Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:15])[CH:12]=2)[CH2:7][N:6]1[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[OH:24])=[O:4].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][CH2:39][CH3:40]>CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:15])[CH:12]=2)[CH2:7][N:6]1[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[O:24][CH2:38][CH2:39][CH3:40])=[O:4]
Reactant: CCCBr
Reactant: COC(=O)C1Cc2cc(Br)ccc2CN1C(=O)c1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1c(C)cccc1C(=O)N1Cc2ccc(Br)cc2CC1C(=O)OC
Temperature: 79 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
A 100 mL round bottom flask which contains 6-bromo-(2-hydroxoxy-3-methyl-benzoylamino)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester (373, 0.39 g, 0.932 mmol) and a stirring bar is charged with dry DMF (10 mL). Stirring is initiated. K2SO4 (0.258 g, 1.86 mmol), KI (1 mg, 6 μM), and 1-bromopropane (0.2 mL, 2.24 mmol) are added in turn. The reaction flask is immersed in an oil bath and fitted with a reflux condenser. The oil bath is heated to 79° C. The reaction is stirred for 2 h at this temperature then the oil bath is turned off. After 16 h at ambient temperature, heating is reinitiated at 53° C. for an additional hour. Analysis by ttlc (silica, 1:1 EtOAc:Heptanes), indicates consumption of starting material and appearance of a spot with a slightly lower Rf. The reaction is again allowed to cool to ambient temperature and filtered through a bed of Celite. The resulting solution is diluted with EtOAc (60 mL) and washed repeatedly with brine (4×40 mL), and then dried over MgSO4, filtered and evaporated by pumping to a constant weight yields light yellow oil (0.42 g, 98%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH:3](O)[CH2:4][N+:5]([O-:7])=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][C:2]([CH3:10])([CH3:9])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CC(C)(C)C(O)C[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C=C[N+](=O)[O-]
Reaction time: 2 h
Yield: 96 %

Procedure:
To a cold mixture of 3,3-dimethyl-1-nitro-butan-2-ol (7.35 g, 50.0 mmol), and triethylamine (17.4 mL, 125 mmol) in dichloromethane (70 mL) at −78° C. was added MsCl (4.64 mL, 60 mmol) dropwise; the mixture was stirred for 2 hours at −78° C. to room temperature. Then solvents were removed, the residue was partitioned between EtOAc and diluted HCl aqueous solution, the EtOAc phase was washed with saturated NaCl aqueous solution, then dried over anhydrous sodium sulfate, filtered, concentrated, to give an oil, the title compound (6.2 g); The title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=7.25 (d, 1H, J=13.4 Hz), 6.88 (d, 1H, J=13.4 Hz), 1.16 (s, 9H).
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:8][C:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=O)=O.[NH2:28][CH3:29]>CO>[C:9]12([CH2:8][CH:7]([NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:6][NH:28][CH3:29])[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH2:10]2
Reactant: CN
Reactant: CS(=O)(=O)OCC(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1
Solvent: CO
Product: CNCC(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
2-(benzyloxycarbonylamino)-3-(bicyclo[2.2.2]octan-1-yl)propyl methanesulfonate (830 mg, 2.1 mmol) was dissolved in 15 mL of NH2Me in MeOH and stirred at 30-40° C. overnight. The mixture was concentrated to give benzyl 1-(bicyclo[2.2.2]octan-1-yl)-3-(methylamino)propan-2-ylcarbamate (1.0 g, crude) as an oil, which was used in the next step without further purification. MS ESI +ve m/z 331 (M+H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[CH3:6][C:7]1[C:15]([CH3:17])([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[OH-].[Na+].CO>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:6])[C:15]2([CH3:17])[CH3:16])([O-:4])=[O:2]
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=Nc2ccc([N+](=O)[O-])cc2C1(C)C
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
Sodium nitrate (3.84 g, 45.2 mmol) was dissolved in concentrated sulphuric acid (100 ml). After cooling in ice, this solution was added to a solution of 2,3,3-trimethylindole (6.65 g, 41 .8 mmol) in concentrated sulphuric acid (100 ml) such that the temperature was maintained in the range 0-5° C. The reaction was stirred at 0-5° C. for 90 minutes after completing the addition, then allowed to warm to room temperature and stirred for a further 16 hours. The mixture was poured onto ice (200 g) then made basic by the addition of 50% aqueous sodium hydroxide solution to pH12 (pH paper). The crude product was collected by filtration and washed with water until the washings were neutral (˜1000 ml). The off-yellow solid was dried at the pump, dissolved in ethyl acetate (250 ml) and dried further (MgSO4). The solution was filtered and the red filtrate was rotary evaporated to dryness. The solid was dissolved in chloroform:ethyl acetate (95:5, 30 ml) and purified by silica flash chromatography. This gave a dark yellow solid, 5.12 g, 25 mmol, 60% yield. UV analysis (methanol) showed a single peak with λmax=300 nm. Mass spectrometry (MALDI-TOF with a gentisic acid matrix) gave m/z=203.8 (for C11H12N2O2=204.23). 1H NMR:δ=1.97 (s, 6H), 2.95 (s, 3H), 8.58 (d, J=10 Hz, 1H), 8.70 (s, 1H), 8.78 (d, J=10 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[O:6][C@H:7]1[C@@H:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:14]=2)[O:9][CH2:8]1.Cl.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:34][N:35]([CH3:40])[CH2:36][C:37]([O:17][C@H:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:14]=2)[O:9][CH2:8][C@H:7]1[O:6][C:5]1[CH:30]=[CH:31][CH:32]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:38]
Reactant: CN(C)CC(=O)O
Reactant: COc1cccc(O[C@@H]2COc3ccc(OCc4ccc5ccccc5n4)cc3[C@@H]2O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(O[C@@H]2COc3ccc(OCc4ccc5ccccc5n4)cc3[C@@H]2OC(=O)CN(C)C)c1
Reaction time: 18 h

