Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24]1([S:34](Cl)(=[O:36])=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][S:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)(=[O:36])=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 1-naphthalenesulfonyl chloride (107 mg, 0.47 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (109 mg, 50%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]4[O:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[C:13]=4[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[C:15](=[O:20])[C:16]=3[C:17](O)=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.S(Cl)(Cl)=O.[C:51]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]4[O:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[C:13]=4[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[C:15](=[O:20])[C:16]=3[C:17]([NH:60][S:57]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:59])=[O:58])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1c(-c2ccc3c(c2)OCCO3)c2oc3ccccc3c2n(Cc2ccc3c(c2)OCO3)c1=O
Reactant: NS(=O)(=O)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(NS(=O)(=O)c1ccccc1)c1c(-c2ccc3c(c2)OCCO3)c2oc3ccccc3c2n(Cc2ccc3c(c2)OCO3)c1=O
Reaction time: 10 h

Procedure:
A solution of 4.85 g of 4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxobenzofuro-[3,2-b]pyridine-3-carboxylic acid and 0.2 g of dimethylaminopyridine in 50 ml of pyridine is treated with 5 ml of thionyl chloride and 1.57 g of phenylsulfonamide. The mixture is stirred for 10 hours and worked up in the customary manner, and 4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxo-3-(phenylsulfonamidocarbonyl)benzofuro[3,2-b]pyridine is obtained.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:16]N1CCCCC1.[CH3:27][N:28]([CH:30]=O)[CH3:29]>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:16][CH:6]1[CH2:7][CH2:29][N:28]([CH2:27][C@H:3]([OH:10])[CH2:4][N:2]2[C:3](=[O:10])[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:11])[CH2:30][CH2:5]1
Reactant: Clc1ccc(ON2CCCCC2)cc1Cl
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione (Tetrahedron Asymmetry, 1996, 7, 1641, 5 g) in a mixture of 50 ml of ethanol and 15 ml of DMF was treated with 4 (3,4-dichlorophenoxy)-piperidine (6 g). The mixture was stirred overnight at room temperature. The solution was concentrated under vacuum and the residue was azeotroped twice with toluene. The crude material was purified by chromatography (ethyl acetate) to give the subtitle compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:23]([CH2:27][C:28](Cl)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[C:4]([NH:13][C:28](=[O:29])[CH2:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1
Reactant: Nc1cc(Br)ccc1NCC1CC1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCC1CC1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a solution of 4-bromo-N1-(cyclopropylmethyl)benzene-1,2-diamine (Step B, 11.3 g, 46.9 mmol) and N,N′-diisopropylethylamine (6.06 g, 46.9 mmol) in ethyl acetate (88 mL) was added tert-butylacetyl chloride (6.31 g, 46.9 mmol) at 0° C. and the mixture was allowed to warm to room temperature for 15 h. The mixture was washed with saturated sodium hydrogencarbonate aqueous solution-(100 mL×2), brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate to afford the title compound (11.2 g, 70%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33]([NH:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([NH:36][CH2:37][C:38]([NH:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC(=O)NCC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (13 mg, 28 mmol) was dissolved in abs. pyridine (2.0 ml). At room temperature, acetamidoacetyl chloride (8 mg, 57 mmol, 2 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (9.6 mg, 65% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[O:8])[CH:2]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH:9]([CH3:20])[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1cccnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28 g of 2,4-dichlorobenzyl 3-pyridyl ketone are dissolved in 800 ml of dimethylformamide and treated portionwise at 0° C. with 5.5 g of sodium hydride (50% dispersion in oil). After 2 hours at room temperature 14.9 g of methyl iodide are added and the mixture is stirred at room temperature for a further 3 hours. The mixture is then poured into water and extracted with diethyl ether. The organic phase is washed, dried over anhydrous sodium sulfate and subsequently concentrated. By chromatography on silica gel with n-hexane/ethyl acetate (1:2) there is obtained 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:4]=2[N:3]=1.CN(C=O)C.