Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[Cl-:20].[CH3:21][N+:22](=[CH2:24])[CH3:23]>C(#N)C>[ClH:20].[CH3:19][O:18][C:14]1[CH:13]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:15]=1[O:16][CH3:17])[CH:6]=[C:7]1[CH2:11][CH2:10][CH:9]([CH2:21][N:22]([CH3:24])[CH3:23])[C:8]1=[O:12]
Reactant: [Cl-]
Reactant: COc1cc(C=C2CCCC2=O)cc(OC)c1OC
Reactant: C=[N+](C)C
Solvent: CC#N
Product: COc1cc(C=C2CCC(CN(C)C)C2=O)cc(OC)c1OC
Product: Cl
Yield: 63.9 %

Procedure:
0.03 mol of 2-(3,4,5-trimethoxybenzylidene)cyclopentanone was dissolved in 30 mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product which was then suction filtered, dried and recrystallized in acetonitrile/chloroform to yield 2-(3,4,5-trimethoxy-benzylidene)-5-dimethylaminomethyl-cyclopentanone hydrochloride with a yield of 63.9%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]1[O:16][CH2:15]1.[C:17](O)(=[O:19])[CH3:18]>>[OH:19][CH2:17][CH2:18][N:1]([CH2:15][CH2:14][OH:16])[C:2]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)O
Reactant: C1CO1
Reactant: COC(=O)c1cc(C)cc(C)c1N
Product: COC(=O)c1cc(C)cc(C)c1N(CCO)CCO
Temperature: 25 °C
Reaction time: 19 h
Yield: 96 %

Procedure:
Methyl 2-amino-3,5-dimethylbenzoate (7.0 g, 0.039 mol) and ethylene oxide (10 g, 0.23 mol) were dissolved in 150 mL acetic acid to form a reaction mixture. The mixture was stirred at room temperature for 19 hours. and then concentrated to about 100 mL on a rotary evaporator, diluted with H2O (300 mL), and extracted with chloroform (5×200 mL). The organic extract was concentrated to give the intermediate methyl 2-bis(2'-hydroxyethyl)amino-3,5-dimethylbenzoate as an off-white oil (10.0 g, 96%). 1H NMR (300 MHz, CDCl3): 7.31 (br s, 1H), 7.16 (br s, 1H), 3.91 (s, 3H), 3.73 (m, 2H), 3.63 (m, 2H), 3.26 (br m, 4H), 2.32 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33])[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]1[CH:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:33])[CH3:24]
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: CCc1ccccc1N=C=O
Product: CCc1ccccc1NC(=O)NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 2-ethylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: COC1([S:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])C=CC=CC1OC.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](I)[C:24]=1[F:30]>>[F:30][C:24]1[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=1[S:11][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:21])[CH3:20])[CH:13]([CH3:14])[CH3:15]
Reactant: COC1C=CC=CC1(OC)S[Si](C(C)C)(C(C)C)C(C)C
Reactant: Fc1cccc(I)c1F
Product: CC(C)[Si](Sc1cccc(F)c1F)(C(C)C)C(C)C

Procedure:
Prepared as described for (1,2-dimethoxy-phenylsulfanyl)-triisopropyl-silane starting from 1,2-difluoro-3-iodobenzene.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH3:18][NH2:19]>C(O)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:19][CH3:18])#[N:2]
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 22 h

Procedure:
A solution of 12.3 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 20 ml of 33% ethanolic methylamine in 200 ml of ethanol was heated at reflux with stirring for 22 hours. The solvent was then removed by evaporation in vacuo, leaving the crude product as a glassy, amorphous solid. Crystallization from a mixture of isopropyl acetate, methylcyclohexane and 2-propanol gave 7.03 g of N"-cyano-N-methyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 169°-170° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[C:12]([C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:18]([CH2:27][CH3:28])[C:17](=[O:29])[C:16]=1[N+]([O-])=O)(=[O:14])[CH3:13].Cl>C1COCC1.C(OCC)(=O)C>[C:12]([C:15]1[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:19][N:18]([CH2:27][CH3:28])[C:17](=[O:29])[C:16]=1[NH:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11])(=[O:14])[CH3:13]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2c(Cl)cncc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To a stirred suspension of 50 mg (1.25 mmol) of sodium hydride in 5 ml of THF, 100 mg (0.62 mmol) of 4-amino-3,5-dichloropyridine in 5 ml of THF was added. The mixture was allowed stirring 30 minutes at room temperature and then cooled to 0° C. 150 mg (0.52 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 10 ml of THF was added. The reaction was allowed to warm to room temperature and to continue stirring for 12 hours. The mixture was acidified with 2N HCl to pH 2. Ethyl acetate was added and the organic layer was washed with water, brine, dried over Na2SO4 anhydride and evaporated. The residue obtained (210 mg) was purified by column chromatography (silica gel, hexane/ethyl acetate 1:1) to yield the title compound (35 mg, 16.7% yield).
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=CC=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][NH:31]2)[CH2:28]1)=[O:26].ClC1N=C(C)C=CN=1>>[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][N:31]2[C:9]2[N:8]=[C:15]([CH3:14])[CH:16]=[CH:11][N:10]=2)[CH2:28]1)=[O:26]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1ccnc(Cl)n1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 19 and 2-chloro-4-methylpyrimidine. MS (ESI) mass calcd. for C23H22N4O, 370.46; m/z found, 371.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([CH3:26])[CH:20]=[C:19]2[NH2:27])=[O:14].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][C:13]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([CH3:26])[CH:20]=[C:19]3[NH2:27])=[O:14])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1cc(N)c2cc(NC(=O)CCN)ccc2n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NCCC(=O)Nc2ccc3nc(C)cc(N)c3c2)nc(N)n1
Yield: 36.6 %

