Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH2:16])[CH:5]=[CH:6][C:7]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[CH2:16])[CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C=Cc1ccc(O)cc1C#N)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C=C(CCc1ccc(O)cc1C#N)OCC
Yield: 67.7 %

Procedure:
To a solution of 2-(3-ethoxy-buta-1,3-dienyl)-5-hydroxy-benzonitrile (600 mg) in EtOAc (50 mL) was added 5% Pd/C (0.3 g). The reaction was exposed to hydrogen gas in a Parr apparatus at 60 psi overnight at ambient temperature. The reaction mixture was filtered and concentrated to give the title compound (410 mg). MS [EI] m/z 218 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].[OH-].[Na+].C1(C)C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A mixture of 3,4,5-triphenyl-lH-pyrazol-1-hexanol (5 g, 12 mmol), tert-butyl bromoacetate (4.92 g, 4.10 mL, 25 mmol), tetrabutylammonium hydrogen sulfate (0.4 g), 50% aqueous sodium hydroxide solution (80 mL) and toluene (80 mL) was stirred vigorously at room temperature. After 18 hours, the reaction mixture was diluted with water (100 mL), the organic layer separated and the aqueous layer extracted twice with diethyl ether. The combined extracts were dried over sodium sulfate and the solvent evaporated to give an oil which was chromatographed on a column of silica gel. Elution with a mixture of hexane and diethyl ether (2:1) afforded 1,1-dimethylethyl [[6-(3,4,5-triphenyl-lH-pyrazol-1-yl)hexyl]oxy]acetate (5.84 g, 95%) as an oil that slowly crystallized to a white solid; m.p. =69°-72° C. MS(CI): m/e =511 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.[O-:13][C:14]#[N:15].[K+].CC(O)C>C(O)(=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]2[NH:15][C:14](=[O:13])[O:1][CH:2]=2)[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: O=C(CO)c1ccc(Cl)c(Cl)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Cl)c(Cl)c2)co1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 2-hydroxy-3′,4′-dichloroacetophenone (10.3 g), potassium cyanate (8.1 g) and 2-propanol (100 mL) was heated to 50° C., and acetic acid (6.0 g) was slowly added dropwise. The mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated and poured into iced water (200 mL). The precipitated solid was collected by filtration, washed with water and air-dried to give the title compound as crystals (6.0 g, 52%). Recrystallization from tetrahydrofuran-hexane gave pale-yellow prism crystals. melting point: 262-263° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:57]/[O:58][C:59]2([C:62]([OH:64])=[O:63])[CH2:61][CH2:60]2)/[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]([S:16]([OH:19])(=[O:18])=[O:17])[C@@H:12]2[CH2:20][N:21]2[N:25]=[C:24]([CH2:26][NH:27]/[C:28](=[N:48]/C(OC(C)(C)C)=O)/[N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[C:23]([CH3:56])=[N:22]2)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:28](=[NH:48])[NH:27][CH2:26][C:24]1[C:23]([CH3:56])=[N:22][N:21]([CH2:20][C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])/[C:7](=[N:57]\[O:58][C:59]3([C:62]([OH:64])=[O:63])[CH2:61][CH2:60]3)/[C:5]3[N:6]=[C:2]([NH2:1])[S:3][CH:4]=3)[C:14](=[O:15])[N:13]2[S:16]([OH:19])(=[O:18])=[O:17])[N:25]=1
Reactant: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN/C(=N/C(=O)OC(C)(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CNC(=N)NCCCN
Temperature: 0 °C
Yield: 47.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-((Z)-4-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)imino)-11,11-dimethyl-9-oxo-10-oxa-2,4,8-triazadodecyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid (58.5 mg, 0.062 mmol), DCM (621 μL), anisole (20.4 μL, 0.186 mmol) and TFA (427 μL, 4.55 mmol). The reaction mixture was diluted with ice-cold water (1 mL) and the layers were separated. The organic layer was extracted with water (1 mL) and the combined aqueous layers were washed with DCM (1 mL) and then purified by reverse phase preparative HPLC (XSELECT C18, 5μ, 30×100 mm, 1-20% ACN/H2O w/0.1% formic acid buffer over 18 min, 60 mL/min), affording the title compound (19 mg, 44%) as an off-white solid. LCMS: Rt=0.54 min, m/z=643.2 (M+1) Method 2m_acidic_polar. 1H NMR (400 MHz, D2O) δ 7.11 (s, 1H), 5.62 (d, J=5.6 Hz, 1H), 5.01-4.94 (m, 1H), 4.91-4.74 (m, 2H assumed; obscured by solvent residual peak), 4.50 (br s, 2H), 3.36 (t, J=6.9 Hz, 2H), 3.11 (t, J=7.8 Hz, 2H), 2.29 (s, 3H), 2.01 (p, J=7.2 Hz, 2H), 1.35-1.25 (m, 2H), 1.21-1.05 (m, 2H).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([C:22]([O-:24])=[O:23])[C:19]([O-:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH-].