Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[O:6][C@H:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.[CH2:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:29])([F:28])[CH3:27])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[CH2:18]([N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:28])([CH3:29])[CH3:27])[CH2:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)[OH:6])[CH3:19]
Reactant: CCNCCCCCC(C)(C)F
Reactant: CS(=O)(=O)Nc1ccc([C@@H]2CCC(O)O2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN(CCCCCC(C)(C)F)CCC[C@H](O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
N-[4-[(2S)-Tetrahydro-5-hydroxy-2-furanyl]phenyl]methanesulfonamide (10.0 g, 38.9 mmol) from Preparation 4 and N-ethyl-6-methyl-6-fluoroheptane amine (99% pure, 6.8 g, 38.9 mmol) from Preparation 7 were stirred with EtOAC (25 ml) in a flask for 1 hour. The slurry became clear solution, indicating formation of the iminium salt. Sodium triacetoxyborohydride (11.5 g, 54.4 mmol) was placed in a separate flask with EtOAc (50 ml). The mixture was cooled to 0° C. The first solution (iminium salt) was added slowly to the second mixture with vigorous stirring. The temperature was maintained at 0 to 4° C. After the addition was complete, the flask was rinsed with EtOAc (10 ml), and that was added also. The mixture was stirred overnight at 0° C. Water (100 ml) was added to quench the excess reagent, while the temperature was maintained at 0 to 4° C. While cooling was maintained, the pH was raised to 6.5 using a 10% aqueous sodium hydroxide solution. The layers were separated, and the aqueous was extracted with EtOAc (2×50 ml). The aqueous layer was then adjusted to pH 8.2, and the product was extracted with EtOAc (3×100 ml). The solvent was removed under reduced pressure to provide the title product as a colorless oil (14.9 g) in 92% yield. TLC 100% EtOAc, Rf=0.15.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>ClCCl>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:6]2)[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(CC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (19 mg, 0.040 mmol, racemic intermediate from Example 139, Step 6) and triethylamine (20 μL, 0.14 mmol) in dichloromethane (0.5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 mg, 0.048 mmol). The resulting mixture was stirred overnight at room temperature. The solvents were evaporated under reduced pressure and the crude mixture purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (3.8 mg, 19%). The product was isolated as a racemic mixture. LCMS calculated for C21H24ClF4N6O (M+H)+: m/z=487.2; Found: 487.1.
Reaction SMILES: ClC1C=C(C=CC=1[N+]([O-])=O)C[P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([O:31][CH3:32])[C:23]=1[F:33]>>[F:33][C:23]1[C:24]([O:31][CH3:32])=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=[CH:27][C:22]=1[CH2:21][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Reactant: COc1c([N+](=O)[O-])ccc(CCl)c1F
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1F)OCC

Procedure:
The title compound was prepared using the procedure from Compound 104C (Diethyl (3-chloro-4-nitrobenzyl)phosphonate) with 1-(chloromethyl)-2-fluoro-3-methoxy-4-nitrobenzene (Compound 147C). 1H NMR (CDCl3, 400 MHz): δ=1.28-1.32 (m, 6 H), 3.19-3.31 (m, 2 H), 7.14-7.22 (m, 1 H), 7.54-7.61 (m, 1 H). MS (ES+): m/z 322.08 [MH+] (TOF, polar).
Reaction SMILES: C(O)C.Cl.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-])=O)=[CH:13][N:12]=2)=[CH:8][C:7]=1[C:23]([F:26])([F:25])[F:24]>[Fe].O>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([NH2:18])=[C:15]([CH3:17])[CH:16]=2)=[CH:8][C:7]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1N
Temperature: 50 °C
Yield: 87 %

Procedure:
A 100 ml two-necked round-bottomed flask equipped with a KPG-stirrer, a thermometer and a reflux condenser is charged with ethanol (50 ml), water (5 ml), iron (1.29 g) and hydrochloric acid 37% (0.2 ml). The reaction mixture is heated at 50° C. 2-(4-chloro-3-trifluoromethyl-phenoxy)-4-methyl-5-nitro-pyridine (2.4 g) is added portionwise. The mixture is heated at reflux for 1 hour. After cooling the mixture to 50° C. is filtered through celite. The filtrate is poured into water (100 ml) and extracted with ethylacetate (2×50 ml). The combined organic layers are washed with brine (100 ml), dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification by flash chromatography over silica gel with hexane/ethyl acetate 1:1 (v:v) gives 1.90 g of the compound as a brownish solid (MP: 105-107° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([S:4]([NH:6][C:7]1([C:11](=[NH:13])[NH2:12])[CH2:10][O:9][CH2:8]1)=[O:5])[CH3:3].CN(C)/[CH:17]=[CH:18]/[CH:19]=O.C[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:3][C:2]([S:4]([NH:6][C:7]1([C:11]2[N:12]=[CH:19][CH:18]=[CH:17][N:13]=2)[CH2:10][O:9][CH2:8]1)=[O:5])([CH3:14])[CH3:1]
Reactant: CN(C)/C=C/C=O
Reactant: CC(C)(C)S(=O)NC1(C(=N)N)COC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)S(=O)NC1(c2ncccn2)COC1
Reaction time: 0.17 h

