Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([C:19]#[N:20])[N:3]=1.[SH2:21].CCN(CC)CC>C(O)(C)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([C:19](=[S:21])[NH2:20])[N:3]=1
Reactant: S
Reactant: N#Cc1nc(N)nc2c1ncn2Cc1ccccc1F
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: NC(=S)c1nc(N)nc2c1ncn2Cc1ccccc1F
Temperature: 50 °C
Yield: 100 %

Procedure:
A suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-carbonitrile (680 mg, 1.85 mmol) in isopropanol (50 mL) was treated with H2S gas for 15 min, then treated with Et3N (0.51 mL, 3.7 mmol), heated at 50° C. for 1 h, concentrated in vacuo, diluted with Et2O and filtered to give the title compound (757 mg, 100%) as a yellow solid; NMR δH (400 MHz, DMSO) 5.36 (2H, s), 6.66 (2H, br s), 7.06-7.43 (4H, m), 8.15 (1H, s), 9.81 (1H, br s) and 10.22 (1H, br s).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([CH:60]2[CH2:62][CH2:61]2)[NH2:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:59][CH:58]([C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][CH:56]=2)[CH:60]2[CH2:62][CH2:61]2)=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: NC(c1ccc(Cl)cc1)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: NC1(C(=O)NC(c2ccc(Cl)cc2)C2CC2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.228 g) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g), (4-chlorophenyl)(cyclopropyl)methanamine (Intermediate 3) (0.091 g) and DIPEA (0.261 mL) in DMA (5 mL) at 25° C. The resulting solution was stirred at 50° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This crude material was suspended in dichloromethane (25 mL), and TFA (5 mL) was added. The reaction mixture was stirred for 1 hour, then the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford the crude material as a white solid. This material was triturated under cold methanol to give the pure product, 4-amino-N-((4-chlorophenyl)(cyclopropyl)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.167 g, 79%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>C(O)(=O)CC>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[C:16]3[NH:12][C:13]([C:8]([C:7]4[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=4)=[C:13]4[N:12]=[C:16]([C:8]([C:7]5[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=5)=[C:13]5[NH:12][C:16](=[C:8]([C:7]6[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:11][CH:10]=6)[C:13]6[CH:14]=[CH:15][C:16]=2[N:12]=6)[CH:15]=[CH:14]5)[CH:15]=[CH:14]4)=[CH:14][CH:15]=3)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-c2c3nc(c(-c4ccc(C(=O)O)cc4)c4ccc([nH]4)c(-c4ccc(C(=O)O)cc4)c4nc(c(-c5ccc(C(=O)O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Yield: 17.5 %

Procedure:
In refluxed propionic acid, 30 g of 4-carboxybenzaldehyde was reacted with 13.4 g of pyrrole to obtain 6.9 g of 5,10,15,20-tetra(4-carboxyphenyl)porphine. This porphine derivative was reacted with an aqueous solution containing four equivalents of sodium hydroxide to obtain tetrasodium 5,10,15,20-tetra(4-carbonatophenyl)porphine.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C=O.[OH-].[Na+]>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1N1CCOCC1
Temperature: 50 °C

Procedure:
Refer to synthesis of (D46) for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (1.85 g, 9.70 mmol) and morpholine (1.69 mL, 19.4 mmol) in anhydrous dimethylformamide (20 mL) was heated to 50° C. for 2.5 h. The reaction was then cooled to room temperature and diluted with 0.1 M NaOH (600 mL) and extracted with ethyl acetate (3×500 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound (2.49 g) as an orange oil, which later solidified upon standing. Compound 6-Chloro-2-morpholin-4-yl-nicotinamide (2) was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) δ7.89 (br s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.56 (br s, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.67 (br t, J=4.7 Hz, 4H), 3.31 (br t, J=4.7 Hz, 4H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.[NH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]([O:39][C:40]([CH3:43])(C)C)=[O:38])[CH2:31][CH2:30]1.[OH-].[Na+]>C1COCC1>[N:29]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:43])=[O:38])[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (13.3 mmol) NaBH(OAc)3 were added batchwise to a solution of 2.58 g (11.1 mmol)) tert. butyl 4-oxo-piperidine-1-carboxylate and 2.80 g (12.4 mmol) tert. butyl (piperidin-4-yloxy)-acetate in 30 mL THF and the reaction mixture was stirred overnight at RT. 50 mL of 1 M NaOH was added, the mixture was stirred for 1 h at RT, extracted exhaustively with EtOAc and the combined organic phases were dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (Alox, activity stage II-III, DCM/MeOH 100:1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][C:29]=2[C:30]2[N:34]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:33]=[N:32][N:31]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23]C(=O)C)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][C:29]=2[C:30]2[N:34]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:33]=[N:32][N:31]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccccc1Oc1ccc(-c2nnnn2Cc2ccccc2)c(-c2nnnn2Cc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: Nc1ccccc1Oc1ccc(-c2nnnn2Cc2ccccc2)c(-c2nnnn2Cc2ccccc2)c1

