Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]=1[N+:33]([O-:35])=[O:34].Cl.[CH3:37][O:38][CH2:39][CH:40]([NH2:42])[CH3:41]>>[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH:40]([CH3:41])[CH2:39][O:38][CH3:37])[C:20]=1[N+:33]([O-:35])=[O:34]
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Reactant: COCC(C)N
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-]
Yield: 48.9 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.1 g, 2.49 mmol) and 2-methoxy-1-methyl-ethylamine HCl (208 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 318 mg of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[N:20][N:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:24]=4)[CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:40][CH2:41][CH2:42][OH:43])=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[N:20][N:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[O:30])=[CH:27][CH:28]=4)[CH:22]=3)=[N:9]2)=[CH:37][CH:38]=1
Reactant: OCCCBr
Reactant: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(O)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(OCCCO)ccc32)cc1
Yield: 63 %

Procedure:
A solution of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-ol (60 mg; 0.12 mmol; 1.0 eq.), 3-bromo-1-propanol (24 mg; 0.18 mmol; 1.5 eq.) and cesium carbonate (77 mg; 0.24 mmol; 2.0 eq.) in DMF (1.2 mL) was stirred at RT O/N. The reaction mixture was then diluted with DCM and washed with brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude by preparative HPLC gave the title compound as a white powder (43 mg, 64%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[CH:17]([Mg]Br)=[CH2:18].CCOCC>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]([OH:13])[CH:17]=[CH2:18])[CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1cccc(COC2CCCCO2)c1
Reactant: C=C[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CC(O)c1cccc(COC2CCCCO2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To the aldehyde of Step 10 (85 g, 386 mmol) in toluene (1 L) at 0° C. was slowly added vinyl magnesium bromide in Et2O (450 mL, 1M, 450 mmol) over a 30 minute period. After stirring for 1 hr at 0° C., the reaction mixture was quenched with 25% aq. NH4OAc and extracted with EtOAc (3×). Evaporation and purification by flash chromatography (15%→25% EtOAc in toluene) yielded 82 g (86%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[N:20]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH:30]([C:34](O)=[O:35])[CH2:29][CH2:28]3)[CH:24]=[N:23][N:22]=[N:21]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClC(Cl)C>[O:1]=[C:2]1[CH2:7][N:6]([C:34]([CH:30]2[C:31]3[C:27](=[CH:26][C:25]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[CH:33][CH:32]=3)[CH2:28][CH2:29]2)=[O:35])[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: O=C(O)C1CCc2cc(-n3cnnn3)ccc21
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C(=O)C3CCc4cc(-n5cnnn5)ccc43)CC1=O)C2

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40 mg, 0.16 mmol) (20 mg, 0.078 mmol), 5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid (18 mg, 0.078 mmol), DMAP (14 mg, 0.12 mmol), and EDC (23 mg, 0.12 mmol) was stirred in dichloroethane (2 mL) for 2 hours. The solvent was removed under vacuum, and the residue was redissolved in methanol, and purified by reverse phase HPLC to give the title product. LC-MS (IE, m/z): 468 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: NCCCCn1cnc2c(N)nc3c(c21)CCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A catalytic amount of platinum (IV) oxide was added to a solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.75 g, 10.8 mmol) in trifluoroacetic acid (150 mL). The reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.44×105 Pa). After 1 week analysis by mass spectroscopy indicated the presence of both starting material and the tetrahydro product. Fresh catalyst was added to the reaction mixture and hydrogenation was continued at 50 psi (3.44×105 Pa). After 2 weeks the reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was dissolved in 1N hydrochloric acid (120 mL) and the solution was stirred at ambient temperature for 1 hour. The solution was made basic (pH 10) by the addition of 50% sodium hydroxide and then extracted with dichloromethane (5×100 mL). The extracts were combined and concentrated under vacuum to provide 2.08 g of 1-(4-aminobutyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:7][N:6]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccc(Br)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccc(N2CCOCC2)cn1
Temperature: 150 °C
Yield: 22.8 %