Procedure:
To a solution of the title product of Example 26 (0.493 g), 4-(dimethylamino)pyridine (0.226 g) and N,N-dimethylglycine hydrochloride (0.193 g) in 30 ml of CH2Cl2 was added a solution of dicyclohexylcarbodiimide in 5 ml of CH2Cl2. After stirring 18 hours, by-product dicyclohexyl urea was recovered by filtration and the filtrate stripped to an oily solid which was chromatographed on a silica gel column with ether as eluant to yield purified title product, 0.44 g. 1H-NMR(CDCl3)delta(ppm): 2.15 (s, 6H), 3.15 (s, 2H), 3.80 (s, 3H), 4.30 (d, J=5Hz, 2H), 4.90 (m, 1H), 6.30 (d, J=3, 1H), 6.30-8.30 (m, 13H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>Cl>[NH2:9][C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a stirred suspension of 5-bromo-2-chloro-3-nitropyridine (20.0 g, 84.2 mMol) in conc. HCl (90 mL) was added 5 nCl2.2H2O (60.0 g, 266 mMol) portionwise over 2 h. (The reaction got very warm to the touch.) The reaction was stirred at RT for 18 h, poured onto ice, and basified with aq. 6 N NaOH (300 mL). The resultant slurry was filtered, washed with H2O, and dried under vacuum to give the title compound (15.53 g, 89%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (d, J=2.3 Hz, 1 H), 7.30 (d, J=2.3 Hz, 1 H), 5.90 (br. s., 2H); MS(ES) m/e 206.7 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[NH2:15]O.Cl>O.CCO>[C:6]1([C:2]2[O:1][N:5]=[C:4]([NH2:15])[CH:3]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a stirred solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) and NaOH (452 mg, 11.3 mmol) in water (10 mL)/EtOH (10 mL) was added hydroxylamine hydrochloride (785 mg, 11.3 mmol). The mixture was stirred at 80° C. for overnight. At this point, conc. HCl (1.3 mL, 15.5 mmol) was added and the resulting mixture was heated at 80° C. for 2 h. It was then basified to pH 10 and extracted with ethyl acetate. The combined extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with ethyl acetate/petroleum ether (1:50 to 1:10) to afford 299a as a yellow solid (1.1 g, 68%). MS-ESI: [M+H]+ 161.3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:18])[N:14]([O:16][CH3:17])[CH3:15])[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:17][O:16][N:14]([CH3:15])[C:13]([C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1)=[O:18]
Reactant: CON(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of [4-(methoxy-methyl-carbamoyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (1.0 g, 3.48 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5.0 mL, 64.9 mmol) at 0° C. The reaction was warmed to ambient temperature and stirred for 4 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was removed to give 2-amino-thiazole-4-carboxylic acid methoxy-methyl-amide as a foam (585 mg, 90%).
Reaction SMILES: Cl.Cl[CH:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[C:15]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[CH:14]2.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>C(#N)C>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:5]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[C:15]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[CH:14]2
Reactant: Cc1cccc(C(Cl)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: C1CCNC1
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(C(c2ccccc2)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 100 °C