Procedure:
N-{2-[3,4-Bis-(1-benzyl-1H-tetrazol-5-yl)phenoxy]phenyl}acetamide (40 mg, 0.07 mmol) was dissolved in ethanol (10 ml). 4N hydrochloric acid (10 ml) was added and the reaction mixture was refluxed for 15 hours. The mixture was evaporated in vacuo and redissolved in methylene chloride and 0.5 N aqueous sodium hydroxide (1:1) (20 ml). The organic phase was dried over magnesium sulphate and evaporated in vacuo to give 2-[3,4-bis-(1-benzyl-1H-tetrazol-5-yl)phenoxy]phenylamine as an oil (yield: 37 mg (100%)). 1H-NMR (CDCl3 in ppm): 3.9 (2H, broad s); 5.58 (4H, s); 6.75 (1H, d.d.); 6.85 (1H,d.d.); 6.9 (1H,d.d.); 7.0 (1H,d.d.); 7.1 (1H,d.d.); 7.2-7.4 (10H,m); 7.48 (1H,d); 7.8 (1H,d).
Reaction SMILES: [BrH:1].[CH3:2][O:3][CH2:4][C@H:5]([NH:30][C:31]([C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1)=[O:32])[C:6]([NH:8][C@@H:9]([CH2:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11])=[O:7]>O1CCOCC1.C(Cl)Cl>[Br:1][CH2:18][C@:16]([OH:17])([CH3:19])[C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[C@@H:5]([NH:30][C:31]([C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1)=[O:32])[CH2:4][O:3][CH3:2])[CH2:27][O:28][CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Reactant: Br
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Hydrobromic acid (2 eq., 0.314 mL) was added to N—((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (1.0 g, 1.88 mmol) in dioxane (20 mL) at 0° C., the reaction allowed to warm to room temperature and stirred overnight. The mixture was diluted with DCM, washed with aqueous saturated sodium bicarbonate, brine, dried (Na2SO4) and evaporated. The residue was purified by Biotage flash column chromatography to give product as a white solid (0.722 g, 48%); 1H NMR (CDCl3): δ 8.06(s, 1H), 7.28-7.18 (m, 6H), 7.02 (d, J=7.6 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 5.45-5.40 (m, 1H), 4.71-4.66(m, 1H), 4.53-4.48 (m, 1H), 4.20 (s, 1H), 3.85-3.75 (m, 3H), 3.57-3.52 (m, 2H), 3.44-3.39 (m, 4H), 3.31 (s, 3H), 3.23-3.18 (m, 1H), 2.94-2.89 (m, 1H), 2.75 (s, 3H), 1.18 (s, 3H); MS for C25H33BrN4O7S m/z 614 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][C:12]3([CH2:16][C:15](O)([C:17]4[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=4)[CH2:14]3)[CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]2[CH2:11][C:12]3([CH2:16][C:15]([C:17]4[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=4)=[CH:14]3)[CH2:13]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CC3(C2)CC(O)(c2cc(F)c(F)c(F)c2)C3)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H](C2CC3(C=C(c4cc(F)c(F)c(F)c4)C3)C2)CC1