Procedure:
To a yellow solution of 3-(1,1-dimethylethylsulfinamido)oxetane-3-carboximidamide (crude from above, assumed 0.494 mmol) in MeOH (2 ml) in a 50 ml sealed tube was added (E)-3-(dimethylamino)acrylaldehyde (0.090 g, 0.912 mmol), and the reaction mixture stirred for 10 min. Sodium methoxide (0.43 ml, 1.824 mmol, 25 wt % in MeOH) was added to the mixture, which was then stirred at 65° C. for overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was back extracted with ethyl acetate (3×25 ml). The combined organic layers was washed with saturated brine solution, dried over Na2SO4, filtered and concentrated. The crude material was purified by pre-HPLC. Overall yield of two steps: (30 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](O)=[O:23])=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:25][N:27]([CH3:28])[C:22]([C:17]1[NH:18][C:19]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH:12][S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:10])=[O:11])=[CH:21][CH:20]=2)=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
110 mg 5-(3,5-dichloro-phenylsulphonylamino)-1H-indole-2-carboxylic acid are dissolved in 4 ml of tetrahydrofuran, combined with 51 mg carbonyldiimidazole and stirred for 3 hours at ambient temperature and for 1 hour at 40° C. After cooling to ambient temperature 600 μl of a 2 M solution of dimethylamine in tetrahydrofuran are added and the mixture is stirred overnight at ambient temperature. The solvent is eliminated in vacuo, the residue is divided between ethyl acetate and 0.5 N hydrochloric acid and the organic phase is washed with water and saturated sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo and the residue is chromatographed on silica gel (ethyl acetate).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([CH:9]([CH3:22])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)O)([O-:8])=[O:7].[C:23]1([O:29][CH2:30][CH3:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].[Br-]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:10]([C:26]2[CH:27]=[CH:28][C:23]([O:29][CH2:30][CH3:31])=[CH:24][CH:25]=2)[CH:9]([N+:6]([O-:8])=[O:7])[CH3:22])=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C(O)c1ccc(C(C)(C)C)cc1)[N+](=O)[O-]
Reactant: CCOc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Product: CCOc1ccc(C(c2ccc(C(C)(C)C)cc2)C(C)[N+](=O)[O-])cc1
Temperature: 50 °C

Procedure:
A 1.0 kg portion of 80% sulfuric acid was added dropwise to a solution of 237g of Example 2 in 732g of phenetole and the mixture was heated to 50° C for 2 hr. The acid layer was removed and the organic phase was diluted with ether. The ethereal solution was washed with water and with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated. The crude residue which weighed 322g was triturated with 30/60 pet ether and recrystallized from isopropyl alcohol to afford a pure, white solid: mp 79°-82° C; ir (KBr) 3.4 (m), 6.5 (s), 6.6 (m), 8.0 (s), 9.5 (m), 12.2 (m) microns; nmr (CDCl3) 7.4 to 6.7 (8H, m), 5.3 (1H, doublet of quartets), 4.3 (1H, d), 3.97 (2H, q), 1.45 (3H, d), 1.29 (3H, t), 1.22 (9H, s) ppm; ms (molecular ion) 341.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:32])([CH3:31])[CH2:10][C:11]([CH:17]=[N:18][C:19]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]3[C:20]=2[CH:21]=[N:22][C:23]([CH3:30])=[N:24]3)([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:19]([NH:18][CH:17]2[C:6]3[C:5](=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[C:9]([CH3:31])([CH3:32])[CH2:10][C:11]2([C:12]([F:14])([F:15])[F:13])[OH:16])=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:30])[N:22]=[CH:21]2
Reactant: COc1cccc(C(C)(C)CC(O)(C=Nc2ccc(F)c3nc(C)ncc23)C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc2c(NC3c4ccc(O)cc4C(C)(C)CC3(O)C(F)(F)F)ccc(F)c2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33.7 %

