Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:43])[N:30](COC(=O)C(C)(C)C)[CH:31]=[N:32]2)=[C:27]([OH:44])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:43])[NH:30][CH:31]=[N:32]2)=[C:27]([O:44][CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC1CCOCC1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)cc(O)c2c1=O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Temperature: 5 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Di-tert-butyl azodicarboxylate (16.3 g) was added portionwise to a stirred mixture of 7-benzyloxy-5-hydroxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (17 g), 4-hydroxytetrahydropyran (5.4 g) and methylene chloride (200 ml) that had been cooled to 5° C. The mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was evaporated and the residue was dissolved in a saturated methanolic ammonia solution. The resultant mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was dried under vaccuum to give 7-benzyloxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (12.5 g); NMR Spectrum: (DMSOd6) 1.6-1.7 (m, 2H), 1.85-1.95 (m, 2H), 3.5 (m, 2H), 3.9 (m, 2H), 4.75 (m, 1H), 5.22 (s, 2H), 6.7 (d, 1H), 6.8 (d, 1H), 7.3-7.5 (m, 5H), 7.9 (s, 1H); Mass Spectrum: M+H+ 353.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:15]=1[N:24]=[C:25]=[O:26].O>CN(C)C=O>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:25]([NH:24][C:15]1[C:16]([O:22][CH3:23])=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[O:13][CH3:12])=[O:26])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)C(C#N)c2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
Phenylacetonitrile (2.64 mL, 22.8 mol) was added dropwise to an ice-cooled solution of sodium hydride (0.91 g, 22.8 mmol) in dimethyl formamide (50 mL), and the mixture stirred for 15 minutes while allowing to warm to room temperature. 2,4,6-Trimethoxyphenyl-isocyanate (4.78 g, 22.8 mmol) was added portionwise over 2 minutes, and then the mixture was stirred vigorously for 0.5 hour and poured into water (200 mL). The solid obtained was washed with water (100 mL) and taken up in chloroform (1 L). The organic layer was separated and dried with MgSO4, filtered, and concentrated to yield a pale purple solid (6.13 g, 82%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:19])[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(Cl)Cl.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:19][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21)c1ccccc1
Reaction time: 1 h

Procedure:
To a 0° C. solution of 8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroquinolin-8-amine (62 mg, 0.136 mmol) and DCM (1 mL) was added DIEA (0.035 mL, 0.201 mmol) and then benzoyl chloride (0.0175 mL, 0.151 mmol) dropwise. After 1 h, the reaction was poured into water and the aqueous layer back extracted with DCM (5 mL). The combined DCM layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0-30% EtOAc in hexane, to provide the title compound as a white solid. MS (ESI, positive ion) m/z: 397.0 (MH+). 1H NMR (300MHz, CDCl3) δ: 8.46-8.63 (m, 2H), 7.74-7.88 (m, 2H), 7.33-7.66 (m, 8H), 7.24-7.28 (m, 1H), 3.55 (dt, J=14.0, 4.2 Hz, 1H), 2.89 (dd, J=9.6, 6.8 Hz, 1H), 2.54-2.82 (m, 2H), 1.86-2.01 (m, 1H), 1.65-1.83 (m, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:16](Cl)(Cl)=[O:17].[CH2:20](N)[CH2:21][NH2:22]>C1(C)C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:16]([NH2:22])=[O:17])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1.[CH3:20][CH2:21][NH2:22]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: O=C(Cl)Cl
Reactant: NCCN
Solvent: Cc1ccccc1
Product: CCN
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 0 °C

Procedure:
Iminostilbene (1.93 g) is dissolved in anhydrous toluene (50 ml). This solution is added dropwise with stirring to 10 ml of a 12.5% w/w solution of phosgene in toluene (1.1 g of phosgene) and the mixture heated under reflux with exclusion of moisture for 1 h. To the solution at 0° C. is added 1.3 ml (1.2 g) of freshly re-distilled ethylenediamine and the mixture heated under reflux with exclusion of moisture for 3h. On cooling to 0° C. a white precipitate forms, and is separated by filtration. The filtrate is evaporated to dryness under vacuum then extracted into dilute hydrochloric acid from chloroform. The inorganic extract is basified with concentrated ammonia and re-extracted with chloroform. The organic extract is dried (Na2SO4) and evaporated to dryness to yield carbamazepine-N-beta-ethylamine, 1.6 g.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CI>CN(C)C=O>[CH3:1][O:22][C:21]([C@H:18]1[CH2:17][CH2:16][C@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20][CH2:19]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (877 mg, 6.34 mmol, 1.05 eq) is added at room temperature to a stirred solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.50 g, 6.04 mmol, 1.0 eq) in N,N-dimethylformamide (30 mL), followed by methyl iodide (395 μL, 6.34 mmol, 1.05 eq). After 5 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×30 mL) and water (30 mL). The combined organic layers are washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester as a yellow solid (1.60 g, 98% yield).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:6]([O:25][CH2:26][CH2:27][O:28][CH3:29])[C@H:5]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:43])C(=O)C1>C(O)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[C:16]([Br:43])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:6]([O:25][CH2:26][CH2:27][O:28][CH3:29])[C@H:5]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:3])[CH3:2]
Reactant: COCCO[C@H]1[C@H](OC(=O)C(C)(C)C)c2ccn3cc(C)nc3c2N(C(C)=O)[C@@H]1c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Product: COCCO[C@H]1[C@H](OC(=O)C(C)(C)C)c2ccn3c(Br)c(C)nc3c2N(C(C)=O)[C@@H]1c1ccccc1
Reaction time: 1 h

