Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH:28]CC6C=CC(OC)=CC=6)=[N:25][N:24]=5)[CH:21]=4)[N:16]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[CH:15]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O.O1CCOCC1>[F:48][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH2:28])=[N:25][N:24]=5)[CH:21]=4)[N:16]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[CH:15]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(N5CCC(F)(F)CC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(F)(F)CC4)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Yield: 72.2 %

Procedure:
A solution of 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (590 mg) in TFA (5 mL) was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 20 min. The volatiles were removed under reduced pressure. The brown residue was diluted with EtOAc and washed with 0.5 N NaOH. The EtOAc layer was concentrated. The off white solid was stirred with 5 mL Et2O, filtered, rinsed with 2×5 ml of Et2O to give 350 mg of crude material of 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine that was used without further purification. A glass microwave reaction vessel was charged with the above obtained 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (350 mg) in p-dioxane (3 mL) followed by 1 N NaOH (2 mL). The reaction was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 20 min. The mixture was partitioned between 5 mL of H2O and 50 mL of EtOAc. The EtOAc layer was concentrated and the residue purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in MeCN] in [0.1% TFA in H2O]. The desired fractions were collected, concentrated, the residue was extracted with EtOAc and washed with 0.5 N NaOH to give 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (20 mg, 5%) as an off white crystalline solid. MS (ESI, pos. ion) 398.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (1H, br. s.), 8.85 (1H, d, J=1.2 Hz), 8.45 (1H, s), 8.29 (1H, s), 8.19 (1H, s), 7.67 (1H, m), 8.57 (1H, d, J=8.6 Hz), 7.06 (2H, br. s.), 3.89 (4H, t, J=5.6 Hz), 2.12 (4H, m).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[O:5]1.[CH2:19](Cl)[O:20][CH3:21].O>CN(C=O)C>[CH3:19][O:20][CH2:21][O:17][C:14]1[CH:15]=[CH:16][C:11]([B:6]2[O:5][C:4]([CH3:18])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]2)=[CH:12][CH:13]=1
Reactant: COCCl
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 0.17 h

Procedure:
NaH (60% in oil, 4.00 g) was added portionwise at 0° C. to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (11.00 g) in DMF (125 mL). After stirring for 10 min, MOMCl (7.60 mL) was added dropwise, and the mixture was stirred for 1 h. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (8.86 g).
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C=O)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:2][CH3:1])[CH:11]=1
Reactant: C[S-]
Reactant: BrCc1cccc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
Sodium thiomethoxide (0.616 g, 8.8 mmol) was added to DMF (8 mL) and cooled to 0° C. To this solution was added 1-bromo-3-bromomethyl-benzene (2 g, 8 mmol). The mixture was allowed to warm to rt and stir for 18 h. The mixture was then poured into cold water (50 mL) and extracted with EtOAc (3×20 mL). The organics were combined and dried with sodium sulfate. The solution was concentrated in vacuo to yield the crude product, which was then purified via flash chromatography (5% ethyl acetate—hexanes) to yield 1.3 g (68.5%) of 1-bromo-3-methylsulfanylmethyl-benzene as a pure product. 1H-NMR (methylene chloride -d2) δ 7.48-7.47 (m, 1H), 7.392 (dt, J=7.9, 1.5 Hz, 1H), 7.28-7.207 (m, 2H), 3.64 (s, 2H), 1.99 (s, 3H); LC-MS RT: 3.70, [M+H]+: 354.1.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=[O:11].[Na+]>O>[OH:11][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CSCC[C@@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Product: CSCC[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
D-Methionine (100 g, 0.67 mol) was dissolved in 600 ml of 10% H 2SO4 and cooled to 0°-5° C. A solution of NaNO2 (58 g, 0.84 mol) in 100 ml of H2O, also chilled to 0°-5° C., was added dropwise over 1.5 hours, maintaining the temperature of the reaction mixture at 10° C. or less by means of an ice water bath. After stirring for 18 hours at room temperature, the mixture was extracted 9×200 ml ethyl acetate. The organic extracts were combined, dried over MgSO4, and stripped to yield 10.1 g of title product as oil; tlc Rf 0.15 (ethyl acetate), 0.08 (1:1 hexane:ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH-:10].[Na+]>C(O)CCC.O>[CH2:9]([O:10][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[CH2:4][CH2:5][CH3:6]
Reactant: Cc1cc(N)cc(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CCCCOc1cc(N)cc(C)n1
Temperature: 25 °C

