Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]2[S:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1S
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)cc1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution of 4-nitrobenzoyl chloride (1.49 g, 8.0 mmol) in benzene anhydrous, 10 mL) was added dropwise to 2-aminothiophenol (1.0 g, 8.0 mmol in 10 ml of benzene) at room temperature. The reaction mixture was allowed to stir for 16 hr. The reaction was quenched with water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried and evaporated. The crude product was purified with flush column, (hexane:ethyl acetate=85:15) to give 1.5 g (73.2%) of product as light yellow solid.
Reaction SMILES: C(OC[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][S:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH2:25][CH2:26][N:27]([CH2:49][CH:50]([CH3:52])[CH3:51])[C:28]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:37][CH:36]=4)=[CH:31][C:29]=3[CH:30]=2)=[O:23])=[CH:17][CH:16]=1)=[O:14])(=O)C.[OH-:53].[Na+].Cl.[CH2:56]([OH:58])C>>[CH2:45]([O:44][CH2:43][CH2:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[CH:33]=[CH:34][C:28]3[N:27]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:26][CH2:25][C:24]([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([S:13]([CH2:12][C:8]5[N:7]([CH2:6][C:56]([OH:58])=[O:53])[CH:11]=[CH:10][N:9]=5)=[O:14])=[CH:16][CH:17]=4)=[O:23])=[CH:30][C:29]=3[CH:31]=2)=[CH:40][CH:39]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCOC(C)=O)cc2)CCN3CC(C)C)cc1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC(=O)O)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]sulfinyl]methyl]-1H-imidazol-1-yl]ethyl acetate (85 mg) in ethanol (5 ml) was added 1N aqueous solution of sodium hydroxide (0.14 ml) at room temperature. The mixture was stirred at room temperature for 1 hour, 1N hydrochloric acid (0.14 ml) was added to the mixture, and the mixture was concentrated under reduced pressure. To the residue was added 2-propanol, and the precipitated crystals were collected by filtration. The crystals were washed with 2-propanol and diisopropyl ether, to give [2-[[[4-[[[7-[4-(2-butoxyethoxy) phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]sulfinyl]methyl]-1H-imidazol-1-yl]acetic acid (Preparation of Compound 412) (65.7 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11].[Br:13]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][Br:13]
Reactant: COC(=O)c1c(C)cccc1Cl
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cccc1CBr

Procedure:
A mixture of 2-chloro-6-methyl-benzoic acid methyl ester (1.84 g, 10 mmol), N-bromosuccinamide (1.95 g, 11 mmol), and benzoyl peroxide (0.056 g, 0.21 mmol) in carbon tetrachloride (20 mL) was heated at reflux until the starting materials were mostly consumed. Workup afforded 2-bromomethyl-6-chloro-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([NH:27][C:28]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Yield: 33.4 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and t-butylisocyanate (0.31 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×100 mL), dried (MgSO4) and concentrated. The crude product was purified by prep-HPLC (35/65 CH3CN/H2O). The product fractions were combined, concentrated and dried in vacuo to give 1-tert-butyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.40 g, 84% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.89 min (97.00%); mp: 202-204° C.; 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 1.97-2.14 (m, 1H), 2.53-2.71 (m, 2H), 2.79-3.02 (m, 1H), 4.34 (d, J=5.9 Hz, 2H), 5.14 (dd, J=5.4, 12.9 Hz, 1H), 5.89 (s, 1H), 6.34 (t, J=6.0 Hz, 1H), 7.65-7.79 (m, 2H), 7.87 (d, J=7.7 Hz, 1H), 11.08 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 29.2, 30.9, 42.3, 48.9, 49.2, 121.4, 123.4, 129.5, 131.5, 133.0, 149.6, 157.3, 167.0, 167.2, 169.8, 172.7; Anal Calcd for C19H22N4O5+0.3H2O: C, 58.24; H, 5.81; N, 14.30. Found: C, 58.15; H, 5.52; N, 14.16.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(OCCO)C>[NH:10]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[NH2:11]
Reactant: Cc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCOCCO
Product: Cc1ccc(NN)nc1

