Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:29][CH2:30]2)[CH:24]=1
Reactant: CC(C)Oc1ccc(Cl)cc1N1CCNCC1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Cl)cc1N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.3 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.206 g, 0.887 mmol, 1 eq) and 1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.328 g, 0.977 mmol, 1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.535 g, 2.524 mmol, 2.84 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with Ethyl Acetate and quenched with saturated NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.164 g, 39%). MS: APCI: M+1: 471.2 (Exact Mass: 470.21).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Cc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2
Temperature: 0 °C

Procedure:
2.7 g of 1-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin--10-yl)-piperazine are treated, together with 4.3 g of powdered potassium carbonate, 200 mg of potassium iodide and 90 ml of toluene, with 3.2 g of N-(β-chloroethyl-oxazolidinone and the mixture is heated for 24 hours under reflux. Then the mixture is poured on to ice-water, diluted with benzene and the organic phase washed with saturated soda solution and water, dried over sodium sulphate and concentrated under reduced pressure. There is obtained 3-[2-[4-(10,11-dihydro--2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]--2-oxazolidinone which is recrystallised from acetone/petroleum ether. The maleate melts at 159°-161° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[Br:16]Br>C([O-])(O)=O.[Na+]>[Br:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][C:5]2=[O:15]
Reactant: BrBr
Reactant: O=C1CCCc2ccccc21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCCc2c(Br)cccc21
Temperature: 90 °C
Yield: 44.3 %

Procedure:
(Cornelius, L. A. H.; Combs, D. W. Synthetic Communications 1994, 24(19), 2777-2788) Into a round bottom flask kept at 0° C., AlCl3 (19.6 g, 146.8 mmol) was added and the reaction system was put under nitrogen. 8 mL of tetralone (8.62 g, 58.9 mmol) were added during a 10-minute period, at which point, the reaction mixture was heated in an oil bath at 90° C. for about 45 minutes before adding 3.6 mL of Br2 (11.2 g, 70.1 mmol). The reaction mixture was stirred at 90° C. for an hour before 30 mL of ice-water and 20 mL of NaHCO3 were added. The product was extracted twice from the aqueous phase with Et2O and, the resultant organic phase was washed once with NaHCO3, once with brine and dried under Na2SO4. The crude reaction mixture was purified by flash chromatography (2.5% EtOAc/97.5% hex) which afforded 5.87 g (26.1 mmol) of the product in a 44% yield.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:33])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([C:27]2([OH:33])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: OC1(c2cc(F)cc(F)c2)CCOCC1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3(O)CCOCC3)cc2F)OC1(C)C
Yield: 97 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 equiv.), butyllithium (2.4 equiv.) and 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol (1.0 equiv.) to give 4-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol in 97% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.32-1.42 (m, 12H), 1.56-1.65 (m, 2H), 2.11 (d, J=3.13 Hz, 2H), 3.86-3.92 (m, 4H), 6.99 (d, J=9.00 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:51][C:52]1[CH:53]=[CH:54][C:55](O)=[N:56][CH:57]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:31][C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][N:56]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Yield: 77 %

Procedure:
(S)-1-[(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethanol (17) and PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (614 mg, 1.87 mmol) were suspended in THF (10 mL). To the mixture were added 5-chloro-pyridin-2-ol (0.243 g, 1.87 mmol) and then DBAD (0.431 g, 1.87 mmol). The reaction mixture was stirred at 45° C. over night. The mixture was diluted with ethyl acetate and filtered on celite and concentrated under vacuo. The residue was purified by column chromatography (SiO2, EtOAc/H, 1:15) yielded 571 mg (77%) of the title compound as a colorless oil. ES-MS m/e: 593.3 (M+H+).
Reaction SMILES: [CH:1]1([N:7]([CH3:25])[CH2:8][CH2:9][NH:10][C:11](=[O:24])[CH2:12][N:13]2[C:17]3C=[CH:19][C:20](OC)=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1([N:32](C)CCNC(=O)CN2C3C=C(OC)C=CC=3N=C2)CCCCC1>>[CH:1]1([N:7]([CH3:25])[CH2:8][CH2:9][NH:10][C:11](=[O:24])[CH2:12][N:13]2[C:17]3=[N:32][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=[CH:14]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)ncn2CC(=O)NCCN(C)C1CCCCC1
Reactant: COc1ccc2ncn(CC(=O)NCCN(C)C3CCCCC3)c2c1
Product: CN(CCNC(=O)Cn1cnc2cccnc21)C1CCCCC1

