Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[N:12]1.[I:22][CH3:23]>C(#N)C>[I-:22].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N+:13]([CH3:23])=[N:12]1
Reactant: COCCOCCOCCn1cc(-c2ccccc2)nn1
Reactant: CI
Solvent: CC#N
Product: COCCOCCOCCn1cc(-c2ccccc2)[n+](C)n1
Product: [I-]
Temperature: 25 °C

Procedure:
The 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-phenyl-1H-1,2,3-triazole was refluxed with excess iodomethane in acetonitrile for more than 12 hours and concentrated after cooling to room temperature. The product was rinsed with organic solvent, recrystallized with ethyl acetate and dried in vacuo. The following 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium iodide structure was confirmed:
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[ClH:16].Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH:39]4[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]4)[CH2:35]3)=[O:33])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.O>CN(C=O)C>[ClH:16].[CH:1]1([NH:6][C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([C@@H:34]4[CH:39]5[CH2:38][CH2:37][N:36]([CH2:41][CH2:40]5)[CH2:35]4)=[O:33])=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCC1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1)NC1CCCC1
Reaction time: 18 h

Procedure:
33.8 mg (0.30 mmol) of cyclopentyl isocyanate and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)-N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. A preparative HPLC is carried out for further purification. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 28 mg (39.2% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.F[P-](F)(F)(F)(F)F.[CH3:26][N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[F:57][C:58]1[CH:59]=[N:60][C:61]2[NH:62][C:63]3[CH:64]=[CH:65][CH:66]=[C:67]([CH:80]=3)[CH2:68][CH2:69][C:70]3[CH:78]=[C:74]([NH:75][C:76]=1[N:77]=2)[CH:73]=[CH:72][C:71]=3[NH2:79]>CN(C)C=O.C(N(CC)C(C)C)(C)C>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[F:57][C:58]1[CH:59]=[N:60][C:61]2[NH:62][C:63]3[CH:64]=[CH:65][CH:66]=[C:67]([CH:80]=3)[CH2:68][CH2:69][C:70]3[CH:78]=[C:74]([NH:75][C:76]=1[N:77]=2)[CH:73]=[CH:72][C:71]=3[NH:79][C:16](=[O:18])[CH2:15][CH:12]1[CH2:11][CH2:10][N:9]([C:7]([C:4]2[CH:3]=[C:2]([CH2:1][CH3:26])[O:6][N:5]=2)=[O:8])[CH2:14][CH2:13]1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(F)c(n1)N2
Reactant: Cc1cc(C(=O)N2CCC(CC(=O)O)CC2)no1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(F)c(n3)N4)CC2)no1
Reaction time: 8 h
Yield: 8.4 %

Procedure:
A solution of {1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}acetic acid (16 mg, 0.063 mmol) (prepared in Example C49, step I), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (65 mg, 0.17 mmol) in N,N-dimethylformamide (0.8 mL) and N,N-diisopropylethylamine (26 μL) was stirred for 15 minutes. A solution of 6-fluoro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) (20 mg, 0.06 mmol) in N,N-dimethylformamide (0.3 mL) and was added to the previous solution and stirred overnight. The reaction mixture was purified by preparative HPLC (pH 2) to give the desired product (4 mg, 12%). LCMS for C30H31FN7O3 (M+H)+: m/z=556.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9](Cl)(=[O:11])[CH3:10]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(N)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
Dissolve 2,6-diaminopyridine (9.822 g, 90 mmol) in dioxane (100 mL) and cool to 0° C. Add acetyl chloride (2.355 g, 2.1 mL, 30 mmol) slowly and stir for 1 hr. at 0° C. Remove the ice bath and stir at room temperature overnight. Quench the reaction mixture with saturated NaHCO3 solution, extract with ethyl acetate three times. Combine the organic layers, dry over Na2SO4, filter, and concentrate to give a solid. Chromatography on silica gel, eluting with a gradient of 60-70% ethylacetate in hexanes affords the title intermediate (3.45 g, 76%): mass spectrum (ion spray): m/z=152.1 (M+1); 1H NMR (CDCl3, ppm): 7.49 (m, 3H), 6.28 (d, 1H), 4.31 (s, br, 2H), 2.19 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:21])[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:5]=1.[OH-].[Na+]>CO>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][NH:11][C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:22])=[O:2])=[O:21]
