Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:33]1[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]1)=[O:19])=[N:5]2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(Cl)ccc4nc3OC)CC2)c1
Yield: 81 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 81%). MS (ESI) m/z 458 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl>ClCCl>[O:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1CCN(C2CCOCC2)CC1

Procedure:
A solution of EXAMPLE 173A (52.57 g) in dichloromethane (900 mL) was treated with 4M HCl (462 mL), mixed vigorously at room temperature for 16 hours and concentrated.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([Cl:36])[C:15]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([Cl:36])[C:15]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(CCO[Si](C)(C)C(C)(C)C)CC3)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(CCO)CC3)cc1C(F)(F)F
Yield: 56.3 %

Procedure:
N-(2-(2-Tert-butyldimethylsilyloxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.09 g) in tetrahydrofuran (10 ml) was treated with tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.16 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, the organic phase dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ammonia/methanol/dichloromethane mixtures as eluant) to give the title compound (0.04 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:14]1[CH2:13][S:12][C:11]([NH:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[N:10]2.O.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][OH:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:39][C:40](=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.4 %

Procedure:
N-((4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (3.99 g, 6.169 mmol) was taken up in formic acid (12 mL) at RT. The mixture was stirred at RT for 2.5 hours, then water (12 mL) was added. The mixture was stirred for 10 minutes and then filtered—washing with formic acid/water (1:1, 20 mL). The filtrate was evaporated and the residue was azeotroped with toluene (×2). The residue was taken up in dry MeOH (20 mL) and treated with potassium carbonate (1.0 g, 7.2 mmol). The mixture was stirred at RT for 30 minutes. The volatiles were removed in vacuo and the residue was partitioned between DCM and water. The layers were separated and the aqueous layer was further extracted with DCM (×4). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 40% to 90% EtOAc in n-hexane) to give the title compound (2.23 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.85-3.05 (m, 1 H) 3.10-3.27 (m, 2 H) 3.68-3.80 (m, 2 H) 4.02 (br. d, J=7.90 Hz, 1 H) 4.36-4.43 (m, 1 H) 4.47 (d, J=9.16 Hz, 1 H) 6.95-7.13 (m, 2 H) 7.39-7.50 (m, 2 H) 7.50-7.60 (m, 2 H) 7.96-8.16 (m, 2 H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[C:22](Br)[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)N[C@@H]1C(=O)NC2C=CC=CC=2NC1)(C)(C)C.BrCC1C2C(=CC=CC=2)C=CC=1OC>>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: COc1ccc2ccccc2c1CBr
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Yield: 69.6 %

Procedure:
In a similar manner to that described for the preparation of [(S)-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (Intermediate 5), ((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (Intermediate 4)(400 mg, 1.44 mmol) and 1-bromomethyl-2-methoxy-naphthalene (435.15 mg, 1.733 mmol) were converted to the title compound (450 mg, 69.6%) which was obtained as a white solid. LC-MS 448 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH2:12][CH3:13])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([N:21]2[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCC(=O)CCC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A mixture of 1-(4-chlorophenyl)hexane-1,4-dione (2.10 g, 9.35 mmol, as obtained in Step-1), 4-chloro aniline (1.31 g, 10.29 mmol), and p-toluene sulfonic acid (0.321 g, 1.80 mmol) in toluene (5.0 ml) was refluxed over molecular sieves or using a Dean Stark apparatus. The progress of the reaction was monitored by TLC and after three hours, toluene was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), washed with aqueous sodium bicarbonate solution (2×75 ml), followed by washing with water (2×50 ml) and brine (1×25 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent evaporated off. The solid so obtained was washed with hexane to give 2.39 g (81%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:24])[N:6]([CH2:8][CH:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH3:10])[CH:7]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][CH:9]([CH3:10])[CH2:8][N:6]3[CH:7]=[C:2]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)[CH:3]=[CH:4][C:5]3=[O:24])=[CH:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc2c(OC(C)Cn3cc(Br)ccc3=O)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1ccc2c(OC(C)Cn3cc(-c4cccs4)ccc3=O)ccnc2c1
Temperature: 80 °C

