Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1.ClCCl>[C:32]([NH:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1[nH]cc(N)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Nc1c[nH]c(C(N)=O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To 0.15 g (0.328 mmol) of 4-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-2-carboxamide hydrochloride dissolved in 4.5 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.023 cm3 of acetyl chloride, 0.091 cm3 of triethylamine and 8 mg of 4-dimethylaminopyridine. After stirring for 16 hours at a temperature in the region of 20° C., the reaction mixture is diluted with 15 cm3 of dichloromethane and then washed with twice 10 cm3 of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a solid, which is recrystallized while hot from 5 cm3 of dichloromethane. The recrystallized solid is filtered off through a No 3 sinter funnel, washed with twice 3 cm3 of dichloromethane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. for 5 hours to give 0.084 g of 4-acetylamino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide in the form of a white solid melting at 228.5° C.; ES+: m/z=464: [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:17][CH:18]2[O:22][CH2:21][CH2:20][O:19]2)[CH2:15][OH:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)[CH2:17][CH:18]1[O:19][CH2:20][CH2:21][O:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 101.4 %

Procedure:
Methanesulphonyl chloride (5.5 g) was added over 10 minutes to an ice-cooled solution of 2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propan-1-ol (12 g) (see Preparation 15) and triethylamine (5.7 g) in dichioromethane (100 ml). The mixture was stirred for 30 minutes before further addition of dichioromethane (50 ml). The solution was then washed sequentially with water (3×50 ml) and brine (50 ml) before drying over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 1-methanesulphonyloxy-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane as a yellow oil (15.6 g) which solidified upon standing.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:12][NH:13][C:9]([C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:10]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: NNc1nc2ccccc2s1
Product: O=C(NNc1nc2ccccc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4a was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and 2-hydrazino-benzothiazole (300 mg, 1.5 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 245 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH:12]C(=O)C)[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4].C(Cl)(=O)C.O>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4]
Reactant: CCOc1c(Cl)ccc(-c2cc(NC(C)=O)c(Cl)c(C(=O)OC)n2)c1F
Solvent: CO
Solvent: CC(=O)Cl
Solvent: O
Product: CCOc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)OC)n2)c1F

Procedure:
To a solution of 4-acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)pyridine-2-carboxylic acid methyl ester (0.5 g, 0.0013 mol) in methanol (10 mL) was added acetyl chloride (1 mL) and the solution heated under reflux for 1 hour. Water (2 mL) was added and resulting solid collected and dried to give 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)pyridine-2-carboxylic acid methyl ester: mp 154-156° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1.Cl[CH2:12][O:13][CH3:14]>CN(C=O)C.C(OCC)(=O)C.O.[Cl-].[Na+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][O:13][CH3:14])=[CH:6][N:5]=1
Reactant: COCCl
Reactant: Oc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
Suspend sodium hydride (3.7 g, 93 mmol) in DMF (50 mL) and add a solution of 2-chloro-5-hydroxypyridine (10 g, 77 mmol) in DMF (20 mL) dropwise over 45 min. Stir the resulting solution at RT for 1.5 h. Add chloromethylmethyl ether (6.6 mL, 86 mmol) dropwise over 45 min. Stir the resulting mixture at RT for 12 h. Dilute the mixture with ethyl acetate, water, and saturated aqueous sodium chloride. Isolate the organic solution and wash with three portions of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by column chromatography on 330 g of silica gel eluting with a gradient from hexane to 30% ethyl acetate in hexane over 20 min and then hold at 30% ethyl acetate in hexane for 30 min to give the title compound 10.8 g (81%) as a clear oil. MS (ES) m/z 174.0 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.CN(C)CCN=C=NCC.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:9])=[CH:10][CH:11]=1
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(methylthio)benzoic acid (6.76 g, 40.2 mmol) and N-[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride (9.24 g, 48.2 mmol) in THF (100 mL) was added morpholine (4.2 mL, 48.2 mmol). After stirring for 2 hours, the reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and 2M hydrochloric acid (150 mL). The organic phase was separated, washed with 1M aqueous sodium carbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound LC retention time 3.52 mins MS m/z 238 (MH+).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].[I:18]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[I:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
In a round-bottomed flask, 5-(tert-butyl-dimethyl-silanyloxy)-1H-indazole (1.20 g, 4.83 mmol) was dissolved in DMF (12 ml). Iodine (2.45 g, 9.66 mmol) was added followed by potassium carbonate (2.58 g, 18.7 mmol). The dark suspension was stirred at room temperature for 3 h then quenched with 10% aqueous NaHSO3 and extracted with diethyl ether (2×). The combined organic layers were washed with 10% aqueous NaHSO3, three times with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 1.65 g (91%) of 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1H-indazole as a dark brown foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[N:4][CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.O>[Br:23][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[N:4][CH:5]=1
Reactant: O=C(NNc1nccnc1Cl)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Temperature: -40 °C
Reaction time: 1 h