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:18][CH2:17][C:15]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:2]([Cl:1])=[N:3][C:4]=2[CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCCOCn1c(Cl)nc2cc(CO)ccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCn1c(Cl)nc2cc(COCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of [2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-5-yl]-methanol (100 mg, 0.370 mmol) and DMF (3 mL) was added NaH (30.0 mg, 0.740 mmol, 60% suspension in mineral oil) at 0° C. The reaction mixture was stirred for 1 h at 0° C., then treated with benzyl bromide (52.0 μL, 0.440 mmol). The reaction mixture was stirred for 16 h. Water (5 mL) was added and the product was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-50% EtOAc/hexanes) to provide the titled compound (100 mg, 75%). MS (ESI/CI): mass calcd. for C19H21ClN2O3, 360.1; m/z found, 361.1 [M+H]+
Reaction SMILES: Cl.[Sn].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=[O:21])[CH:16]=3)[C:11]2=O)=[CH:7][CH:6]=1.[C:26](O)(=O)C>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([O:22][CH3:26])=[O:21])[CH:16]=3)[CH2:11]2)=[CH:24][CH:25]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CN2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1
Agent: Cl
Agent: [Sn]
Product: COC(=O)c1ccc2c(c1)C(=O)N(Cc1ccc(OC)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Concentrated hydrochloric acid (30 ml) and a tin powder (3.2 g) were added to a suspension of 2-(4-methoxybenzyl)-1,3-dioxoisoindoline-5-carboxylic acid (3.13 g) in acetic acid (30 ml), followed by stirring at room temperature for 12 hours, and a tin powder (1.2 g) was further added thereto, followed by stirring at room temperature for one day. An insoluble substance was filtered with celite, water was added to the filtrate, followed by extraction with ethyl acetate, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was made into a DMF (50 ml) solution, potassium carbonate (7.0 g) and iodomethane (6.3 ml) were added thereto, followed by stirring at room temperature for 4.5 days. The reaction solution was concentrated and ethyl acetate was added to the residue, followed by washing with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain methyl 2-(4-methoxybenzyl)-3-oxoisoindoline-5-carboxylate (910 mg) as a colorless solid.
Reaction SMILES: [S:1]1[C:5]2[C:6](C(Cl)=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:13]([O-:19])(=[O:18])[CH2:14][C:15]([O-:17])=[O:16].C(N(CC)CC)C.O1C[CH2:30][CH2:29][CH2:28]1>CN(C)C1C=CN=CC=1.ClCCl>[S:1]1[C:5]2[C:6]([CH:14]3[C:13](=[O:19])[O:18][C:29]([CH3:30])([CH3:28])[O:16][C:15]3=[O:17])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: C1CCOC1
Reactant: O=C([O-])CC(=O)[O-]
Reactant: O=C(Cl)c1cccc2nnsc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)C(c2cccc3nnsc23)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5.5 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in 10 ml of tetrahydrofuran are added dropwise to a solution, stirred at 0° C., of 3.6 g of cycloisopropylidene malonate, 7.6 ml of triethylamine and 2.0 g of 4-dimethylaminopyridine in 25 ml of dichloromethane. The reaction mixture is stirred for 2 hours at 0° C. and then applied directly to a silica gel column and extracted with ethyl acetate, resulting in the title compound in the form of a salt with 4-dimethylaminopyridine (2:1), m.p. 170°-172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[CH:4][CH:3]=1.C([O-])(O)=[O:28].[Na+].OOS([O-])=O.