Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C1C=CC=CN=1)C.[OH:10][CH:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:12]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[C:33](OC(=O)C)(=[O:35])[CH3:34].Cl>N1C=CC=CC=1>[C:33]([O:10][CH:11]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:12]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)CCC(C(=O)OC(C)C)C(O)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccccc1)C(CCC(=O)OC(C)C)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
70 mg of dimethylaminopyridine was added to a mixed solution comprising 6.13 g of diisopropyl 4-hydroxy-4-phenyl-1,3-butanedicarboxylate, 30 ml of pyridine and 6 ml of acetic anhydride, followed by stirring at room temperature for 1.5 hours. 2N hydrochloric acid was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with 2N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 4.68 g of the above-identified compound as a colorless oily substance.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][CH:56]3[CH2:58][CH2:57]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([Cl:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[C:68]([CH2:70][C:71](O)=[O:72])#[N:69]>C(Cl)Cl>[Cl:54][C:50]1[CH:49]=[C:48]([NH:47][C:45]([C:42]2[N:40]3[N:41]=[C:36]([NH:35][C@H:32]4[CH2:31][CH2:30][C@H:29]([NH:28][C:71](=[O:72])[CH2:70][C:68]#[N:69])[CH2:34][CH2:33]4)[CH:37]=[C:38]([NH:55][CH:56]4[CH2:57][CH2:58]4)[C:39]3=[N:44][CH:43]=2)=[O:46])[CH:53]=[CH:52][N:51]=1
Reactant: N#CCC(=O)O
Reactant: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (60.2 mg, 0.136 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (20.00 mg, 0.045 mmol), DIEA (0.032 mL, 0.181 mmol) and 2-cyanoacetic acid (7.72 mg, 0.091 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 min, concentrated and diluted with MeOH and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to isolate N-(2-chloropyridin-4-yl)-6-((trans)-4-(2-cyanoacetamido)cyclohexylamino)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (11 mg, 0.022 mmol, 47.7% yield) as white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.772 minutes. [M+H]=508.11. 1H NMR (400 MHz, MeOD) δ ppm 8.24-8.39 (1H, m), 7.95-8.03 (1H, m), 7.87-7.97 (1H, m), 7.51-7.67 (1H, m), 5.98-6.11 (1H, m), 3.60-3.83 (2H, m), 2.47-2.66 (1H, m), 2.19-2.37 (2H, m), 1.96-2.19 (2H, m), 1.28-1.55 (4H, m), 0.77-0.96 (2H, m), 0.52-0.75 (2H, m).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8]O.C(N(CC)CC)C.[Cl-].[C:18]([O:21]CC)(=[O:20])[CH3:19]>C1COCC1>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH2:6]2.[CH3:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH:7]=[CH:19][C:18]([O-:21])=[O:20]
Reactant: CCOC(C)=O
Reactant: OCC1CC2C=CC1C2
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C1=CC2CCC1C2
Product: Cc1ccccc1C=CC(=O)[O-]
Temperature: 0 °C
Yield: 88 %

Procedure:
15 g (0.121 mol) of the 5-norbornene-2-methanol prepared in Example 1, 61.2 g (0.605 mol) of triethylamine (produced from Aldrich Inc.), and 20 ml of THF were loaded into a 250 ml 2-neck flask and then stirred at 0° C. in an ice-water bath. 22.1 g (0.133 mol) of cinamoil chloride dissolved in 60 ml of THF was slowly added to the prepared mixture using an additional flask for 10 minutes. Then, the temperature of the reactant was increased to room temperature and then stirred for one hour. The resulting solution was diluted using an ethyl acetate. The diluted solution was loaded into a separatory funnel, washed using water and NaHCO3 several times, and then distilled in at a reduced pressure to remove a solvent. The result was refined using a column chromatography (Hexane: Ethyl acetate=20:1) to attain a product. (Yield: 88%)