Procedure:
N′-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide E-1 (19.5 g; 81.1 mmol) is dissolved in 300 ml anhydrous DCM and cooled down to −40° C. Afterwards NBS (18.8 g; 105 mmol) is added and stirred for 1 hour. The solution is diluted with water and extracted with DCM. The organic phase is then purified with flash chromatography: cHex/(EtOAc/CH3COOH=9/1)=80%/20% to 70%/30% within 10 column volumes.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>ClCCl.CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH+:9]([O-:25])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(C(=O)[NH+]([O-])c2ccc(F)cc2)cn1
Yield: 13.2 %

Procedure:
To a solution of 6-dimethylamino-N-(4-fluoro-phenyl)-nicotinamide (0.027 g, 0.11 mmol, prepared as in Example 1) in 2 mL of dry dichloromethane/methanol (4:1) was added 3-chloroperoxybenzoic acid (0.020 g, 0.12 mmol) at 0° C. The reaction mixture was then heated to reflux and additional 3-chloroperoxybenzoic acid (0.040 g, 0.24 mmol) was added. After heating for a total of 7 h the reaction mixture was cooled, diluted with chloroform and washed with aqueous sodium carbonate (1M), dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography, using 10% methanol/dichloromethane saturated with ammonia, yielded 4 mg (13%) of the desired product as a white solid. MS (EI) m/z 274.18 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([NH2:23])=[N:20][C:21]=1[F:22].CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:21]1[N:20]=[C:19]([NH2:23])[CH:18]=[CH:17][C:16]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH:8]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: Nc1ccc(Br)c(F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(N)nc3F)cc2c1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
5-Methoxybenzofuran boronic acid (230 mg, 1.20 mmol), 5-bromo-6-fluoro-pyridin-2-ylamine (191 mg, 1.00 mmol), Pd(PPh3)2Cl2 (16.8 mg, 0.024 mmol) and Et3N (317 μL, 2.27 mmol) were mixed in EtOH (10 mL) in a microwave vial. The reaction mixture was stirred at 140° C. for 15 minutes in a microwave reactor. The volatiles were then removed under reduced pressure, the residue was suspended in water and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude product by flash column chromatography using 25% ethyl acetate in hexane gave 6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridin-2-ylamine (130 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.05-8.21 (m, 1 H) 7.36 (d, J=8.59 Hz, 1 H) 7.03 (d, J=1.95 Hz, 1 H) 6.97 (d, J=3.12 Hz, 1 H) 6.86 (dd, J=8.78, 2.54 Hz, 1 H) 6.45 (d, J=6.63 Hz, 1 H) 4.66 (br. s., 2 H) 3.86 (s, 3 H)
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@H:10]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)([CH3:4])[CH3:3].C[Si](C#[N:36])(C)C.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[NH2:36][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@H:10]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(N)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reaction time: 12 h

Procedure:
A mixture, cooled to 0° C., of N-[(S)-6-(1-hydroxy-1-methylethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.30 g), glacial acetic acid (1 ml) and trimethylsilyl cyanide (145 mg) was admixed dropwise with sulfuric acid (1.2 ml; 96%). The cooling bath was removed and the mixture was stirred for another 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was taken up in 1,4-dioxane (20 ml) and boiled at reflux with dilute hydrochloric acid for 30 minutes. The reaction mixture was washed with ethyl acetate and basified with concentrated sodium hydroxide solution. Extraction with dichloromethane gave rise to an organic phase which was dried over sodium sulfate and concentrated. (Alternatively, the hydrolysis of the intermediate formamide can also be achieved by boiling with sodium hydroxide solution.) The product was thus obtained with the molecular weight of 408.55 (C25H32N2O3); MS (ESI): 409 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH:7]=O)[N:6]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[C:23](O)(=[O:25])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]2[CH2:7][C:5]3=[CH:4][N:3]=[C:2]([CH3:1])[N:6]3[C:23]2=[O:25])[CH2:11][CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ncc2n1C(=O)N(C1CCN(Cc3ccccc3)CC1)C2
Yield: 60 %

Procedure:
To a solution of 2-methylimidazole-4-carbaldehyde (11.0 g), 4-amino-1-benzylpiperidine (19 g) and acetic acid (6.7 ml) in 1,2-dichloroethane (200 ml), under ice-cooling, was added sodium triacetoxyborohydride (32 g), and mixed at room temperature for 15 hours. The reaction solution was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was dissolved in THF (200 ml), N,N′-carbonyldiimidazole (18 g) and DBU (17 g) were added thereto, and mixed at room temperature for 15 hours. The reaction solution was concentrated, water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column to obtain the title compound (19 g, 60%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:3].[CH3:16][Br:17]>>[Br-:17].[CH3:3][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:16])[CH3:1]
Reactant: COc1ccc(CCCCN(C)C)cc1
Reactant: CBr
Product: COc1ccc(CCCC[N+](C)(C)C)cc1
Product: [Br-]