Procedure:
2-chloro-6-methylpyridin-4-amine (36 g, 0.25 mol) and sodium hydroxide (24 g, 1 mol) were dissolved in 1-butanol (400 mL). The solution was heated at reflux for 10 h, and then cooled to rt. The reaction mixture was diluted with water (300 mL) and then extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated to afford 2-butoxy-6-methylpyridin-4-amine. 1H NMR (400 MHz, CDCl3) δ 6.05 (d, J=0.6 Hz, 1H), 5.75 (d, J=0.6 Hz, 1H), 4.18 (t, J=6.4 Hz, 1H), 2.30 (s, 3H), 1.71 (m, 2H), 1.48 (m, 2H), 0.98 (t, J=7.6 Hz, 3H). LRMS calc'd for (C10H16N2O) [M+H]+, 181; found 181.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=[O:18]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)CCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH:17]=[O:18])=[CH:6][CH:5]=1
Reactant: O=Cc1sccc1Br
Reactant: Fc1ccc(S)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Product: O=Cc1sccc1Sc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A mixture of sodium hydride (0.20 g) and n-butanol (10 mL) was treated with 4-fluorothiophenol (0.64 g), and the resulting mixture was added to a mixture of 3-bromothiophene-2-carbaldehyde (0.96 g), tetrakis(triphenylphosphine)palladium (0) (0.12 g) and n-butanol (5.0 mL). The resulting mixture was stirred at 100° C. for 2 hours and then at 120° C. for 4 hours. The mixture was cooled to room temperature, concentrated under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the combined organic solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (2:1 to 0:1 by volume) to afford the title compound as a yellow solid (0.78 g).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][CH:15]([F:19])[C:16](F)=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:14][CH:15]([F:19])[C:16](=[O:17])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C(F)C(F)F
Reactant: CCOC(=O)C=CN1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initially charged in toluene (100 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced into the reaction mixture. Triethylamine (5.2 g, 51 mmol) was then added to the reaction mixture. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (50 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml) and the solvent was then removed under reduced pressure. This gave ethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 12.6 g; purity according to GC: 85.5%; yield: 85.5%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.BrC1C=CC=CC=1>COC(C)(C)C>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[NH:16][C:10]([C:4]1[C:3](=[O:15])[N:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=1[OH:9])=[O:12]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Nc1cnccn1
Solvent: Brc1ccccc1
Solvent: COC(C)(C)C
Product: Cc1cc(O)c(C(=O)Nc2cnccn2)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
211 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 95 mg of aminopyrazine were added to 6 ml of bromobenzene, and the mixture was stirred for 3 hours under the heat-refluxing condition. The reaction mixture was cooled to room temperature, and t-butyl methyl ether was added to the mixture. The resulting solid was collected by filtration, washed with t-butyl methyl ether, and dried to obtain 258 mg of N-(2-pyrazinyl)-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 1) represented by the formula:
Reaction SMILES: Cl[C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5].[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.[H-].[Na+]>O1CCOCC1.ClCCl>[CH2:7]([N:6]([CH2:9][CH3:10])[C:4](=[O:5])[C:3]1[CH:11]=[CH:12][CH:13]=[N:14][C:2]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH3:8]
Reactant: CCN(CC)C(=O)c1cccnc1Cl
Reactant: Cc1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1cccnc1Nc1ccccc1C
Temperature: 100 °C
Yield: 44.9 %

Procedure:
To a solution of 2-chloro-N,N-diethylnicotinamide (10.0 g, 47.2 mmol) and o-toluidine (5.0 g, 47.2 mmol) in 1,4-Dioxane (50 mL) was added sodium hydride (60%, 4.72 g, 118 mmol). After addition, the reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (100 mL), washed with water (3×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 50% hexane in ethyl acetate) to afford the desired product, N,N-diethyl-2-(o-tolylamino)nicotinamide (6.0 g) as a yellow oil. LCMS: 284 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(CC)CC)C>C(O)(C)C>[Br:26][C:24]1[N:25]=[C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]3)=[CH:6][CH:7]=2)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(Br)nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c1=O
Yield: 78.5 %

