Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:33]1([C:39](=[O:47])[CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:44]3[CH2:45][CH2:46][N:41]([CH2:40][C:39]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[O:47])[CH2:42][CH2:43]3)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 16) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H38N7O4Cl2 [(M+H)+] 666.2357, observed 666.2358.
Reaction SMILES: BrC1C=CC2C(=N)NC[CH2:9][O:10]C=2C=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([F:23])[CH:16]=1.C[O-].[Na+]>CO>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[NH:20])[O:10][CH3:9])=[C:17]([F:23])[CH:16]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: N=C1NCCOc2cc(Br)ccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(Br)cc1F

Procedure:
Scheme 13 shows an alternative synthesis of 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-imine 33 from 4-bromo-2-fluorobenzonitrile 11. Reaction of 11 with sodium methoxide in methanol gives methyl 4-bromo-2-fluorobenzimidate 35. Alkylation of 35 with 2-aminoethanol gives 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzimidamide 36, followed by cyclization to 33.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3F)[C:11](=[O:26])[C:10]([C:27]([OH:29])=[O:28])=[CH:9]2)[CH2:7][CH2:6]1>C(O)C>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3[O:2][CH3:1])[C:11](=[O:26])[C:10]([C:27]([OH:29])=[O:28])=[CH:9]2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
To the solution of sodium methoxide prepared from sodium (0.2 g) and absolute ethanol (9 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (0.5 g) and the mixture in sealed tube was heated for 72.5 hours at 140° to 150° C. After cooling, the reaction mixture was concentrated, water (4 ml) was added to the residue, and the solution was adjusted to pH 7 with acetic acid. The insoluble materials were filtered off and the filtrate was allowed to stand in a refrigeretor. The resulting precipitate was collected by filtration and recrystallized from dichloromethane-methanol (2:1; 6 ml) to give the title compound (0.12 g) as colorless prisms, mp 185°-187.5° C. (decompd.).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[C:20](O)(=[O:24])[C:21](O)=[O:22].Cl>C(O)C.C(OCC)(=O)C.[Ni]>[CH:1]1([N:7]2[C:8]3[C:9](=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[NH:15][C:21](=[O:22])[C:20]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)ccc1NC1CCCCC1
Reactant: O=C(O)C(=O)O
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1[nH]c2cc(F)ccc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A solution of 2.0 g (8.4 mmol) N-cyclohexyl-4-fluoro-2-nitroaniline in a mixture of 100 ml ethanol and 50 ml ethyl acetate was hydrogenated at atm. pressure by using Ra-Ni (1 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give an oil. A mixture of the oil, 2.8 g (23 mmol) oxalic acid dihydrate, 10 ml ethanol and 150 ml 4N hydrochloric acid was refluxed for 11/2h. After cooling to 25° C. the precipitate was filtered off and washed with water to give 1.1 g (50%) 1-cyclohexyl-6-fluoroquinoxaline-2,3(1H,4H)-dione. M.p. 289.8° C., 1H-NMR (DMSO-d6): 12.0 (1H, broad s), 7.6 (1H, M), 7.0 (2H, M), 4.5 (1H, M), 2.6-0.9 (10H, M).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:31][O:32][CH3:33])[C:12]([NH:14][C@H:15]2[C@@H:18]([CH2:19][NH:20][C:21]([O:23][CH2:24][CH2:25]S(C)(=O)=O)=[O:22])[NH:17][C:16]2=[O:30])=[O:13])[N:10]=1)=[O:4].[OH-:34].[Na+].Cl.[CH2:37](O)[CH3:38]>CN(C)C=O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:31][O:32][CH3:33])[C:12]([NH:14][C@H:15]2[C@@H:18]([CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]3[CH:38]=[CH:37][C:11]([N+:31]([O-:32])=[O:34])=[CH:9][CH:8]=3)=[O:22])[NH:17][C:16]2=[O:30])=[O:13])[N:10]=1)=[O:4]
Reactant: [OH-]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CNC(=O)OCCS(C)(=O)=O)c1csc(NC(=O)CCl)n1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CNC(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a mixture of 25 ml of ethanol and 5 ml of N,N-dimethylformamide is suspended 525 mg of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(2-methylsulfonylethoxycarbonylaminomethyl)-2-oxoazetidine (syn-isomer) as obtained in Reference Example 119C, followed by addition of 5 ml of ethanolic sodium hydroxide (0.5N). The mixture is stirred at room temperature for 20 minutes, after which 2.5 ml of 1N HCl is added. The ethanol is distilled off under reduced pressure and the residue is dissolved in a mixture of 8 ml of water and 10 ml of tetrahydrofuran. Under