Procedure:
To a of 0° C. cooled solution of 0.40 g (0.83 mmol) (7R,8R,9R)-10-acetyl-8-(2-methoxyethoxy)-2-methyl-9-phenyl-7-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in ethanol (5 ml) is added 0.15 g (0.83 mmol) NBS and the mixture is stirred for 1 h. Afterwards the reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution and it is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ether/triethylamine: 95/5) to provide 0.30 g (0.53 mmol/65%) of the title compound as an amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=0.96 (s, 9H), 2.09(s, 3H), 2.42(s, 3H), 3.23(s, 3H), 3.40–3.53 (m, 2H), 3.69–3.98 (m, 2H), 4.23(t, 1H), 5.75 (d, 1H), 6.02 (s, 1H), 6.80(d, 1H), 7.16(s, 5H), 8.18(d, 1H).
Reaction SMILES: C([O:3][CH2:4][C:5]1[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]2[C:18](=[O:29])[C@@H:19]([NH:20][C:21](=[O:28])[CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C@H:8]2[S:7][CH:6]=1)=O.Cl.C1OC1C>CO>[OH:3][CH2:4][C:5]1[CH:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[N:9]2[C:18](=[O:29])[C@@H:19]([NH:20][C:21](=[O:28])[CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C@H:8]2[S:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1C(COC=O)=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N12
Agent: CC1CO1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)C1C(CO)=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
t-Butyl (6R,7R)-3-formyloxymethyl-7-(2-thienylacetamido)ceph-2-em-4-carboxylate (50 mg.; 0.115 mmole), warm methanol (2 ml) and 2N hydrochloric acid (0.025 ml) were stirred together at 25° C. at an apparent pH of 2. T.l.c. after 2 hours 20 minutes showed a virtually complete reaction. Propylene oxide (0.1 ml) was added and the mixture was stirred at 25° C. for 5 minutes. The mixture was partitioned between ethyl acetate (40 ml) and water (40 ml). The aqueous layer was extracted with ethyl acetate (20 ml) and the combined organic layers were washed with water (2 × 20 ml) and dried over anhydrous sodium sulphate and filtered and evaporated to a gum. This gum was dissolved in ethyl acetate (2 ml) and added dropwise to stirred 40 to 60° petroleum ether (100 ml) to give a pale yellow solid (23mg.; 50%). T.l.c. after work up indicated approximately 20% lactone. τ (d6DMSO) 0.81 (d, J 9Hz; NH), 2.6, 3.0 (mult.; thienyls), 3.5 (broad s; Δ2 2-H), 4.51 (d,d J 9, 5Hz; 7-H), 4.80 (d, J 5Hz; 6-H), 4.92 (broad s; --CH2OH), 5.10 (broad s; 4-H), 5.95 (mult; 3 CH2), 6.20 (s; ##STR5## and 8.55 (s; tBu).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[NH2:6][C:7]1[C:12]([S:1]([OH:5])(=[O:4])=[O:3])=[CH:11][C:10]([S:1]([OH:3])(=[O:5])=[O:4])=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)O)cc1S(=O)(=O)O
Temperature: 200 °C

Procedure:
225.5 g (2.3 mol) of 100% strength sulphuric acid were added to 257.0 g (2.76 mol) of aniline in 460 ml of ortho oil. The suspension obtained was heated at 200° C. for 2.5 hours in a 1.3 1 enamel autoclave. After cooling, the mixture was filtered off with suction and the filter residue was dried. The 475.6 g of solid contained 80.7% of p-sulphanilic acid in addition to unchanged anilinium hydrogensulphate, based on the excess sulphuric acid employed. Aniline-2,4-disulphonic acid was not formed.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.[ClH:41].C(OCC)C.B(Br)(Br)Br>ClCCl>[ClH:41].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:30]=[CH:31][C:32]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])=[CH:33][CH:34]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)N(C)C)cc3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 77 %

