Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[S:12][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][C:16]=4[NH:22][S:23]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:10][CH2:9]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:37][CH:38]([F:40])I>CN(C)C=O.C(OCC)(=O)C>[F:37][CH:38]([F:40])[N:22]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[NH:14][C:13]([C:11]1[S:12][CH:8]([CH2:7][N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH2:9][N:10]=1)=[CH:21]2)[S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:25]
Reactant: FC(F)I
Reactant: O=S(=O)(Nc1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccs1)N(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of N-{2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (200 mg) in N,N-dimethylformamide (3 mL) were added potassium carbonate (90.0 mg) and difluoroiodomethane (77.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (60 mg, yield 27%) as white crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 513 (MH+). melting point 185-186° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:16].C(O)=O.[OH-].[Na+]>C(O)C>[CH3:13][NH:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[S:16])[N:11]=1
Reactant: NC(N)=S
Reactant: CNc1nc(Cl)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Product: CNc1nc(=S)[nH]c2ccccc12
Temperature: 25 °C
Yield: 18.1 %

Procedure:
A mixture of 2-chloro-N-methylquinazolin-4-amine (Example 39) (100 mg, 0.52 mmol), thiourea (47.5 mg, 0.62 mmol) and formic acid (0.02 mL, 0.52 mmol) in ethanol (5 mL) was refluxed for 1.5 h. After cooling to room temperature, the reaction mixture was neutralized with diluted NaOH aqueous solution. The solvent was removed under vacuum and the residue was purified by preparative HPLC eluting with acetonitrile and water to give the title compound (18 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 2.99 (d, J=4.8 Hz, 3H), 7.25 (t, J=7.6 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.65-7.61 (m, 1H), 8.0 (d, J=8.0 Hz, 1H), 8.70 (d, J=4.4 Hz, 1H), 12.32 (s, 1H). MS 192 (MH+).
Reaction SMILES: [C:1]([N:4]([C:8]1[N:9]([CH3:30])[C:10](=[O:29])[C:11]([O:27][CH3:28])=[C:12]2[C:17]=1[CH2:16][CH2:15][N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:13]2=[O:26])C(=O)C)(=[O:3])[CH3:2].C[O-].[Na+].Cl>CO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[CH2:15][CH2:16][C:17]3[C:12](=[C:11]([O:27][CH3:28])[C:10](=[O:29])[N:9]([CH3:30])[C:8]=3[NH:4][C:1](=[O:3])[CH3:2])[C:13]2=[O:26])=[CH:24][CH:23]=1
Reactant: COc1c2c(c(N(C(C)=O)C(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1c2c(c(NC(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C

Procedure:
To N-acetyl-N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide (0.149 g, 0.36 mmol) in MeOH (5 mL) cooled to 0° C. was added 30% weight solution NaOMe in MeOH (0.2 mL, 1.07 mmol). The reaction was warmed to room temperature for 40 minutes, then 1 N HCl was added (1.07 mL) and the reaction was concentrated, and CHCl3 and 10% KHSO4 were added. The layers were separated and the aqueous was extracted repeatedly. The organic layer was dried over Na2SO4, filtered, combined with the collected solid and evaporated to give the crude product.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5](C(=O)C)[CH2:4][CH2:3]1.[OH-].[Na+].O>C(O)C>[S:2]1(=[O:16])(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC(=O)N1CCS(=O)(=O)c2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S1(=O)CCNCc2ccccc21
Yield: 76.6 %

Procedure:
To a solution of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (240 g, 1.0 mol) in ethanol (1.0 L) was added sodium hydroxide (200 g, 5.0 mol) and water (700 mL). The mixture was refluxed overnight and then concentrated in vacuo. The residue was extracted by ethyl acetate (1500 mL×4). The combined organic layers were extracted by hydrochloric acid (2000 mL, 3 N). The acidic aqueous layer was washed with ethyl acetate (1500 mL×2), then basified with a saturated aqueous solution of sodium bicarbonate to pH >7, and extracted with ethyl acetate (1500 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 151 g of 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (yield was 76%), MS obsd. (ESI+) [(M+H)1] 198, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J=1.2, 7.6 Hz, 1 H), 7.56 (t, J=7.6 Hz, 1 H), 7.47 (t, J=7.6 Hz, 1 H), 7.42 (d, J=7.6 Hz, 1 H), 4.04 (s, 2 H), 3.32-3.30 (m, 2 H), 3.30-3.25 (m, 2 H), 2.64 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH3:15][C:16]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:17]=1[O:18][CH2:19][CH2:20][NH2:21]>>[CH3:13][C:6]1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:21][CH2:20][CH2:19][O:18][C:17]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:16]=2[CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1ccc(OCCN)c(C)c1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Product: CCOC(=O)c1c(NCCOc2ccc(C)cc2C)cc(C)nc1C