Procedure:
A solution of 0.05 g (0.35 mmol) 2-amino-4-chloro-6-methylpyrimidine, 0.204 mg (0.35 mmol) 3-amino-N-(4-amino-2-methyl-quinolin-6-yl)-propionamide and 0.18 mg (1.39 mmol) diisopropyl ethylamine in 5 ml dimethylacetamide was stirred at 100° C. for 2 h. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 45 mg of the title compound. MS 352.3 (M+H)+, 1H-NMR (DMSO-d6) δ 2.20 (s, 3H), 2.55 (s, 3H), 2.70 (m, 2H), 3.65 (m, 2H), 6.1 (s, NH), 7.70-7.90 (m, 5H), 8.60-8.80 (br.s., NH), 13.85 (br.s., NH).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1.C(N(CC)CC)C>[CH3:8][S:9]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:11])=[O:10]
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (20 g) in tetrahydrofuran (150 mL) and triethylamine (28.5 mL) is slowly added methanesulfonyl chloride (15.5 mL), while keeping the temperature below 30° C. The mixture is stirred for 12 hours at room temperature. The precipitate is filtered off and washed twice with tetrahydrofuran. The combined organic phases are concentrated and partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 29.4 g; TLC: rf=0.36 (silicagel, petrole ether/ethyl acetate 1:1); Mass spectrum (ESI+): m/z=198 [M+NH4]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O1CCCC1.C([N:22](CC)CC)C.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>ClCCl.O>[CH:27]1([C:31]([NH:1][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([NH2:22])=[O:6])=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CCC1
Reactant: CCN(CC)CC
Reactant: Nc1nc(C(F)(F)F)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(C(F)(F)F)nc1NC(=O)C1CCC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 28.2 %

