Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[N:27][C:26]([NH2:29])=[N:25][CH:24]=2)=[CH:19][C:18]=1[F:30]>C(O)(C)(C)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26]3[N:27]([C:2]([CH2:5][C:6]4[CH:7]=[C:8]5[C:13](=[CH:14][CH:15]=4)[N:12]=[CH:11][CH:10]=[N:9]5)=[CH:3][N:29]=3)[N:28]=2)=[CH:19][C:18]=1[F:30]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: O=CC(Cl)Cc1ccc2nccnc2c1
Solvent: CC(C)(C)O
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5nccnc5c4)n3n2)ccc1Br
Temperature: 110 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture of 2-chloro-3-quinoxalin-6-ylpropanal (110 mg, 0.52 mmol), and 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (140 mg, 0.52 mmol) in tert-butyl alcohol (4 mL) was stirred at 110° C. overnight. After cooling to RT, it was concentrated and purified by chromatography on silica gel with EtOAc in Hexane (0-40%) to afford the desired product (140 mg, 62%). LCMS: (M+H)=435.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][N:21]4C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][NH:21]4)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4)CC2)ccc1[N+](=O)[O-]
Yield: 52.2 %

Procedure:
To 1,1-dimethylethyl (1S,4S)-5-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 2.3 mmol) in DCM (10 mL) was added TFA (10 mL). After reaction was shown to be complete by TLC, the volume is reduced on the rotovap until it weighs 4 g. The solution is diluted with DCM and poured into saturated NaHCO3 solution. The layers are separated and the aqueous layer washed with DCM. The organics are combined, dried (MgSO4), filtered and rotovaped to give the title compound of step B (400 mg, 1.2 mmol, 50%). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J=9.3 Hz, 1H), 6.37 (dd, J=9.3, 2.6 Hz, 1H), 6.27 (d, J=2.6 Hz, 1H), 3.90 (s, 3H), 3.80-3.73 (m, 2H), 3.60 (br s, 2H), 3.20 (d, J=10.6 Hz, 1H), 3.12-2.95 (m, 4H), 2.87-2.81 (m, 1H), 2.64-2.55 (m, 1H), 2.36 (d, J=9.3 Hz, 1H), 1.94-1.77 (m, 3H), 1.64 (d, J=9.3 Hz, 1H), 1.59-1.46 (m, 2H). The aqueous layer is re-extracted with EtOAc and then with 85:15 DCM:iPrOH to give more of the title compound of step B (400 mg, 1.2 mmol, 50%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([N:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([N:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(N(C)C)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-dimethylamino-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K28) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (309 mg, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a stirring solution of 1-(4-hydroxyphenyl)ethanone (5 g, 36 mmol) in Acetonitrile 50 mL was added potassium carbonate (9.9 g, 72 mmol) and benzyl bromide (7.5 g, 44 mmol) and stirred at RT for overnight, reaction mass was diluted with water and extracted with ethyl acetate, organic layer was given water and brine washes, dried over Na2SO4, evaporation under reduced pressure yields titled compound as white solid (7 g Yield: 84.1%): 1H NMR (300 MHz, CDCl3): δ 7.85-7.88 (d, 2H), 7.25-7.37 (m, 5H), 6.92-6.95 (d, 2H), 5.06 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].C(N(CC)CC)C.P(Cl)(Cl)([Cl:19])=O.[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:19])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc[n+]([O-])c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
2-Chloro-3-methylpyridine 1-oxide (9.00 g, 62.7 mmol) and triethylamine (10.4 ml, 75.2 mmol) were dissolved in dichloromethane (70 ml), and a solution of phosphorus oxychloride (7 ml, 75.3 mmol) in dichloromethane (40 ml) was added dropwise at 0° C. After stirring for 3 hours while elevating reaction temperature to room temperature, the reaction mixture was stirred under reflux for 1 hour. After the reaction was completed, water (30 ml) was added and the reaction mixture was neutralized with a sodium hydroxide solution, and after extracted with dichloromethane (70 ml), dried over magnesium sulfate. The solvent was evaporated and purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=3/100), thereby yielding the title compound (3.47 g) as a white solid 10:3 mixture with 2,4-dichloro-3-methylpyridine.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]2)[N:12]=1)=[O:7])[CH3:4].CCN(C(C)C)C(C)C.[CH:29]1[CH:34]=[C:33]([CH2:35][O:36][C:37](Cl)=[O:38])[C:32]([Cl:40])=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:37]([O:36][CH2:35][C:33]3[CH:34]=[CH:29][CH:30]=[CH:31][C:32]=3[Cl:40])=[O:38])[CH:16]=[N:15]2)[N:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1nc(Cn2cc(N)cn2)cs1
Reactant: O=C(Cl)OCc1ccccc1Cl
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(4-amino-pyrazol-1-ylmethyl)-thiazole-2-carboxylic acid ethyl ester (1.43 g, 5.65 mmol) in CH2Cl2 (56.0 mL) was treated with DIPEA (1.15 mL, 8.47 mmol) followed by 2-chlorobenzylchloroformate (1.04 mL, 6.78 mmol). The reaction mixture was stirred at rt for 1 h before being quenched with water (50 mL), extracted with CH2Cl2 (3×40 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (96:4 CH2Cl2-MeOH) gave the title compound as a pink foam. TLC: rf (96:4 CH2Cl2-MeOH)=0.28. LC-MS-conditions 02: tR=0.99 min; [M+H]+=421.14.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[S:13])[CH3:2].[Cl-].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH2+:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:24][Cl:25])=[CH:18][CH:17]=1>>[ClH:25].[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[N:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[C@@H:23]([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=2)[CH2:24][S:13]1)[CH3:2]
Reactant: CCc1cc(C#N)ccc1N=C=S
Reactant: CC(C)C[NH2+][C@H](CCl)Cc1ccc(O)cc1
Agent: [Cl-]
Product: CCc1cc(C#N)ccc1N=C1SC[C@H](Cc2ccc(O)cc2)N1CC(C)C
Product: Cl