ice-cooling and stirring, 185 mg of sodium hydrogen carbonate is added, followed by dropwise addition of a solution of 432 mg of p-nitrobenzyl chloroformate in 10 ml of tetrahydrofuran over 50 minutes. The mixture is stirred under ice-cooling for 20 minutes and to this reaction mixture are added 10 ml of water and 20 ml of ethyl acetate. The mixture is shaken well, whereupon the organic layer separates out. The aqueous layer is extracted with ethyl acetate and this ethyl acetate extract and the above organic layer are combined, washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is crystallized from ethyl acetate and recovered by filtration to give cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(p-nitrobenzyloxycarbonylaminomethyl)-2-oxoazetidine (syn-isomer), m.p. 235°-245° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.[C:31](Cl)(=[O:33])[CH3:32].CO>N1C(C)=CC(C)=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][O:17][C:31](=[O:33])[CH3:32])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: Cc1cc(C)nc(C)c1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a vigorously stirred solution of (1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol (1A, 0.481 g, 1.1 mmol) in collidine (2.5 mL) cooled to −35 degrees Celsius was added drop-wise over 10 minutes acetyl chloride (0.149 mL, 2.1 mmol). After 1 hour, methanol (0.5 mL) was added and the reaction mixture was allowed to warm to room temperature. The crude mixture was concentrated under reduced pressure and codistilled three times with toluene. The crude material was purified by flash chromatography over silica gel using the biotage automated chromatography unit (50 g silica gel column) and eluting with a gradient of 0 to 15% methanol in dichloromethane. 456 mg (87% yield) of product obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:18]([N+:15]([O-:17])=[O:16])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc(Cl)cc1)[N+](=O)[O-]
Temperature: 105 °C
Yield: 40 %

Procedure:
2.00 g (14.2 mmol) 4-chlorobenzaldehyde (Aldrich, Milwaukee, Wis.), 5.48 g (71.1 mmol) ammonium acetate (Fluka), and 50 g (666 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a dark yellow liquid which was recrystallized from cold methyl alcohol three times to give yellow needles in 40% yield. 1H NMR spectra is shown in FIG. 2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]=2[CH:13]=1.[CH3:14][N:15](C)C=O>C(N)CN.O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]=2[CH:13]=1)#[N:15]
Reactant: CN(C)C=O
Reactant: CC1(C)CNc2cc(Br)ccc2O1
Solvent: O
Solvent: NCCN
Product: CC1(C)CNc2cc(C#N)ccc2O1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 480 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine, 206 mg of cuprous cyanide and 5 ml of N,N-dimethylformamide was stirred at 130° C. for 4 hours and further at 150° C. for 5 hours. This reaction mixture was diluted with 0.5 ml of ethylenediamine and 10 ml of water and extracted with benzene. The organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with ethyl acetate-hexane (10:1). The crude crystals from the eluate were washed with hexane and dried to give 160 mg of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine. This compound has the following physicochemical properties.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH2:15]3)[CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[ClH:1].[CH2:17]1[C:18]2[C:14](=[CH:13][C:12]([C:4]3[CH:3]=[C:2]([NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: Clc1cc(-c2ccc3c(c2)CCC3)nc2ccccc12
Reactant: NCC(O)CO
Product: Cl
Product: OCC(O)CNc1cc(-c2ccc3c(c2)CCC3)nc2ccccc12

Procedure:
The title compound, m.p. 157-160° C., MS: m/e=334 (M+), was prepared from 4-chloro-2-indan-5-yl-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: CC(C[AlH]C[CH:7]([CH3:9])[CH3:8])C.[CH:10]([N-:13][CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11].[Li+:17]>CN(C)C1C=CN=CC=1.C(Cl)Cl.C1COCC1>[Li:17][CH2:10][CH2:9][CH2:7][CH3:8].[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)C[AlH]CC(C)C
Reactant: [Li+]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)NC(C)C