[Li+].C(O)(C(F)(F)F)=O>O.C(#N)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:22]([OH:24])=[O:23])=[O:15])=[CH:6][CH:5]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)NCC(C(=O)[O-])C(=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NN=Cc1ccc(NC(=O)CCC(=O)NCC(C(=O)O)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Dimethyl [[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aminomethyl]propanedioate prepared in Example 23, Step 2 (500 mg) was added to water/acetonitrile (20 ml) followed by lithium hydroxide (100 mg) at 25° C. The mixture was stirred for 30 min. The course of the reaction was monitored by RPHPLC. After satisfactory product was formed the reaction was neutralized with TFA and purified by reverse phase chromatography (0.5% TFA water/acetonitrile) to result in 350 mg of a white solid: 1H NMR (d6 -DMSO) δ2.41 (m, 2H), 2.57 (m, 2H), 3.35 (m, 1H), 3.47 (m, 2H), 7.79 (s, 4H), 8.1 (t, 1H, J=6.1 Hz), 7.78 (s, 4H), 8.02 (m, 1H), 8.87 (bs, 2H), 9.15 (bs, 2H), 10.39 (s, 1H); MS (FAB) m/z 350 (MH+).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Cl.N1C=CC=CC=1>>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: COc1ccc2nc(C#N)sc2c1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1nc2ccc(O)cc2s1

Procedure:
In greater detail, 2-cyano-6-methoxybenzothiazole is used as a starting material and reacted with pyridine hydrochloride to yield 2-cyano-6-hydroxybenzothiazole. Next, the 2-cyano-6-hydroxybenzothiazole is reacted with allyl bromide to yield 6-allyloxy-benzothiazole-2-carbonitrile.
Reaction SMILES: C1COCC1.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:41]1[CH2:46][CH2:45][CH:44]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][C:62]([F:65])([F:64])[F:63])=[CH:57][CH:56]=3)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1>O>[O:9]1[CH2:10][CH2:11][CH2:12][O:7][CH:8]1[CH2:13][CH2:14][CH:41]1[CH2:42][CH2:43][CH:44]([CH:47]2[CH2:48][CH2:49][CH:50]([CH2:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([O:61][C:62]([F:63])([F:64])[F:65])=[CH:59][CH:60]=3)[CH2:51][CH2:52]2)[CH2:45][CH2:46]1
Reactant: O=C1CCC(C2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Reactant: c1ccc([PH](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(CCC2CCC(C3CCC(CCC4OCCCO4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
THF (100 ml) was added to 1,3-dioxan-2-ylethyltriphenylphosphinebromide (10.0 g, 21.9 mmol), followed by adding thereto potassium-t-butoxide (2.46 g, 21.9 mmol), stirring the mixture at the same temperature for 3 hours, dropwise adding to the reaction solution, a 20 ml THF solution of the above 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexane (5.7 g, 15.6 mmol), stirring the mixture at the same temperature for one hour, stirring for 3 hours at room temperature, adding water (100 ml) to the reaction solution, extracting the product with ethyl acetate, washing the organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the resulting residue according to column chromatography treatment using heptane/ethyl acetate (3/1) as a developing solvent, on silica gel, distilling off the solvent, hydrogenating the residue (5.1 g) in the presence of a catalyst of 5% Pd/C (0.30 g) in an ethanol solution, filtering off the catalyst, distilling off the solvent under reduced pressure, and recrystallizing the residue from heptane/ethanol (5/1), to obtain 4-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexane (3.25 g, 6.94 mmol). The yield of this product from 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexane was 44.5%.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)C>[C:1]1([C:2]2[C:2]3[CH:3]=[C:4]4[C:5]([CH2:3][CH2:4][CH2:5]4)=[CH:6][C:1]=3[CH2:6][CH:1]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: C1=C(c2ccccc2)c2cc3c(cc2C1)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 180.5 %

Procedure:
3,5,6,7-Tetrahydro-s-Hydrindacen-1(2H)-one (12.00 g, 0.06967 moles) was stirred in diethyl ether (200 mL) at 0° C. as PhMgBr (0.105 moles, 35.00 mL of 3.0 M solution in diethyl ether) was added slowly. This mixture was then allowed to stir overnight at room temperature. After the reaction period the mixture was quenched by pouring over ice. The mixture was then acidified (pH=1) with HCl and stirred vigorously for 2 sours. The organic layer was then separated and washed with H2O (22×100 mL) and then dried over MgSO4. Filtration followed by the removal of the volatiles resulted in the isolation of the desired product as a dark oil (14.68 g, 90.3% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1O.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(=O)=O.C(OCC)C>CN(C)P(N(C)C)(N(C)C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[C:3](=[O:18])[N:4]=[C:5]2[N:6]([C@@H:7]3[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@@H:8]3[O:17]2)[CH:16]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: Cc1cn2c(nc1=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Temperature: 150 °C