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[C:20]#[N:21])[CH2:3][CH2:2]1.C(=O)([O-])[O-:28].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[C:20]([NH2:21])=[O:28])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To an ice/water cooled suspension of (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carbonitrile [P2] (6.0 g, 17.1 mmol) and potassium carbonate (7.09 g, 51.37 mmol) in DMSO (120 mL) was added hydrogen peroxide (25 mL, 35 wt. % in H2O) drop wise at a rate to ensure the temperature remained below 20° C. The mixture was stirred for 2 hours then diluted with DCM (800 mL). The solution was washed with water (3×500 mL) before the organic phase was dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave crude product that was purified by trituration with methanol giving (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carboxamide [P3] (4.50 g, 71% yield); LC/MS (r.t. 10.1 minutes [5 to 95% B]), 369 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>ClCCCl>[C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][N:18]([C:21](=[O:23])[CH3:22])[CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (40 mg, 0.15 mmol), acetic anhydride (18 mg, 0.18 mmol), and triethylamine (0.06 mL, 0.45 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 8 (5 mg, 11% yield) as a tan solid. LC-MS (M+H=307, obsd.=307).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[C:28]([CH3:39])[C:27]=1[CH3:40]>>[F:24][C:18]1[CH:17]=[C:16]([C:8]2[C:7]([CH2:6][O:5][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:28]([CH3:39])[C:27]=3[CH3:40])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1F
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(3-fluoro-4-methoxyphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, DMSO) δ 12.12 (s, 1H), 7.48-7.58 (m, 2H), 7.31 (t, J=8.7 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 5.09 (s, 2H), 3.89 (s, 3H), 2.76 (t, J=7.2 Hz, 2H), 2.41 (t, J=7.5 Hz, 2H), 2.14 (s, 3H), 1.97 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H21F4NO4S, 482.1 (M−H). found 482.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[CH:27]=2)=[O:25])[CH:18]=1)=O.C1COCC1.CC(O)C.[OH-].[NH4+:43]>O>[Cl:32][C:28]1[CH:27]=[C:26]([C:24]([NH:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][NH:15][C:10]2[C:9]3[C:14](=[C:5]([C:3]([NH2:43])=[O:2])[CH:6]=[CH:7][CH:8]=3)[N:13]=[CH:12][N:11]=2)=[O:25])[CH:31]=[CH:30][N:29]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccnc(Cl)c4)c3)ncnc12
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccnc(Cl)c4)c3)ncnc12
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 40-mL vial with magnetic stirbar at r.t. was added the 4-{3-[(2-Chloro-pyridine-4-carbonyl)-amino]-benzylamino}-quinazoline-8-carboxylic acid methyl ester (0.6 g, 1.34 mmol, 1 eq.) and THF (6 mL) and 2-propanol (6 mL). An approx. equal volume (i.e.; 6 mL) of concentrated aqueous ammonium hydroxide solution (28-30% soln.) was then added and stirring continued overnight. Water (15 mL) was added to the reaction mixture and a white precipitate immediately began to form. The precipitate was collected and dried thoroughly in vacuo and afforded 314 mg (55% yield). Material was carried on to the next synthetic step without further purification. LCMS (ESI) 433 (M+H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([OH:11])=O)=[O:7])=[CH:2]1.[NH2:12][CH:13]1[C:27](=[O:28])[N:15]2[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][N:21]=[N+:22]=[N-:23])[CH2:18][S:19][C@H:14]12>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([NH:12][CH:13]2[C:27](=[O:28])[N:15]3[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][N:21]=[N+:22]=[N-:23])[CH2:18][S:19][C@H:14]23)=[O:11])=[O:7])=[CH:2]1
Reactant: O=C(O)CS(=O)c1ccsc1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)c3ccsc3)[C@H]2SC1

Procedure:
380 mg. of 3-thienylsulfinylacetic acid of the R form and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 410 mg. of 7-(3-thienylsulfinylacetamido)-3-azidomethyl-3-cephem-4-carboxylic acid of the R form were obtained.