Procedure:
A suspension of 5-bromo-1-(2-(7-methoxyquinolin-4-yloxy)propyl)pyridin-2(1H)-one (20 mg, 51 μmol), thiophen-2-ylboronic acid (13 mg, 103 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (2 mg, 3 μmol), and Na2CO3 (77 μl, 154 μmol) in DME (0.5 mL) was heated to 80° C. for 2 h. The mixture was purified on RP-HPLC and the product was netralized with CH2Cl2/NaOH (1 M). The product was lyophilized from 1:1 acetonitrile/water (1 mL) to give a white fluffy powder. MS (ESI pos. ion) m/z (MH+): 393. Calc'd exact mass for C22H20N2O3S: 392. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.55 (d, J=6.02 Hz, 3H) 3.49 (d, J=3.01 Hz, 1H) 3.91 (s, 3H) 4.03 (dd, J=13.55, 8.03 Hz, 1H) 4.58 (dd, J=13.55, 3.01 Hz, 1H) 5.10-5.22 (m, 1H) 6.58 (d, J=9.54 Hz, 1H) 6.66 (d, J=5.02 Hz, 1H) 6.88 (d, J=3.01 Hz, 1H) 6.96-7.01 (m, 1H) 7.05 (dd, J=9.03, 2.51 Hz, 1H) 7.19 (d, J=5.02 Hz, 1H) 7.30 (d, J=2.01 Hz, 1H) 7.52 (dd, J=9.54, 2.51 Hz, 1H) 7.63 (d, J=2.51 Hz, 1H) 8.05 (d, J=9.03 Hz, 1H) 8.59 (d, J=5.52 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ ppm 17.37, 53.44, 55.03, 55.49, 71.85, 100.05, 107.33, 114.41, 116.10, 118.50, 120.89, 122.78, 124.20, 127.97, 135.11, 138.95, 139.26, 151.43, 151.71, 160.01, 160.98, 161.84.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].Cl.O.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:6][C:2]([CH3:7])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([OH:5])=[O:4]
Reactant: c1ccccc1
Reactant: CC(C)(Br)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C(=O)O)c1ccccc1
Temperature: 5 °C

Procedure:
Molten alpha-bromoisobutyric acid, 328 g, 2 moles, was added to a 5-L flask equipped with a reflux condenser and large magnetic stirrer. Anhydrous benzene 2000 mL, was added to the flask, followed by fresh anhydrous AlCl3, 900 g, 6.75 moles, in small portions. The solution was then slowly heated to the reflux temperature and at this time the exit of the reflux condenser was connected to a flowing-water HBr trap. The mixture was heated a total of 24 hours without interruption. The reaction mixture was then cooled to ca. 5° C. and treated with 2 L of 50/50 (by volume) conc. HCl/H2O to decompose the catalyst complex. The benzene layer was then separated, washed once with ice-cold H2O (1200 mL) and twice with dilute aqueous sodium hydroxide. The aqueous sodium hydroxide extracts were combined, heated to 80° C. to drive out any physically trapped benzene and decolorized with activated charcoal. After filtration through diatomaceous earth filter aid ("Celite") the aqueous basic filtrate was neutralized slowly with conc. HCl. The precipitated acid was filtered, washed with a minimum amount of ice-cold water, and dried in a vacuum oven at 25°-30° C. The crude yield was 209 g (65%), and the melting point at this stage was 75.5°-77° C. The crude acid was recrystallized from n-heptane (450 mL for ca. 200 g acid). The final yield was 180 g of mp=76°-78°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.C1C(=O)N([Cl:22])C(=O)C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:22]
Reactant: N#Cc1cc(Br)cc2ccc(O)cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12

Procedure:
The title compound was prepared by reacting 3-bromo-7-hydroxy-1-naphthonitrile (0.32 g, 1.28 mmol) with NCS (0.24 g, 1.8 mmol) in THF (25 mL) at 45° C. for 3 hr according to method C to yield 0.30 g (83%) of a yellow solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 148–150° C.; 1H NMR (DMSO-d6): δ 7.47 (1H, d, J=8.98 Hz), 7.95 (1H, d, J=9.02 Hz), 8.32 (1H, d, J=2.08 Hz), 8.55 (1H, d, J=2.08 Hz), 11.33 (1H, s); MS (ESI) m/z 280/282/284 (M−H)−
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH:17]=[N:18]O)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.C(O)(=O)C>[Pd]>[NH2:18][CH2:17][CH2:16][CH2:15][C:11]1[N:10]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCC=NO)n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cccc(CCCN)n1
Reaction time: 18 h