Procedure:
N,N-Dimethyl-4-(4-methoxyphenyl)butylamine (4.35 g.) was reacted with methyl bromide according to the procedure of Example 46 to provide 4.95 g. of N,N,N-trimethyl-4-(4-methoxyphenyl)butylammonium bromide, which was recrystallized from acetone and methanol. M.P. 166°-168° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:21][CH2:22][O:23][CH3:24])[N:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c([N+](=O)[O-])cnn1CCOC
Reaction time: 0.08 h
Yield: 25 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg, 0.54 mmol) in DMSO (1 mL) was added potassium carbonate (164 mg, 1.19 mmol) and the reaction mixture was stirred for 5 min. 1-Bromo-2-methoxyethane (110 μl, 1.19 mml) was added and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The product was obtained as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 72 mg (55%) of the desired regioisomer and 33 mg (25%) of 2-(2-methoxyethyl)-4-nitro-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([I:29])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([I:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3I)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (50 mg, 0.17 mmol), NIS (94 mg, 0.4 mmol), TFA (20 mg, 13.4 L, 0.17 mmol) in CH2Cl2 (200 L) was stirred at room temperature overnight. After solvent removal, the desired product 18 (6 mg, 8.5%) was purified by silica gel column chromatography (CHCl3:EtOAc at 9:1 to 4:6). 1H NMR (400 MHz, DMSO-d6) 7.6 (bs, 2H), 7.38 (s, 1H), 6.95 (s, 1H), 6.03 (s, 2H), 4.12 (s, 2H); MS m/z 414.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1>C(Cl)Cl>[O:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCCCN2CCOCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCN1CCOCC1)C1CCNCC1
Yield: 93.8 %

Procedure:
Trifluoroacetic acid (4.4 ml) is added to a solution of tert-butyl 4-(3-morpholinopropylcarbamoyl)piperidine-1-carboxylate (2.3 g) in CH2Cl2 (30 ml), and the mixture is stirred over night. The solvent is removed under reduced pressure to give crude N-(3-morpholinopropyl)piperidine-4-carboxamide (1.55 g).
Reaction SMILES: C([C:4]1[NH:8][C:7]([C:9]([O:11]C)=[O:10])=[C:6]([Cl:13])[CH:5]=1)(=O)C.CO.[Li+].[OH-].C1C[O:21][CH2:20][CH2:19]1>>[C:20]([C:5]1[C:6]([Cl:13])=[C:7]([C:9]([OH:11])=[O:10])[NH:8][CH:4]=1)(=[O:21])[CH3:19]
Reactant: COC(=O)c1[nH]c(C(C)=O)cc1Cl
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1c[nH]c(C(=O)O)c1Cl
Temperature: 60 °C
Yield: 67 %

Procedure:
Methyl 5-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.034 g, 0.169 mmol) was dissolved in THF (1 mL), methanol (1 mL) and 1N LiOH (1 mL). The reaction mixture was heated to 60° C. and stirred. The reaction mixture was evaporated and purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.033 g, 67%) as an impure product which was used with no further purification. LCMS: m/z 187.9 (M+1).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:5][CH:4]1[O:6][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:1][CH2:2][CH2:3]1
Reactant: CCCCCCCCCC=O
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCC1OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed in a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 8.58 grams (0.055 moles) n-decanal is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with 10% aqueous sodium bicarbonate to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 11.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 4 fractions:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CN1CCN(C)C1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(C)C1=Nc1ccccc1-c1ccccc1

Procedure:
A mixture of 1,3-dimethyl-2-imidazolidinone (5.5 g) in benzene (30 ml), 2-aminobiphenyl (5.1 g) in benzene (20 ml) and phosphorus oxychloride (4.4 ml) was heated at 80°-85° C. for 20 hours to yield 2-(1,3-dimethyl-2-imidazolidinylideneamino)biphenyl (m.p. 90°-91° C.) which was recrystallised from hexane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4)c3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3[nH]c4cccc(-c5ccccc5)c4c3CC2)cc1
Yield: 95 %

Procedure:
A solution of lithium aluminum hydride (0.73 g, 19.2 mmol) in tetrahydrofuran (10.0 mL) and a solution of 3-benzoyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.73 g, 2.0 mmol) in tetrahydrofuran (20.0 mL) at 0° C. were reacted in a manner similar to Example 1 to give 0.67 g (96%) of the title compound as a white crystalline solid: mp 161-163° C.; 1H NMR (400 MHz, CDCl3) δ 7.83, 7.43-7.23, 7.14-7.10, 6.91, 3.70, 2.93-2.90, 2.86-2.83, 2.65-2.62, 2.42-2.40; 13C NMR (100 MHz, CDCl3) δ 142.0, 139.3, 137.2, 135.0, 134.7, 129.7, 128.9, 128.2, 127.6, 126.9, 126.6, 126.0, 121.6, 120.6, 113.6, 109.5, 61.8, 55.8, 53.4, 28.5, 25.9; IR (drift) 3407, 2810, 1454, 1377, 1347, 1334, 1319, 1175, 1120, 932, 785, 762, 754, 742, 700 cm−1; MS (EI) m/z 352 (M+); HRMS (FAB) calcd for C25H24N2+H: 353.2018, found: 353.2039; Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 84.83; H, 6.94; N, 7.83.