Procedure:
(1S)-1-(4-Hydroxyphenylmethyl)-2-hydroxyethylamine was made from (L)-tyrosine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4-(4-hydroxyphenylmethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1-(4-hydroxyphenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((1S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method C1b to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(4-hydroxyphenylmethyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: Cl.CO[CH:4]([C:8]1C=CC=C[N:9]=1)C(Cl)=O.[CH3:14][O:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:17](O)=[O:18].S(Cl)(Cl)=O.[CH3:30][NH:31][CH3:32].[OH-].[Na+]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[C:8]([NH2:9])(=[O:15])[CH3:4].[CH3:14][O:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:17]([N:31]([CH3:32])[CH3:30])=[O:18]
Reactant: COC(C(=O)O)c1ccccn1
Reactant: COC(C(=O)Cl)c1ccccn1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(N)=O
Product: COC(C(=O)N(C)C)c1ccccn1
Reaction time: 4 h

Procedure:
Alternatively, 2-methoxy-N,N-dimethyl-2-pyridyl)acetamide is prepared by the following procedure. 2-Methoxy-2-(2-pyridyl)acetyl chloride hydrochloride, 22 g., [prepared by reacting 2-methoxy-2-(2-pyridyl)acetic acid in benzene with thionyl chloride] in 100 ml. of chloroform is added dropwise and with cooling to 50 g. of dimethylamine in 100 ml. of chloroform. The mixture is stirred for 4 hours, then 50 ml. of 5% aqueous sodium hydroxide is added and the chloroform solution is dried and concentrated to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide.
Reaction SMILES: C([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([CH2:28][S:29][C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([CH2:28][S:29][C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH2:11]1
Reactant: Cn1nnnc1SC[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1nnnc1SC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a solution of (2S,4S)-4-benzoylthio-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.60 g) in methanol (30 ml) was added sodium methoxide (28% solution in methanol) (0.78 ml) under ice-cooling. After stirring at the same temperature for 30 minutes, to this solution was added glacial acetic acid (1 ml). The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.78 g).
Reaction SMILES: [Cu:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Cu].[NH3:8].S([O-])([O-])(=O)=[O:10].N.[NH2-].[NH2-].[NH2-].[NH2-].OS(O)(=O)=O.[Cu+2]>>[NH2-:8].[NH2-:8].[NH2-:8].[NH2-:8].[OH:5][S:2]([OH:6])(=[O:4])=[O:3].[Cu+2:1].[NH4+:8].[OH-:10]
Reactant: N
Reactant: [Cu]
Reactant: O=S(=O)([O-])[O-]
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: [NH2-]
Product: [NH4+]
Product: [OH-]