Procedure:
To a solution of (tert-butoxy)-N-[6-(3-(hydroxyimino)propyl)(2-pyridyl)]carboxamide in ethanol/acetic acid (4 eq/1 eq, 0.1M) under nitrogen was added 5% palladium on carbon. The reaction was stirred under hydrogen at 60 psi for 18 hr. The reaction was filtered thru celite and concentrated in vacuo to yield the product. EI-MS m/z 252(M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C)C(=O)Nc1ccc(F)cc1F
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1ccc(F)cc1F

Procedure:
The acid was prepared according to Procedure B using ethyl 3-(2,4-difluorophenylamino)-2-methyl-3-oxopropanoate (5.1 g, 19.83 mmol) in THF (19.8 mL) to give 3-(2,4-difluorophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=230.1 (M+1).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13][C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1[Cl:20].O>ClCCl>[Br:13][C:14]1[C:18]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:17]([CH3:19])[S:16][C:15]=1[Cl:20]
Reactant: Cc1cc(Br)c(Cl)s1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C)sc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Under a nitrogen atmosphere, ethyl chlorooxoacetate (898 μL, 8.04 mmol) and aluminum chloride (III) (2.14 g, 16.07 mmol) were added successively at −10° C. to a solution of 3-bromo-2-chloro-5-methylthiophene (44a) (1.7 g, 8.04 mmol) in dichloromethane (84 mL). After 1 hour at 0° C., the mixture was stirred at room temperature for 8 hours. The reaction mixture was slowly hydrolyzed at 0° C. with water. The organic layer was separated, washed with hydrochloric acid 1 N, brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to give the desired keto-ester (44b) as an orange solid (1.44 g, 4.6 mmol, 56%).
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].OC1C(O)([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH3:43])[CH:27]=3)=[CH:24][N:25]=2)CCNC(=O)C1.[O:46]1[C:50]2([CH2:55][CH2:54][C:53](=[N:56][S:57]([C:59]([CH3:62])([CH3:61])[CH3:60])=[O:58])[CH2:52][CH2:51]2)[O:49][CH2:48][CH2:47]1>O1CCCC1.ClCCl.CO>[CH3:60][C:59]([S:57]([NH:56][C:53]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH3:43])[CH:27]=3)=[CH:24][N:25]=2)[CH2:52][CH2:51][C:50]2([O:49][CH2:48][CH2:47][O:46]2)[CH2:55][CH2:54]1)=[O:58])([CH3:62])[CH3:61]
Reactant: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNC(=O)CC3O)s2)c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC4(CC3)OCCO4)s2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
To diisopropyl amine (318 μL, 2.23 mmol) in tetrahydrofuran (3.7 mL) at 0° C. was added N-butyllithium (2.5 M in hexanes, 892 μL, 2.23 mmol). The mixture was stirred for 15 minutes, then cooled to −78° C. INTERMEDIATE 4 (250 mg, 0.74 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The mixture was stirred for 30 minutes at −78° C., then the product of Step 1 (212 mg, 0.82 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred for 21), and then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate:hexanes gradient, then 0:100 to 15:85 methanol:dichloromethane gradient) afforded 2-methyl-N-{8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]dec-8-yl}propane-2-sulfinamide (318 mg, 0.40 mmol, 75% yield) as a brown solid. MS ESI: [M+H]+ m/z 596.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:42])=[C:5]([C:38]([O:40][CH3:41])=[O:39])[CH:6]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:7]=1[C:8]([O:10][CH2:11][C:12]([CH3:28])([CH3:27])[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:9].Cl.C(OC(C)C)(C)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:42])=[C:5]([C:38]([O:40][CH3:41])=[O:39])[CH:6]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:7]=1[C:8]([O:10][CH2:11][C:12]([CH3:27])([CH3:28])[CH2:13][N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCN(C(=O)OC(C)(C)C)CC2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCNCC2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
9.7 g of 3-[4-(tert-butyloxycarbonyl)-1-piperazinyl]-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was dissolved in ethanol and 50 ml of an ethanol solution of 9.9N hydrogen chloride was added under cooling with ice. After stirring the mixed solution for 1 hour under cooling with ice, isopropyl ether was added. The solid which separated was collected by filtration, dissolved in saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and acetone was added to the residue. The crystal which separated was collected by filtration to give 3.5 g of the subject compound (yield: 43%). The IR and NMR data of the compound thus obtained are as follows: ##STR63##
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:10]([CH3:13])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(O)=C(C(C)=CC=1)C(OC)=O>>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:10]([CH3:13])=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1c(C)ccc(Br)c1OC
Agent: COC(=O)c1c(C)ccc(Br)c1O
Product: COC(=O)c1c(C)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 90, starting from methyl 3-bromo-2-hydroxy-6-methylbenzoate (Intermediate 93).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:23]=[CH:22][CH:21]=[CH:20][CH:9]1[CH2:10][CH:11]2[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[NH2:1][CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:23]=[CH:22][CH:21]=[CH:20][CH:9]1[CH2:10][CH:11]2[CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: [N-]=[N+]=NCCCOC12C=CC=CC1CC2C(=O)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCOC12C=CC=CC1CC2CN1CCCCC1