Procedure:
1.0 g (7.8 mmol) 2-chloro-5-methylpyridine are stirred under reflux in 5.7 ml (5.9 g, 117.6 mmol) hydrazine hydrate for 12 h. 10 ml ethylene glycol monoethyl ether are added to the cooled reaction mixture and the solvent is then removed completely on a rotary evaporator. This working step is repeated twice, methylene chloride is then added to the residue, the precipitate is filtered off, the filtrate is concentrated in vacuo and the residue is dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH:8]2[C:15](O)=[O:16].C(Cl)(=O)C(Cl)=O.Cl.[CH3:31][NH:32][O:33][CH3:34].N1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:33][N:32]([CH3:31])[C:15]([CH:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7]1)=[O:16]
Reactant: CNOC
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (5 g, 16 mmol), from Step 3, was suspended in 100 mL of toluene and 5 mL of oxalyl chloride was added. The reaction mixture was heated at reflux temperature for 1.5 h under a nitrogen atmosphere. The solvent was evaporated and excess reagents removed from the residue as an azeotrope with toluene (2×40 mL). The acid chloride and 2 g (20 mmol) of N,O-dimethylhydroxylamine hydrochloride was dissolved in 80 mL of ethanol-free chloroform. The solution was cooled to 0° C. and 3.3 mL of pyridine was added slowly. The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for approximately 4 h then evaporated to dryness. The residue was dissolved in a 1:1 mixture of diethyl ether and methylene chloride and washed with brine. The layers were separated and the organic layer dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil in 98% yield. The product of Step 4 was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[O:16]=[S:17]1(=[O:23])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:20]2[CH2:21][CH2:22][S:17](=[O:23])(=[O:16])[CH2:18][CH2:19]2)=[O:15])=[CH:4][N:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCS(=O)(=O)CC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 1,1-dioxidothiomorpholine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].II.Cl[CH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].Cl>C1COCC1.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: O=C1CCCC1Cl
Agent: Cl
Agent: II
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2CCCC2=O)c(OC)c1
Temperature: 0 °C
Yield: 67 %

Procedure:
A solution of 1-bromo-2,4-dimethoxybenzene (345 μL, 1.2 eq.) in dry THF (0.5 mL) was added dropwise, under N2, to a suspension of Mg turnings (64 mg, 1.3 eq.) in dry THF (0.7 mL) and in presence of a catalitic amount of I2. The reaction mixture was stirred at reflux for 1 hr and then cooled down to 0° C. To this mixture was added dropwise a solution of 2-chlorocyclopentanone (0.2 mL, 2 mmol) in anh. THF (0.5 mL) and the reaction mixture was heated to reflux for 2 hr. The mixture was allowed to cool at r.t., it was diluted with Et2O and slowly mixed with ice and 1M HCl. The organic layer was then separated, washed twice with brine and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude red oil was purified by flash chromatography (silica gel, cHex/EtOAc 8:2) to give the title compound (297 mg, 67%) as a yellow oil.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:11][C:12](=O)[C@H:13]([OH:31])[CH2:14][C@H:15]([NH2:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:19][CH:18]=1)C.Cl.O1CCOCC1>>[CH2:1]([O:8][C:12](=[O:11])[C@H:13]([OH:31])[CH2:14][C@H:15]([NH2:30])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
Benzyl alcohol (13.0 mL, 126 mmol) was added to (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (1.9 g, 5.3 mmol) followed by 4.0 M HCl in 1,4-dioxane (5.3 mL, 21.3 mmol), and the mixture was stirred at 60° C. for 1 hour. The mixture was purified (Interchim reverse phase chromatography column; 30-90% MeCN in water with 0.05% TFA) to yield (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-pentanoic acid benzyl ester (2.2 g) as a white solid. (evaporated in vacuo with water (4×300 mL) to remove excess benzyl alcohol).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:29])[N:4]([CH2:24][CH2:25][C:26]([OH:28])=O)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH:6]=2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:52]([CH2:54][NH2:55])[OH:53]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:53][CH2:52][CH2:54][NH:55][C:26](=[O:28])[CH2:25][CH2:24][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH:6]=2)[N:11]=[C:2]([CH3:1])[C:3]1=[O:29]
Reactant: Cc1nc2ccc(NCc3cccc(C(F)(F)F)c3)cc2n(CCC(=O)O)c1=O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(NCc3cccc(C(F)(F)F)c3)cc2n(CCC(=O)NCCO)c1=O
Reaction time: 8 h