Procedure:
was synthesized analogously to Example 8 using ethyl 4-chloro-2,6-dimethylnicotinate and 2-(2,4-dimethylphenoxy)ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>C(O)C>[NH2:12][C:11]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[N:10][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC#N
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2ccc(Cl)cc2)c1N
Yield: 77.4 %

Procedure:
Reaction of p-chlorophenyl azide (7.48 g; 0.0487 mole) with ethyl cyanoacetate (5.5 g; 0.0487 mole) as described in example 1a gave 10.057 g (81%) of the triazole of mp (ethanol) 162-164° C. (lit mp 165-167° C.; Ger Offen No. 2,009,134[1970]) (Found; C, 49.78; H, 4.31; N, 21.15; C11H11CIN4O2 requires; C, 49.54; H, 4.16; N, 21.01%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:29])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[C@H:10]([OH:11])[CH2:9][S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[CH:34][CH:33]=1)[CH3:26]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1ccccc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3[C@H](O)CSCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (S)-2-benzylsulfanyl-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:14][OH:15]>>[OH:15][CH2:14][CH:13]([N:12]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11])[CH2:16][CH2:17][CH3:18]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCC(N)CO
Product: CCCC(CO)N1C(=O)c2ccccc2C1=O
Yield: 62 %

Procedure:
2-(1-hydroxypentan-2-yl)isoindoline-1,3-dione was prepared in a similar manner to example 9c using isobenzofuran-1,3-dione and 2-aminopentan-1-ol. Yield 62%. 1H NMR (500 MHz, CDCl3): δ 0.92 (t, 3H); 1.33 (m, 2H); 1.76 (m, 1H); 1.95 (m, 1H); 3.88 (m, 1H); 4.06 (m, 1H); 4.39 (m, 1H); 7.72 (m, 2H); 7.83 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH3:21][NH2:22]>C1COCC1.O>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([NH:22][CH3:21])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: CN
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 85 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
A mixture of compound 6 (25 mg, 0.06 mmol) and 2M methylamine in THF (1 mL) and 40% methylamine in water (1 mL) was stirred for 14 h at 85° C. After removal of volatiles in vacuo, the residue was triturated with methanol-water, and the solid that formed was collected by suction filtration, washed with water (10 mL), and dried to give compound 11 (22 mg, 89.0%). 1H NMR (DMSO-d6) δ 2.76 (d, J=4.6 Hz, 3 H, NHCH3), 3.55 (s, 3 H, 9-CH3), 4.59 (br s, 2 H, CH2), 6.28 (br d, J=4.3 Hz, 1 H, exchangeable with D2O, NHCH3), 7.10 (pseudo t, J=7.9 and 7.6 Hz, 1 H, H-16), 7.38 (d, J=7.6 Hz, 1 H, H-17), 7.57 (d, J=7.6 Hz, 1 H, H-15), 7.67 (s, 1 H, H-13), 7.35 (s, 1 H, H-8), 7.83 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [CH3:1][NH2:2].[ClH:3].[Cl:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:7]=1>[Pd].CO>[ClH:4].[ClH:3].[CH3:1][NH:2][CH2:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][NH:7]1
Reactant: CN
Reactant: ClCC1=NCC(c2ccccc2)c2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21

Procedure:
To a stirred solution of methanol (1 liter) and monomethylamine (300 ml) maintained under nitrogen and cooled in an ice bath was added portionwise 1-chloromethyl-3,4-dihydro-4-phenylisoquinoline hydrochloride (83.0 g, 0.28 m) and the mixture heated to reflux (ca 50°-55°) for 2 hours . After cooling, the solution was poured into a pressure bottle and hydrogenated on a Parr apparatus over 5% Pd/C catalyst (5.0 g) at 40 psi for 16 hours. The catalyst was removed by filtration and the solvent evaporated to a gummy residue. This was dissolved in a mixture of methanol (200 ml) and isopropanol (200 ml) and acidified with HCl gas. Upon cooling and standing, a white solid crystallized which was collected by filtration and dried to give 64.0 g of the major isomer cis-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenylisoquinoline dihydrochloride, m.p. 276°-277°. A second crop of solid was obtained from the crystallization (26.1 g) which consisted (TLC) mostly of the minor isomer. Two recrystallizations of this crop provide the pure minor isomer trans-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenylisoquinoline dihydrochloride, m.p. 269°-270°.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(-c2csc(Br)n2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Yield: 85.8 %