Procedure:
2-Chloro-6-trifluoromethylnicotinic acid (3000 mg, 13.30 mmol) was added under argon to 24% aqueous ammonia solution (5 ml), and copper(I) chloride (1580 mg, 15.96 mmol) was added. The resulting reaction mixture was stirred at a temperature of 100° C. and at an elevated pressure of approx. 5 bar in a pressure vessel for 15 h. After cooling to room temperature and lowering the pressure to standard pressure, ethyl acetate and dilute hydrochloric acid (2N) were added to the reaction mixture. The aqueous phase was extracted repeatedly with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification (ethyl acetatein-heptane gradient) of the crude product gave 2-amino-6-trifluoromethylnicotinic acid (1640 mg, 58% of theory) as a colorless solid. 2-Amino-6-trifluoromethylnicotinic acid (500 mg, 2.43 mmol) was dissolved in abs. tetrahydrofuran (8 ml), and triethylamine (369 mg, 3.64 mmol) was added. Thereafter, the reaction solution was cooled under argon to 0° C., and cyclobutanecarbonyl chloride (316 mg, 2.69 mmol) was slowly added dropwise. The resulting reaction mixture was stirred at room temperature for a further 7 h, then dist. water and dichloromethane were added. The aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Preparative HPLC purification (acetonitrile/water/trifluoroacetic acid gradient) of the crude product gave 2-[(cyclobutylcarbonyl)amino]-6-(trifluoro-methyl)nicotinamide (197 mg, 28% of theory) as a colorless solid. 2-[(Cyclobutyl-carbonyl)amino]-6-(trifluoromethyl)nicatinamide (197 mg, 0.68 mmol) was dissolved in acetic anhydride (5 ml) and stirred under reflux conditions under argon for 5 h. After cooling to room temperature, concentrated ammonia solution was added (10 ml) and the reaction mixture was stirred at room temperature for a further 6 h. The precipitated solid was filtered off with suction and dried. Preparative HPLC purification of the crude product gave 2-cyclobutyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one (55 mg, 30% of theory) as a yellowish solid. 1H NMR (400 MHz, CDCl3 δ, ppm) 8.79 (d, 1H), 7.78 (d, 1H), 7.28 (br. s, 1H, NH), 3.62 (quint, 1H), 2.64 (m, 2H), 2.48 (m, 2H), 2.18 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17](O)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([NH:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)NCC(=O)OC(C)(C)C)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-methoxyquinoline (142 mg, 0.30 mmol) in tetrahydrofuran (THF) (5 mL) was added glycine t-butyl ester hydrochloride (44 mg, 0.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (64 mg, 0.33 mmol), 1-hydroxybenzotriazole (HOBT) (45 mg, 0.33 mmol) and diisopropylethylamine (DIEA) (0.43 g, 0.33 mmol). The reaction was stirred at ambient temperature overnight. The resultant solution was partitioned between water and ethyl acetate. The organic layer was concentrated in vacuo to afford an oil. The crude product was purified by elution through silica gel with 20:1 methylene chloride-methanol to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(((1,1-dimethylethoxycarbonyl)methyl)aminocarbonyl)propyl]aminocarbonyl-4-methoxyquinoline (62 mg, 35%); NMR (CDCl3) 1.25 (t, 3), 1.50 (s, 9), 2.00 (m, 1), 2.15–2.50 (m, 3), 3.31–3.95 (m, 9), 4.10–4.32 (m, 7), 5.40 (m, 1), 759 (t, 1), 7.63 (s, 1), 7.75 (t, 1), 8.14 (d, 1), 8.22 (d, 1), 9.41 (d, 1) ppm.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C@:30]21[CH2:45][C:44]1[C:39](=[CH:40][CH:41]=[C:42]([C:46]([OH:48])=O)[CH:43]=1)[CH2:38]2.Cl.[NH2:50][C@H:51]1[CH2:56][C@@H:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:54]([CH3:63])[N:53]([CH2:64][C:65]([F:68])([F:67])[F:66])[C:52]1=[O:69].C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:63][C@H:54]1[N:53]([CH2:64][C:65]([F:68])([F:66])[F:67])[C:52](=[O:69])[C@@H:51]([NH:50][C:46]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[CH2:38][C@:30]2([C:31]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:37][C:29]2=[O:28])[CH2:45]3)=[O:48])[CH2:56][C@H:55]1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 23 °C
Reaction time: 16 h

Procedure:
Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (679 mg, 1.53 mmol) was added to a solution of (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (described in Intermediate 1) (364 mg, 1.30 mmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 4) (380 mg, 1.18 mmol), and N,N-diisopropylethylamine (2.06 mL, 11.8 mmol) in DMF (6 mL), and the resulting mixture was stirred at 23° C. for 16 h. The reaction mixture was then diluted with water (200 mL), and the precipitate was collected by filtration, washed with water, and air dried. The crude product was purified by flash column chromatography on silica gel, eluting with hexanes initially, grading to 100% EtOAc to afford the title compound. HRMS: m/z=549.2123, calculated m/z=549.2108 for C30H28F3N4O3. 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 8.14 (dd, 1H, J=5.3, 1.5 Hz), 7.76 (s, 1H), 7.73 (d, 1H, J=7.8 Hz), 7.37-7.33 (m, 3H), 7.28 (t, 1H, J=7.6 Hz), 7.22-7.19 (m, 3H), 7.00 (d, 1H, J=7.4 Hz), 6.82 (dd, 1H, J=7.4, 5.3 Hz), 4.99-4.89 (1H, m), 4.53 (dt, 1H, J=11.6, 5.9 Hz), 3.93 (p, 1H, J=6.0 Hz), 3.69 (dd, 2H, J=16.1, 9.5 Hz), 3.64 (m, 1H), 3.34-3.24 (m, 1H), 3.11 (dd, 2H, J=16.0, 6.5 Hz), 2.81 (m, 1H), 2.56 (q, 1H, J=12.5 Hz), 1.06 (d, 3H, J=6.5 Hz).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]([N:26]([C:35]4[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=4)[C:27](=[O:34])C4C=CC=CC=4)[CH3:25])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[CH:45]([N:48]=C=O)([CH3:47])[CH3:46].C(Cl)Cl>CCOC(C)=O>[CH:45]([NH:48][C:27](=[O:34])[N:26]([CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:3])=[O:4])([CH3:7])[CH3:6])[CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:19]=1)[CH3:25])[C:35]1[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][CH:40]=1)([CH3:47])[CH3:46]
Reactant: CC(C)N=C=O
Reactant: CC(c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)N(C(=O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)N(c1ccc(S(C)(=O)=O)cc1)C(C)c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 41 but using (1-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-ethyl)-(4-methylsulfanyl-phenyl)-amine (EXAMPLE 44, step 1) and iso-propyl isocyanate as the starting materials. Flash chromatography (CH2Cl2:EtOAc; 4:1) afforded the title compound as a foam.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>ClCCl>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:20]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1)c1ccccc1Cl
Reaction time: 1 h