Yield: 72.2 %

Procedure:
A mixture of 5-methyluridine (16.77 g, 69.2 mmol), diphenyl carbonate (17.8 g, 83.1 mmol) and sodium bicarbonate (100 mg) in hexamethylphosphoramide (175 ml) was heated to 150° C. with stirring until evolution of CO2 ceased (approximately 1 hr). The reaction mixture was cooled and then poured into diethylether (1 l) while stirring to furnish a brown gum. Repeated washings with diethylether (4×250 ml) furnished a straw colored hygroscopic powder. The solid was purified by short column chromatography on silica gel (400 g). Pooling and concentration of appropriate fractions, which were eluted with CH2Cl2-MeOH (85:15, v/v) furnished the title compound as a straw colored solid (12 g, 77.3%) which crystallized from EtOH as long needles, m.p. 226-227° C.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:12][C:13]2[O:14][C:15]3[C:21]([CH2:22][CH:23]=[O:24])=[CH:20][C:19]([Cl:25])=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.O>C(O)C>[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:12][C:13]2[O:14][C:15]3[C:21]([CH2:22][CH2:23][OH:24])=[CH:20][C:19]([Cl:25])=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc(Cc2nc3cc(Cl)cc(CC=O)c3o2)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2nc3cc(Cl)cc(CCO)c3o2)cc1OC1CCCC1
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Sodium borohydride 0.05 g, 0.0013 mol) was added to a stirred solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chlorobenzoxazole-7-ethanal (1.0 g, 0.0025 mol) in 10 ml ethanol. Stirring was continued for 1 hour. Water (15 ml) was added and the reaction mixture was extracted with 2×50 ml ethyl acetate. The ethyl acetate layer was washed once with water (50 ml), dried and evaporated to give 1.1 g of pale yellow crystals. A small sample of this solid was recrystallized from a blend of ether-hexane to give the title compound as a white solid, mp 74-76° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH:19]1([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:20]1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH:19]1([CH:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])[CH2:21][CH2:20]1
Reactant: CCOC(=O)C=CC1CC1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(CC(=O)OCC)C1CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
29.1 ml (72.8 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution, cooled to −40° C., of 10.2 ml (72.8 mmol) of diisopropylamine in 35 ml of abs. THF. After the end of the addition, the mixture was stirred at −40° C. for another 30 min and then cooled to −78° C., and a solution of 7.1 ml (72.8 mmol) of ethyl acetate in 10 ml of abs. THF was added dropwise. The reaction mixture was stirred at −78° C. for 30 min, and a solution of 8.50 g (60.54 mmol) of ethyl 3-cyclopropylacrylate in a little THF was then added dropwise. After 1 h at −78° C., the mixture was slowly warmed to −40° C., then to 0° C., and a saturated aqueous ammonium chloride solution was finally added. After extraction with ethyl acetate, the organic phase was washed with 1 N hydrochloric acid and sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1→6:1). This gave 3.28 g of the target product (23.7% of theory).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]3=[O:17])[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2cc(N3CCN(C)CC3)ccn2c1=O
Temperature: 70 °C
Yield: 106.8 %

Procedure:
Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (755 mg, 3.0 mmol), the product of Step 3 of Example 58, was suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 6.0 mL (6.0 mmol) of N-methylpiperazine and the reaction mixture was heated at 70° C. for 8 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) was dissolved in 125 mL of methylene chloride and the methylene chloride solution was washed with 125 mL of saturated sodium chloride solution (brine). The aqueous layer was extracted with 125 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford 1.01 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(N(CC)CC)C>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine, 10.8 g (62.7 mmol) of 4-nitrobenzylchloride, 23.8 ml (171 mmol) of triethylamine in 100 ml of dichloromethane is stirred for 12 hours at 70° C. After diluting with water the organic phase is separated off, dried and evaporated down.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].CS(C)=O.Cl.[CH:26]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:32]2[CH:26]3[CH2:31][CH2:30][CH:29]2[CH2:28][CH2:27]3)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