Procedure:
For the preferred copper-sulfate system, the leach solution 10 containing dissolved copper-ammonia-sulfate is next ammoniated or pressurized with ammonia (E) or aqueous ammonia which can be recycled 11 and 16 from subsequent steps. It has been unexpectedly discovered that the mineral values, which were dissolved as a complex with ammonia, precipitate as a complex when pressurized with ammonia. The soluble complex copper ammine sulfate solution enters a low pressure ammoniator (Step E) where ammonia is used to precipitate an insoluble complex ammine. The complex is precipitated by the application of low pressure ammonia. The slurry is filtered (Step F), leaving the solid copper ammine sulfate wet with NH4OH. The gas-liquid stream 13 is recycled. No washing of the complex is necessary. Typically, more than 99 percent of the copper is precipitated in this step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=[O:22])C1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1

Procedure:
To a solution of 100 g (0.33 mol) of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone in 1 L of DMSO, 75 g (0.42 mol) of NBS was added and the mixture was stirred over a weekend. The reaction was poured into 8 L of water and stirred for 30 min. The yellow solid formed was filtered and dried. This solid was purified by passing through a plug of 1 Kg of silica gel using hexane and 5% EtOAc-hexane to isolate the title compound.
Reaction SMILES: [Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:8](O)=[O:9])=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C(Cl)Cl>[Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:8]([Cl:18])=[O:9])=[O:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccco1
Solvent: ClCCl
Product: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1ccco1
Temperature: 0 °C

Procedure:
To an ice-cold stirred suspension of 2-dichloroacetoxyimino-2-(fur-2-yl)acetic acid (1.5 g) in dry methylene chloride (70 mls) was added dropwise a freshly prepared solution of phosphorus pentachloride (1.0 equiv.) in methylene chloride. When solution was complete the solvent was evaporated at low temperature and the residual oil azeotroped with benzene to give 2-dichloroacetoxyimino-2-(fur-2-yl)acetyl chloride (syn-isomer) as a pale yellow oil which was used directly.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[CH:9]3[O:11][CH:10]3[C:5]=2[CH:4]=1)#[N:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22].[H-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C@@H:9]([OH:11])[C@H:10]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[C:5]=2[CH:4]=1)#[N:2]
Reactant: O=C1CCCCN1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCCC2=O)[C@@H]1O
Reaction time: 6 h

Procedure:
6-Cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran and 2-piperidone was stirred in dimethyl sulphoxide under nitrogen at room temperature. Sodium hydride (81% dispersion in mineral oil) was added during 5 mins. and the reaction stirred for a further 6 hours. Addition of water, extraction with ethyl acetate, drying of the organic phase with magnesium sulpate, filatration, evaporation and recrystallisation from ethyl acetate gave 6-cyano-3,4-dihydro-2, 2-dimethyl-trans-4-(2-oxo-1-piperidinyl)-2H-benzo[b]pyran-3-ol was prepared, as crystals of m.p. 155° C.
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[C:13](B(O)O)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[CH:10]=2)[N:5]=1.[NH4+].[Cl-]>CCOCC.O>[Br:3][C:4]1[C:13]([OH:1])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[CH:10]=2)[N:5]=1
Reactant: OO
Reactant: COc1ccc2nc(Br)c(B(O)O)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2nc(Br)c(O)cc2c1
Reaction time: 13 h
Yield: 100 %