Reactant: COC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(C(=O)NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of (18(b)) (3.85 g, 11.4 mmol) in MeOH (100 mL) at room temperature under argon was treated with 2N NaOH (12 mL, 24 mmol). The reaction mixture was allowed to stir at room temperature for 4 h. concentrated to 1/5 volume and acidified to pH4 with 2N HCl. The resulting precipitate was then collected by filtration. washed with water (2×25 mL) and dried under high vacuum to yield 3-(3,4-dichlorobenzyl-carbamoyl)-benzoic acid (18(c)) as a white powder: 2.9 g (79%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.O1CCCC1.[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23].Cl>C/C(/[O-])=C\C(C)=O.C/C(/[O-])=C\C(C)=O.C/C(/[O-])=C\C(C)=O.[Fe+3].CN1CCCC1=O>[CH2:21]([C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C[Mg]Br
Reactant: Clc1ncnc2c1ccc1ccccc12
Agent: [Fe+3]
Agent: CC(=O)/C=C(\C)[O-]
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)Cc1ncnc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
In a 100-mL three-neck flask were put 0.53 g (2.5 mmol) of 4-chlorobenzo[h]quinazoline, 52 mg (0.148 mmol) of tris(2,4-pentanedionato)iron(III) (abbreviation: Fe(acac)3), 25 mL of dehydrated tetrahydrofuran (THF), and 2.0 mL of 1-methyl-2-pyrrolidone (abbreviation: NMP), and the air in the flask was replaced with nitrogen. The flask was cooled with ice, 2.6 mL of isobutylmagnesium bromide solution (1 M in THF) (abbreviation: iBuMgBr) was added, and the mixture was stirred at room temperature for 16 hours. Then, 1 M hydrochloric acid was added, and an organic layer was subjected to extraction with ethyl acetate. The solution of the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. After washing, anhydrous magnesium sulfate was added to the organic layer for drying. The resulting mixture was subjected to gravity filtration, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography. As the developing solvent, first, dichloromethane was used; then, a 10:1 dichloromethane-ethyl acetate mixed solvent was used. The resulting fraction was concentrated to give 0.14 g of an orange oily substance in a yield of 24%. Synthesis Scheme (b-1) of Step 1 is shown below.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCCOC2C=CC(C(O)=O)=CC=2)C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCc1ccccc1N
Reactant: O=C(Cl)c1ccc(OCCCCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1ccc(OCCCCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCc1ccccc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of p-(4-phenylbutoxy)benzoyl chloride prepared from 1 g of p-(phenylbutoxy)benzoic acid and 2 ml of oxalyl chloride in methylene chloride was added to a solution of 0.6 g of ethyl 6-(o-aminophenyl)hexanate obtained in Reference Example 17 in 10 ml of pyridine at temperature less than -30° C. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. Toluene was added to the residue. The mixture was washed with diluted hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The systems was concentrated under reduced pressure to obtain 1.0 g of oily ethyl 6-[o-[p-(4-phenylbutoxy)benzamido]phenyl]hexanate.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH3:22].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH3:22]