Procedure:
In this example 3-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylamino)-quinoxalin-I (2H)-yl)propanoic acid (50 mg) was dissolved in chloroform (1 mL). HOBt (20 mg), EDC hydrochloride (29 mg), triethylamine (75 μL), and ethanolamine (9 μL) were added sequentially to the reaction flask and stirred overnight. Concentrated and residue chromatographed on silica gel using 5% MeOH in dichloromethane as eluent. Product N-(2-hydroxyethyl)-3-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylamino)-quinoxalin-1(2H)-yl)propanamide is isolated as yellow solid.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[C:39](=[O:40])[NH:38][N:37]=[CH:36]2)[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[C:39](=[O:40])[N:38]([CH2:14][C:15]3[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:37]=[CH:36]2)[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)nc1C
Yield: 56 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 2-(bromomethyl)-5-(trifluoromethyl)furan to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 56% yield: 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 6.69-6.62 (m, 1H), 6.29-6.20 (m, 1H), 5.03 (s, 2H), 4.32 (q, J=7.0 Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.0 Hz, 3H); MS (ES+) m/z 403.3 (M+1).
Reaction SMILES: [Li][CH2:2]CCC.[CH:6]([C:8]1[S:9][CH:10]=[C:11]([CH3:14])[C:12]=1[CH3:13])=O.CCOC(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC.CCCCCC>[CH:6]([C:8]1[S:9][CH:10]=[C:11]([CH3:14])[C:12]=1[CH3:13])=[CH2:2]
Reactant: Cc1csc(C=O)c1C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=Cc1scc(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (714 mg, 2 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (1.25 mL, 2.00 mmol). The resultant solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-3,4-dimethylthiophene trimer (432 mg, 1.2 mol) was added slowly and the mixture was stirred overnight. The reaction mixture was quenched with ammonium chloride solution and diluted with ether. The organic phase was washed with water and brine, and dried with MgSO4. The ether was removed in vacuo to afford the crude product as an oil (260 mg). Column chromatography (2% EtOAc in hexane) afforded the purified 2-vinyl-3,4-dimethylthiophene trimer (140 mg, 37% yield). EI-MS: 358 (M+). 1H NMR (CDCl3) δ 6.98 (s, 1H), 6.90 (dd, 1H), 5.52 (d, 1H), 1.15 (d, 1H), 2.22 (s, 1H), 2.19 (s, 1H), 2.11 (s, 1H), 2.10 (s, 1H), 2.09 (s, 1H), 2.08 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CCOCC.[Br:16]Br>O1CCOCC1>[CH:5]1[C:4]([C:2]([CH2:1][Br:16])=[O:3])=[CH:9][CH:8]=[C:7]([Cl:10])[CH:6]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(Cl)cc1

Procedure:
To a stirred, cooled solution of 4-chloroacetophenone (100 g, 0.65 mole), anhydrous ether (650 ml) and dioxane (325 ml) was added bromine (35 ml, 0.65 mole) dropwise over a period of 1.25 hours, keeping the temperature at 20° C. (±5° C.). The solution was then washed with water (3 × 1 l). The collected ether layer was dried over magnesium sulfate and the ether solution was evaporated under reduced pressure to give a solid. The solid was washed with water, collected by filtration, and air-dried to give the α-bromo-4-chloroacetophenone.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][NH:5][C:4](=[S:9])[C:3]=1[C:10]#[N:11].C([O-])(=O)C.[Na+].Cl[CH2:18][C:19]#[N:20]>C(O)C.CC(O)C>[NH2:11][C:10]1[C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[N:5][C:4]=2[S:9][C:18]=1[C:19]#[N:20]
Reactant: N#CCCl
Reactant: Cc1n[nH]c(=S)c(C#N)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: Cc1nnc2sc(C#N)c(N)c2c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 5,6,-dimethyl-3-thioxo-2,3-dihydropyridazine-4-carbonitrile (99 mg, 0.60 mmol) was stirred in ethanol (6.0 mL). Sodium acetate (50 mg, 0.60 mmol) and chloroacetonitrile (0.040 mL, 0.60 mmol) were added and the mixture was stirred at ambient temperature for 90 minutes. The mixture was then diluted with IPA, stirred for 15 minutes, and filtered. The solute was concentrated in vacuo, and the resulting solid was dried overnight at 60° C. in a vacuum oven to give the product. LC/MS: RT=0.38 min., m/z=205 [M+H]+.
Reaction SMILES: [H-].[Na+].O[CH2:4][C@H:5]1[O:9][C:8](=[O:10])[CH2:7]C1.C(Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[C:8]([O:9][CH2:5][CH3:4])(=[O:10])[CH3:7].[CH3:16][CH2:17][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C1CC[C@@H](CO)O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.2 %

Procedure:
40 mL of DMF were added to 1.27 g (31.67 mmol, 60% dispersion in mineral oil) NaH and 5.26 g (31.67 mmol) KI at 0° C. under N2. A solution of 3.50 g (30.16 mmol) of (S)-(+)-dihydro-5-hydroxymethyl-2(3H)furanone (Aldrich) in 15 mL of DMF was then added drop wise. Slurry was allowed to warm to room temperature and stir for 2.5 hours, 5.4 mL (45.24 mmol) benzyl bromide were then added drop wise and mixture was heated to 50° C. and allowed to stir for 16 hours. Reaction was partitioned between 250 mL saturated NH4Cl(aq) and 250 mL ethyl acetate/hexane (60%). Organic layer was washed with water (3×200 mL), 200 mL brine, dried over Magnesium Sulfate and concentrated under reduced pressure. Crude residue was purified via chromatography, eluting with 35% ethyl acetate/hexane yielding 3.37 g (16.34 mmol, 54% yield) (S)—O-Benzyl-dihydro-5-hydroxymethyl-2(3H)furanone as a yellow oil. Step 2
Reaction SMILES: [F:1][C:2]1[C:3]([CH:22]([C:30]#[N:31])C(OC(C)(C)C)=O)=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][N:8]3[N:7]([CH3:21])[CH2:6][CH2:5]2)[CH:11]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:30]([CH2:22][C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][N:8]3[C:9]=2[C:4]=1[CH2:5][CH2:6][N:7]3[CH3:21])#[N:31]
Reactant: CCOC(=O)c1cn2c3c(c(C(C#N)C(=O)OC(C)(C)C)c(F)cc3c1=O)CCN2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cn2c3c(c(CC#N)c(F)cc3c1=O)CCN2C
Reaction time: 1.5 h
Yield: 33.4 %