[K+].O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16]([CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[O:28])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylic acid (11) (261 mg, 0.68 mmol) in acetone (7 mL) was added 0.2 M NaHCO3 (7 mL) and Oxone (1.05 g, 1.71 mmol) and stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazole-5-carboxylic acid (20) as a white solid.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[CH2:16][CH2:17][C:18](=[CH:20][C:21]#[N:22])[C:19]=3[C:11]=2[N:10]=[C:9]1[CH3:23])C1C=CC=CC=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N.C(O)C.[Co]>[CH3:23][C:9]1[NH:10][C:11]2[C:19]3[CH:18]([CH2:20][CH2:21][NH:22][C:31](=[O:33])[CH3:32])[CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][C:12]=2[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=CC#N
Agent: [Co]
Agent: N
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)NCCC1CCc2ccc3nc(C)[nH]c3c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
(3-Benzyl-2-methyl-6,7-dihydroindeno[4,5-d]imidazol-8(3H)-ylidene)acetonitrile was dissolved in 2M ammonia/ethanol solution (14 mL), Raney cobalt (10 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL), triethylamine (34.9 μL, 0.25 mmol) and acetic anhydride (18.9 μL, 0.20 mmol) were added, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→15/85). The purified product was dissolved in methanol (3 mL), palladium-carbon powder (20 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→20/80) to give the title compound (13.4 mg, yield 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][O:11][CH2:12]Cl.CCN(C(C)C)C(C)C.[O:23]=C1C2C=CC=CC=2OC=C1>C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:23][CH2:12][O:11][CH3:10])[C:2]=1[F:1]
Reactant: O=c1ccoc2ccccc12
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(Cl)c1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 51.3 g (350 mmole) of 3-fluoro-4-chlorophenol in 700 mL of CH2Cl2 under N2 was prepared and cooled to 5° C. The stirred mixture was treated with 35.3 mL (37.5 g, 465 mmole) of chloromethyl methyl ether. The reactor was equipped with a thermocouple and an addition funnel. To the stirred mixture was added dropwise 61 mL of DIEA (45.2 g, 350 mmole) such that the temperature did not exceed 10° C. After 30 min, an additional 30 mL of DIEA was added dropwise. After a total of 1 h, an additional 30 mL of DIEA was added. The mixture was allowed to stand overnight. The solution was washed with 900 mL of 1N HCl and the aqueous layer extracted three times with Et2O. Combined extracts were dried with Mg2SO4, carefully concd and distilled in vacuo 78-81° C. @ 9 torr to afford 62.5 g (93.7%) of a clear, colorless liquid: 1H NMR (CDCl3/400 MHz) 3.46 (s, 3H), 5.13 (s, 2H), 6.77 (ddd, J=1H, 8.9 Hz, 2.8 Hz, 1.3 Hz), 6.87 (dd, 1H, J=10.7 Hz, 2.8 Hz), 7.26 (t, 1H, J=8.7 Hz); 19F NMR (CDCl3/400 MHz) −113.5 (t, 1F, J=9.7 Hz); 13C NMR (CDCl3/100 MHz) 56.1, 94.6, 105.2 (d, J=24.2 Hz), 112.8 (d, J=3.4 Hz), 130.5 (d, J=1.1 Hz), 156.9 (d, J=9.7 Hz), 158.3 (d, J=248.1 Hz); MS (EI+) 190 (M+, 12), 129 (8), 117 (8), 45 (100); HRMS (EI) m/z calcd for (C8H8O2ClF) 190.0197, found 190.0175.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.[O:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36].[H-].[Na+].CCOC(C)=O>CN(C=O)C>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][N:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:33]2[CH2:34][CH2:35][O:31][C:32]2=[O:36])[N:4]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10]
Reactant: COc1ccc(CN(C(=O)NCc2cccc(F)c2)c2nc(CCl)cs2)c(OC)c1
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)NCc2cccc(F)c2)c2nc(CN3CCOC3=O)cs2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Chloromethyl-thiazol-2-yl)-1-(2,4-dimethoxy-benzyl)-3-(3-fluoro-benzyl)-urea (Intermediate 21, 0.3 mmol) was taken up in DMF (2 ml). A solution of the oxazolidin-2-one (or sultam) (1 eq.) with NaH (1 eq.) in DMF (2 ml) was added. The reaction was allowed to stir at room temperature for 2 hours. An aqueous workup with EtOAc was performed. Purified by column chromatography using a gradient of 0-100% EtOAc/hexanes to give 1-(2,4-dimethoxybenzyl)-3-(3-fluorobenzyl)-1-(4-((2-oxooxazolidin-3-yl)methyl)thiazol-2-yl)urea.
