Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:6]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:1]([S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:6]=1)=[O:27])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Sc1cccc(-c2ccc(Cl)cc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)c1cccc(-c2ccc(Cl)cc2Cl)c1
Yield: 84.5 %

Procedure:
To 1.0 g (3.4 mmol) of [3-(2,4-dichlorophenyl)phenyl] isopropyl sulfide in 50 ml of chloroform, 0.7 g (4.1 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred for 2 hours. The reaction mixture was stirred at room temperature for another 12 hours, and 5% aqueous sodium bicarbonate was added for separation. The chloroform layer was washed with 5% aqueous sodium sulfite and water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.9 g of [3-(2,4-dichlorophenyl)phenyl] isopropyl sulfoxide (yield 85.0%) as a colorless dough (nD20 1.6169).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:13][CH:12]3[NH:14][CH:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C[Si](C)(C)CCOC[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH:32]=O.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:13][CH:12]3[N:14]([CH2:32][C:24]4[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:23]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: Clc1ccc(CC2CC3CCC(C2)N3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Clc1ccc(CC2CC3CCC(C2)N3Cc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 113.3 %

Procedure:
A mixture of 0.5 g of 3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]octane, 0.5 g of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde, 5 mL of 1,2-dichloroethane and 0.5 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The crude SEM ether was heated to reflux in 50 mL of ethanol containing 5 mL of 3N HCl for 2 h, cooled, concentrated and partitioned between 10 ml of saturated aqueous Na2CO3 and 3×25 mL of chloroform. The chloroform extracts were dried over MgSO4 and concentrated. Purification by chromatography eluting with 90:10 CHCl3:MeOH gave 0.75 g of 2-[3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-ylmethyl]-1H-benzimidazole as a 2:1 mixture of exo:endo isomers. Chromatography on a Chiralpak™ AS column eluting with a 90:10 mixture of hexane with 0.10% diethylamine and isopropanol gave 0.25 g of endo 2-[3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-ylmethyl]-1H-benzimidazole: RT=5.34 min; MS (m+1)=366; 1H NMR (400 MHz, CDCl3 3.8 (s, 2H), 3.2 (s, 2H), 2.75 (d, 2H), 2.05 (m, 2H), 1.8 (d, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.C([N:34](C(C)C)[CH:35]([CH3:37])[CH3:36])C.CC(N)C>CN(C=O)C>[CH:35]([NH:34][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)([CH3:37])[CH3:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and propan-2-amine (11.5 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 64.8 mg (65%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.84 (s, 1H), 9.93 (br. s., 1H), 8.64 (d, J=2.0 Hz, 1H), 8.02-8.11 (m, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 4.43-4.63 (m, 3H), 4.25 (s, 2H), 4.07 (dd, J=14.1, 6.6 Hz, 1H), 3.93-4.02 (m, 1H), 3.37-3.55 (m, 1H), 2.96-3.25 (m, 4H), 2.68 (td, J=12.9, 2.5 Hz, 1H), 2.02-2.11 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.72 (m, 4H), 1.14 (d, J=6.8 Hz, 6H). [M+H] calc'd for C25H33N7O2, 464. found, 464.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].Cl.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]3[N:1]=[N:20][NH:10][C:8](=[O:9])[C:7]=3[CH:6]=[CH:5][N:4]=2)=[CH:12][CH:13]=1
Reactant: O=N[O-]
Reactant: COc1ccc(-c2nccc(C(N)=O)c2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nccc3c(=O)[nH]nnc23)cc1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
300 mg of 3-amino-2-(4-methoxyphenyl)-4-pyridinecarboxamide were stirred at 0° C. in 5 ml of glacial acetic acid and 1 ml of concentrated hydrochloric acid during the addition of 128 mg of sodium nitrite in 2 ml of water. The cooling bath was removed, 3 ml of water were added, the mixture was stirred for 0.5 hour and the precipitated product was removed by filtration. Recrystallization from aqueous dimethylformamide yielded 275 mg of 8-(4-methoxyphenyl)pyrido[3,4-d]-1,2,3-triazin-4(3H)-one as yellow needles of melting point 226° C. (dec.).