Procedure:
1.60 g of the compound (162) obtained in Example 39 (2) was added to 20 ml of methylene chloride, and 6 ml of trifluoroacetic acid was added to the solution. The solution was stirred for 1.5 hours. 4 ml of trifluoroacetic acid was added to the solution, and the solution was stirred overnight. The solvent was removed by distillation, and the residue was crystallized from ethyl ether. Crystals were filtered off to obtain 410 mg of the subject compound (165).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][O:6][CH3:7])=[O:4].[OH:8]/[N:9]=[C:10](/[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)\[C:11]([OH:13])=[O:12]>CS(C)=O>[CH3:7][O:6][NH:5][C:3]([CH2:2][O:8]/[N:9]=[C:10](/[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)\[C:11]([OH:13])=[O:12])=[O:4]
Reactant: O=C(O)/C(=N\O)c1cccs1
Reactant: CONC(=O)CCl
Solvent: CS(C)=O
Product: CONC(=O)CO/N=C(\C(=O)O)c1cccs1
Yield: 34 %

Procedure:
This compound was prepared by the method of Preparation 4 from methyl chloroacetohydroxamate and E-2-hydroxyimino-2-(thien-2-yl)acetic acid, νmax (Nujol) 3380 (--NH--), 1750, 1729 (--CO2H), 3700-2400 (bonded OH), 1690 cm-1 (--CONH--), τ(DMSO d6) 2.2-3.0 (thienyl), 5.49 (--OCH2CO--), 6.38 (--OCH3). Yield 34%.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([O:20][CH3:19])=[O:30])[CH:23]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(CSc2nc3ccccc3n2CC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
A mixture of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-1,264 mg, 1 mmol), 3-bromomethyl-benzoic acid methyl ester (252 mg, 1.1 mmol) and K2CO3 (276 mg, 2 mmol) in acetone (4 ml) is allowed to stir at rt for 2.5 h. The suspension is cooled down to rt and filtered on a funnel filled with cotton wool. Evaporation of the solvent in vacuo affords a residue that is purified by flash-chromatography on silica-gel (AcOEt/heptane, 1:3), yielding the title compound (310 mg) in 75% as a colourless syrup: tR=7.19 min (LC-1), ESI-MS (pos.): m/z 413.3 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.42 (s, 9H, tBu), 3.92 (s, 3H, OMe), 4.65 (s, 2H), 4.69 (s, 1H), 7.19-7.26 (m, 3Harom), 7.36 (t, 1Harom), 7.59 (d, 1Harom), 7.73 (m, 1 Harom), 7.92 (d, 1Harom), 8.06 (s, 1Harom).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([CH3:17])=[C:12]([CH2:14][CH2:15][OH:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[CH3:18][S:19]([O:16][CH2:15][CH2:14][C:12]1[N:13]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=2)[S:10][C:11]=1[CH3:17])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(-c2nc(CCO)c(C)s2)ccn1
Product: CCc1cc(-c2nc(CCOS(C)(=O)=O)c(C)s2)ccn1

Procedure:
The product was obtained starting from 2-(2-(2-ethylpyridin-4-yl)-5-methylthiazol-4-yl)ethanol (200 mg, 805 μmol, prepared as described in WO 2003/037327) and methanesulfonyl chloride (111 mg, 75.3 μL, 966 μmol) according to the method described in example 46, step 1 as yellow oil (226 mg, 692 μmol, 86%) which was used without further purification for the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=[O:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:14]([Mg]Br)[CH3:15].[Cl-].[NH4+]>O1CCCC1>[OH:13][CH:12]([CH2:14][CH3:15])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)CCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 65 %

Procedure:
N-Methyl-(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester (2.00 g, 10.7 mmol) was dissolved in tetrahydrofuran (20 ml) under nitrogen and cooled to 0° C. with stirring. To the resulting solution was added ethylmagnesium bromide and the mixture stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature with stirring over 20 h. The mixture was then poured into saturated ammonium chloride solution and then extracted with diethyl ether three times. The combined organic fractions were then washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 40% diethyl ether/isohexane as eluent to give 1.70 g (65%) of the title compound as an oil.