Procedure:
A Smith synthesizer vial containing 6-(2-(chloro(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine hydrochloride (0.050 g, 0.104 mmol) and ACN (0.42 mL) was treated with pyrrolidine (0.052 mL, 0.624 mmol). The reaction mixture was warmed to 100° C. for 1 h and then allowed to cool to RT. The mixture was purified by HPLC (1-70% ACN/H2O, TFA modifier). A single clean fraction was treated with NH4OH and concentrated to ¼ volume. The resulting precipitate was collected and dried under a stream of N2 to afford 6-(2-methyl-6-(phenyl(pyrrolidin-1-yl)methyl)phenyl)-3-morpholinoquinolin-2-amine. MS (ESI, pos. ion) m/z: 479 (M+1).
Reaction SMILES: C1COCC1.[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][C:11]=1[Cl:21])([CH3:9])([CH3:8])[CH3:7].C1N=CN(C(N2C=NC=C2)=O)C=1.C(C1C=CC(OCC([NH:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]3[NH:52][C:53](=[O:55])[NH:54][C:50]=3[CH:49]=2)=O)=CC=1)(C)(C)C>C(N(CC)CC)C>[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([NH:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]3[NH:52][C:53](=[O:55])[NH:54][C:50]=3[CH:49]=2)=[O:18])=[CH:12][C:11]=1[Cl:21])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(OCC(=O)NCc2ccc3[nH]c(=O)[nH]c3c2)cc1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc3[nH]c(=O)[nH]c3c2)cc1Cl
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a THF (3.0 ml) solution of the compound of 4A (109 mg, 0.45 mmol) was added CDI (73 mg, 0.45 mmol) at room temperature and the mixture was stirred for 2 hours followed by the additional stirring for 10 hours after the injection of triethylamine (0.3 ml) and the amine compound of Example 1 (156 mg, 0.5 mmol). The resulting precipitate was removed by filtration, followed by evaporation under reduced pressure to give the crude residue which was purified through silica gel column chromatography eluting with DCM/MeOH (9:1) to furnish the title compound as a white solid (19 mg, 11%). 1H NMR (CDCl3): δ 1.40 (9H, s), 4.29 (2H, d, J=5.9 Hz), 4.53 (2H, s), 6.78-6.92 (4H, m), 7.01 (1H, d, J=2.6 Hz), 7.37 (1H, d, J=8.5 Hz), 8.61 (1H, bt, J=6.6 Hz), 10.55, 1H, bs), 10.57 (1H, bs). MS (ESI) m/z 388 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[OH:22].[CH2:23]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=O)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:23]([C:31]1[CH:39]=[CH:38][C:34]([C:35]2[O:22][C:3]3[CH:4]=[CH:5][C:6]([C@H:8]4[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13]4)=[CH:7][C:2]=3[N:1]=2)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC[C@H]1CC[C@H](c2ccc(O)c(N)c2)CC1
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Solvent: O
Product: CCCCCCCCc1ccc(-c2nc3cc([C@H]4CC[C@H](CCCCCCCC)CC4)ccc3o2)cc1
Temperature: 250 °C
Reaction time: 4 h