4-Fluoro-1-nitro-2-(trifluoromethyl)benzene (18) (901 g, 4.309 mol) was introduced into a 30 L jacketed vessel along with Na2CO3 (959.1 g, 9.049 mol) and DMSO (5 L, 5.5 vol) under nitrogen atmosphere and stirring. 7-azabicyclo[2.2.1]heptane hydrochloride (7a) (633.4 g, 4.740 mol) was then added to the vessel in portions. The temperature was gradually raised to 55° C. When the reaction was substantially complete, the mixture was diluted with 10 vol EtOAc and washed with water (5.5 vol) three times or until DMSO in the aqueous layer disappeared (HPLC). The organic layer was concentrated to 4 vol and then the solvent was swapped with cyclohexane until all the EtOAc was removed, and the total volume in the flask was about 4 vol containing cyclohexane. The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min. Then the solution was cooled to room temperature with stirring or rotation for 3 h. When all the solid crystallized, the solution was concentrated to dryness to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (19).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.CCOCC.[F:20][C:21]1[CH:22]=[C:23]2[C:40](=[CH:41][CH:42]=1)[O:39][C:26]1([CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[CH2:25][C:24]2=[O:43].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:25]1[C:26]2([CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:30][CH2:31]2)[O:39][C:40]2[C:23](=[CH:22][C:21]([F:20])=[CH:42][CH:41]=2)[C:24]1=[O:43])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(F)ccc1O2
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22 %

Procedure:
To triethyl orthoformate (20.2 mL, 121.5 mmol) in dry dichloromethane (115 mL) under argon at −10° C. was added drop-wise BF3.OEt2 (15.4 mL, 121.5 mmol). The solution was allowed to warm to 0° C. and was stirred for 10 minutes. After, the solution was cooled to −78° C. prior to the slow drop-wise addition of tert-butyl 6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (13.6 g, 40.5 mmol) in dichloromethane (10 mL). iPr2NEt (24.7 mL, 141.7 mmol) was added drop-wise over 30 minutes, and the mixture was slowly warmed to room temperature and was stirred at 25° C. for 2 hours. The reaction mixture was diluted with the addition of dichloromethane (200 mL) followed by saturated aqueous sodium bicarbonate solution (200 mL). The mixture was shaken in a separatory funnel and separated. The organic layer was washed with additional sodium bicarbonate solution (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield a residue that was purified by silica gel column chromatography (0-25% EtOAc/hexanes gradient) to give tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (3.9 g, 22%). ESI-MS m/z calc. 437.2, found 438.7 (M+1)+. Retention time 2.14 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24].[C:27](Cl)(=[O:29])[CH3:28]>>[C:27]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:23]([O-:25])=[O:24])[CH:11]=2)=[O:15])[CH2:18][CH2:19]1)(=[O:29])[CH3:28]
Reactant: O=C(NC1CCNCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 199 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(piperidin-4-yl)thiophene-2-carboxamide (0.2 g, 0.46 mmol) and acetyl chloride (53.0 mg, 0.69 mmol). The title compound was obtained as a solid (75 mg, 35% yield). 1H NMR (400 MHz, d6-DMSO) δ:8.98 (2H, m), 8.67 (1H, m), 8.48 (1H, s), 4.28 (1H, m), 3.89 (1H, m), 3.80 (1H, m), 3.61 (1H, m), 3.13 (1H, m), 2.70 (1H, m), 2.00 (3H, s), 1.83 (1H, m), 1.76 (1H, m), 1.41 (1H, m), 1.28 (1H, m). MS m/z: 473.23, 475.25 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[N:31]#[C:32]Br>CCO>[NH2:31][C:32]1[N:18]([C@@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:3]2[CH:4]=[C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COc1ccc(COc2ccc(N)c(N[C@H]3CC[C@@H](C(=O)NC(C)C)CC3)c2)cc1
Reactant: N#CBr
Solvent: CCO
Product: COc1ccc(COc2ccc3nc(N)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cis-4-(2-amino-5-(4-methoxybenzyloxy)phenylamino)-N-isopropylcyclohexanecarboxamide (400 mg, 0.972 mmol) in EtOH (4.8 mL) was added cyanic bromide (165 mg, 1.555 mmol) and the mixture was stirred at RT for 2 hours. The solvent was evaporated, and the residue was diluted with DCM (about 10 mL), washed with water, 1N aqueous NaOH, and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed to afford cis-4-(2-amino-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide (424 mg).