Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C@@:19]([CH3:31])([C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:18][C@@:19]([CH3:31])([C:23]([NH:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: C[C@@](O)(C(=O)O)C(=O)NCC(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@](O)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 16 h
Yield: 79.6 %

Procedure:
A solution of 70.0 mg (0.31 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 73.9 mg (0.34 mmol) (S)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid in 6 ml tetrahydrofuran were cooled to 0° C. and 46.4 mg (0.34 mmol) 1-hydroxy-benzotriazole hydrate, 117 μl (0.69 mmol) diisopropylethylamine and 65.8 mg (0.34 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued for 16 hours. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 100/0 to 25/75) yielded 104 mg (79%) (S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide, MS (m/e): 422.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C@@H:12]([CH3:22])[N:11](CC3C=CC(OC)=CC=3)[C:10]2=[O:32])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:33](OCC)(OCC)OCC>>[NH:1]1[C:2]2[CH:3]=[C:4]([N:9]3[C@@H:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C@@H:12]([CH3:22])[NH:11][C:10]3=[O:32])[CH:5]=[CH:6][C:7]=2[N:8]=[CH:33]1
Reactant: COc1ccc(CN2C(=O)N(c3ccc(N)c(N)c3)[C@@H](c3ccc(OC)cc3)[C@H]2C)cc1
Reactant: CCOC(OCC)OCC
Product: COc1ccc([C@H]2[C@@H](C)NC(=O)N2c2ccc3nc[nH]c3c2)cc1
Reaction time: 0.5 h

Procedure:
(4R,5S)-1-(3,4-diaminophenyl)-3-(4-methoxybenzyl)-5-(4-methoxyphenyl)-4-methylimidazolidin-2-one (0.105 g, 0.24 mmol) obtained from step F was dissolved in 3 mL triethyl orthoformate. The reaction was stirred for 30 minutes at reflux. After cooling the solvent was removed and the remains were dissolved in 8 mL trifluoroacetic acid. The reaction was stirred for 14 hours at ambient temperature. The TFA was removed under reduced pressure and the residue was re-dissolved in 20 mL of buffer (pH7) and three times extracted by means of 25 mL dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and the solvent was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0→10%). The product elutes at about 5% methanol.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C@H:8]([F:13])[CH2:9][CH2:10][CH2:11][CH3:12])(=O)=O.O[C@@H](CCCC)CC(OC)=O.[CH2:25]([O:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][C:41](O)=[C:40](F)[CH:39]=2)=[N:36][CH:37]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:25]([O:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([O:5][CH2:6][CH2:7][C@H:8]([F:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:40][CH:39]=2)=[N:36][CH:37]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCOc1cnc(-c2ccc(O)c(F)c2)nc1
Reactant: CCCC[C@@H](F)CCOS(C)(=O)=O
Agent: CCCC[C@H](O)CC(=O)OC
Product: CCCCCCOc1cnc(-c2ccc(OCC[C@H](F)CCCC)cc2)nc1
Yield: 48.5 %

Procedure:
The titled compound was synthesized from (R)-3-fluoroheptyl methanesulfonate, derived from methyl (S)-3-hydroxyheptanoate (98.0% ee, [α]D20 =-8.71°), and 5-n-hexyloxy-2-(4-hydroxy-3-fluorophenyl)pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33])#[N:26]>>[Cl:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:32]([F:33])=[C:27]([C:25]#[N:26])[CH:28]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:23])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: N#Cc1cc(B(O)O)ccc1F
Product: CC(c1ccc(-c2ccc(F)c(C#N)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with 3-cyano-4-fluorophenylboronic acid to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=463.2 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:20])[CH:10]=[C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])(=[O:24])=[O:23]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:20])[C:10](=[C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH:15]2)[C:28]([C:27]2[CH:26]=[C:25]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:33]=[CH:32][CH:31]=2)=[O:29])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(C=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Solvent: C1COCCO1
Product: O=C(C(C(=O)c1cccc(S(=O)(=O)Cl)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1