Procedure:
60 mg (0.133 mmol) of 4-(3-methoxyphenyl)-1,1,1-trifluoro-2-{[8-fluoro-2-methylquinazolin-5-ylimino]-methyl}-4-methylpentan-2-ol is mixed with 1.3 ml of a 1 M solution of boron tribromide in dichloromethane while being cooled in an ice bath. After 45 minutes of stirring at room temperature, the reaction mixture is mixed with ice, and saturated sodium bicarbonate solution is added drop by drop until a pH of 8 is reached. The cold bath is removed, and the mixture is stirred vigorously for 15 minutes. After extraction with ethyl acetate, the combined organic extracts are washed with water and then with brine. After drying, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). Ultimately, 19.5 mg (33.5%) of the desired compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:11][CH3:12])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: Cc1cscc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cscc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Methyl-3-thiophenecarboxylic acid (1.42 g) (synthesized in accordance with the method described in J. Org. Chem., 51, 230 (1986)) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (0.8 ml) and potassium carbonate (1.38 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water. and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-methyl-3-thiophenecarboxylate (1.7 g). Ethyl 4-methyl-3-thiophenecarboxylate (1.7 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.2 ml) in acetonitrile (20 ml) was added. The mixture was stirred at room temperature for 1 hour, and then 10% aqueous sodium thiosulfate (100 ml) was added and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and ethyl 2,5-dichloro-4-methyl-3-thiophenecarboxylate. The mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and 2,5-dichloro-4-methyl-3-thiophenecarboxylate was dissolved in ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (20 ml) was added. The mixture was stirred at room temperature for 2 hours, and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 5-chloro-4-methyl-3-thiophenecarboxylic acid and 2,5-dichloro-4-methyl-3-thiophenecarboxylic acid. The mixture was suspended in toluene (15 ml). Oxalyl chloride (1.31 ml) was added dropwise and then N,N-dimethylformamide (1 drop) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and added dropwise into a mixture of 25% aqueous ammonia solution (16 ml) and ethyl acetate (50 ml) with stirring under ice-cooling. The resulting mixture was stirred at room temperature for 10 minutes. The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-4-methyl-3-thiophenecarboxamide (0.83 g) and 2,5-dichloro-4-methyl-3-thiophenecarboxamide (0.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([F:16])[CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:6]3[CH:11]([F:16])[CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1Cc2c([nH]c3ccc(Cl)cc23)C(F)C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1Cc2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)C(F)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-4-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][CH2:25][OH:26])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:30]>C1COCC1>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][CH2:25][O:26][CH3:30])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:2][CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCCO)cc2cccnc12)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl cyclopropyl{[6-(3-hydroxypropyl)-8-quinolinyl]methyl}carbamate (1 eq.) from the previous step in THF (0.3 M) was added sodium hydride (60% (w/w) dispersion in paraffin oil, 1.2 eq.). The resulting suspension was stirred at RT for 15 min before iodomethane (1.4 eq.) was added. The now yellow solution was stirred at RT for 12 h before the reaction was quenched with the addition of 1 N aq. NaOH. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+].O>[C:16]1([C:15]([NH:1][CH:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=3)[CH2:3]2)=[O:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCc2ccc([N+](=O)[O-])cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCc2ccc([N+](=O)[O-])cc2C1)c1ccccc1

Procedure:
To 2-amino-7-nitrotetralin (1.8 g, 9.39 mmol, derived from dibenzoyl-L-tartaric acid) in THF (50 ml) and 10% K2CO3 (100 ml) was added benzoyl chloride (1.2 ml, 10.1 mmol). After the addition was complete, the mixture was diluted with water to a volume of 250 ml. The precipitated solids were collected by filtration, washed with water and dried in vacuo: (2.8 g, 100%), m.p. 208°-209° C., [α]D -24.0° (c 0.87 DMSO).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[CH:18]=[CH:19][CH:20]=[N:21][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>O1CCCC1>[CH3:29][N:30]([CH:32]=[C:14]1[CH2:15][CH2:16][N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[C:11]2[N:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]1=[O:17])[CH3:31]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc21
Solvent: C1CCOC1
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a slurry of 0.50 g of 6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyrido[2,3-b]azepin-5-one in 10 ml of tetrahydrofuran under argon is added 0.70 g of tert-butoxy-bis(dimethylamino)methane and the mixture is stirred at room temperature overnight. The volatiles are removed under vacuum and the residue in ethyl acetate-CH2Cl2 (2:8) filtered through a short column of silica gel. The silica gel is washed with ethyl acetate (discard) and then with chloroform containing 3% methanol to give 0.51 g of the product as a yellow solid.
Reaction SMILES: [CH3:1][P:2]([O-:9])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][C:11]([O:13][CH:14]([C:17]#[N:18])[CH:15]=[CH2:16])=[O:12]>>[C:11]([O:13][CH:14]([C:17]#[N:18])[CH2:15][CH2:16][P:2]([CH3:1])(=[O:9])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH3:10]
Reactant: CCCCCOP(C)[O-]
Reactant: C=CC(C#N)OC(C)=O
Product: CCCCCOP(C)(=O)CCC(C#N)OC(C)=O
Reaction time: 0.08 h
Yield: 101.1 %