Procedure:
A solution of 2-bromo-4-(2,4-difluorophenyl)-1,3-thiazole (3.23 mg, 11.7 mmol), tert-butyl piperazine-1-carboxylate (4.36 g, 23.4 mmol) and potassium carbonate (1.62 g, 11.7 mmol) in dimethylformamide (40 ml) was stirred at 120° C. for 12 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 3.83 g (85.9%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: O=C(c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
1-(2-Chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)-2,2,2-trifluoroethanone (1.5 g, 0.0036 mol) in MeOH (22 mL) was treated with sodium tetrahydroborate (0.27 g, 0.0072 mol), and stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The crude material was purified with ISCO with 0-80% EtOAc/hexane to give the pure 1-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)-2,2,2-trifluoroethanol (1.3 g, 86% yield). LC/MS (ESI+): m/z 423 (M+H)
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH2:3]1.S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:19]([O-:21])=[O:20])[CH:10]=2)[NH:5][C:4](=[O:12])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)Nc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 17.5 g. (0.1 mole) 1,2,3,4-tetrahydro-4,4-dimethylquinolin-2-one in 200 ml. 80% sulphuric acid is added dropwise, while cooling with ice, a mixture of 5 ml. 96% nitric acid and 20 ml. 80% sulphuric acid, followed by stirring for 1 hour at ambient temperature. Subsequently, the reaction mixture is pured on to ice and the crystallisate is filtered off with suction and then washed with water. The crude product is purified by column chromatography on silica gel with butan-2-one/ethyl acetate (20/1 v/v) as elution agent. Yield 17.2 g. (78% of theory); m.p. 202°-204° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:28])=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23](OCC)=[O:24])=[CH:15][CH:14]=2)[N:10]=1.[H-].C([Al+]CC(C)C)C(C)C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:28])=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:18]=2)[N:10]=1
Reactant: CCOC(=O)/C=C/C=C/c1ccc(/C=C/c2nc(-c3ccco3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(-c2ccco2)nc1/C=C/c1ccc(/C=C/C=C/CO)cc1

Procedure:
Ethyl (E,E,E)-5-[4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]vinyl]phenyl]2,4-pentadienoate was reduced with diisobutylaluminum hydride in the same manner as in Reference Example 22 to yield (E,E,E)-5-[4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]vinyl]phenyl]-2,4-pentadien-1-ol, which was then recrystallized from ethyl acetate to yield colorless needles having a melting point of198°-199° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][CH2:28][NH2:29])[CH:18]=1.CCOP(O)N(C(C)C)C(C)C>ClCCl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:29][CH2:28][CH2:27][NH:26][C:19]1[CH:18]=[C:17]([CH3:16])[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1cc(NCCN)ncc1[N+](=O)[O-]
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(NCCNC(=O)/C=C/C(F)(F)F)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.1 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (23 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(4-methyl-5-nitro-2-pyridyl)ethane-1,2-diamine (29 mg, 0.15 mmol) and EDIPA (70 μl, 0.5 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 2.4 mg of a solid (0.0076 mmol, 5% yield).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2.[CH3:22][N:23]([CH:25](N(C)C)OC(C)(C)C)[CH3:24]>CN(C)C=O>[CH3:22][N:23]([CH:25]=[C:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][C:3]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=3[F:1])=[C:13]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:8][CH2:9]1)[CH3:24]
Reactant: O=[N+]([O-])c1cc2c(cc1Oc1ccc(F)cc1F)CCC2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1CCc2cc(Oc3ccc(F)cc3F)c([N+](=O)[O-])cc21