Procedure:
1-(3,5-Difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone and 3-(chlorosulfonyl)benzoyl chloride were heated under reflux in dioxane for 1 hour, followed by cooling. After dilution with ethyl acetate, the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. This was further diluted with ethyl acetate, washed with an aqueous saturated sodium hydrogencarbonate solution and water successively, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:8][N:7]=1.CS(C)=[O:29]>CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:29])=[N:8][N:7]=1
Reactant: CS(C)=O
Reactant: Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1Br
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Nc2nnc(C(=O)c3ccncc3)c3ccccc23)cc1Br
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 1.22 g (3 mmol) 1-(3-brom-4-methyl-anilino)-4-(4-pyridyl-methyl)-phthalazine (expl. 14h) and 336 mg (3 mmol) potassium-tert.butylate in 10 ml DMSO is stirred in an open vessel for 10 days at RT. Then the yellow mixture is diluted with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and partly concentrated. After adding 10 g of SiO2, the residue is dried in vacuo and the resulting powder put on top of a SiO2-column. Eluation with dichloromethane/EtOAc (5:1→1:1→EtOAc) yields [4-(3-brom-4-methyl-anilino)phthalazin-1-yl](pyridin-4-yl)ketone (A) followed by [4-(3-brom-4-methyl-anilino)phthalazin-1-yl](pyridin-4-yl)methanol (B). A: m.p. 249-250° C.; FAB MS (M+H)+=419/421. B: m.p. 240° C.; FAB MS (M+H)+=421/423.
Reaction SMILES: Br[CH2:2][C:3](=[O:27])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:26])[C@@H:14]([O:24][CH3:25])[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:28]([OH:31])(=[O:30])[CH3:29].C(N(CC)CC)C>CC(C)=O.C(Cl)(Cl)Cl>[C:28]([O:31][CH2:2][C:3](=[O:27])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:26])[C@@H:14]([O:24][CH3:25])[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)COC(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
21-Bromo-3α-hydroxy-2β-methoxy-5α-pregnane-11,20-dione (600 mg.) was dissolved in dry acetone (15 ml.) and added to a mixture of glacial acetic acid (2 ml.) and triethylamine (3ml.) and refluxed for 41/2 hours. The mixture was diluted with chloroform, washed with water, dried and evaporated to a foam. Purification by preparative tlc followed by crystallisation from ethyl acetate and petrol gave the title compound (230 mg.) as colourless plates; m.p. 177°-180° [α]D + 112°.
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:3]2[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:4]=2[C:5]#[N:6])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2c(F)cccc2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2c(F)cccc2C#N)c1CN(C)C
Yield: 13 %