Reactant: CC1CCCN1CCOc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CCCN1CCOc1ccc(NC(=O)c2ccc(F)c(F)c2)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenylamine (95 mg, 0.25 mmole), 3,4-difluoro-benzoyl chloride (40 μL, 0.301 mmole), and triethylamine (70.2 μL, 0.501 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 60 mg, 46% yield). 1H NMR (DMSO-d6, 400 MHz) δ 1.22 (dd, J=19.71, 6.57 Hz, 3H), 1.45-1.53 (m, 1H), 1.72-1.89 (m, 2H), 2.07-2.14 (m, 1H), 2.79-2.98 (m, 1H), 3.08-3.15 (m, 1H), 3.31-3.44 (m, 2H), 3.59-3.65 (m, 1H), 3.68 (d, J=4.80 Hz, 3H), 4.21-4.46 (m, 2H), 7.29 (dd, J=9.85 Hz, 6.82 Hz, 1H), 7.60-7.67 (m, 1H), 7.66 (s, 1H), 7.70-7.72 (m, 1H), 7.84-7.88 (m, 1H), 7.94 (dt, J=9.09, 2.78, 2.53 Hz, 1H), 8.01-8.06 (m, 1H), 9.22-9.48 (m, 1H from TFA), 10.4 (s, NH). Exact mass calculated for C24H2579BrF2N4O2, 518.1, found 519.3, 521.5 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[O:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH2:12]1.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:12]2[C:13](=[O:21])[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:11]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C1COc2ccccc2N1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C=C2Oc3ccccc3NC2=O)cc1
Reaction time: 8 h

Procedure:
4-Cyanobenzaldehyde (1.98 g, 0.015 mol) was added to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0.01 mol), acetic anhydride (4 ml) and triethylamine (2 ml). The reaction mixture was refluxed for 7 h, left overnight at room temperature and poured into crushed ice. The precipitated solid was collected by filtration and washed with acetonitrile. The crude product was purified by recrystalization from DMF:ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:45])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:31][C:30]1[CH:29]=[CH:28][C:27]([NH:32][C:33](=[O:45])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH:35]=2)=[CH:26][C:25]=1[NH:24][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCCC3)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Product: Cc1ccc(NC(=O)c2cccc(N3CCCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 69 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-pyrrolidin-1-ylbenzamide to give N-[2-methyl-5-(3-pyrrolidin-1-ylbenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 69% yield; NMR Spectrum: (DMSOd6) 1.39 (s, 9H), 1.56 (m, 2H), 1.87 (m, 2H), 3.2 (m, 2H), 3.64 (m, 2H), 4.62 (m, 1H), 6.69 (d, 1H), 7.02 (s, 1H), 7.2 (m, 4H), 7.42 (t, 1H), 7.56 (m, 3H), 7.79 (s, 1H), 9.83 (s, 1H), 10.05 (s, 1H); Mass Spectrum: M+H+ 599.
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CS(C)=O>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:14][C:11]5[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=5)[CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)c2nccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3)n2)cc1
Reaction time: 5 h
Yield: 81 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol) and sodium hydroxide (38 mg, 0.96 mmol) were added in dimethylsulfoxide (1 mL), and mixed at 100° C. for 30 minutes. This solution was added with a solution of benzyl bromide (63.1 μL, 0.53 mmol) in dimethylsulfoxide (1 mL) at 100° C. for 30 minutes, followed by stirring for 5 hours. This solution was cooled and added with water (100 mL) and a saturated saline solution, and then allowed to stand for 24 hours. The precipitated crystalline material was purified by column chromatogram (silica gel, hexane: EtOAc=8:1) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[OH-:21].[K+]>C(O)(C)(C)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:19][CH:20]=1)(=[O:21])[NH2:2]
Reactant: N#Cc1ccc(OC2CCN(c3ccncc3)C2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(OC2CCN(c3ccncc3)C2)cc1
Yield: 57.8 %

Procedure:
A mixture of 4-[3-(4-cyanophenoxy)-1-pyrrolidinyl]pyridine (269 mg) and powdered potassium hydroxide (568 mg) in t-butanol (10 ml), under an atmosphere of argon, was heated under reflux for 18 hours. The mixture was filtered hot. The filtercake was washed with water and ethanol to give 4-[3-(4-carbamoylphenoxy)-1-pyrrolidinyl]pyridine (166 mg) as a colourless solid, mp 298-300° C.