Procedure:
N-[2-(Cyclohexyl-methyl-amino)-ethyl]-2-(5-methoxy-benzoimidazol-1-yl)-acetamide (3x1)/N-[2-(Cyclohexyl-methyl-amino)-ethyl]-2-(6-methoxy-benzoimidazol-1-yl)-acetamide (3x2) (ratio 1:1): LC-MS (Method A, retention time=1.478 min. MS calc'd for C19H29N4O2 (MH+): 345.2. Found 345.5.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1(=O)O[C:10](=[O:11])[CH2:9][CH2:8]1>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[CH2:3]([C:4]1[CH2:7][C@H:8]2[C@@H:6]([CH:5]=1)[C:10](=[O:11])[CH2:9]2)[CH3:2]
Reactant: c1ccncc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCC1=C[C@H]2C(=O)C[C@H]2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To this solution, DMAc (200 mL), pyridine (145 g, 2.5 eq.), DMAP (8.97 g, 0.10 eq.), and succinic anhydride (73.5 g, 1.0 eq.) were added in this order, and the mixture was stirred at 60° C. for 8 hours. The reaction mixture was cooled to room temperature and then washed with water (600 mL) to obtain an organic layer. The aqueous layer was subjected to extraction twice with TBME (200 mL for each). The combined organic layers were washed with 2 M hydrochloric acid (1.0 L), then further washed twice with a 5% aqueous sodium bicarbonate solution (1.0 L for each), and concentrated. The concentrated residue was diluted with hexane (500 mL), washed with a 5% aqueous sodium bicarbonate solution (500 mL) and 20% saline (200 mL) in this order, and then concentrated. The residue was distilled (pressure: 2.8 to 3.0 kPa, distillation temperature: 102 to 104° C.) to obtain (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (41.3 g, yield: 41%, 97.7% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]([OH:19])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.[NH2:32][OH:33].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1.O>[OH:33][NH:32][C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:19]
Reactant: COc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[4-Methoxybenzenesulfonyl]-pyrrolidine-2(R)-carboxylic acid (1.12 g, 3.93 mmol) is dissolved in methylene chloride (40.0 mL). To this solution is added oxalyl chloride (0.69 mL, 7.85 mmol) and dimethylformamide (0.30 mL, 3.93 mmol), and the reaction is stirred at room temperature for 30 minutes. Meanwhile, in a separate flask, hydroxylamine hydrochloride (1.1 g, 15.7 mmol) and triethylamine (3.3 mL, 23.5 mmol) are stirred in tetrahydrofuran (20.0 mL) and water (4.0 mL) at 0° C. for 15 minutes. After 30 minutes, the methylene chloride solution is added in one portion to the second flask, and the combined contents are stirred overnight as the flask gradually warms up to room temperature. The reaction is then diluted with acidic water (pH=~3), and extracted several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (50% ethyl acetate/hexane) to give N-hydroxy-1 -[4-methoxybenzenesulfonyl]-pyrrolidine-2(S)-carboxamide, m.p. 163.5°-165.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:6]([CH:33]=1)[CH2:7][N:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:6]([CH:33]=1)[CH2:7][N:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Solvent: O=CO
Product: COC(=O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)O)cc2)cc1
Reaction time: 18 h
Yield: 86 %