Product: [Li]CCCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Synthesis of Dienes 23 and 24 as illustrated in FIG. 4. EDC Coupling of Alcohol 18a with Keto Acid 21. A solution of keto acid 21 (2.43 g, 14.3 mmol, 1.2 equiv), 4-(dimethylamino)pyridine (4-DMAP, 0.145 g, 1.2 mmol, 0.1 equiv) and alcohol 18a (4.048 g, 11.9 mmol, 1.0 equiv) in methylene chloride (40 mL, 0.3 M) was cooled to 0° C. and then treated with 1-ethyl-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (EDC, 2.74 g, 14.3 mmol, 1.2 equiv). The reaction mixture was stirred at 0° C. for 2 h and then at 25° C. for 12 h. The solution was concentrated to dryness in vacuo, and the residue was taken up in EtOAc (10 mL) and water (10 mL). The organic layer was separated, washed with saturated NH4Cl solution (10 mL) and water (10 mL) and dried (MgSO4). Evaporation of the solvents followed by flash column chromatography (silica gel, 4% EtOAc in hexanes) resulted in pure keto ester 22a (5.037 g, 86%). Step B. Aldol Condensation of Ester 22a with Aldehyde 7. A solution of keto ester 22a (1.79 g, 3.63 mmol, 1.0 equiv) in THF (15 mL) was added via cannula to a freshly prepared solution of lithium diisopropylamide [LDA; formed by addition of n-BuLi (2.83 mL, 1.6 M solution in hexanes, 4.58 mmol, 1.25 equiv) to a solution of diisopropylamine (0.61 mL, 4.36 mmol, 1.2 equiv) in THF (30 mL) at −10° C. and stirring for 30 min] at −78° C. After 15 min the reaction mixture was allowed to warm to −40° C. and was stirred for 45 min. The reaction mixture was cooled to −78° C. and a solution of aldehyde 7 (0.740 g, 5.8 mmol, 1.6 equiv) in THF (15 mL) was added dropwise. The resulting mixture was stirred for 15 min, then warmed to 40° C. for 30 min, cooled back to −78° C. and then quenched by slow addition of saturated aqueous NH4Cl solution (10 mL). The reaction mixture was warmed to 25° C., diluted with EtOAc (10 mL) and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and subjected to flash chromatographic purification (silica gel, 5 20% EtOAc in hexanes) to afford a mixture of aldol products 23 (926 mg, 42%) and 24 (724 mg, 33%), along with unreacted starting keto ester 22a (178 mg, 10%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[CH:7][C:8]([CH3:28])=[C:9]([CH:27]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)([F:18])[CH2:14][CH2:13]1)=[O:11])=O.Cl.[C:34](=[NH:37])([NH2:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:29]1([C:6]2[C:5]([C:3]3[NH:37][C:34]([CH3:35])=[N:36][CH:2]=3)=[CH:27][C:9]([C:10]([N:12]3[CH2:13][CH2:14][C:15]([C:19]4[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=4)([F:18])[CH2:16][CH2:17]3)=[O:11])=[C:8]([CH3:28])[CH:7]=2)[CH2:30][CH2:31][CH2:32]1
Reactant: Cc1cc(C2CCC2)c(C(=O)CBr)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ncc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 236.1, 40 mg, 0.08 mmol, 1.00 equiv) in CH3CN (10 mL). Acetimidamide hydrochloride (7.6 mg, 0.08 mmol, 1.00 equiv) and potassium carbonate (33.4 mg, 0.24 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 80° C. in an oil bath, then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate. The organic layer was washed with 2×20 mL of water, 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (29.0% CH3CN up to 43.0% in 8 min, up to 100.0% in 2 min, down to 29.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 13 mg (35%) of the title compound as a white solid. m/z (ES+) 457 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.78 (d, 2H), 7.65 (d, 2H), 7.50-7.46 (m, 2H), 7.35 and 7.23 (2 s, amide rotamers, 1H), 4.91-4.83 (m, 1H), 3.76-3.63 (m, 1H), 3.54-3.49 (m, 2H), 3.32-3.30 (m, 1H), 2.70 (s, 3H), 2.49 and 2.39 (2 singlets, amide rotamers, ArCH3, 3H), 2.34-2.28 (m, 7H), 1.98-1.80 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:22](OC)[N:23]([CH3:26])[CH2:24][CH3:25].C1CCCCC1.C(OCC)(=O)C>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N:18]=[CH:22][N:23]([CH2:24][CH3:25])[CH3:26])=[CH:13][C:12]=2[CH3:19])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N
Reactant: CCN(C)C(OC)OC
Solvent: CO
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCN(C)C=Nc1cc(C)c(-c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 45 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
To a mixture of 2.1 g (6.3 mmol) of 4′-tert-butyl-2,5-dimethylbiphenyl-4-amine in 2.5 ml methanol a solution of 8.8 mmol of N-(dimethoxymethyl)-N-methylethanamine (60% in methanol) was added. The reaction mixture was stirred for 24 hrs at 45° C. The reaction mixture was concentrated in vacuo. Column chromatographic (gradient: cyclohexane->ethyl acetate) yielded 0.96 g (3.0 mmol) 47% of N′-(4′-tert-butyl-2,5-dimethylbiphenyl-4-yl)-N-ethyl-N-methylimidoformamide; log P (pH 2.3)=2.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.S([C:27]#[N:28])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([C:27]#[N:28])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: COc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2cc(C#N)sc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.9 %