Procedure:
A solution of the azidobenzocyclobutenylamide compound of Step 2. above (3.2 g) in THF (20.4 ml) is added dropwise to a suspension of LAH (0.93 g) in anhydrous ether (122 ml) stirred under nitrogen maintained at ice bath temperatures. The reaction mixture is refluxed for 15 hours, cooled and quenched with water (0.93 ml), aqueous sodium hydroxide (15% solution, 0.93 ml) and water (2.79 ml) and filtered. The solid is washed with ether and the combined filtrate dried, filtered, evaporated in vacuo and chromatographed (silica gel: ethyl acetate/methanol). The pure fractions are combined and evaporated in vacuo yielding an oil, which is identified at the desired product by NMR.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=3)[NH:7][C:6]=2[C:5](=[O:26])[N:4]([CH2:27][CH2:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:3]1=[O:37].[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45]Cl)=[N:43][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][N:7]2[C:6]3[C:5](=[O:26])[N:4]([CH2:27][CH2:28][CH2:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[C:3](=[O:37])[N:2]([CH3:1])[C:10]=3[N:9]=[C:8]2[O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:23])([F:25])[F:24])[CH:16]=2)=[N:43][CH:44]=1
Reactant: ClCc1ccc(Cl)cn1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2[nH]c(OCCOc3cccc(OC(F)(F)F)c3)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cn1
Temperature: 50 °C

Procedure:
To a solution of 3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (60 mg, 0.14 mmol, intermediate 17) in DMF (5 mL) was added 5-chloro-2-(chloromethyl)pyridine (33 mg, 0.20 mmol), potassium carbonate (37 mg, 0.27 mmol) and TBAI (2 mg, 0.02 mmol). The reaction was heated at 50° C. for 8 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give crude product, which was used without purification. LCMS MH+-THP 570.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[N:18]([C:19]2[N:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[N+:56]([C:59]1[S:63][C:62]([S:64](Cl)(=[O:66])=[O:65])=[CH:61][CH:60]=1)([O-:58])=[O:57]>C(Cl)Cl>[N+:56]([C:59]1[S:63][C:62]([S:64]([N:15]2[CH2:16][CH2:17][N:18]([C:19]3[N:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:28])([F:29])[F:27])=[CH:21][N:20]=3)[C@@H:13]([CH2:12][N:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:14]2)(=[O:66])=[O:65])=[CH:61][CH:60]=1)([O-:58])=[O:57]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 49.8 %

Procedure:
A 5-mL vial was charged with tert-butyl (3R)-3-(((methylsulfonyl)(phenyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.229 g, 0.373 mmol), TFA (1.0 mL, 13 mmol) and CH2Cl2 (2 mL). The mixture was stirred at room temperature for 35 min and then concentrated. CH2Cl2 (1 mL) was added to the residue followed by triethylamine (0.60 mL, 4.3 mmol). The mixture was stirred at room temperature for 10 min and then a solution of 5-nitrothiophene-2-sulfonyl chloride (0.104 g, 0.456 mmol, Enamine LLC, Monmouth Jct. NJ) in CH2Cl2 (1 mL) was added drop wise. After stirring at room temperature for 40 min, the mixture was concentrated and purified by column chromatography (50 g of silica gel, 0 to 60% EtOAc in hexanes) to afford N-(((2R)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.131 g) as a light-brown foam.