Procedure:
Step iii) In a 50 ml-round-bottomed flask, 10 g of polyphosphoric acid, 0.40 g (1.32 mM) of 2-amino-4-(trans-4-octylcyclohexyl)phenol and 0.31 g (1.32 mM) of 4-octylbenzoic acid were placed, followed by stirring for 4 hours at about 250 ° C. After the reaction, the reaction mixture was poured into water and an insoluble matter was recovered by filtration. The insoluble matter was added to 10% K2CO3 and sufficiently stirred, followed by recovery of a solid. The solid was washed with water and purified by silica gel column chromatography (eluent: toluene) to obtain 0.11 g of 2-(4-octylphenyl)-5-(trans-4-octylcyclohexyl)benzoxazole (yield: 16.7%). ##STR18##
Reaction SMILES: [CH2:1]([C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]CC3C=CC=CC=3)[CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11][O:12][CH3:13])[C:4]1=[O:14])[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11][O:12][CH3:13])[C:4]1=[O:14])[CH3:2]
Reactant: CCC1(c2cccc(OCc3ccccc3)c2)CCCCN(CCOC)C1=O
Agent: [Pd]
Solvent: CO
Product: CCC1(c2cccc(O)c2)CCCCN(CCOC)C1=O

Procedure:
To a solution of 3-ethyl-1-(2-methoxy-ethyl)-3-(3-benzyloxy-phenyl)-azepan-2-one, as described above in Step A, (0.120 g, 0.412 mmol) in MeOH (20 mL) was added 10% Pd on C (0.025 g), and the mixture was hydrogenated under a H2 balloon at ambient temperature for 48 h. The reaction mixture was filtered, and the filtrate concentrated to dryness to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:30][CH:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:30][CH:31]2[CH:36]3[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]3)[CH2:32]2)=[O:15])[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: CN1CCSc2c(C(=O)O)cc(Cl)cc21
Reactant: NC1CN2CCC1CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCSc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc21

Procedure:
To a solution of 1.8 g of 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.05 g of triethylamine, and then added 0.891 g of pivaloyl chloride dropwise with stirring at -10° C. to -5° C. followed by stirring the mixture at the same temperature for 30 minutes. To the resultant mixture was added a solution of 1.12 g of 3-aminoquinuclidine in 15 ml of ethyl acetate at -10° to -5° C. and then stirred at room temperature for an hour. After the reaction solution was washed with water, dried over anhydrous sodium sulfate and concentrated, the crystalline residue thus obtained was recrystallized from ethyl acetate to give 6-chloro-4-methyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzothiazine-8-carboxamide as yellow crystals. Melting point: 195°-196° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH:5]=[O:6]
Reactant: COc1cccc(CBr)c1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(COc2c(Br)cc(C=O)cc2Br)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 3,5-dibromo-4-hydroxybenzaldehyde (0.28 g), 1-bromomethyl-3-methoxybenzene (0.15 mL), potassium carbonate (0.29 g) and potassium iodide (42 mg) in 10 mL absolute ethanol was stirred at 80° C. for 2 days. The reaction mixture was concentrated and the title compound was obtained as a off-white solid after flash column chromatography (silica gel, heptane/ethyl acetate (3/7, v/v)), Rf=0.51).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[Cl:17][C:18]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:19]=1[CH2:20][NH:21][CH2:22][CH:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:21]([CH2:20][C:19]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:37])([F:35])[F:36])[C:18]=2[Cl:17])[CH2:22][CH:23]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH3:24])[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Reactant: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2cccs2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.1 %

Procedure:
A solution of (3-{3-bromo-propoxy}-phenyl)acetic acid methyl ester (41 mg, 0.14 mmol) and (2-chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amine (50 mg, 10.14 mmol) in acetonitrile (10 ml) was treated with solid potassium carbonate (24.9 mg, 0.18 mmol). The reaction was heated to reflux and stirred for 48 h. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (25 mg, 30%). MS m/e 540.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8](=[O:13])[CH:7]=[C:6]1[CH3:14])=[O:4].C(OCC)(OCC)O[CH2:17][CH3:18].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][C:8]([O:13][CH2:17][CH3:18])=[CH:7][C:6]=1[CH3:14])=[O:4]
Reactant: COC(=O)C1C(C)=CC(=O)CC1(C)C
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC1=CC(C)=C(C(=O)OC)C(C)(C)C1
Reaction time: 4 h

