Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH:9][C:3]2([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: C#CC1(N)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC1(NS(=O)(=O)c2cccc(Cl)c2)CCCCC1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 1-ethynylcyclohexanamine (40 mg, 0.32 mmol) in CH2Cl2, was added triethylamine (68 mL, 0.48 mmol), followed by 3-chlorobenzenesulfonyl chloride (68.2 mg, 0.32 mmol). After 30 min, the mixture was partitioned between ethyl acetate and 3N aq. HCl. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated in vacuuo to give the title compound as a white solid (90 mg, 93% yield).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][N:17]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[O:27])=[CH:13][CH:12]=1>>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[O:27])=[CH:13][CH:12]=2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: Nc1ccc2ccn(CCCCCCC(=O)NS(=O)(=O)c3ccccc3)c2c1
Product: O=C(CCCCCCn1ccc2ccc(NC(=O)OC3CCCC3)cc21)NS(=O)(=O)c1ccccc1
Yield: 51 %

Procedure:
Using similar procedure to that described in Example 157, but using cyclopentyl chloroformate and N-(7-[6-aminoindol-1-yl]heptanoyl)benzenesulphonamide, N-(7-[6-(cyclopentyloxycarbonyl)aminoindol-1-yl]heptanoyl)benzenesulphonamide was obtained in 51% yield as a solid, m.p. 74°-76° C.; microanalysis, found, C,62.74; H,6.54; N,7.84%; C27H33N3O5S, 1/4H2O requires: C, 62.83; H,6.54; N,8.14%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]2=[O:14])=[CH:4][CH:3]=1.COC1C=CC=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27]NCC1.N1CCCC1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:23]3[CH2:18][CH2:19][CH2:27][CH2:28]3)[C:9]2=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=C1CCN(c2ccc(Br)cc2)C1=O
Solvent: C1CCNC1
Solvent: O
Product: O=C1C(CN2CCCC2)CCN1c1ccc(Br)cc1
Yield: 106.6 %

Procedure:
There were mixed 1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone, 2.00 g of 4-(2-methoxyphenyl)piperazine and 5 ml of pyrrolidine. The mixture was refluxed for 1 hour and then cooled. Thereto was added water. The mixture was subjected to extraction with ethyl acetate twice. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform/methanol=40/1 to obtain 1.79 g of 1-(4-bromophenyl)-3-pyrrolidinomethyl-2-pyrrolidinone.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(4-tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the combined filtrate and washings are evaporated. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product a white, crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[CH2:11][N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=3)[CH2:11][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:31][CH:32]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)Cc1ccccn1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)Cc1ccccn1

Procedure:
Intermediate 11 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 490. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (d, 1H) 8.3 (d, 1H) 7.9 (s, 2H) 7.6 (m, 1H) 7.4 (m, 2H) 7.3 (m, 2H) 7.2 (m, 1H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.5 (m, 1H) 4.5 (d, 4H) 3.7 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[F:20][C:21](I)([F:23])[F:22].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:20][C:21]([F:23])([F:22])[C:11]1[N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: Nc1ncnc2c1nc(C(F)(F)F)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 6.7 %

Procedure:
0.27 g (1.0 mmol) of adenosine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 4.0 ml of dimethyl sulfoxide, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethyladenosine (19F-NMR yield: 6.7%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethyladenosine was obtained as a white solid (0.01 g, yield: 3.1%) by column chromatography.
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[C:8]([F:13])=[CH:7][CH:6]=1.[S:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1>>[F:13][C:8]1[C:9]([CH:11]=[O:12])=[N:10][C:5]([C:16]2[CH:17]=[CH:18][S:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1nc(Br)ccc1F
Reactant: OB(O)c1ccsc1
Agent: OBO
Product: O=Cc1nc(-c2ccsc2)ccc1F

Procedure:
3-fluoro-6-(thiophen-3-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromo-3-fluoropicolinaldehyde and thiophen-3-ylboronic acid (80.5 mg, 101.5 mg theoretical, 79.3%). LC-MS m/z 208.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Cl)cc1-n1cncn1
Temperature: 80 °C