Procedure:
5-Bromo-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (35 mg, 0.08 mmol) and morpholine (1 ml, 11.5 mmol) were placed in a microwave vial. Pd2dba3 (4 mg, 0.004 mmol), BINAP (5 mg, 0.008 mmol) and cesium carbonate (40 mg, 0.12 mmol) were added and the mixture was heated at 150° C. for 75 mins under microwave irradiation. The reaction mixture was concentrated in vacuo to give a crude residue that was suspended in 1:1 DMSO/MeOH (1 ml) and filtered to give an orange solution that was purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (8 mg) as a pale orange solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[CH:22]2.O>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)[C:24]([CH3:30])([CH3:29])[CH:23]=[CH:22]2
Reactant: O=C(Cl)c1cccnc1
Reactant: CC1(C)C=Cc2cc(Cl)ccc2N1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)C=Cc2cc(Cl)ccc2N1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
5.34 g of nicotinic acid chloride hydrochloride was suspended in 50 ml of methylene chloride and 7.56 g of triethylamine was added thereto. After the resulting suspension was stirred at room temperature for 30 minutes, 3.88 g of 6-chloro-2,2-dimethyl-1,2-dihydroquinoline dissolved in 20 ml of methylene chloride was added thereto. Further, 1.00 g of 4-dimethylaminopyridine was added thereto. After refluxing the resulting solution mixture for 7 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was subjected to thin-layer chromatography (silica gel; ethyl acetate/hexane 1:1 (V/V)) to obtain 1.01 g of 6-chloro-2,2-dimethyl-1-nicotinoyl-1,2-dihydroquinoline (the present compound (1)).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]I.C([O:14][C:15](=[O:36])[C:16]([S:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][CH2:26][NH:27][C:28]2[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=2)[N:24]=1)([CH3:18])[CH3:17])(C)(C)C.CC(C)CCCCCO.[BrH:46].C(O)(=O)C>C(OCC)C>[BrH:46].[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:27]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:9])[CH3:1])[CH2:26][CH2:25][C:23]2[N:24]=[C:20]([S:19][C:16]([CH3:17])([CH3:18])[C:15]([OH:36])=[O:14])[S:21][CH:22]=2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CC(C)CCCCCI
Agent: Br
Agent: CC(C)CCCCCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1cnc(N(CCCCCC(C)C)CCc2csc(SC(C)(C)C(=O)O)n2)nc1

Procedure:
A compound obtained using 6-methyl-1-iodoheptane, which is synthesized using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 6-methylheptanol as starting materials and in reference to non-patent reference [Tetrahedron, 38, 11461 (1998)], and by an operation similar to that of Example 326, was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9](=[O:21])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)[S:5][C:6]=1[CH2:7][CH3:8].[CH2:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)[CH3:23]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:7]([C:6]1[S:5][C:4]([C:9](=[O:21])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:22][CH3:23])[CH3:8]
Reactant: CCc1ccccc1B(O)O
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCc1ccccc1-c1cc(C(=O)CCc2cc(C)c(O)c(C)c2)sc1CC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(4-Bronno-5-ethyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (45 mg, 123 μmol) and 2-ethylphenylboronic acid (22 mg, 148 μmol) are dissolved in degassed dioxane (0.8 mL) and degassed 2 M aq. Na2CO3 solution. To this solution PdCl2(dppf) (5 mg, 7 μmol) is added under a stream of argon. The mixture is stirred at 80° C. for 8 h. The mixture is cooled to rt and an aliquot is purified by prep. HPLC to give 1-[5-ethyl-4-(2-ethyl-phenyl)-thiophen-2-yl]-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one as a colourless resin; LC-MS: tR=1.10 min, [M+1]+=383.25.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1)CCC.[F-].[K+]>C1(C)C(C)=CC=CC=1>[S:22]1[CH:23]=[CH:24][C:20]([C:2]2[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=2)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21]1
Reactant: CCOC(=O)COc1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)COc1cccc(-c2ccsc2)c1
Yield: 64.6 %

Procedure:
2.6 g of the resulting ether compound, 5.3 g of tri-n-butyl(3-thienyl)tin and 20 mg of tetrakis(triphenhylphosphine)paladium were dissolved in 10 ml of xylene, and the mixture was refluxed for 5.5 hours. A 25% aqueous solution of potassium fluoride was added to the solution, and then the precipitate was removed by filtration. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=20/1→15/1] to give 1.7 g of ethyl 3-(3-thienyl)phenoxyacetate as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([O:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[OH:51].CCN(C(C)C)C(C)C>C(O)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([O:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[OH:51])=[O:16]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 23.5 mg (0.072 mmol) 5-(2,4-dichloro-phenyl)-6-propoxy-nicotinic acid, 29 mg (0.09 mmol) TBTU, 10 mg (0.086 mmol) (1R,2R)-2-amino-cyclohexanol and 47.8 mg (0.37 mmol) DIPEA in 1 DMF was shaken at room temperature over night. Acetic acid was added and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 24.9 mg (85%) of the title compound. MS (m/e): 423.2 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Cl>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: ClCc1ccccn1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccn3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and pyridin-2-yl-methyl chloride. The crude product is purified by column chromatography eluting with 2% MeOH/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C(Cl)Cl>C1COCC1.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:9]([NH2:13])[CH:10]([CH3:12])[CH3:11])=[O:5]
Reactant: CC(C)C#N
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CSC(=C(N)C(C)C)S(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
1.78 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of THF, and to which 375 mg of sodium hydride was added under cooling with ice, followed by 30 minutes' stirring at room temperature. Thereafter 1.6 ml of isobutyronitrile was added and stirred for 16 hours at room temperature, and for 6 hours at 50°C., followed by further addition of 70 ml of methylene chloride and 2 ml of water, and subsequent an hour's stirring at room temperature. The reaction mixture was dried with Glauber's salt, and concentrated under reduced pressure to leave a yellow solid. Washing the solid with a carbon tetrachloride-n-hexane system, 1.525 g of 1-methylsulfinyl-1-methylthio-2-amino-3-methyl-1-butene was obtained as a light yellow solid. The washing was concentrated under reduced pressure, and subjected to a column chromatography (silica gel, methylene chloride, ethyl acetate, and methanol) to allow the recovery of 117 mg of methyl methylthiomethyl sulfoxide and 480 mg of 1-methylsulfinyl-1-methylthio-2-amino- 3-methyl-1-butene. The isolation yield was 72.3%, and the conversion yield was 77.5%.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC(C)C)cn3)ccc2n1CC1CCOCC1
Yield: 74.2 %