Procedure:
In a round bottom flask place the product of Example 64 (120 mg, 0.214 mmol), dichloromethane (5 mL) and a 1.0 M hydrochloric acid in diethyl ether solution (0.43 mL, 0.43 mmol). Shake this solution at ambient temperature for 2 minutes then evaporate it in vacuo. After drying on vacuum, add dichloromethane (10 mL) and place this solution in an ice bath with stirring. Add a solution of 1.0 M boron tribromide in dichloromethane (0.750 mL, 0.750 mmol) and stir the reaction for 3-4 hours, keeping the temperature between 0° C.-10° C. Quench the reaction over saturated aqueous sodium bicarbonate then extract it into ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, water and brine; then dry (sodium sulfate) and evaporate them in vacuo. Purify the crude solid on a Chromatotron (silica gel; 5%-11% MeOH gradient in CH2Cl2; loaded with 7% MeOH/CHCl3). Dissolve the purified material in methanol (5 mL) and add a 1.0 M hydrochloric acid in diethyl ether solution (0.43 mL). Shake the resulting solution for two minutes at room temperature then evaporate it in vacuo to give 96 mg of the title compound (77%). MS (IS+) m/e 547 (M+1−HCl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][C@@H:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[Cl:27][CH2:28][C:29]1[N:33]=[C:32]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[O:31][N:30]=1>CCOC(C)=O>[Cl-:27].[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][C@@H:13]2[CH:18]3[CH2:19][CH2:20][N+:15]([CH2:28][C:29]4[N:33]=[C:32]([C:34]5[S:35][CH:36]=[CH:37][N:38]=5)[O:31][N:30]=4)([CH2:16][CH2:17]3)[CH2:14]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1noc(-c2nccs2)n1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(F)c1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O[C@H]1C[N+]2(Cc3noc(-c4nccs4)n3)CCC1CC2)C(Nc1cccc(F)c1)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 30.8 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(3-fluorophenylamino)-2-phenylacetate (I41) (76 mg, 0.21 mmol) in EtOAc (5 mL), was added 3-(chloromethyl)-5-(thiazol-2-yl)-1,2,4-oxadiazole (I55) (43 mg, 0.21 mmol). The mixture was stirred at room temperature for 17 hours. Then the mixture was heated under microwave irradiation at 100° C. for 1 hour. The solvent was evaporated and the crude was triturated with Et2O and filtrated to collect (3R)-3-(2-(3-fluorophenylamino)-2-phenylacetoxy)-1-((5-(thiazol-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-1-azoniabicyclo[2.2.2]octane chloride (36 mg, 30.4% yield, mixture of diastereomers).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>ClCCCl.CC(O)(C)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[S:9][C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1nc(Cl)c2cc(-c3ccc(F)cc3)sc2n1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Cc1nc(Nc2ccc(F)c(Cl)c2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 90 °C
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidine (15 mg, 0.05 mmol) in 1,2-dichloroethane/t-BuOH (1:1, 2 ml) was added 3-chloro-4-fluoroaniline (16 mg, 0.11 mmol). The mixture was heated at 90° C. for 2 days. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (11 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:25])[CH:21]=2)[N:16]=1.[C:26](=[O:37])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:25][C:26]([NH:45][CH:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)=[O:37])[CH:21]=2)[N:16]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCC(N)CC1
Reactant: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from rac-N2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine, bis(trichloromethyl) carbonate and 1-methyl-piperidin-4-ylamine; MS: m/e=515.7 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]3[O:9][C:5]=2[CH:4]=1.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[O:9][C:5]=2[CH:4]=1
Reactant: C1=CCCC=C1
Reactant: COc1cccc(O)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)OC1CCCCC21
Product: COc1ccc2c3c(oc2c1)CCCC3
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of AuCl3 (0.303 g, 1.0 mmol) and AgOTf (0.770 g, 3.0 mmol) was stirred in anhydrous CH2Cl2 (150 mL) for 2 hours. 3-methoxy-phenol (2.48 g, 20 mmol) in CH2Cl2 (25 mL) was added, followed by addition of cyclohexadiene in CH2Cl2 (25 mL) at 40° C. over two hours. The reaction mixture was stirred at 40° C. overnight. The reaction mixture was passed through a silica gel plug. The filtrate was concentrated. The residue was purified by silica gel chromatography (5-30% CH2Cl2/heptane) to give 0.393 g of the title compound and 0.67 g of 7-methoxy-1,2,3,4-tetrahydro-dibenzofuran.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4](Br)=[CH:5][CH:6]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C.CCOC(C)=O>[Br:1][C:2]1[O:3][C:4]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)=[CH:5][CH:6]=1
Reactant: Brc1ccc(Br)o1
Reactant: Clc1ncccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Clc1nccc(-c2ccc(Br)o2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a cooled (−78° C.) solution of 2,5-dibromofurane (3.06 g, 8.88 mmol) in anhydrous diethyl ether (50 ml) was added n-Butyllithium (3.9 ml of 2.5M solution in Hexanes, 9.77 mmol). The mixture was stirred at this temperature for 90 minutes before the addition of 2-chloropyrimidine. The mixture was stirred for a further 30 minutes before being warmed to room temperature and stirred for further 2 hours. DDQ (2 g, 8.88 mmol) was them added to the solution which was stirred for 30 minutes before being concentrated in vacuo to give a thick brown syrup. The syrup was dissolved in EtOAc and washed with saturated sodium carbonated solution. The organic extract was removed, dried (MgSO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO2) (100% hexane going to 7:2—hexane:EtOAc) to give the title compound (3.06 g, 40.20%) in pure form. m/z (LC-MSW, ESP):346 [M+H]+, R/T=4.41 mins
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:6][CH3:7])=[CH:8][CH:9]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1ccc(Br)cc1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of 4-bromo-N-methyl-2-nitroaniline (6 g, 25.97 mmol) in ethanol (100 ml) was added SnCl2.2H2O (29 g, 128.52 mmol). The resulting solution was stirred for 3 h at 70° C., adjusted to pH 8 with potassium hydroxide (4M), extracted with ethyl acetate (2×200 ml), and the organic layers combined and concentrated under vacuum to afford 4-bromo-N1-methylbenzene-1,2-diamine as a white solid (5 g, 96%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH-:33].[Na+]>C1COCC1>[OH:33][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: BrCc1ccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reaction time: 24 h