Procedure:
In a microwave reaction vessel are combined 4-chloro-2-fluoro-benzaldehyde (200 mg. 1.26 mmol), 1H-1,2,4-triazole (113 mg, 1.64 mmol) and potassium carbonate (350 mg, 2.52 mmol) in DMSO (5 mL) and warmed to 80° C. for 5 minutes in a microwave. The reaction mixture is cooled to room temperature and poured into water and extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-3% MeOH/CH2Cl2) affords 4-chloro-2-1,2,4-triazol-1-yl-benzaldehyde which is used without further purification.
Reaction SMILES: [CH2:1]([C:8]1([OH:32])[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:31])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][Si](C(C)(C)C)(C)C)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:51]>C1COCC1.CO>[ClH:51].[CH2:1]([C:8]1([OH:32])[CH2:9][CH2:10][N:11]([CH2:14][C:15](=[O:31])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)cc1)CN1CCC(O)(Cc2ccccc2)CC1
Yield: 36 %

Procedure:
1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propan-2-one (0.400 g, 0.88 mmol) was dissolved in THF (4 ml) and stirred for 16 hours at room temperature in the presence of 1N tetra-n-butylammonium fluoride (1 ml, 1 mmol). The reaction mixture was quenched with 20% NH4Cl (15 ml) and the aqueous phase was extracted with ethyl acetate (3×20 ml). Combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (ethyl acetate) to give a yellow oil which was dissolved in MeOH (2 ml) and treated with 1N HCl (0.5 ml). The solution was concentrated, the residue was dissolved in isopropanol (i-PrOH) and ether was added to provide 1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-3-(4-hydroxy-phenyl)-propan-2-one hydrochloride (0.120 g, 36%) as white solid, m.p. 180°-181° C. and MS: m/e=340.3 (M+H+).
Reaction SMILES: [OH:1][CH:2](C)[CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:27]I>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:27])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1)(=[O:8])=[O:9]
Reactant: CI
Reactant: CC(O)CCCNS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: CN(CCCCO)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Using a method analogous to that described in Example 4, 4′-trifluoromethylbiphenyl-4-sulfonic acid-(4-hydroxypentyl)-amide and methyl iodide were reacted to give the title compound as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:24]=3)[CH:15]=[CH:14][N:10]2[C:11](=[O:13])[CH:12]=1)(=O)=O.B1([C:36]2[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=2)OCCCO1.[Br-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[CH:25]([C:23]1[N:24]=[C:20]([CH2:19][CH2:18][C:16]2[CH:15]=[CH:14][N:10]3[C:11](=[O:13])[CH:12]=[C:7]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[N:8]=[C:9]3[CH:17]=2)[S:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(OS(=O)(=O)C(F)(F)F)nc3c2)n1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)c1csc(CCc2ccn3c(=O)cc(-c4cccnc4)nc3c2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
2-Trifluoromethanesulfonyloxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one(499 mg), pyridine-3-boronic acid 1,3-propanediol cyclic ester (364 mg), palladium tetrakistriphenylphosphine (65 mg), potassium bromide (146 mg) and potassium carbonate (231 mg) were added with dioxane(8 ml) and stirred overnight at 85° C. under nitrogen atmosphere. The reaction mixture was cooled and then added with ethyl acetate. Insoluble solids were removed by filtration, and the solvent of the filtrate was evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (400 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[CH3:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[CH3:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(F)c(-c4ccc(Cl)cc4C)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccc(Cl)cc4C)c3O2)cc1
Yield: 99.5 %

Procedure:
Treatment of ((2R)-8-(4-chloro-2-methylphenyl)-7-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.09 mmol) with platinum (IV) oxide (84% Pt, 0.21 g) in ethanol (25 mL) and ethyl acetate (5 mL) according to the procedure described for Example 69, Step 8 provided 0.5 g (100%) of ((2R)-8-(4-chloro-2-methylphenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH2:17][CH2:16]2)[N:3]=1.I[CH2:31][CH:32]1[CH2:35][CH2:34][CH2:33]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[CH2:17][CH2:16]2)[N:3]=1
Reactant: ICC1CCC1
Reactant: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1O
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1OCC1CCC1