Reaction SMILES: C(O)C.[CH2:4]([CH:6]1[CH2:15][CH:14]2[C:9](=[CH:10][C:11]([O:24][CH3:25])=[C:12]([O:16]CC3C=CC=CC=3)[CH2:13]2)[CH2:8][N:7]1[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=1)[CH3:5]>C1COCC1.[Pd]>[CH2:4]([CH:6]1[CH2:15][CH:14]2[C:9](=[CH:10][C:11]([O:24][CH3:25])=[C:12]([OH:16])[CH2:13]2)[CH2:8][N:7]1[CH2:26][C:27]1[CH:28]=[C:29]([O:37][CH3:38])[C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=1)[CH3:5]
Reactant: CCC1CC2CC(OCc3ccccc3)=C(OC)C=C2CN1Cc1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC1CC2CC(O)=C(OC)C=C2CN1Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Pd/C (10%, 30.7 mg) was covered with THF (2.0 mL) and ethanol (2.0 mL) and stirred under an atmosphere of hydrogen (balloon pressure) for 15 min at room temperature. Then 262 (334 mg, 0.7 mmol) was added as a solution in THF (4.0 mL). The reaction mixture was stirred for 18 h at room temperature, then filtered through celite. The celite was washed with ethyl acetate (4×5 mL) and the combined filtrates were concentrated in vacuo. The residue was recrystallised from ether/dichloromethane to obtain the title compound as yellow solid (253 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 0.98 (3H, t, J 7.4, CH2CH3), 1.41 (1H, sept, J 7.0, one of CH2CH3), 1.68 (1H, sept, J 6.9, one of CH2CH3), 2.51 (1H, dd, J 16.4, 5.9, one of ArCH2CH), 2.75-2.84 (2H, m, one of ArCH2CH, CHN), 3.51-3.75 (4H, m, 2×ArCH2N), 3.80 (3H, s, OCH3), 3.83 (9H, s, 3×OCH3), 6.44 (1H, s, CH), 6.60 (2H, s, 2×CH), 6.65 (1H, s, CH). 13C NMR (100 MHz, CDCl3) δ 11.1, 23.0, 29.4, 50.8, 55.2, 55.9, 56.0, 58.3, 60.9, 105.3, 108.8, 114.6, 125.4, 126.7, 135.6, 136.5, 143.9, 144.9, 153.1. LC/MS (ES+) tr 1.03 min; m/z 388.13 ((M+H)+, 100%); MeOH/H2O 95:5 (1.0 mL/min), HPLC tr 2.58 min (>97%); CH3CN/H2O 90:10 (1.0 mL/min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:27]C.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][C:3]=1[OH:27]
Reactant: COc1cc(C(=O)c2nc(Nc3cc(C)[nH]n3)c3ccccc3n2)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(O)c3)nc3ccccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a stirred suspension of (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 76 (100 mg, 0.265 mmol) in DCM (4 mL) at 0° C., was added dropwise 1.0 M boron tribromide/DCM (2.12 mL, 2.12 mmol). The mixture was stirred at 0° C. for 30 min. Additional 1.0 M boron tribromide/DCM (1.50 mL, 1.50 mmol) was added and the mixture was allowed to warm to rt and stir for a further 2.5 h. Water (10 mL) was added, and the mixture was extracted with 25% 2-propanol/DCM (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was collected by filtration and dried. The solid was further purified by reverse-phase HPLC eluting with a mixture of water and acetonitrile to afford (4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone as a yellow solid (20 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 6.51 (s, 1H), 7.28 (dd, J=10.8, 8.4 Hz, 1H), 7.39 (m, 1H), 7.58 (dd, J=8.7, 1.8 Hz, 1H), 7.67 (ddd, J=8.1, 8.1, 1.5 Hz, 1H), 7.83-7.92 (m, 2H), 8.73 (d, J=8.4 Hz, 1H), 10.65 (br s, 1H), 12.22 (br s, 1H); LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.[N:26]1[C:27]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)=[CH:28][N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12>CN(C)C=O>[N:26]1[C:27]([C:35]2[CH:36]=[C:37]([NH:41][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:38]=[CH:39][CH:40]=2)=[CH:28][N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc12
Temperature: 25 °C

Procedure:
Diisopropylethylamine (DIEA, 0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.05 g, 0.23 mmol) and O-(7-Azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU, 0.096 g, 0.25 mmol) in 2 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (0.048 g, 0.023 mmol) was added and allowed to react for approximately 30 minutes, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 1541: 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.92 (s, 1H), 8.54 (d, J=7.0 Hz, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.73 (m, 2H), 7.60 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.44 (m, 3H), 7.26 (dd, J=5.5, 6.8 Hz, 1H), 6.90 (dd, J=5.5, 6.8 Hz, 1H), 3.96 (s, 3H); LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O>FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C(O)c1cc(I)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.3 %