Procedure:
800 g. of crude 3,5,5-trimethyl-2-cyclohexen-1-on-4-carboxylic acid methyl ester prepared in Example 1, and 720 g. of triethyl orthoformate were mixed with 1.5 l. of anhydrous ethanol containing 4 ml. of sulfuric acid. After standing for 4 hours at room temperature, the dark blue solution was poured onto petroleum ether over a sodium bicarbonate solution. The ether layer was washed twice with water, dried over sodium sulfate, and concentrated by removing all of the ether solvent. The resulting dark residue was distilled over a vigreux column under high vacuum to yield 2,6,6-trimethyl-4-ethoxy-1,3-cyclohexadien-1-carboxylic acid methyl ester.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:15]([CH3:18])[C:16]#[N:17].[I-].[K+]>CC(CC)=O.O>[O:7]([CH:15]([CH3:18])[C:16]#[N:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C#N)Oc1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of phenol (18.8 g.) and anhydrous potassium carbonate (25 g.) in dry ethyl methyl ketone (35 ml.) was stirred and heated to reflux, during the dropwise addition of a solution of 2-chloropropionitrile (19.7 g.) in dry ethyl methyl ketone (15 ml.) containing finely-powdered potassium iodide (0.5 g.). The addition took 20 minutes. Stirring and heating were continued for a total of 2 hours after which the mixture was cooled, poured into water (200 ml.) and extracted with ether (200, 75 and 75 ml.). The combined ether extract was washed several times with 2N-sodium hydroxide to remove phenol, dried over anhydrous sodium sulphate, and evaporated. The residue was distilled under water-pump vacuum to give pure 2-phenoxypropionitrile, b.p. 117°-118°/13 mm.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH2:8]1)[CH3:4].Cl>C(O)C>[CH2:3]([O:5][CH2:6][CH:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH2:8]1)[CH3:4]
Reactant: CCOCC1CC(C(=O)OCC)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCC1CC(C(=O)O)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A 1M solution of sodium hydroxide (5 mL; 5 mmol) was added to the solution of ethyl 5-(ethoxymethyl)-4,5-dihydroisoxazole-3-carboxylate (0.135 g, 0.67 mmol) in ethanol (1 mL). The reaction mixture was stirred at room temperature overnight. The solution was acidified to pH 0-1 by addition of 6N hydrochloric acid and was extracted with ethyl acetate. Combined ethyl acetate extracts were dried over magnesium sulfate and evaporated to provide 0.109 g (94%) of 5-(ethoxymethyl)-4,5-dihydroisoxazole-3-carboxylic acid as a white solid, which was directly used in the next step.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:19])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([CH3:9])[CH3:8])C.Cl.O>CO>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:19])=[O:5]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.4 %

Procedure:
A 5 N aqueous NaOH solution (0.83 ml) was added to a solution of 2-(2,4-dichloro-phenoxy)-2-methyl-propionic acid ethyl ester (383 mg, 1.38 mmol) in MeOH (6 ml) at room temperature. The mixture was stirred at room temperature for four hours, and 1 N HCl (4.5 ml) and H2O were then added, followed by extraction with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure to give 2-(2,4-dichloro-phenoxy)-2-methyl-propionic acid (359 mg).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[BH4-].[Na+].[OH-].[Na+]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:10][C:8]2[CH:7]=[CH:6][C:5]3[N:1]=[CH:2][NH:3][C:4]=3[CH:9]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(CNc2ccc3nc[nH]c3c2)cc1

Procedure:
Alternatively the compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-chlorobenzaldehyde (3.09 g; 22 mmol; 1.1 eq.), NaBH4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 3.94 g (76.7%); MS m/z: 258.3/260.3 [M+H]+