Reaction SMILES: Cl.CN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O[N:36]1[C:40]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:36][CH3:40])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: On1nnc2ccccc21
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC)c3[nH]2)S1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
To an ice-cooled and stirred mixture of methylamine hydrochloride (48 mg) and triethylamine (0.10 mL) in N,N-dimethylformamide (10 mL) were added (2-{7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.16 g), 1-hydroxybenzotriazole (94 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg). After stirring at 4° C. to room temperature for 7 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow oil, which was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give a colorless oil. The oil was crystallized from ethyl acetate-hexane to give the title compound (144 mg, 88%) as colorless needles. MS 474 (MH+). mp 125-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:19]=[N:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:7]([CH:18]=1)[O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:7]([CH:18]=1)[O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc(C=NCCc2ccccc2)c(OCCCN2CCOCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCCc2ccccc2)c(OCCCN2CCOCC2)c1
Yield: 77.8 %

Procedure:
4-[3-[5-Methoxy-2-[[(2-phenylethyl)imino]methyl]phenoxy]propyl]morpholine (33 g) is reduced with 9.8 g of sodium borohydride in 150 ml of methanol following the procedure described in Example 1C, yielding 25.8 g of the title compound, boiling point 249°-254° C. at 0.3-0.4 mm of Hg.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C([NH:35][C:36](NC(OC(C)(C)C)=O)=[N:37]S(C(F)(F)F)(=O)=O)(OC(C)(C)C)=O.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)[C:36]([NH2:37])=[NH:35]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=N)N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.43 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.87 μmol), 1,3-di-boc-2-(trifluoromethylsulfonyl)guanidine (38.45 mg, 98.25 μmol) and triethylamine (22.82 μL, 163.7 μmol) in DCM was stirred at room temperature for 5 hours. Then to the mixture was added TFA (6.308 μL, 81.87 μmol) and the mixture was stirred overnight. The crude product was purified by column chromatography to afford the title compound as brown oil in 49.43% yield. LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 3.5 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9 (s, 3H) 4.1 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.1 (d, J=5.6 Hz, 1H) 7.2 (d, J=9.1 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.5 (d, J=2.0 Hz, 1H) 7.6 (d, J=3.0 Hz, 1H) 7.8 (dd, J=8.8, 2.8 Hz, 1H).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].Cl[S:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([OH:16])=[O:15])(=[O:10])=[O:9].[OH-].[Na+]>O>[F:20][C:19]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[S:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(F)c(S(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium sulphite (130 g, 1.034 mol) was added slowly to a solution of 3-chlorosulfonyl-4-fluoro-benzoic acid (49.39 g, 0.207 mol) in water (150 ml) at 0° C. with a vigorous stirring. After the addition was completed the reaction was warmed back to room temperature for 1 hour and the pH of the solution was kept around pH 6-7 with 2N sodium hydroxide solution. The white milky suspension was filtered and the solid washed with 2N sodium hydroxide solution (150 ml) and then water (100 ml). The filtrate was then cooled in an ice bath and concentrated HCl was added until no more precipitate was formed (pH<1). The white precipitate was then filtered, pressed dry and left in a dessicator overnight under vacuum and over activated silica (27.92 g, 66%). m/z (LC-MS, ESP), RT=0.98 min, (M−−1)=203
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[NH:5][C:6]=1[Br:7].CC(C)([O-])C.[K+].[CH3:26][S:27][CH2:28]Cl>O1CCCC1.O.CCOCC>[Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=2)[N:5]([CH2:26][S:27][CH3:28])[C:6]=1[Br:7]
Reactant: N#Cc1c(-c2ccc(C(F)(F)F)cc2)[nH]c(Br)c1Br
Reactant: CSCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CSCn1c(Br)c(Br)c(C#N)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 4,5-dibromo-2-(α,α,α-trifluoro-p-tolyl)pyrrole-3-carbonitrile (0.56 g, 1.42 mmol) in dry tetrahydrofuran, under nitrogen, is treated portion-wise with potassium t-butoxide (0.21 g, 1.81 mmol), stirred at 25° C. for 3/4 hour, treated dropwise with chloromethyl methyl thioether (0.18 g, 1.81 mmol), stirred at room temperature for 16 hours, heated at 49°-60° C. until reaction is complete by thin layer chromatography. The reaction mixture is diluted with water and ether. The phases are separated and the organic layer is dried over MgSO4 and concentrated in vacuo to give a black oil residue. The residue is flash chromatographed (silica/ 100:100:1 ether:petroleum ether:ethyl acetate) to give the title product as a red solid, mp 140°-145° C., identified by H1NMR and mass spectral analyses.