Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[N:21]1([CH2:28][CH2:29][OH:30])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:24]2[CH2:25][CH2:26][CH2:27][N:21]([CH2:28][CH2:29][OH:30])[CH2:22][CH2:23]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: OCCN1CCCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CCCN(CCO)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
350 mg (1.2 mmol) of 8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (for preparation see: DE 3420743) are dissolved according to DE 3635218 in 3 ml of dry pyridine and heated at reflux with 202 mg (1.4 mmol) of hexahydro-1H-1,4-diazepine-1-ethanol for 4 hours. After standing overnight the mixture is concentrated, taken up with water and brought to pH 6 using dilute hydrochloric acid. The solution is saturated with sodium chloride at boiling heat. After it has cooled to room temperature, it is extracted a number of times with dichloromethane. The organic extracts are filtered over a little silica gel and concentrated. 288 mg of the target compound are obtained this way. The compound is used as a crude product in the subsequent reaction stages.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:22][C:23]([F:26])([F:25])[F:24])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].Cl.C[N:29](C)CCCN=C=NCC.CN(C)C=O>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:22][C:23]([F:25])([F:26])[F:24])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:29])=[O:21])=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (2.50 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.89 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.38 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (2.23 g, yield 89%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point >300° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:8]([O:35][CH3:36])=[C:9]([NH:11][C:12](=[O:34])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31](O)=[O:32])[CH:26]=3)=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:43][N:44](C)[CH2:45]CCN=C=NCC.C(N(CC)CC)C.CNC>CN(C=O)C.O>[CH3:43][N:44]([CH3:45])[C:31]([C:27]1[CH:26]=[C:25]([O:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([NH:13][C:12]([NH:11][C:9]3[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=[C:7]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:8]=3[O:35][CH3:36])=[O:34])=[CH:15][CH:16]=2)[CH:30]=[CH:29][N:28]=1)=[O:32]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1c(NC(=O)Nc2ccc(Oc3ccnc(C(=O)O)c3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(NC(=O)Nc2ccc(Oc3ccnc(C(=O)N(C)C)c3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a cold solution (0° C.) of 4-{4-[3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid (Example 12) (58 mg, 0.1 mmol) in DMF (1 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol) and triethyl amine (0.070 mL, 0.5 mmol). The solution was allowed to stir at 0° C. for 30 min, then dimethylamine (2M solution in THF, 0.25 mL, 0.5 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 12 h. Water (4 mL) was added and the product was extracted with EtOAc, dried over magnesium sulfate and concentrated via rotary evaporation. The resulting crude solid was purified by column chromatography (CH2Cl2:MeOH, 93:7) to give the title compound as a light tan solid (42 mg, 70% yield).
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([N:31](C1CCNC1)C)(=O)C>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:31]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 196.5 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.300 g, 0.770 mmol, 1 eq, Example 56, Step D) was suspended in Dioxane (20 mL) under Ar. 3-(N-Acetyl-N-methylamino)-pyrrolidine (0.330 g, 2.320 mmol, 3 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (60%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 434 (M+1); Anal. Calcd for C26H31N3O3.1HCl.1.25H2O: C, 63.40; H, 7.06; N, 8.53; Found: C, 63.51; H, 6.95; N, 8.30.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=O.C([O-])([O-])=[O:11].[K+].[K+].[CH2:16]1COC[CH2:17]1>>[C:16]([C:3]1([OH:11])[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)#[CH:17]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: O=C1CC2CCN1CC2
Agent: [K+]
Product: C#CC1(O)CN2CCC1CC2
Reaction time: 16 h

Procedure:
Quinuclidinone (76 g, 0.608 mol) was added to a stirred suspension of lithium acetylide ethylene diamine complex (85.7 g, 0.791 mol) in dry THF (500 ml) under nitrogen, at 0° C. After 16 hours at room temperature, a saturated aqueous solution of K2CO3 was added and the mixture was extracted with THF (3 times). Organic phases were combined, dried over MgSO4 and evaporated under vacuum. The white solid was triturated in ether, filtered and dried to give 3-ethynylquinuclidin-3-ol 47 (56.22 g, 61
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=2)[CH2:17][CH2:16]1.CN1CCCC1=O.N>CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:26]2[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=[C:22]2[NH:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:2]3[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=3)[CH2:16][CH2:17]2)=[CH:29][CH:30]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: N
Solvent: CN1CCCC1=O
Solvent: CO
Product: Nc1nc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of 3.4 parts of 6-chloro-3-nitro-2-pyridinamine, 7.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl ]-1H-benzimidazol-2-amine and 10 parts of 1-methyl-2-pyrrolidinone was stirred and heated for 2 hours at 150° C. The reaction mixture was cooled and taken up in methanol saturated with ammonia. The whole was evaporated and water was added to the residue. The product was extracted three times with 4-methyl-2-pentanone. The combined extracts were dried, filtered and evaporated in vacuo. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 5 parts (50%) of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinyl]ethyl]-3-nitro-2,6-pyridinediamine; mp. 205.7° C. (compound 63).
Reaction SMILES: C(O[Cl:6])(C)(C)C.[CH2:7]([CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:17])[CH:8]=[CH2:9]>CO>[Cl:6][C:10]1([CH2:7][CH:8]=[CH2:9])[C:11](=[O:17])[CH2:12][CH2:13][CH2:14][C:15]1=[O:16]
Reactant: C=CCC1C(=O)CCCC1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: C=CCC1(Cl)C(=O)CCCC1=O
Yield: 91.1 %