Procedure:
4.58 g of 5-(2,4-difluorophenoxy)-6-nitroindan and 8.2 g of bis(dimethylamino)tert.-butoxymethane were stirred in 5 ml of dimethylformamide for 60 minutes at 140° C. Concentration under vacuum yielded crude 1-dimethylaminomethylene-5-(2,4-difluorophenoxy)-6-nitroindan.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:19][CH2:18][C@@:10]3([NH:14]C(=O)N(C)[C:11]3=[O:17])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[O:22]1CCOCC1.Cl>O.C(O)(=O)C>[NH2:14][C@:10]1([C:11]([OH:22])=[O:17])[CH2:18][CH2:19][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: C1COCCO1
Reactant: CN1C(=O)N[C@@]2(CC[C@H](c3ccc(Br)cc3)C2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N[C@]1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a slurry of (5R,7S)-7-(4-bromo-phenyl)-3-methyl-1,3-diaza-spiro[4.4]nonane-2,4-dione (79 g, 0.24 mol) in water (1 L) was added 2 M aqueous NaOH (1 L, 2 mol) and dioxane (200 mL). The resulting mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with water (2 L) and acidified with concentrated HCl until a precipitate began to form (about pH 7). Acetic acid (about 20 mL) was added, producing a thick precipitate. The white precipitate was collected and washed with water (2×1 L) and EtOAc (1 L). The filter cake was suspended in toluene (1 L) and concentrated in vacuo at 45° C. This process was repeated once more. The white precipitate was dried to a constant weight under vacuum to give (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid (65 g, 95%).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(O)=O)[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C=CN=CC=1)CCCC.[OH:26]O>C(O)(=O)C.C(Cl)Cl>[CH2:1]([C:6]1[CH:11]=[CH:10][N+:9]([O-:26])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccnc(C(=O)O)c1
Reactant: OO
Agent: CCCCCc1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCc1cc[n+]([O-])cc1
Yield: 100 %

Procedure:
4-Pentylpyridine-2-carboxylic acid (10b) (R9=pentyl) was made by employing general Method P. To 4-pentylpyridine (3 g, 20 mmol) in acetic acid (30 mL), hydrogen peroxide (0.7 g, 30%, 20 mmol) was added and refluxed overnight. Removal of solvent resulted in residue which was dissolved in DCM (100 mL) dried over MgSO4 and filtered. Removal of DCM resulted in a brown liquid, 4-pentylpyridine-N-oxide, (3.3 g, 100%). To trimethylsilyl cyanide (2.37 g, 24 mmol), 4-pentylpyridine N-oxide (3.3 g, 20 mmol) in DCM (10 mL) was added followed by dropwise addition of dimethylcarbamoyl chloride (2.56 g, 24 mmol) in DCM (10 mL). After stirring at room temperature overnight, sodium bicarbonate (100 mL, 10%) was added and the organic layer was separated. The aqueous layer was extracted twice with DCM (50 mL) and the combined organic layer was dried over magnesium sulfate. Removal of solvent resulted in compound 10a (R9=pentyl) (4.1 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CCC2CCc3ccccc3O2)C1
Reaction time: 16 h
Yield: 71.7 %

Procedure:
First 1.57 g (10 mmol) of piperidine-3-carboxylic acid ethyl ester and then 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman in 35 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 2.28 g (90.1%) of crude product are obtained and are chromatographed on 120 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.82 g (72.2%) of 1-[2-(chroman- 2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are then obtained in the form of a yellow oil. The 1-[2-(chroman-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 148°-151°.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:33][C:34]#[N:35]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:33][C:34]#[N:35])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC#N)CC1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]methanone (example 13), sodium hydride and bromoacetonitrile, to give the desired product as a light yellow oil (61%).
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2.OI1(=O)C2C=CC=CC=2C(=O)O1>CC#N>[C:2]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)(=[O:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(C(O)c2ccccc2)c2ccccn2c1=O
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: CC#N
Product: O=C(O)c1cc(C(=O)c2ccccc2)c2ccccn2c1=O
Temperature: 75 °C

Procedure:
To a solution of 1-[hydroxy(phenyl)methyl]-4-oxo-4H-quinolizine-3-carboxylic acid (0.142 g, 0.508 mmol) in 3 mL CH3CN was added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (0.075 g, 0.254 mmol). The mixture was heated to 75° C. for 3 h, cooled to rt, and concentrated in vacuo. The resultant residue was subjected to purification via reverse phase HPLC to yield the title compound that gave a mass ion (ES+) of 294.2 for M+H+.