Procedure:
To a solution of 1-benzothien-7-yl methyl ether (1 g, 6.1 mmol) in THF (12 mL) at −78° C. was added a solution of 2.5 M n-butyllithium in hexanes (2.9 mL, 7.3 mmol). After stirring for 1.5 hr this solution was added dropwise to a solution of tosyl cyanide (1.66 g, 9.1 mmol) in THF (8 mL), this was left stirring at −78° C. for 0.5 hr and then warmed to room temperature. After 16 h this was poured onto ice-water and extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, dried MgSO4) and the solvent removed in vacuo to give an oil. This was purified by flash chromatography with a gradient of 0-30% ethyl acetate in hexane to give the title compound (0.31 g, 27%); δH (300 MHz, CDCl3) 7.79 (1H, s, 3-ArH), 7.46-7.38 (1H, m, 4-ArH), 7.37-7.31 (1H, m, 5-ArH), 6.88-6.82 (1H, m, 6-ArH) and 3.94 (3H, s, OCH3). Starting material 1-benzothien-7-yl methyl ether was recovered from the reaction (0.56 g, 56%); δH (300 MHz, CDCl3) 7.45-7.29 (4H, m, ArH), 6.75 (1H, m, ArH), 4.00 (3H, s, OCH3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1)(=[O:21])[CH3:20]
Reactant: Oc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1
Reaction time: 1 h

Procedure:
200 mg of 3-(5-hydroxy-3-indolyl)quinuclidine are dissolved in 10 ml of pyridine and 5 ml of acetic anhydride are added with cooling. After one hour, the mixture is worked up as is customary. 3-(5-acetoxy-3-indolyl)quinuclidine is obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.[C:20]1([CH3:33])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([O:31][NH2:32])(=[O:30])=[O:29]>ClCCl>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH3:33])[C:21]=1[S:28]([O-:31])(=[O:30])=[O:29].[NH2:32][N+:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:5]([N:10]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[S:11]([CH3:14])(=[O:12])=[O:13])[CH:6]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC(C)CCN(c1cnccc1C1CC1)S(C)(=O)=O
Solvent: ClCCl
Product: CC(C)CCN(c1c[n+](N)ccc1C1CC1)S(C)(=O)=O
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(4-cyclopropylpyridin-3-yl)-N-isopentylmethanesulfonamide (Example 17G, 474 mg, 1.68 mmol) in dichloromethane (3 mL) at 0° C. was treated with the solution of O-(mesitylsulfonyl)hydroxylamine (solution used directly from Example 17H). The solution was immediately warmed to room temperature and stirred for 1 hour. The solution was then used directly in Example 17K.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[O:10])[CH:7]=1.S(Cl)(Cl)(=O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Al+3].[Cl-].[Cl-].[Cl-].[CH:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:9](=[O:10])[NH:8][C:6]=2[CH:7]=1
Reactant: c1ccccc1
Reactant: Cc1ccc(Cl)cc1N=C=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=C1Nc2cc(Cl)ccc2Cc2ccccc21
Reaction time: 4 h
Yield: 14 %

Procedure:
To a mixture of 5-chloro-2-methylphenyl isocyanate (100 μL, 0.73 mmol) in CCl4 (2 mL) was added sulfuryl chloride (118 μL, 0.88 mmol) and 2,2′-azobis(isobutyronitrile) (catalytic amount) and the resulting mixture was refluxed for 20 h. The mixture was allowed to obtain room temperature, then diluted with CH2Cl2, washed with saturated aqueous NaHCO3-solution, dried (Na2SO4) and concentrated. The mixture was taken up in benzene (2 mL) and a mixture of AlCl3 (160 mg, 1.2 mmol) in benzene (1 mL) was added. The resulting mixture was stirred at 80° for 4 h, and then allowed to obtain room temperature. The mixture was filtered through a short column (SiO2, heptane:EtOAc, 1:1) to give 25 mg (14%) of the title compound (189JO59). 1H NMR (CDCl3) δ 8.18 (bs, 1H), 7.92 (dd, 1H, J=1.2, 7.8 Hz), 7.46 (dt 1H, J=1.4, 7.4 Hz), 7.34 (dt, 1H, J=1.2, 7.4 Hz), 7.23 (m, 2H), 7.07 (m, 2H), 3.92 (s 2H). MS (ESI) 244 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2n1Cc1cccc(Cl)c1
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Ethyl N-(3-chlorobenzyl)indole-2-carboxylate (0.47 g) was dissolved in THF/MeOH (1:1) and sodium hydroxide (2M, 4.5 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo to dryness and the residue dissolved in water. The solution was acidified to pH 3 by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered off, washed with water and dried in vacuo to give the desired end product (0.35 g, 82%), mp 188-189°; NMR δ(CD3SOCD3) 5.85 (s, 2H), 6.90 (d, 1H), 7.1 (m, 2H), 7.3 (m, 4H), 7.55 (d, 1H), 7.70 (d, 1H); M/z (−) 284 (M−H+).