Procedure:
t-Butylhypochlorite (104.6 g, 0196 mol) was added dropwise to a solution of 2-allyl-1,3-cyclohexanedione (132 g, 0.87 mol) in 650 ml of methanol at 0° C. The temperature was not allowed to rise above 20° C. The methanol was removed at reduced pressure in a 40° water bath and the residual oil was taken up in benzene. The benzene solution was washed with 5 percent sodium thiosulfate (3 × 250 ml), 5 percent sodium bicarbonate (3 × 250 ml) and water (1 × 250 ml). Evaporation of the benzene gave 148 g (91 percent) of 2-chloro-2-allyl-1,3-cyclohexanedione as a light yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[C:32]([F:37])[C:31]=1[N+:38]([O-:40])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.O>[CH:1]1([C:4]2[C:5]([N:24]([C:34]3[CH:33]=[C:32]([F:37])[C:31]([N+:38]([O-:40])=[O:39])=[C:30]([F:29])[CH:35]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c([N+](=O)[O-])c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 1,3,5-trifluoro-2-nitrobenzene (0.91 g, 5.11 mmol), K2CO3 (1.06 g, 7.67 mmol) in HMPA (7 mL) was stirred at 50° C. for 8 h. An additional portion of 1,3,5-trifluoro-2-nitrobenzene (0.91 g, 5.11 mmol) was added and the reaction mixture was stirred at 50° C. for another 15 h. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was taken up in 1:1 CH2Cl2:acetone. The desired isomer precipitated out and was collected by vacuum filtration and dried to afford the title compound (0.92 g, 65%) as a white solid. LCMS (m/z, ES+)=560.2 (M+H).
Reaction SMILES: C1(COC([NH:11][CH2:12][CH2:13][C:14]2[O:15][C:16]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)=O)C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[NH2:11][CH2:12][CH2:13][C:14]1[O:15][C:16]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(CCNC(=O)OCc3ccccc3)nc2-c2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NCCc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
A solution of 4-[2-[2-(N-phenylmethoxycarbonylamino)ethyl]-4-phenyl-oxazol-5-yl]benzenesulfonamide (Step 1) (0.75 g, 1.6 mmol) in MeOH (15 mL) containing acetic acid (0.1 mL) was treated with 10% Pd on carbon (0.35 g) and stirred under an atmosphere of hydrogen at 50 psi at room temperature for 2.5 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford a white powder which was purified by reverse-phase HPLC using a gradient of 10-90% CH3CN in H2O to afford 0.55 g of 4-[2-(2-aminoethyl)-4-phenyloxazol-5-yl]benzenesulfonamide as its trifluoroacetate salt: 1H NMR (CD3OD/300 MHz) δ 7.91 (d, 2H, J=7.9 Hz), 7.74 (m, 2H,), 7.63 (m, 2H), 7.44 (m, 3H), 3.49 (t, 2H, J=6.6 Hz), 3.33 (t, 2H, J=6.6 Hz). FABMS m/z =344 (M+H). HRMS calcd for C17H18N3O5S 344.1069. Found 344.1048.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[CH:23][CH:22]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A mixture of ethyl 3-[3-(4-fluorophenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (500 mg), 1N aqueous sodium hydroxide solution (2 ml), ethanol (3 ml), and tetrahydrofuran (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[3-(4-fluorophenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (330 mg, yield: 69%). This was recrystallized from ethyl acetate-hexane. Melting point: 139–140° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.IC>C1COCC1>[CH3:22][O:21][C:19]([C:16]1([CH3:1])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)=[O:20]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCOCC1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCOCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml) at −78° C., n-BuLi (25.2 ml, 1.6 M in heptane) is added. The reaction is removed from the bath and stirred for 10 min. It is then cooled to −78° C. again and methyl tetrahydro-2H-pyran-4-carboxylate (6.48 ml, 48.6 mmol) is added. After 30 min, iodomethane (6.07 ml, 97 mmol) is added and the reaction allowed to reach rt. The reaction is then quenched with 1 N HCl (200 mL) and extracted with EtOAc. The organic layer is dried and evaporated to give 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester. MS (ESI) m/z 159.3 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2([CH3:23])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[C-:24]#[N:25].[K+]>C1(C)C=CC=CC=1>[CH3:23][C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:24]#[N:25])[CH:13]2[CH:9]1[CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12]2
Reactant: CC1(c2cccc(I)c2)C2CN(CCCc3ccccc3)CC21
Reactant: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(c2cccc(C#N)c2)C2CN(CCCc3ccccc3)CC21
Temperature: 80 °C
Yield: 44.2 %

