN(CC)CCCCn1c2cc(C)c(C)cc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(4-Diethylamino-n-butyl)-3,8,9-trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3,8,9-trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and 4-bromodiethylaminobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[C:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])[CH3:22]>>[C:21]([N:24]1[CH2:29][CH2:28][N:27]([C:18](=[O:20])[CH2:17][C:4]2[C:5]3[C:6](=[C:7]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[O:8][N:9]=3)[CH:16]=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)Cc2cc(Cl)cc3c(-c4ccccc4)onc23)CC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with N-acetylpiperazine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[CH2:14][CH:15]([CH:17]=[O:18])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)c3c(c2)OC(CO)C3)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)c3c(c2)OC(C=O)C3)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a suspension of 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (222a) (1.05 g, 2.77 mmol) in CH2Cl2 (25 mL) was added Dess-Martin periodinane (1.41 g, 3.32 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO3, extracted with 3×EtOAc, dried over Na2SO4, concentrated, and purified by flash column chromatography eluting with 55-100% EtOAc in hexanes to give a yellow foam (850 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([S:16][CH:17]([CH3:19])[CH3:18])[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.[O:20]1CCOCC1>O>[CH:17]([S:16][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH:1]=[O:20])[CH:15]=1)([CH3:19])[CH3:18]
Reactant: Cc1cc(SC(C)C)c2ccc3cccnc3c2n1
Reactant: C1COCCO1
Solvent: O
Product: CC(C)Sc1cc(C=O)nc2c1ccc1cccnc12
Yield: 41 %

Procedure:
A solution of SeO2 (1.06 g, 9.6 mmol) in a mixture of dioxane (50 mL) and water (2 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 2-methyl-4-isopropylsulfanyl-[1,10]phenanthroline (1.03 g, 3.8 mmol) in hot dioxane (50 mL) was added through an addition funnel over a period of 30 minutes and the reaction mixture was refluxed for 1 hour. The reaction mixture was filtered while hot and the residue rinsed with more hot dioxane (20 mL) and filtered. The filtrates were combined and concentrated in vacuo and the residue was treated with methylene chloride (100 mL) and a 10% K2CO3 aqueous solution (100 mL). The aqueous layer was extracted several times with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (neutral Al2O3, MeOH/DCM, 1:50 to 1:15) to afford the pure product as a light yellow solid (0.44 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20][CH2:19]4)=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C1COCC1.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20][CH2:19]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1CCCc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: Fc1ccc2c(C3CCN(CCN4CCCc5ccccc54)CC3)noc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(1,2,3,4-tetrahydroquinolin-1-yl)ethanone (5.5 g, 14 mmol) in THF (0.50 ml) was charged with lithium aluminum hydride (17 ml, 17 mmol, 1M in ether) dropwise under N at room temperature. The mixture was stirred for 8 hours at room temperature. At the end of this period the excess of hydride was quenched with ice chips and 3 ml of 20% NaOH. The mixture was diluted with EtOAc (150 ml) and stirred for 1 hour. The EtOAc was dried with MgSO4 and filtered. The solvent was removed to dryness. The residue was purified by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1-3% CH3OH: DCM). The product thus obtained weighed 1.83 g. This material was dissolved into hot ethanol and was treated with a solution of fumaric acid (700 mg) in ethanol. The crystals were collected and weighed 1.85 g, m.p. 192°-193° C.
Reaction SMILES: [N+:1]([C:4]1[S:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]=1[NH2:13])([O-])=O.[ClH:14].CCOC(C)=O>CCO.[Ni]>[ClH:14].[S:12]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([NH2:13])=[C:4]1[NH2:1]
Reactant: Nc1c([N+](=O)[O-])sc2ncccc12
Agent: [Ni]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1sc2ncccc2c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-nitrothieno[2,3-b]pyridin-3-amine (1.1 g, 5.6 mmol) in EtOH (60 mL) was added Raney Ni (1 g), followed by slow addition of N2H4.H2O (1.4 g, 22 mmol). The mixture was stirred at room temperature for 2 h. A solution of HCl in EtOAc (1 M, 18 mL, 18 mmol) was added to the reaction mixture slowly, and the mixture was filtered. The filter cake was washed with EtOAc (20 mL×3), then dried under reduced pressure to give the crude product as a yellow solid (2.7 g). ESI MS: m/z 166 [M+H]+.