Procedure:
Aqueous H2O2 (30%, 32.8 mL, 321 mmol) was added dropwise to a stirred solution of (2-bromo-6-methoxyquinolin-3-yl)boronic acid (4.64 g, 16.45 mmol) and NH4Cl (3.29 g, 61.5 mmol) in Et2O (82 mL) and water (82 mL). After 13 h, NH4Cl (3.29 g, 61.5 mmol) and aqueous H2O2 (30%, 32.8 mL, 321 mmol) were added, and the mixture was stirred for 48 h. The precipitate was collected and washed with water, then dried at 50° C. to afford the title compound (4.18 g, 100%) as a solid that was used directly in the subsequent step. LCMS (ES+) m/z 254, 256 (M+H)+,
Reaction SMILES: [CH:1]1([C@@:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(N(CC)CC)C>C(#N)C>[NH3:10].[C:41]([O:40][C:38]([N:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][N:11]2[CH:12]=[N:13][C:9]([C@:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([OH:8])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10]2)[CH2:16][CH2:17]1)[C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCBr)C(=O)OC(C)(C)C
Reactant: O[C@](c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1)C(=O)OC(C)(C)C
Product: N
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(R)-cyclohexyl(phenyl)[1-(piperidin-4-ylmethyl)-1H-1,2,4-triazol-3-yl]methanol (Preparation 4, 2.00 g, 5.64 mmol) and di-tert-butyl (9-bromononyl)imidodicarbonate (U.S. Pat. No. 4,167,167, 2.38 g, 5.64 mmol) were dissolved in acetonitrile (60 ml) and triethylamine (2.35 ml, 16.9 mmol) added. After stirring at 50° C. for 18 hours, the solvent was removed in vacuo, and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2, by volume) to furnish the title compound as a clear oil, in 60% yield, 2.6 g (contains 10% of other triazole regio-isomer)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC([N:33]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34]1)=O)(C)(C)C.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:39][CH2:38][CH:35]3[CH2:36][CH2:37][NH:33][CH2:34]3)=[O:22])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCC1CCNC1)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (2.2 mmol) was coupled with 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5 mmol) using EDC (3 mmol) in DMF (20 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.9 (s, 1H) 8.5-8.75 (m, 2H) 8.3 (m, 1H) 8.0 (d, 1H) 7.65 (m, 1H) 7.3 (m, 1H) 7.05 (m, 2H) 6.68 (d, 2H) 3.6 (m, 2H) 3.4 (m, 2H) 3.2-3.4 (m, 2H) 2.48 (m, 3H) 2.0 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: Oc1cc(Br)c2c(c1)CCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Br)c2c(c1)CCCC2

Procedure:
5,6,7,8-tetrahydro-4-bromo-2-naphthol (7 g, 30.8 mmol; step c) in example 29) is dissolved in dry acetone (100 ml) and treated with K2CO3 (15 g, 0.11 mol) and methyliodide (7.25 ml, 0.13 mmol). The reaction mixture is kept at RT over night. After filtration and removal of the solvent the residue is purified over silica gel (methylene chloride/cyclohexane 1/1) affording the compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16])(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16])(=[O:7])=[O:8])([CH3:1])[CH3:3]
Reactant: Ic1ccccc1
Reactant: CSc1ccccc1S(=O)(=O)NC(C)(C)C
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CSc1cccc(-c2ccccc2)c1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 11.3 g (0.0436 mol) N-(1,1-dimethylethyl)-2-(methylthio)benzenesulfonamide in 300 ml tetrahydrofuran (THF) was treated with 60.5 ml (0.096 mol) 2M n-butyllithium in hexanes at -30° under a nitrogen atmosphere. The mixture was stirred for 1 hour at ambient temperature then recooled to -20° and treated with 8.3 g (0.0436 mol) of cuprous iodide (anhydrous). After 10 minutes at -15°, 4.9 ml (0.0438 mol) iodobenzene was added and the mixture was then heated to reflux overnight. Acetic acid (10 ml) was added after cooling the mixture to 15°, then 200 ml concentrated ammonium hydroxide plus 200 ml ethyl acetate was introduced and the mixture was stirred vigorously in the presence of air to facilitate removal of the copper salts. The aqueous phase was separated, extracted with more ethyl acetate and the combined organic extracts were washed successively with concentrated ammonium hydroxide, water and brine, then dried (MgSO4) and evaporated to an oil. The product crystallized from ether/hexanes to afford 10 g of material, m.p. 162°-165°.