Reaction SMILES: [OH:1][C:2]([C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1)([CH3:8])[C:3](OCC)=[O:4].O.[NH2:16][NH2:17]>CCO>[OH:1][C:2]([C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1)([CH3:8])[C:3]([NH:16][NH2:17])=[O:4]
Reactant: CCOC(=O)C(C)(O)c1nc(C)cs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1csc(C(C)(O)C(=O)NN)n1
Yield: 77.5 %

Procedure:
A solution of Intermediate 106 (4.14 g, 19.23 mmol) in EtOH (60 mL) was treated with hydrazine monohydrate (FLUKA, 9.35 mL, 192 mmol). Mixture was heated at reflux for 3 h. Reaction mixture was concentrated. Residue was triturated with a mixture of DCM/Hexane and finally ether, and was filtered. Crude was purified by silica gel chromatography using a linear gradient of DCM/MeOH (0-5%) as eluents to obtain the title compound (3 g, 14.91 mmol, 78% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.05 (br s, 1H), 7.16 (s, 1H), 6.59 (s, 1H), 4.23-4.25 (m, 2H), 2.32 (s, 3H), 1.67 (s, 3H). [ES+MS] m/z 202 (MH+).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:20][C:19]=3[C:29]([F:32])([F:31])[F:30])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:20][C:19]=3[C:29]([F:30])([F:32])[F:31])(=[O:16])=[O:17])[CH2:12][N:11]2[C:33](=[O:35])[CH3:34])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-n4ccnc4)cc3C(F)(F)F)CN2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)N1C[C@H](S(=O)(=O)c2ccc(-n3ccnc3)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(4-imidazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment D10 was acylated with acetic anhydride in analogy to experiment L29 to give (2S,4R)-1-acetyl-4-(4-imidazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 496.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:5]2O[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)[CH2:4][CH2:3]1.[OH-].[NH4+:13]>>[CH3:1][C:2]1([C:5]2[NH:13][CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: [NH4+]
Reactant: CC1(c2cc(=O)cco2)CC1
Agent: [OH-]
Product: CC1(c2cc(=O)cc[nH]2)CC1

Procedure:
A mixture of 2-(1-methyl-cyclopropyl)-pyran-4-one (Step 40.6) (440 mg, 2.93 mmol) and a 30% aqueous solution of ammonium hydroxide (100 mL) is stirred for 1 h at reflux, allowed to cool and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1→92:7:1) to afford 333 mg of the title compound as a yellow solid: ESI-MS: 150.0 [M+H]+; tR=1.25 min (System 1).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:25])[CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.C([Cl:29])(=O)C>C(O)C>[ClH:29].[CH3:1][NH:2][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:25])[CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:15]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)CCN2CCCCC2)CC1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CNC1CCN(C(=O)CCN2CCCCC2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
tert-Butyl methyl(1-(3-(piperidin-1-yl)propanoyl)piperidin-4-yl)carbamate (2.461 mmol, 1 eq) was dissolved in ethanol (9 ml), and acetyl chloride (12.31 mmol, 5.0 eq) was added while cooling with ice. The reaction mixture was stirred for 16 hours at RT and then concentrated. The residue was taken up in a small amount of acetone, and a solid was precipitated by addition of diethyl ether. The solid was filtered off, washed with diethyl ether and dried. Yield: >99%
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]2[C:11]([CH3:12])=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1.S(Cl)([Cl:15])=O>C1COCC1>[ClH:15].[Cl:1][CH2:3][C:4]1[N:5]2[C:11]([CH3:12])=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncc2scc(CO)n12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ncc2scc(CCl)n12
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
3-Hydroxymethyl-5-methylimidazo[5,1-b]thiazolehydrochloride (1.10 g) is suspended in 20 ml of THF, 0.7 ml of thionyl chloride is added thereto, and the mixture is stirred at 85° C. for 3.5 hr. The solvent is removed by evaporation to give 1.10 g of 3-chloromethyl-5-methylimidazo[5,1-b]thiazolehydrochloride. This compound is dissolved in 7 ml of DMF, 1.36 g of triphenylphosphine is added thereto, and the mixture is stirred at 83° C. for 15 hr and at 90° C. for 4 hr. The resultant precipitate is collected by filtration and washed with diethyl ether to give 1.87 g of (5-methylimidazo[5,1-b]thiazol-3-yl)methyltriphenylphosphonium chloride hydrochloride.