Procedure:
The title compound was prepared from 4-amino-6-hydroxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline and iodomethyl cyclobutane [Bailey et al J Org Chem, 60, 297-300 (1995)] following a similar procedure to that described in Example 2(b), and was obtained as a solid (14%). Rf 0.40 (0.880 aqueous ammonia:methanol:dichloromethane 1:7:92, v/v). MS m/z 471 (MH)+. Found: C, 59.35; H, 7.12; N, 17.44; C24H34N6O4 0.15CH2Cl2 0.15 H2O, requires C, 59.68; H, 7.18; N, 17.28%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19](OC)=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:23]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:23])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Reactant: N
Product: NC(=O)c1cccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12

Procedure:
Following standard procedure C, methyl 2-(4'-nitrophenyl)-1-H-benzimidazole-4-carboxylate was dissolved in liquid ammonia and heated under constant volume in a pressure vessel. The product was purified by column chromatography from dichloromethane/methanol 99:1 and recrystallised from methanol.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1
Reactant: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Product: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccc(F)cc3F)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 24 %

Procedure:
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 68, was N-debenzylated according to the method of Example 11. The intermediate was N-alkylated according to the method of Example 20, substituting 2,4-difluorobenzylbromide in place of 4-fluorobenzyl bromide to provide the title compound (yield: 65 mg, 24%). mp 236-238° C. 1H NMR (300 MHz, CDCl3) δ 4.78 (s, 2H), 5.43 (s, 2H), 6.88 (m, 2H), 6.97 (t, J=9 Hz, 2H), 7.18 (d, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.55 (m, 1H), 7.85 (s, 1H), 7.86 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 472 (M+H)+. Anal. calc. for C23H16F3N3O3S: C, 58.59; H, 3.42; N, 8.91. Found: C, 58.44; H, 3.47; N, 8.72.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][CH2:47][CH2:48][OH:49]>CN(C=O)C.CC(OC)(C)C>[CH2:35]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH2:46][CH2:47][CH2:48][OH:49])[CH:12]=1)=[O:7])[CH2:36][CH2:37][CH3:38]
Reactant: OCCCBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCCCN(CCCC)C(=O)c1cn(CCCO)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 40 °C
Yield: 30.7 %