Procedure:
In analogy to example 5b, 3-fluoro-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) afforded the title compound as a light yellow oil (yield: 13%). 1H-NMR (400 MHz, DMSO): δ=1.91 (s, 6H), 2.17 (s, 3H), 3.17 (s, 2H), 7.72-7.92 (m, 4H)
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[N:7]=[C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10][N:9]3[C:22]=2[CH3:23])[CH2:5][CH2:4]1.[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>C1COCC1>[CH:3]1([C:6]2[N:7]=[C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:27][C:26]5[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=5[F:24])=[CH:16][C:15]4=[O:21])=[CH:10][N:9]3[C:22]=2[CH3:23])[CH2:5][CH2:4]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4F)cc3=O)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a stirred suspension of NaH (40% oil dispersion, 19 mg) in THF (6 ml) was added a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2 (1H)-one (75 mg) in THF (1 ml) at 0° C., and then the mixture was stirred at room temperature for 30 min. 2,4-Difluorobenzyl bromide (67 mg) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for further 3 h followed by heating at reflux for 6 h. The reaction mixture was then cooled to room temperature and quenched with ice-water. The mixture was extracted with DCM, and the extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (38 mg) as an off-white solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:43])[CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38]>C1COCC1.C(O)C.O>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C@@H:18]2[OH:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:43])[CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40]
Reactant: CN(CCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCCSCCCC(F)(F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN(CCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCSCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
350 mg of sodium borohydride are added in portions at 0° C. to 2.0 g of 11β-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one in 17 ml of THF, 10 ml of ethanol and 4.2 ml of water. After 30 min, the reaction mixture is stirred into ice-water, extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo. 1.7 g of crude 11β-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17β-ol are obtained as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cccc32)cc1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
4-Bromoindole (1.24 g, 6.3 mmol), p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) and tetrabutyl-ammonium hydrogen sulfate (42 mg, 0.1 mmol) was dissolved in DCM (50 mL). NaOH 2.5 M aq (6 mL, 15 mmol) was added and the mixture was stirred vigorously for 1 h. Diluted with water and DCM, collected the DCM phase and washed it twice with water, dried and concentrated to give the product as white crystalline material (2.07 g, 5.9 mmol). Yield 94%. MS (ESI+) for C15H12BrNO2S m/z 352 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.[OH:17][CH2:18][CH2:19]C1C=C(C=CC=1)C#N>>[OH:16][N:15]=[C:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:11]([CH2:19][CH2:18][OH:17])[CH:12]=1)[NH2:1]
Reactant: N#Cc1cccc(CCO)c1
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Product: NC(=NO)c1cccc(CCO)c1

Procedure:
The title compound was obtained following procedure and work up described for Intermediate 47 step 2 but starting from 3-(2-hydroxy-ethyl)-benzonitrile (2 g, 13.59 mmol). Lyophilization of the reaction mixture gave the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 9.56 (s, 1H), 7.51-7.46 (m, 2H), 7.28-7.19 (m, 2H), 5.75 (bs, 2H), 4.64 (t, J=5.2 Hz, 1H), 3.63-3.57 (m, 2H), 2.71 (t, J=7.1 Hz, 2H). LC/MS (Method B): 181.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]([S:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([CH:42]=O)[CH2:25]1)(=[O:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:20]([S:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([CH:42]2[O:17][CH2:16][CH:13]([NH:12][C:10]([O:9][CH2:8][C:7]3[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[CH2:14][O:15]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: O=C(NC(CO)CO)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)S[C@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@@H](C2OCC(NC(=O)OCc3ccc([N+](=O)[O-])cc3)CO2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 85.7 %

Procedure:
A solution of 2-(4-nitrobenzyloxycarbonyl)amino-1,3-propanediol (1.42 g), (2S,4S)-4-acetylthio-2-formyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.00 g) and 4-toluenesulfonic acid (0.30 g) in toluene was refluxed for 2 hours with removing water under azeotropic condition. The reaction mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (80 ml) and eluted with a mixture of acetone and dichloromethane (1:9, V/V) to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[5-(4-nitrobenzyloxycarbonylamino)-1,3-dioxan-2-yl]pyrrolidine (1.47 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:6]2[CH:5]=[C:4]([CH3:13])[O:3][C:2]=2[CH3:1])[N:8]=1)(=[O:25])=[O:24]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Cc1cc(-c2csc(N)n2)c(C)o1
Product: Cc1cc(-c2csc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)n2)c(C)o1

Procedure:
The title compound was prepared from 4-(2,5-dimethyl-3-furyl)-1,3-thiazol-2-ylamine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (11.6 mg) with purity >90%. MS (pos) m/z 417.1, 419.1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)=[O:19])=[CH:14][CH:13]=3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:2]1.C(N(CC)CC)C.N1([C:41](=[O:43])[CH3:42])C=CN=C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[C:5]([CH:3]3[CH2:4][N:1]([C:41](=[O:43])[CH3:42])[CH2:2]3)=[N:10][CH:9]=[CH:8][N:7]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: O=C(c1ccc(Oc2nccnc2C2CNC2)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 36 %