Procedure:
A mixture of 2.0 g of 5-[4-(bromomethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole from Example 13 and 1N NaOH (5 mL) in THF (20 mL) was stirred for 24 hours. The solvent was evaporated and the aqueous solution extracted with EtOAc. The organic layer was washed with water, dried, and evaporated to give 1.8 g of 5-[4-(hydroxymethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole which was used as is for the next step; MS (EI), 418 (m).
Reaction SMILES: Cl[C:2]1C(Cl)=CC2N=C(S)NC=2C=1.[OH-].[K+].IC.[Cl:17][C:18]1[C:28]([Cl:29])=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[NH:24][C:20]=2[CH:19]=1>C(O)C>[Cl:17][C:18]1[C:28]([Cl:29])=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[N:24]([CH3:2])[C:20]=2[CH:19]=1
Reactant: CSc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Product: CSc1nc2cc(Cl)c(Cl)cc2n1C

Procedure:
5,6-dichloro-2-mercaptobenzimidazole (8.76 g, 0.04 mol) in 50 ml 95% ethanol was treated with 10 ml of 45% aqueous potassium hydroxide to give a solution. Iodomethane (7 ml, 0.096 mol) was added. The reaction mixture was refluxed for two hours. Cooling overnight yielded precipitant, which was filtered, water-washed, and dried to yield 5.61 g, mp 115° C. The reaction filtrate was rotary evaporated and the residue reslurried in water. After filtration and drying, an additional 3.52 g was obtained, mp 110° C. NMR analysis indicated the presence of some 5,6-DiChloro-2-(methylthio)benzimidazole as an impurity.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[O:22]C(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[OH:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1.[CH2:53]([O:55][C:56](=[O:68])[C:57](=O)[CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63](O)=[CH:62][CH:61]=1)[CH3:54]>C1COCC1>[C:49]([O:48][C:46]([N:43]1[CH2:42][CH2:41][CH:40]([O:39][C:63]2[CH:64]=[CH:65][C:60]([C:59](=[O:22])[CH2:58][CH2:57][C:56]([O:55][CH2:53][CH3:54])=[O:68])=[CH:61][CH:62]=2)[CH2:45][CH2:44]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CCOC(=O)C(=O)CCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To triphenylphosphine (2.48 g, 9.48 mmol) in THF (25 mL) was added 40% w/w DEAD in toluene (4.00 mL, 8.95 mmol) and the reaction was cooled at 0° C. before adding a mixture of 4-hydroxy-boc-piperidine (1.44, 7.14 mmol) and 4-(4-hydroxyphenyl)-oxo-butyric acid ethyl ester (1.3 g, 5.8 mmol) in THF (25 mL). After overnight stirring at r.t., the reaction was concentrated and the product was purified using a Single Step column (7:3 hexanes:ethyl acetate) to obtain 2.17 g (91%); MS m/z 406 (M+H).