Procedure:
Following the same procedure in Example 24, Step A, using isopropylamine (21 mg, 31 uL, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 67 mg (74%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.79 (t, J=7.42 Hz, 3 H), 1.20 (d, J=6.64 Hz, 6 H), 1.42-1.58 (m, 4 H), 1.61 (s, 6 H), 1.97 (q, J=7.42 Hz, 2 H), 2.22-2.41 (m, 1 H), 3.26-3.37 (m, 2 H), 3.87-3.96 (m, 2 H), 4.06-4.19 (m, 1 H), 4.43 (d, J=7.62 Hz, 2 H), 7.95 (d, J=8.8 Hz, 1 H), 7.98-8.03 (dd, J=9.0, 2.0 Hz, 1 H), 8.07 (s, 1 H), 8.36 (d, J=1.76 Hz, 1 H), 8.79 (s, 1 H); MS (ESI) (M+H)+=502.0; Anal. Calcd for C25H35N5O4S+110 TFA+0.6H2O (626.48): C, 51.76; H, 5.99; N, 11.18. Found: C, 51.77; H, 5.96; N, 11.27.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH3:11].C(N(CC)CC)C>C1COCC1.O>[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:2][CH2:3][N:4]([CH2:8][CH2:7][OH:6])[C:5]1=[O:9])[CH3:11]
Reactant: O=C1OCCN1CCCl
Reactant: CCOCCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOCCCN1CCN(CCO)C1=O
Yield: 54.6 %

Procedure:
A mixture of 6.5 g of 3-(2-chloroethyl)oxazolidin-2-one, 4.57 g of 3-ethoxypropylamine and 10 g of triethylamine was refluxed for 10 hours, diluted with THF and water. The organic layer was worked up to give 5.13 g of 1-(3-ethoxypropyl)-3-(2-hydroxyethyl)imidazolidin-2-one, b.p. 110° C./0.5 mm. This material was methylated with 4.26 g of iodomethane and 1.13 g of NaH (60% in oil) in 60 ml of THF as mentioned under Example 22. This gave 3.9 g (71.4%) of oil, b.p. 100°-105° C./0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:4][CH:3]=1.O.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(Cl)cc3)C3CCCC3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1cccc(CC2(C(=O)O)CC2)c1)C(c1ccc(Cl)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.60 g (14.1 mmol) of (+/−)-tert-butyl 1-(3-{[(4-chlorophenyl)(cyclopentyl)acetyl]amino}-benzyl)cyclopropanecarboxylate were dissolved in 41.8 ml of dichloromethane and, after addition of a drop of water, 10.9 ml of TFA were added at RT. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was initially dried under high vacuum and then triturated with diisopropyl ether. The resulting solid was filtered off with suction and dried under high vacuum. This gave 4.52 g (77.8% of theory) of the target compound.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[F:11][CH:12]([C:17](OC)=[O:18])[C:13](OC)=[O:14].C[O-].[Na+]>CO>[F:11][C:12]1[C:13](=[O:14])[N:10]=[C:8]([S:7][CH3:6])[NH:9][C:17]=1[OH:18]
Reactant: COC(=O)C(F)C(=O)OC
Reactant: CSC(=N)N
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CSc1nc(=O)c(F)c(O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.1 %

Procedure:
To a stirred solution of 2-methyl-2-thiopseudourea sulfate (41.7 g, 0.15 mol) and dimethyl fluoromalonate (45 g, 0.30 mol) in MeOH (600 mL) at 0° C. (ice bath) was added NaOMe (48.6 g, 0.90 mol) in portions. After the addition was complete, the ice bath was withdrawn and the reaction mixture was stirred at room temperature overnight. LCMS showed the formation of the desired pyrimidinone product. The reaction mixture was concentrated to near dryness under vacuum, diluted with water (50 mL), and acidified with 6N HCl (˜150 mL) to ˜pH 2 to precipitate the product. After filtration, the solid was washed with 1N HCl (2×10 mL) and dried under vacuum to afford 5-fluoro-6-hydroxy-2-methylthio-4(1H)-pyrimidinone (35.7 g, 68%) as a white solid. LCMS: (M+H)+: 177.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:35]=[CH2:36]>>[CH2:34]([N:37]1[CH2:42][CH2:41][N:40]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:39][CH2:38]1)[CH:35]=[CH2:36]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: C=CCN1CCNCC1
Product: C=CCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 3 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 5 equivalents of 1-allylpiperazine as secondary amine. The product was purified by preparative HPLC.