Procedure:
A mixture of 12 mmol of 4F, 100 ml of toluene and 0.5 g of p-toluenesulfonic acid is heated on a water separator for 10 hours. After conventional work-up the product is obtained, which is processed further without purification.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[NH:3]1.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[S:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:11](=[O:12])[NH:10]2)(=[O:15])=[O:14]
Reactant: CNC
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Product: CN(C)S(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
A mixture of 3.91 g (0.015 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% aqueous dimethylamine is stirred at room temperature for 6 hours. Then it is filtered, the separated crystals are washed successively with water and acetone, filtered, dried and recrystallized from water. Thus 1.40 g (35%) of N,N-dimethyl-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide is obtained, m.p.: 258-266° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[S:9])[NH:6][C:7]=1[CH3:8].[OH-].[Na+].CI.[C:15](O)(=O)C>O>[CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([S:9][CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1C
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc(C)c(C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred solution of 5,6-dimethyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (10.0 g, 64.0 mmol, Example 1, Step A) and sodium hydroxide (10.0 g, 260.0 mmol) in water (150 mL) at ambient temperature was added methyl iodide (15.0 g, 320.0 mmol), and the reaction mixture was stirred at ambient temperature overnight. Then the reaction mixture was acidified with acetic acid (50 mL), and the solid was collected by filtration and dried to afford 7.0 g (64%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.87 (s, 3H), 2.18 (s, 3H), 2.45 (s, 3H), 12.38 (bs, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=[O:20])=[N+:2]=[N-:3].[CH2:28](O)[CH2:29][OH:30].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]2[O:30][CH2:29][CH2:28][O:20]2)[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])=[N+:2]=[N-:3]
Reactant: COc1cc(C=O)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C2OCCO2)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A mixture of 4.95 g (12.91 mmol) 3-{2-[2-(2-{2-azidoethoxy}ethoxy)ethoxy]ethoxy}-4,5-dimethoxybenzaidehyde 8, 5 ml (5.57 g, 90 mmol) ethylene glycol and 200 mg (1.0 mmol) p-toluene sulfonic acid monohydrate was refluxed in 120 ml of toluene for 8 hrs using a Dean-Stark trap. After cooling to room temperature the rection mixture was poured into 200 ml of diluted sodium bicarbonate solution, washed with water and brine and dried over magnesium sulfate. After removal of the solvent the residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate 1/1), giving 4.43 g (10.8 mmol, 80%) of the product as a clear oil. 1H-NMR (CDCl3) δ=6.73 (dd, 2H, J=5.0 Hz, J=1.8 Hz), 5.72 (s, 1H), 4.19 (m, 2H), 4.11 (m, 2H), 4.03 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.76-3.71 (m, 4H), 3.70-3.64 (m, 8H), 3.37 (m, 2H) ppm. 13C-NMR δ=153.3, 152.4, 139.2, 133.1, 105.4, 103.6, 103.4, 70.7, 70.6, 70.5 (2 peaks), 69.9, 69.6, 68.7, 65.1, 60.6, 56.0, 50.6 ppm. MS: m/z=427 [M]+. Anal. calcd for C19H29N3O8: C, 53.39, H, 6.84, N, 9.83. Found C, 52.30, H, 6.89, N, 9.72.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]>C(O)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: CNCc1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1ccc(F)cc1)Cc1ccccc1[N+](=O)[O-]

Procedure:
135.8 g (0.67 mol) of methyl-(2-nitrobenzyl)-amine and 187.5 ml (1.339 mols) of triethylamine are dissolved in 1.87 liters of ethanol at room temperature, with stirring, and 148 g (0.682 mol) of 2-bromo-1-(4-fluorophenyl)ethanone are then added in portions. The reaction mixture is stirred for 3 hours. The solvent is then stripped off on a rotary evaporator and the residue is dissolved in 1.3 liters of toluene. The toluene phase is washed several times with H2O and dried over Na2SO4, and HCl/diethyl ether is added. The glutinous precipitate is separated from the toluene by decanting and crystallized with acetone. The colorless precipitate is filtered off with suction and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20]([N:12]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:11])[CH2:9][CH3:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: COC(=O)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(Cl)cc1N(C(=O)C(=O)OC)c1ccccc1
Temperature: 110 °C
Yield: 87.6 %