Procedure:
To a stirred solution of methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (200 mg, 0.38 mmol) in DMF (8 mL) was added K2CO3 (107 mg, 0.77 mmol) and 3-bromopropanol (54 mg, 0.38 mmol). The reaction mixture was heated at 40° C. for 4 h, cooled to room temperature, diluted with MTBE, and quenched with water. The organic layer was separated and the aqueous layer was extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to provide crude product. The crude material was purified by flash chromatography (gradient from 10 to 50% EtOAc/hexanes) to provide the title compound (67 mg, 32%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.19-8.15 (m, 1H), 8.04 (dd, J=11.2, 1.6 Hz, 1H), 7.62 (s, 0.5H), 7.55 (s, 0.5H), 7.50-7.46 (m, 1H), 7.25-7.14 (m, 3.5H), 6.94 (d, J=7.2 Hz, 0.5H), 4.84-4.59 (m, 2H), 4.29-4.13 (m, 2H), 3.96 (s, 3H), 3.82-3.70 (m, 2H), 3.50-3.35 (m, 4H), 3.31-2.88 (m, 4H), 1.89-1.87 (m, 2H), 1.55-1.49 (m, 2H), 1.40-1.05 (m, 6H), 0.93-0.88 (m, 3H), 0.74 (t, J=7.2 Hz, 1.5H), 0.65 (t, J=7.2 Hz, 1.5H); MS(ESI+) m/z 575.6 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:7][CH2:8][NH2:9])[CH2:2][CH2:3][C:4]([OH:6])=O.[C:10]([O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:13])[NH:11][NH2:12]>>[C:10]([NH:11][NH:12][C:4](=[O:6])[CH2:3][CH2:2][CH2:1][CH2:7][CH2:8][NH2:9])([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13]
Reactant: NCCCCCC(=O)O
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Product: NCCCCCC(=O)NNC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Using anhydrous conditions and under a nitrogen gas blanket, a 200 ml round bottom flask was charged with 4.90 g (10.48 mmol) of N-BOC-6-aminocaproate (N-(FMOC) hydrazide), and 10 ml of methylene chloride. The reaction mixture was then stirred at room temperature as 16 ml of trifluoroacetic acid (Schweizerhall) dissolved in 16 ml of methylene chloride was slowly added. The resultant homogeneous solution was allowed to stir for an additional 2 h and then 15 ml of toluene was added. The solvents and any remaining trifluoroacetic acid were then distilled off under reduced pressure. The distillation residue was twice more azeotroped with 15 ml portions of toluene to leave 8.49 g of orange oil. 1H NMR showed this crude material to contain the peaks associated with aminocaproic acid and a FMOC substituent. However, no tert-butyl peak was observed between 1-2 ppm showing removal of the BOC protecting group. This product was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:17][CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[OH-:27].[Na+]>C(O)C>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1)=[O:27]
Reactant: [OH-]
Reactant: CCOC(=O)CC1CCC(CCNS(=O)(=O)c2ccc(C#N)cc2)CC1
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(S(=O)(=O)NCCC2CCC(CC(=O)O)CC2)cc1
Yield: 72 %

Procedure:
by saponification of the ethyl 4-[2-(4-cyanobenzenesulphonylamino)-ethyl]-cyclohexylacetate with 2N sodium hydroxide solution in ethanol analogously to Example 2c). Yield 72% of theory; m.p. 172°-174° C. after recrystallisation from isopropanol.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([NH2:12])[NH:10][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:13][CH:14]([CH:17]=O)[CH:15]=O>>[Br:13][C:14]1[CH:15]=[N:12][C:9]2[N:10]([N:11]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:17]=1
Reactant: Nc1nc(N2CCOCC2)n[nH]1
Reactant: O=CC(Br)C=O
Product: Brc1cnc2nc(N3CCOCC3)nn2c1

Procedure:
The title compound, a light yellow solid, MS: m/e=284.2/286.1 (M+H+), can be prepared in accordance with the general method of example 42, step 1 from 5-morpholin-4-yl-2H-[1,2,4]triazol-3-ylamine (CAS 51420-46-3) and 2-bromomalonaldehyde.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.ClCCl>ClCCl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To an ice cooled solution of tert-butyl 3-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (D34) (1.86 g, 5.613 mmol) in dichloromethane (2 ml), a mixture of trifluoroacetic acid/dichloromethane (4.5 ml/1.5 ml) was added and the mixture stirred at room temperature for 3 h. Solvents were evaporated in vacuo and the resulting residue was purified by SPE-SCX cartridge (10 g). Collected ammonia fractions, after solvent evaporation afforded the title compound (D57) (844 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)c2)cc1Cl
Yield: 39.4 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added 4-trifluoromethyl-benzenesulfonyl chloride (23.4 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-trifluoromethyl-benzenesulfonamide (15 mg, >95% purity, yield: 40%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 3): ESI-MS m/z: 438 [M+H]+, retention time=2.57 min, 1H NMR (500 MHz, DMSO-d6) δ ppm 7.80 (dd, J=8.24, 1.53 Hz, 1H) 7.82 (d, J=1.98 Hz, 1H) 7.93-7.98 (m, 2H) 7.98-8.03 (m, 2H) 8.04 (s, 1H) 8.09 (d, J=8.09 Hz, 1H) 8.31 (s, 1H) 8.68 (br. s., 1H) 11.00 (br. s., 1H).