Procedure:
A mixture of 298a (500 mg, 2.02 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (536 mg, 2.02 mmol) and triethylamine (0.6 mL, 4.04 mmol) in isopropanol (10 mL) was heated at reflux for 4 days. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to afford 298b (690 mg, 66%). MS: [M+H]+ 435.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH:14]1[C:26]2[CH:25]([CH2:27][O:28][C:29](=[O:108])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][O:99][CH2:100][CH2:101][O:102][CH2:103][CH2:104][C:105](O)=[O:106])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1.ClCCl>CO>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:105](=[O:106])[CH2:104][CH2:103][O:102][CH2:101][CH2:100][O:99][CH2:98][CH2:97][O:96][CH2:95][CH2:94][O:93][CH2:92][CH2:91][O:90][CH2:89][CH2:88][O:87][CH2:86][CH2:85][O:84][CH2:83][CH2:82][O:81][CH2:80][CH2:79][O:78][CH2:77][CH2:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][NH:30][C:29](=[O:108])[O:28][CH2:27][CH:25]2[C:26]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:4][CH:3]=1
Reactant: O=C(O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCCCCOc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21)NCCCCOc1ccc(Br)cc1
Reaction time: 8 h
Yield: 71.6 %

Procedure:
4-(4-bromophenoxy)butan-1-amine (21.5 mg, 0.09 mmol), 1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16,19,22,25,28,31,34,37,40,43,46,49,52,55,58,61,64,67,70,73,76-pentacosaoxa-4-azanonaheptacontan-79-oic acid (100 mg, 0.073 mmol), and N,N′-dimethylaminopyridine (5.4 mg, 0.044 mmol) were combined in a round bottom flask flushed with nitrogen and charged with a Teflon stirbar. Next 5 mL of anhydrous dichloromethane was added via syringe. N,N-Dicyclohexylcarbodiimide (23 mg, 0.11 mmol) is transferred to a second flask flushed with nitrogen and charged with a stirbar and 5 mL of anhydrous dichloromethane is added via syringe. While stirring the first solution, add the dicyclohexylcarbodiimide solution slowly, dropwise. The reaction is then allowed to proceed overnight. The following day solids from the reaction were filtered off and the filtrate was concentrated onto silica. Column chromatography in methanol and dichloromethane gave a clear thick oil (83.3 mg, 71% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C:12]1[C:23](=[O:24])[N:22]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]2[N:16]=[C:17]([S:20][CH3:21])[N:18]=[CH:19][C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:38])C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C:12]1[C:23](=[O:24])[N:22]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:15]2[N:16]=[C:17]([S:20]([CH3:21])=[O:38])[N:18]=[CH:19][C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ncc2cc(CNC(=O)OCc3ccccc3)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(CNC(=O)OCc3ccccc3)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
(8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester (1.67 g, 3.93 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (1.34 g, 5.11 mmol) were dissolved in dichloromethane (20 mL) and stirred at ambient temperature for 12 hours. The reaction mixture was then purified by silica gel chromatography to give (8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester as a white solid (0.98 g, 56.6%). 1H NMR δ(400 MHz, CDCl3) 8.89 (s, 1H), 7.68 (s, 1H), 7.32 (m, 5H), 5.96 (m, 1H), 5.52 (t, J=6.4 Hz, 1H), 5.09 (s, 2H), 4.32 (d, J=6.3 Hz, 2H), 2.95 (s, 3H), 2.22 (m, 2H), 2.12 (m, 2H), 1.95 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: C[Si](C)(C)[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[F-].[K+].CN1CCN(C)C1=O.[F:22][C:23]1[CH:24]=[C:25]([Br:30])[CH:26]=[CH:27][C:28]=1I>CN(C)C=O.[Cu]Br>[F:22][C:23]1[CH:24]=[C:25]([Br:30])[CH:26]=[CH:27][C:28]=1[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: Fc1cc(Br)ccc1I
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: [Cu]Br
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCN(C)C1=O
Product: Fc1cc(Br)ccc1C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