Procedure:
2-Chloro-4-hydroxybenzoic acid (5.18 g, 30.02 mmol) was dissolved in trifluoromethanesulfonic acid (25 g) and N-iodosuccinimide (6.75 g, 30.00 mmol) was added by portions at 0° C. After stirring at room temperature for 15 hr, trifluoromethanesulfonic acid (25 g) was further added, and N-iodosuccinimide (2.02 g, 8.98 mmol) was added by portions at 0° C. After stirring at room temperature for 13.5 hr, the reaction mixture was added to ice water (300 ml), and the mixture was stirred for 2 hr. The precipitated solid was collected by filtration, washed with water, and vacuum dried to give a mixture (8:2) (5.76 g) of 2-chloro-4-hydroxy-5-iodobenzoic acid and 2-chloro-3,5-diiodo-4-hydroxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([F:19])[C:12]=2[N:11]=1.Br[CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:15]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[CH:17][C:18]=3[F:19])[N:14]2[CH2:28][CH2:27][CH2:26]1
Reactant: BrCCCBr
Reactant: CCN(CC)c1ccc(F)c2nc(Nc3ccc(Cl)cc3Cl)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(F)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A mixture of N2-(2,4-dichlorophenyl)-N7,N7-diethyl-4-fluoro-1H-benzimidazole-2,7-diamine (96.7 mg, 0.263 mmol), 1,3-dibromopropane (72.6 mg, 0.360 mmol) and potassium carbonate (113 mg, 0.819 mmol) in N,N-dimethylformamide (6 mL) was stirred at 80° C. for 3 hr. After ethyl acetate was added, the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and preparative HPLC eluting with a 10-100% acetonitrile/water gradient mixture to give the title compound as a pale pink solid (38.2 mg, 0.0938 mmol, 36%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH3:29])[N:20]=[CH:19][N:18]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:30][S-:31].[Na+].O>CN(C)C=O>[CH3:30][S:31][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH3:29])[N:20]=[CH:19][N:18]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOS(C)(=O)=O)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCSC)cc1
Yield: 75.8 %

Procedure:
A solution of ethyl 4-(2-(4-(2-methylsulfonyloxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.70 g, 1.66 mmol) in N,N-dimethylformamide (10 ml) was stirred under ice-cooling. Sodium thiomethoxide (0.13 g, 1.85 mmol) was added to the solution. The mixture was stirred under ice-cooling for 2 hours, and then water (40 ml) was added. The mixture was extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-(2-methylthioethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.47 g, 76%).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].OS(O)(=O)=O.[CH2:10]([O:17][C:18]([CH:20]([CH2:24][CH2:25][NH2:26])[C:21]([OH:23])=[O:22])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:2]([O:23][C:21](=[O:22])[CH:20]([C:18]([O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:19])[CH2:24][CH2:25][NH2:26])([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: NCCC(C(=O)O)C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(CCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
600 ml of liquefied isobutylene and 6 ml of conc. H2SO4 were added to a solution of 172 g of benzyloxycarbonyl-4-aminobutyric acid in 600 ml of methylene chloride. The mixture was shaken for 3 days at room temperature in an autoclave, the isobutylene was distilled off, and the methylene chloride solution was washed twice with 10% sodium carbonate solution and once with water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in ether and chromatographed over 620 g of basic Al2O3. Elution with ether followed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NCc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NCc4ccccc4)cc23)CC1
Yield: 39.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.32 mg (0.0852 mMol) benzyl isocyanate, 9.4 mg of the title compound were recovered.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.C1(S[CH2:13][N:14]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:21][CH:22]=3)[S:15]2(=[O:17])=[O:16])C=CC=CC=1.CCCCCC>ClCCl>[Cl:4][CH2:13][N:14]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:21][CH:22]=2)[S:15]1(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CSc1ccccc1)C2=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CCl)C2=O
Reaction time: 3 h
Yield: 87 %