Procedure:
To a degassed solution of 6-(3-iodophenyl)-6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexane (Example 86, 490 mg, 1.18 mmol) in toluene (20 ml) was added tetrakistriphenylphosphine palladium (0) (0.68 g, 0.60 mmol) and a finely crushed mixture of potassium cyanide (320 mg, 5.0 mmol) and neutral activated alumina (640 mg) under nitrogen. The reaction mixture was heated to 80° C. for 3 h, and then at reflux for 30 minutes before cooling to room temperature and concentrating in vacuo. The mixture was absorbed onto silica gel (7 g) and then purified by chromatography on silica gel (100 g) eluting with hexane: ethyl acetate (95:5 and then 50:50) to give a red solid (165 mg, 44%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[N+:1]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH3:11])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Product: Cc1ccccc1[N+](=O)[O-]

Procedure:
There are used 213 parts (about 400 ml) of this catalyst and the reaction is carried out at 140°-145° C. in vacuo under a pressure of 5 mm Hg by introducing separately 208 parts of gaseous toluene and 32.8 parts of gaseous 96% nitric acid (molar ratio of toluene to nitric acid = 2.26 : 0.5) into the reactor. Nitrotoluene is obtained with a yield rate of 68.3% of the theoretical yield, calculated on the starting quantity of HNO3, this yield consisting of 38.8% of o-nitrotoluene and 4.0% of m-nitrotoluene and 57.2% of p-nitrotoluene. The isomer ratio of p/o is 1.47 and represents an isomer distribution of 59.5% of p-nitrotoluene and 40.5% of o-nitrotoluene.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([O:22]CC)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CC(C)=O>[C:13]1([CH3:25])[CH:14]=[CH:15][C:16]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N+:6]=1[CH2:13][CH3:14]
Reactant: COc1ccc2nc(N)sc2c1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: CC[n+]1c(N)sc2cc(OC)ccc21
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C

Procedure:
3.6 g of 2-amino-6-methoxybenzothiazole and 6.0 g of ethyl p-toluenesulfonate were fed into a 200 ml three-necked flask. The resultant mixture was stirred under heating on an oil bath at 120° C. for 3 hours. Acetone was added to the reaction mixture and the resultant mixture was stirred at room temperature for 1 hour. The crystals thus formed were suction-filtered and washed with acetone to obtain the intended compound.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][CH2:5]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1ccc(I)cc1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-7-(2-hydroxy-2-methylpropyl)-7-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazepan-2-one and 4-iodo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 18 Step 2. LC-MS Method 4 tR=1.11 min, m/z=497, 475, 457, 417.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]1([NH:15]N)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[C:4]1(=[O:8])[C:3]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:15][C:2]=2[CH:7]=[CH:6][NH:5]1
Reactant: NNc1ccccc1
Reactant: O=c1cc(O)cc[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccccc1
Product: O=c1[nH]ccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
4-Hydroxypyridin-2(1H)-one (3 g, 27 mmol) and phenylhydrazine (8.74 g, 81 mmol) in diphenyl ether (54 mL) were heated at 240° C. for 5 hours in a Dean Stark apparatus. The reaction mass was cooled to room temperature, diluted with benzene, stirred for 2 hours and filtered. The solid collected was dried under high vacuum and washed with ether to afford 3 g of the product (60% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#N)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:17].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:17])[CH3:22]
Reactant: CCO
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: O=S(=O)(O)O
Product: CCOC(=O)C1CN(Cc2ccccc2)CCO1

Procedure:
A stirred solution of 4-benzyl-morpholine-2-carbonitrile (113.0 g, 0.56 mol) in ethanol (1030 mL) is treated with concentrated sulphuric acid (165 mL) added in portions. (exothermic, internal temperature rises from ambient to 65° C.). The mixture is then warmed under reflux for 66 hrs. The solution is cooled and then concentrated in vacuo to half volume, basified with aqueous potassium carbonate (beware frothing) and the product extracted into diethyl ether. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness in vacuo to yield an oil. This material is evacuated further under high vacuum. Yield=121.3 g (87%).