Procedure:
tert-Butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate (1.79 g) was suspended in formic acid (10 ml) and heated on a steam bath until a clear solution formed. The reaction mixture was cooled and stood at ambient temperature for 18 hours. The resulting solid was filtered and washed with formic acid (2×5 ml) and dried under vacuum at 60° C. to give the title product (1.4 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17](O)=[O:18])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CS(C)=O>[F:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([N:34]4[CH2:35][CH2:36][CH2:37][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:18])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCCNCC1
Reactant: O=C(O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3[nH]2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)Cn2cc(-c3cc4c(-c5cnc(C6(O)CCC6)s5)c(F)cnc4[nH]3)cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of 2-(4-(5-fluoro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (Example 65B) (100 mg, 0.242 mmol) in N,N-dimethylformamide (783 μl) was added 1-methyl-1,4-diazepane (35.9 mg, 0.314 mmol), 4-methylmorpholine (80 μl, 0.726 mmol), 1-hydroxybenzotriazole hydrate (55.6 mg, 0.363 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69.6 mg, 0.363 mmol). The reaction was cooled to room temperature and diluted with dimethyl sulfoxide (1 mL). The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 um column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.29 (bs, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 8.20 (d, J=3.6 Hz, 1H), 8.10 (s, 1H), 7.05 (s, 1H), 6.65 (s, 1H), 5.22-5.17 (m, 2H), 3.67-3.41 (m, 4H), 2.67-2.34 (m, 6H), 2.32-2.23 (m, 3H), 2.05-1.71 (m, 4H); MS ESI(+) m/z 510.1 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][O:36][Si](C(C)(C)C)(C)C)[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(O)(=O)C>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][OH:36])[C:15]=3[N:14]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(OCCO[Si](C)(C)C(C)(C)C)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(OCCO)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
250 mg (0.40 mmol) 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were dissolved in 15 mL THF. 435 μl of a 1 M TBAF-solution in THF and 26 μl acetic acid were added. The resulting mixture was stirred for 48 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was taken up in 50 mL CH2Cl2 and washed once with a saturated NaHCO3-solution and five times with water. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuo. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2-hydroxy-ethoxy)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as its formiate in form of a colorless amorphous material. The title compound was transformed into its acetate. Yield: 132 mg MS (ES+): m/e=515, chloro pattern.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=[O:15])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1.[CH:19]1([C:25]2[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([C:25]2[CH:26]=[CH:27][C:28]([S:31][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[CH:8][C:9]4[NH:14][C:13](=[O:15])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=4[CH:18]=3)=[CH:29][CH:30]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCl)cc21
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(3-chloropropoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCCS2(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CCCN1CCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(1,1-Dioxo-isothiazolidine-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (2.01 g) was treated with 30% trifluoroacetic acid in dichloromethane (10 mL), and the mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo to give 2.46 g of 1-[2-(1,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine trifluoroacetate as a solid. LR-MS: 234 [(M+H)+]
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[OH:10].C(O[C:14]([S-])=[S:15])C.[K+]>N1C=CC=CC=1>[SH:15][C:14]1[O:10][C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[N:2]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(O)ccc1O
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: Oc1ccc2oc(S)nc2c1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a solution of 2-aminobenzene-1,4-diol hydrochloride (3.58 g) in pyridine (40 mL) was added potassium ethylxanthate (3.91 g), and the mixture was stirred with heating under reflux for 3 hr. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in water, and the solution was acidified with 1M hydrochloric acid. The precipitated solid was collected, and washed with water to give the title compound (2.08 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](OC)=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cccc(CO)c2)cc1
Reaction time: 0.33 h