Reaction SMILES: [CH3:1][C@@H:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[CH3:33]/[C:34](=[CH:40]\[C@@H:41]([N:45]([CH3:54])[C:46](=[O:53])[C@H:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[NH2:48])[CH:42]([CH3:44])[CH3:43])/[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH3:1][C@@H:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([NH:48][C@@H:47]([C:49]([CH3:52])([CH3:50])[CH3:51])[C:46]([N:45]([CH3:54])[C@@H:41]([CH:42]([CH3:43])[CH3:44])/[CH:40]=[C:34](\[CH3:33])/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:53])=[O:5]
Reactant: C[C@H](C(=O)O)C(C)(C)c1ccccc1
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](C)C(C)(C)c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
To a cooled (0° C., ice bath) solution of (2S)-2,3-dimethyl-3-phenylbutanoic acid (0.11 g, 0.57 mmol, from Reference Example 25), hydroxybenzotriazole (93 mg, 0.69 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (0.15 g, 0.80 mmol) in anhydrous dimethylformamide (2 ml) is added N-methylmorpholine (95 uL, 0.86 mmol) via syringe under an inert atmosphere. After stirring for 15 minutes at 0° C., the cooling bath is removed, and the resulting mixture is stirred for 1 hour. The solution is cooled at 0° C. (ice water bath), and to this mixture is added a solution of ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate hydrochloride (0.56 mmol) in anhydrous dimethylformamide (2 ml). The cooling bath is removed, and the resulting mixture is stirred for 22 hours at room temperature under an inert atmosphere. The mixture is diluted with water, and the aqueous layer is extracted with ethyl acetate (3 times). The combined extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed (silica gel, flash column), to provide a white foam (0.20 g, 71%). MS (ES+): (M+H)=487.0
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[C:16]12([CH2:26][O:27][C:28]3[C:40](/[CH:41]=[CH:42]/[CH2:43][O:44][CH3:45])=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[C:30]([F:46])[CH:29]=3)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(=O)(O)[O-].[Na+]>ClCCl>[C:16]12([CH2:26][O:27][C:28]3[C:40]([C@@H:41]4[CH2:1][C@H:42]4[CH2:43][O:44][CH3:45])=[CH:39][C:31]([C:32]([OH:34])=[O:33])=[C:30]([F:46])[CH:29]=3)[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH2:25]1)[CH2:17]2
Reactant: COC/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: COC[C@@H]1C[C@H]1c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To a mixture of diethylzinc (1.0 M solution in heptane, 6.8 mL, 6.8 mmol) in anhydrous dichloromethane (3 mL) was added a solution of trifluoroacetic acid (0.52 mL, 6.80 mmol) in anhydrous dichloromethane (2 mL) at 0° C. and the reaction mixture was stirred for 15 minutes at 0° C. A solution of diiodomethane (0.55 mL, 6.82 mmol) in anhydrous dichloromethane (2 mL) was added to the reaction mixture at 0° C. and stirring was continued for 15 minutes at 0° C. To the reaction mixture was then added a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-3-methoxyprop-1-en-1-yl)benzoate (1.17 g) in dichloromethane (3 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. After addition of saturated sodium bicarbonate solution (10 mL), the mixture was diluted with dichloromethane (100 mL). The organic phase was washed with brine (10 mL) dried over sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was treated with trifluoroacetic acid (2 mL) in dichloromethane (20 mL) for 1 hour. After evaporation of all volatiles under reduced pressure, the residue was triturated with diethyl ether (5 mL) to afford the title compound as a colorless solid (0.554 g, 63%): 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.4 Hz, 1H), 6.54 (d, J=12.9 Hz, 1H), 3.57 (dd, J=10.3, 6.3 Hz, 1H), 3.55-3.48 (m, 2H), 3.37 (s, 3H), 3.36-3.29 (dd, J=10.3, 7.2 Hz, 1H), 2.07-1.99 (m, 3H), 1.93 (td, J=8.9, 5.1, 5.1 Hz, 1H), 1.82-1.62 (m, 12H), 1.38-1.25 (m, 1H), 1.00 (td, J=8.4, 5.3, 5.3 Hz, 1H), 0.89 (td, J=8.8, 5.2, 5.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