Procedure:
A solution of 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (13.0 g, 50.2 mmol) in toluene (150 mL) at 25° C. was treated with methyl chlorooxoacetate (42.86 g, 350 mmol). The reaction mixture was then heated at 110° C. for 16 hr. At this time, the reaction mixture was concentrated in vacuo to afford N-(5-chloro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester (15.2 g, 87.6%). The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(CC)CC>CS(C)=O.II>[F:1][C:2]1[C:8]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: NCc1ccc(F)cc1
Agent: II
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1cc(NCc2ccc(F)cc2)c(F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a stirred suspension of compound 2 (0.600 g, 3.40 mmol, 1.00 equiv) in dry DMSO (15 mL) was added 4-fluorobenzylamine (1.20 g, 10.0 mmol, 3.00 equiv) followed by Et3N (0.500 mL, 4.10 mmol, 1.20 equiv) and I2 (catalytic, 1.00 mg). The reaction mixture was heated to 120° C. and stirred at 120° C. for 16 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 2:3) to afford compound 3 (0.550 g, 52.0%) as yellow solid. TLC: 70% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, DMSO-d6): δ 7.60-7.54 (m, 2H), 7.38-7.32 (m, 4H), 7.17 (t, J=8.8 Hz, 2H), 5.92 (d, J=8.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H); LC-MS: m/z=278 (M+-1) at RT 3.59 (99.4% purity).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:26]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[C:15]([O:16][CH3:26])=[C:10]3[CH:9]=[CH:8]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
To methyl 1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.25 g, 0.83 mmol) in DMF (10 mL) were added sodium hydride (0.037 g, 0.92 mmol, 60% in mineral oil) and iodomethane (0.057 mL. 0.92 mmol). The solution was stirred for 3 h at ambient temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (3×50 mL). The organic extracts were washed with brine (3×50 mL), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. Elution with ethyl acetate provided the title compound as a solid (0.10 g, 38% yield). 1H NMR (CD3OD) δ: 8.43 (s, 1H), 7.61 (d, 1H, J=3.1 Hz), 7.24 (t, 2H, J=8.8 Hz), 7.05 (t, 2H, J=8.8 Hz), 6.92 (d, 1H, J=3.1 Hz), 5.52 (s, 2H), 4.16 (s, 3H), 3.91 (s, 3H). LCMS (APCI, M+H+): 315.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH2:10].[C:11](N1C=CN=C1)(N1C=CN=C1)=[S:12]>O1CCCC1>[SH:12][C:11]1[NH:10][C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(F)cc(F)c1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Fc1cc(F)c2[nH]c(S)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A mixture of 1,2-diamino-3,5-difluorobenzene (1 g, 6.94 mmol) and 1,1′-thiocarbonyldiimidazole (2.05 g, 11.52 mmol) in 10 ml of tetrahydrofuran is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is then dried over MgSO4, filtered and concentrated under reduced pressure to yield 763 mg of 2-mercapto-4,6-difluorobenzimidazole. Yield=61%. Analytical LC/MS (method B): retention time=2.49 min. m/z=186.95 (positive ion mode).
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[CH2:7][CH2:6]1)(=O)C>Cl>[NH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)NC1CCN(c2cccc(Cl)n2)CC1
Agent: Cl
Product: NC1CCN(c2cccc(Cl)n2)CC1
Yield: 72 %

Procedure:
A solution of 0.482 mole of 4-acetamido-1-(6-chloro-2-pyridyl)piperidine in 610 ml of 6 N hydrochloric acid is heated at reflux for 8 hours, then the reaction mixture is cooled and concentrated under reduced pressure. The residue is treated with 4 N sodium hydroxide up to a clearly basic pH and the oil which separates is extracted with diethyl ether. The organic phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue is crystallised by diisopropylic ether. 4-amino-1-(6-chloro-2-pyridyl)piperidine is thus obtained; m.p. 36° to 38° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
1-(2-Chloro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1, triethylamine (42.3 uL, 0.30 mmol) and methanesulfonyl chloride (10.4 mg, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.