Procedure:
In an atmosphere of nitrogen, under ice-cooling, methyl 4′-(methylsulfonyl)biphenyl-3-carboxylate was added to a THF suspension of lithium aluminum hydride, followed by stirring for 20 minute to obtain [4′-(methylsulfonyl)biphenyl-3-yl]methanol.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([O:6]C)=O.S(Cl)(Cl)(=O)=O.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([CH3:22])[C:16]=1[CH3:23].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.C(N(CC)CC)C>ClCCl.O>[CH3:23][C:16]1[C:17]([CH3:22])=[C:18]2[C:20]([CH:3]([S:2][CH3:1])[C:4](=[O:6])[NH:19]2)=[CH:21][C:15]=1[O:14][CH3:13]
Reactant: COc1ccc(N)c(C)c1C
Reactant: COC(=O)CSC
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(c(C)c1C)NC(=O)C2SC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To a solution of methyl (methylthio)acetate (40.8 mL, 317 mmol) in dichloromethane (1100 mL) was added sulfuryl chloride (26.6 mL, 331 mmol) at −78° C., and the mixture was stirred for 15 minutes. Further, a solution of 4-methoxy-2,3-dimethylaniline (41.7 g, 276 mmol) and proton sponge (62.1 g, 290 mmol) in dichloromethane (200 mL) was added dropwise over 1 hour and mixture was stirred at the same temperature for 1 hour. Triethylamine (43 mL, 380 mmol) was added, and the temperature was gradually raised to room temperature. After stirring at room temperature for 2 hours, water was added, the organic layer was washed with an aqueous saturated solution of sodium bicarbonate and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To the residue was added toluene (300 mL), and the mixture was stirred at reflux for 1 hour. The solvent was distilled off under reduced pressure, which was recrystallized from ethyl acetate to obtain 30.0 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])#[CH:20]>>[NH2:24][C:23]1[CH:22]=[C:21]([C:19]#[C:20][C:2]2[CH:3]=[C:4]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: C#Cc1cccc(N)c1
Product: CC(C)(C)NS(=O)(=O)c1cc(C#Cc2cccc(N)c2)cc([N+](=O)[O-])c1
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example B5, step E using 3-bromo-N-(tert-butyl)-5-nitrobenzenesulfonamide and 3-ethynylaniline as the starting materials in 32% yield. LCMS for C18H20N3O4S (M+H)+: m/z=374.2.
Reaction SMILES: C1(CBr)CC1.[CH:6]1([CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=2)[CH2:8][CH2:7]1.N1CCCCC1.[O:28]1[CH2:32]C[CH2:30][CH2:29]1>[Pd]>[CH3:21][C:16]1[CH:15]=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH:6]2[CH2:8][CH2:7]2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:30][CH:29]1[O:28][CH2:32]1
Reactant: Cc1cc(OCCOCC2CC2)ccc1O
Reactant: C1CCOC1
Agent: [Pd]
Agent: BrCC1CC1
Solvent: C1CCNCC1
Product: Cc1cc(OCCOCC2CC2)ccc1OCC1CO1

Procedure:
The epoxide starting material is obtained from reaction of 4-hydroxy-3-methylphenyl benzoate with benzyl bromide to give 4-benzyloxy-3-methylphenyl benzoate (M.P. 120°-121° from methanol/ether), followed by de-esterification with 2M NaOH solution to give 4-benzyloxy-3-methylphenol (M.P. 69°-70° from ether/hexane) and reaction with 2-bromoethanol (light brown oil) to form an alcohol which is reacted with cyclopropylmethyl bromide in tetrahydrofuran. Debenzylation of the cyclopropylmethoxyethoxy derivative (unpurified) with 10% Pd on activated charcoal forms 4-(2-(cyclopropylmethoxy)ethoxy)-2-methylphenol which is then reacted withepichlorhydrin in the presence of a catalytic amount of piperidine to give 2-methyl-1-(2,3-epoxypropoxy)-4-(2-(cyclopropylmethoxy)ethoxy)benzene (light brown oil after chromatography on silica gel with toluene/ethyl-acetate (8:2)).