13.2 g (91.9 mmol) of copper(I) bromide were cooled to −5° C. in 80 ml of dry N,N-dimethylformamide. Under nitrogen, 14.7 g (76.7 mmol) of trimethyl-(pentafluoroethyl)silane were added. 4.45 g (76.7 mmol) of potassium fluoride (spray-dried) were added in portions over the course of 30 minutes at a rate such that the internal temperature remained below 0° C. The mixture was stirred at 0° C. for 1 hour and was then warmed to 20° C. over the course of 12 hours. Thereafter 10 ml of dry 1,3-dimethyl-2-imidazolidinone and 22 g (73.1 mmol) of 3-fluoro-4-iodo-bromobenzene were added. The contents were stirred at 75° C. for 14 hours. Then all of the volatile constituents were distilled off to dryness, the distillate being collected in a cold trap cooled with liquid nitrogen. The distillate was subsequently warmed to 20° C. and dissolved in 500 ml of diethyl ether. This solution was washed with four times 100 ml of water and then with two times 100 ml of saturated aqueous NaCl solution. The organic phase was then dried, and the solvent was removed on a Vigreux column. Subsequent distillation of the residue on a Vigreux column gave 16.1 g of product (boiling point: 86-87° C. (75 mmHg)) with a purity of 99% by weight.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O>COCCOC>[Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18](=[S:36])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1cccc(I)c1)c1ccccc1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H](NC(=S)c1cccc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of N-(1-tert-butyldimethylsilyloxy-2(R)-phenylethan-2-yl)-3-iodobenzamide (13.1 g, 27.2 mmol) in 1,2-dimethoxyethane (80 ml) was added Lawesson's reagent (8.2 g, 20 mmol). The reaction mixture was stirred at ambient temperature for 1 h and then at 60° C. for 2 hours, cooled and poured into water (100 ml). The mixture was extracted with CH2 Cl2 (2×50 ml), washed with brine (100 ml), dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (=1:7) to afford N-(1-tert-butyldimethylsilyloxy-2(R)-phenyl-ethan-2-yl)-3-iodobenzthiamide (4.99 g, 50%) as a yellow liquid.
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[C:26](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([OH:7])[CH2:5][O:6][C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(C)CC(O)CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
50 mmol of 1a was treated for 12 hours with 60 mmol of trityl chloride and 120 mmol of triethylamine in 150 ml of boiling toluene. After conventional working up, the remaining oil was chromatographed (Flash chromatography, eluent chloroform) and gave 2a (yield 85%) m.p. 45° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[S:17][C:16]([N+:18]([O-])=O)=[C:15]([C:21]([NH2:23])=[O:22])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:18][C:16]1[S:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[CH:14][C:15]=1[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1N
Temperature: 65 °C

Procedure:
5-(6-Morpholin-4-ylpyridin-3-yl)-2-nitrothiophene-3-carboxamide (2.77 g, 8.28 mmol), iron(III) chloride (0.03 g, 0.17 mmol), and hydrazine monohydrate (1.34 ml, 27.3 mmol) were combined in methanol (166 ml) and the reaction mixture was purged with nitrogen. The reaction was heated to 65° C. for 3 hours. After cooling to room temperature, the reaction mixture was filtered and solid was washed with methanol. Silica gel was added to the filtrate and the mixture was concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol to give the title compound as an orange solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]([CH3:57])([CH3:56])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:58][C:59]([F:71])([F:70])[O:60][C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1>>[CH3:56][C:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:65](=[O:66])[C:64]4[CH:68]=[CH:69][C:61]([O:60][C:59]([F:58])([F:70])[F:71])=[CH:62][CH:63]=4)=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])([CH3:57])[C:52]([O:54][CH3:55])=[O:53]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 522 was prepared analogous to compound of example 97 by reaction of compound of example 515 with 4-trifluoromethoxy-benzoyl chloride.