(+)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.00 g, 2.6 mmol, prepared in example 1a), 4-carboxybenzene boronic acid (627 mg, 3.8 mmol), potassium carbonate (520 mg, 3.8 mmol), tetrakis(triphenyl phosphine)palladium(0) (206 mg, 0.2 mmol) and dioxane/water (112 mL, 3:1) were mixed together in a 250 mL single neck flask and stirred at 80° C. for 4 hours. The reaction was cooled to room temperature and poured into 1N HCl and the desired product was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 1.43 g as a dark oil. This material was purified via silica gel chromatography employing the chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/methanol 9:1 to yield the title compound (355 mg, 36%) as a tan solid. Ion spray M.S. 378.3 (M*−1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1.O>C(OCC)C.CCCCCC.C(C1C=CC(C2(O)CCCC2)=CC=1)(C)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:17]2([OH:22])[CH2:21][CH2:20][CH:19]=[CH:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C=CCC1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: CC(C)(C)c1ccc(C2(O)CCCC2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C2(O)C=CCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 34 g of 4-t-butylphenylbromide (0.16 mole) in 50 ml diethyl ether was slowly added to a stirred mixture of 100 ml of a solution of n-butyllithium in hexane (1.6 mole/l) and 50 ml diethyl ether, while the temperature of the mixture was kept at -25 ° C. After completion of the addition, the temperature of the resultant mixture was allowed to rise slowly to about room temperature. Subsequently the temperature was decreased to -25° C. and 13.2 g of 2-cyclopentene-1-one (0.16 mole) dissolved in a small volume of diethyl ether was slowly added. The suspension thus obtained, was allowed to reach room temperature and then stirred for one hour. An excess amount of water was added to the suspension to result in 1-(4-t-butylphenyl)cyclopentanol. The 1-(4-t-butylphenyl)cyclopent-2-en-1-ol product was isolated from the reaction mixture by extraction with diethyl ether and subsequently purified by chromatography over silica, using dichloromethane as the elution solvent.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][CH2:13][C:15]3[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(C=O)cc2)cc1
Reactant: Nc1nc(-c2ccccc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(OCc2ccc(CNc3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.3 %

Procedure:
To a solution of 4-phenyl-1,3-thiazol-2-amine (0.25 g, 1.4 mmol), methyl 3-[4-[(4-formylbenzyl)oxy]phenyl]propionate (0.58 g, 2.0 mmol) and acetic acid (0.25 g, 4.2 mmol) in 1,2-dichloroethane (15 mL) was added triacetoxysodium borohydride (0.83 g, 3.9 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (0.31 g, yield 49%) as an oil.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12](#[N:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15]>C(OCC)(=O)C>[C:12]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])#[N:20]
Reactant: N#Cc1ccccc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1NC(=O)c1ccccc1C(=O)O

Procedure:
A solution of sublimed phthalic anhydride in ethyl acetate is reacted with a solution of anthranilonitrile in ethyl acetate to form 2'-cyanophthalanilic acid. The 2'-cyanophthalanilic acid is then boiled with acetic anhydride to convert the acid to 2'-cyanophthalanil. The 2'-cyanophthalanil is thereafter boiled in a mixture containing 2% potassium hydroxide and 2.4% hydrogen peroxide, cooled and neutralized with hydrochloric acid to cyclicize it and form isoindolo [2,1-a]quinazoline-5,11-dione. A similar procedure is set forth by Bogert and Hand, 24 J. Am. Chem. Soc., 1031 (1902) for preparing 2-methyl-4-ketodihydroquinazoline from N-acetylanthranilonitrile.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([OH:30])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:19][CH:20]2[CH:21]3[CH2:29][CH:25]4[CH2:24][C:23]([OH:30])([CH2:28][CH:27]2[CH2:26]4)[CH2:22]3)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc(OCc2ccc(F)cc2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCc2ccc(F)cc2)c1

Procedure:
Prepared from 3-(4-fluoro-benzyloxy)-benzoic acid and 4-amino-1-hydroxyadamantane. LC-MS (m/z): 296 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)=[O:4].S(Cl)(Cl)=O.[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[C:29]2[NH2:35]>C1COCC1.N1C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[C:29]2[NH:35][C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])=[O:11]
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 65.2 %

Procedure:
4-(methoxycarbonyl)-2-nitrobenzoic acid (4.8 gr, 21.3 mmol) and thionyl chloride (15.5 mL) were stirred in THF dry (130 mL) at 70° C. for 2 hours. Volatiles were evaporated and the residue dissolved in dry pyridine (100 mL) at 0° C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (4.6 mg, 17.76 mmol) in dry pyridine (10 mL) was added to the cooled reaction mixture. Temperature was allowed to reach room temperature overnight. Reaction was quenched with NaHCO3 sat. sol and extracted with ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and evaporated to dryness. Residue was purified by column chromatography over silica gel (DCM/EtOH/7N NH3 in MeOH=95/5/0.5) affording 5.4 gr (65% yield) of the title compound.