Procedure:
242.0 g of n-pentyl methanephosphonite are heated to 80° C. under nitrogen, and 0.5 g of tert.-butyl perpivalate is added. 63.9 g of acrolein cyanohydrin acetate mixed with 2.5 g of tert.-butyl perpivalate are added dropwise to this solution within 2.25 hours. After reaction is complete, the mixture is stirred for 5 minutes, and 161.5 g of n-pentyl methanephosphonite are distilled out. (Purity: 91.2%, recovery: 93.4%). 142.1 g of n-pentyl (3-acetoxy-3-cyanopropyl)methylphosphinate (purity 94%; yield 97%) remain.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17]([CH3:23])[C:16]4=[O:24])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>[Pd]>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[C:16]5=[O:24])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:25]=2)[CH:31]=[N:30]1
Reactant: CN1C(=O)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C(C)(C)C1=O
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Product: CN1C(=O)N(c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)C(C)(C)C1=O
Yield: 12 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dione was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki palladium conditions to give 492. Yield 12%. MS (ESI+):482.2. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.3, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.39 (dd, J=8.3, 1.8, 1H), 7.24 (t, J=4.4, 1H), 4.73 (s, 1H), 4.34 (t, J=4.9, 2H), 4.03 (s, 2H), 3.26 (t, J=5.0, 2H), 3.02 (s, 3H), 1.81 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu][C:23]#[N:24]>C(OC)(C)(C)C>[C:23]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[CH:15][C:16]=1[F:21])#[N:24]
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(C#N)c(F)c2)C1
Temperature: 180 °C
Yield: 7.9 %

Procedure:
To a 20 mL microwave vial were added 2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.5 g, 4.16 mmol) N-methyl-pyrrolidone (10 ml) and copper(I)-cyanide (559 mg, 6.25 mmol). The vial was capped and heated in a microwave synthesizer (Personal Chemistry Emrys Optimizer) at 180° C. for 30 min. The reaction mixture was poured into tert-butylmethylether (150 ml) and extracted with brine (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 70% ethyl acetate in heptane) to yield a yellow solid (101 mg, 8%), MS (ISP): 307.2 ([M+H]+).
Reaction SMILES: [CH2:1]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH:8]3[CH:9]2[N:4]([C:5](=[O:14])[CH2:6][CH2:7]3)[C:3](=[O:15])[CH2:2]1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl>[CH2:16]([O:23][C:3](=[O:15])[CH2:2][CH2:1][CH:10]1[CH:9]2[CH:8]([CH2:7][CH2:6][C:5](=[O:14])[NH:4]2)[CH2:13][CH2:12][CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC2CCCC3CCC(=O)N1C23
Agent: Cl
Product: O=C1CCC2CCCC(CCC(=O)OCc3ccccc3)C2N1
Temperature: 100 °C

Procedure:
A solution of 0.7 g (0.0033 mol) of decahydro-3H,5H-benzo[ij]quinolizine-3,5-dione (7aα, 10aα, 10bα) in 10 ml of benzyl alcohol is treated with one drop of concentrated hydrochloric acid. The solution is heated at 100° C. for 48 hours and is concentrated at reduced pressure (0.1 mm). The residue is triturated with anhydrous diethyl ether to yield crystalline decahydro-2-oxo-8-quinolinepropanoic acid benzyl ester (4aα, 8aβ, 8aα) with a melting point of 101°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:10]=[C:8]([C:6]2[S:7][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:9][CH:15]=1
Reactant: COc1ccc(C(N)=O)s1
Reactant: O=C(CCl)CCl
Product: COc1ccc(-c2nc(CCl)co2)s1
Yield: 1.2 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-methoxy-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(5-methoxy-2-thienyl)oxazole. The yield was 1.2%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 64-65° C.