Procedure:
To a solution of (4-(3-(azetidin-3-yl)pyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone in DMF (1.0 mL) is added triethylamine (104 μL, 0.743 mmol) and 1-(1H-imidazol-1-yl)ethanone (60.0 mg, 0.545 mmol). The reaction was stirred at rt 7 h. The reaction mixture was added to saturated NaHCO3 (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (5 mL), saturated NaCl (5 mL), dried (MgSO4) and concentrated. Purification by RPHPLC gives 1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidin-1-yl)ethanone (55.4 mg, 36.0% over 3 steps) as a white solid. MS (ESI, pos. ion) m/z: 414.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(O)Cc1ccccc1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A mixture of benzyl phenylacetate (218 mg), methylene chloride (2 ml), aluminum chloride (357 mg), and nitromethane (1 ml) is stirred for 1 hour under ice cooling. The mixture is acidified with cold dilute hydrochloric acid and extracted with methylene chloride. The organic layer is extracted again with 5% aqueous sodium hydrogen carbonate solution. The aqueous extract is acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to give phenylacetic acid (114 mg) melting at 77° C. Yield: 87%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[C-:11]#[N:12].[Na+].O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccc(CC#N)cc1
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Under an atmosphere of nitrogen, 25.9 g (150 mmol) of 4-(methylthio)benzyl chloride were dissolved in 45.5 g of toluene. 9.29 g (180 mmol) of sodium cyanide, 0.92 g (2.9 mmol) of tetrabutylammonium chloride and 14.4 g of water were then added. The mixture was stirred at 80-85° C. for 2 h. The reaction mixture was admixed with 30 g of toluene and 45 g of water, the aqueous phase was decanted off and the organic phase was concentrated. This gave a residue of 24.6 g of the title product in a yield of >95% (according to NMR) in the form of a pink solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[C:13]([C:18]#[N:19])=[CH:12]2)=[CH:7][CH:6]=1)C.[CH2:21](N(CC)CC)[CH3:22].CS(Cl)(=O)=O>O1CCCC1>[C:18]([C:13]1[C:14]([CH2:16][O:17][CH2:21][CH3:22])=[CH:15][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:20])=[CH:10][CH:9]=2)[CH:12]=1)#[N:19]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(CO)c2)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOCc1cn(-c2ccc(C(=O)O)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of 4-(3-cyano-4-hydroxymethylpyrrole-1-yl)benzoic acid ethyl ester (0.022 g) in tetrahydrofuran (1 mL) were added triethylamine (0.0082 g) and methane sulfonylchloride (0.0093 g) under ice-cooling. After warming to ambient temperature, this mixture was stirred for 30 minutes. The insoluble material of this reaction mixture was removed by filtration, and this filtrate was added to a mixture of ethanol (1.125 g) and sodium hydride (60%, 0.13 g), and this mixture was stirred for 5 hours. To this reaction mixture was added water, and this mixture was stirred at room temperature for 1 hours. To this reaction mixture was added 2 mol/L hydrochloric acid (3 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=88/12-81/19) to give the title compound (0.010 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CO[CH:7](OC)[CH2:8][N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)S(C1C=CC(C)=CC=1)(=O)=O>ClC(Cl)C>[F:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[CH:20]=[N:9][CH:8]=[CH:7]2
Reactant: COC(CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Fc1ccc2cnccc2c1
Reaction time: 8 h
Yield: 29.8 %

Procedure:
41.6 g AlCl3 were suspended in 400 ml of dichloroethane. At room temperature, a solution of 22.95 g of N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl-benzenesulfonamide (4) in 150 ml of dichloroethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the organic layer was separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75 g) was purified by silica gel chromatography to yield 2.74 g of 5. Rt=0.30 min (Method #4). Detected mass: 148.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Br:1][C:2]1[C:14]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][S:24]([C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[O:25])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2cc(Br)c(O)cc21
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2cc(Br)c(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 7-bromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.