Procedure:
Sulfuryl chloride (0.34 g) was added dropwise with stirring to a solution of 2-phenylthiomethyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (0.96 g) in dichloromethane. Stirring was continued at room temperature for three hours and the solution was stripped of volatiles. Dichloromethane was added and the solution was stripped again. Hexane was added to the residue and the mixture was stirred at room temperature overnight. The resulting white solid was collected and dried affording 2-chloromethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (0.69 g, 89% yield, mp 113°-115° C.).
Reaction SMILES: C([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C([O-])(O)=O.[Na+].C1C(=O)N([O:30][C:31]([O:33][CH2:34][CH:35]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]3[C:36]2=[CH:37][CH:38]=[CH:39][CH:40]=3)=O)C(=O)C1.Cl>O1CCOCC1.O>[CH:46]1[C:47]2[CH:35]([CH2:34][O:33][C:31]([NH:8][C@H:7]([C:6]([OH:5])=[O:17])[CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[O:30])[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]=2[CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.2 %

Procedure:
To a stirring suspension of L-tyrosine O-t-butyl ester (1.00 g, 4.21 mmol) and NaHCO3 (354 mg, 4.21 mmol) in 1,4-dioxane/water (1:1, 20 mL) was added 9-fluorenylmethyl-N-succinimidyl carbonate (1.42 g, 4.21 mmol) and the resulting mixture was stirred for 18 hr at room temperature. The solvent was reduced to 10 mL followed by the addition of 50 mL of cold 1N HCl. The product was extracted with ethyl acetate (3×). The organic extracts were washed with H2O and saturated aqueous NaCl then dried over Na2SO4. The solution was then concentrated after filtration to give the colourless solid 83 (1.94 g, 100%) which was used without purification: 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.97-3.06 (m, 2H), 4.21 (bt, J=7.1, 1H), 4.33 (dd, J=7.1, 10.5, 1H), 4.41-4.53 (m, 2H), 5.01 (bs, 1H), 5.30, (d, J=8.2, 1H), 6.73 (d, J=8.5, 2H), 7.00 (d, J=8.5, 2H), 7.31 (t, J=7.5, 2H), 7.40 (t, J=7.5, 2H), 7.57 (dd, J=3.3, 7.3, 2H), 7.76 (d, J=7.5, 2H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[O:25][CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:18]([O:25][CH3:26])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(CNCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a stirred solution of benzylamine (13.1 mL, 0.12 mol) and 4-benzyloxy-3-methoxybenzaldehyde (24.2 g, 0.1 mol) in 1,2-dichloroethane (50 mL) and chloroform (250 mL) was added sodium triacetoxyborohydride (31.79 g, 0.15 mol). The mixture was stirred at room temperature for 18 hrs, saturated NaHCO3 was added. The organic phase was separated and aqueous phase extracted with chloroform. The combined extracts were washed with brine, dried over MgSO4 and evaporated to afford the crude product. Purification by flash column chromatography afforded the title compound as a pale yellow oil in 76% yield (25.2 g). Rf: 0.17 (petrol:ethyl acetate; 1:1). 1H NMR (270 MHz, CDCl3) δ 3.73 (2H, s), 3.79 (2H, s), 3.89 (3H, s), 5.13 (2H, s), 6.75-6.84 (2H, m), 6.91 (1H, d, J=1.4), 7.23-7.44 (10H, m); HRMS (ESI+) calcd. for C22H24NO2 (M++H) 334.1802, found 334.1787; LC/MS (ES+) tr=1.19 min, m/z 334.5 (M++H);
Reaction SMILES: [Na].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:14][C:15]#[N:16].CCOCC>C(O)C>[F:12][C:3]([F:2])([F:11])[C:4]1[CH:5]=[C:6]([S:10][CH2:14][C:15]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCCl
Reactant: FC(F)(F)c1cccc(S)c1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: N#CCSc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To sodium (0.62 g, 27.0 mmol) dissolved in 40 mL of ethanol was added 4.79 g (26.9 mmol) of 3-trifluoromethylthiophenol and 2.04 g (27.0 mmol) of chloroacetonitrile. The reaction mixture was heated at reflux for 1 hour and then stirred overnight at room temperature. To the cooled reaction mixture was added one volume of ether and the precipitated solids were removed by filtration. The filtrate was evaporated on the rotary evaporator to give the product as an oil in essentially quantitative yield. This material was used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25]O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1cccs1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1cccs1)c1cc(F)ccc1F
Yield: 69.7 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(100 mg, 0.330 mmol) obtained in Example 5 and 2-thiophenemethanol (0.065 ml, 0.69 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (0.160 ml). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by flash silica gel chromatography (using a hexane/ethyl acetate solvent mixture) to give a white solid. The resulting white solid was washed with hexane, whereby the title compound (92 mg, 0.23 mmol, 70%) was obtained as a white solid.