Procedure:
A suspension of p-aminophenol linked to the Wang's resin from Step A (1 eq) in dichloromethane was treated with triethylamine (2 ml/mmol) and 2-chloro-benzoyl chloride (10 eq). The mixture reaction was stirred for 1 hour and then the resin was filtered, washed with MeOH/CH2Cl2 several times and dried. The resin was then treated with TEA 95% H2O 5% and stirred at room temperature for 30 minutes. Filtered and washed with dichloromethane/methanol and concentrated to dryness to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH3:16][S:17]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:5]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OCCN1c1cccc(CCO)c1
Product: CS(=O)(=O)OCCc1cccc(N2CCOC2=O)c1
Yield: 93 %

Procedure:
The title compound was prepared in 93% yield according to the general procedure for the preparation of amides (Method B) starting from starting from 3-[3-(2-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one and methanesulfonyl chloride. The crude material was purified on SPE cartridge (Silica) using as eluent a gradient from cyclohexane (100%) to cyclohexane-ethyl acetate (8:2) affording the final compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C1([C:17]2[C:18]([I:28]=O)=[C:19]([S:24]([O-:27])(=[O:26])=[O:25])[C:20]([CH3:23])=[CH:21][CH:22]=2)C=CC=CC=1.O1CCOCC1>C(O)(=O)C>[C:20]1([CH3:23])[C:19]([S:24]([O-:27])(=[O:26])=[O:25])=[CH:18][CH:17]=[CH:22][CH:21]=1.[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I+:28][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(-c2ccccc2)c(I=O)c1S(=O)(=O)[O-]
Reactant: C=CCOc1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C=CCOc1ccccc1[I+]c1ccccc1
Product: Cc1ccccc1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 40 g of allyloxybenzene in 50 ml of acetic acid are added dropwise 78.4 g of phenyliodosotoluene sulfonate in 100 ml of acetic acid and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 1l of dioxane, the precipitate of (allyloxyphenyl)-phenyliodonium toluenesulfonate obtained is washed with ether and dried. Conversion into bis-fluorosulfonylimide is carried out by mixing 15 g of (allyloxyphenyl)-phenyliodonium toluenesulfonate and 7 g of KN(SO2F)2 in 150 ml of water at 0° C. The salt is extracted with 2×50 ml of dichloromethane and the solvent is evaporated. The residual salt (consisting of (allyloxyphenyl)-phenyliodonium bis-fluorosulfonylimide) is diluted with 60 ml of THF and is introduced into a three-neck flask provided with a cooler, a mechanical stirrer and a neutral gas inlet (Argon), said flask containing 8.5 g of a copolymer of dimethylsiloxane and (hydrogeno)(methyl)-siloxane (HMS 301 25% SiH, Mw 1900 sold by Gelest Inc., Tullytown, Pa., U.S.A.) in solution in 60 ml of THF and 90 mg of chloroplatinic acid H2PtCl6. The mixture was heated under reflux for 2 hours. 1 g of 1-hexene was thereafter added and the reaction was continued for 1 hour. A sampling enables to confirm the complete disappearance of IR bands of the SiH bond which confirms hydrosilylation between the allyl groups of (allyloxyphenyl)-phenyliodonium bis-fluorosulfonylimide and groups SiH of the copolymer of dimethylsiloxane and (hydrogeno)(methyl)-siloxane. The polymer thus obtained which contains ionic pendant groups is precipitated in methanol and purified by means of three operations of dissolution (THF)/precipitation (methanol and ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(Cl)([Cl:16])=O.CN(C=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:11]([Cl:16])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 3-fluoro-4-nitrobenzene carboxylic acid (18.0 g 1.0 eq, 0.10 mol) in THF (360 ml) at 0° C. was added thionyl chloride (56.7 ml, 8.0 eq, 0.78 mol) and DMF (1 ml.). The reaction was warmed to room temperature and stirred for 3.5 hours, after this point all starting material had been consumed. Thionyl chloride was then removed in vacuo to give 3-fluoro-4-nitrobenzoyl chloride as a yellow solid. This was dissolved in DCM (360 ml) and the solution added dropwise to a cooled solution of 880 ammonia in water (360 ml) with vigorous stirring. After the addition the reaction was stirred at room temperature for 15 minutes. The resultant precipitate was collected by filtration, and the filtrate was then filtered a further two more times. The three precipitates were each washed with cyclohexane (2×100 ml), dried in vacuo and combined to give the title compound as a yellow solid (13.32 g, 72 mmol, 74%). LCMS: [M+H]+=na, Rt=1.41 min, 100% purity.