Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(OCC)(=O)C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc2cccc(Br)c2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cccc2ccc(C)nc12
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of 8-bromo-2-methylquinoline (2.00 g, 9.01 mmol), Pd(PtBu3)2 (0.23 g, 0.45 mmol), Cs2CO3 (11.74 g, 36.02 mmol) and diethyl malonate (2.73 mL, 18.01 mmol) in dioxane (25 mL) was heated at 118° C. in a sealed tube for 1 hour. After cooling to ambient temperature, ethyl acetate (30 mL) and water (15 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1 hexane/ethyl acetate) to give diethyl 2-(2-methylquinolin-8-yl)malonate (2.24 g, 82.54%) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:23]1.C(N(CC)CC)C>CS(C)=O>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]2[CH2:25][CH2:26][N:22]([C:2]3[C:3]([CH:8]4[CH2:11][N:10]([C:12]5[CH:21]=[CH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[N:13]=5)[CH2:9]4)=[N:4][CH:5]=[CH:6][N:7]=3)[CH2:23]2)[CH:28]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: c1cncc(C2CCN(c3nccnc3C3CN(c4ccc5ccccc5n4)C3)C2)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a 3 mL vial was added 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.04000 g, 0.135 mmol), 3-(pyrrolidin-3-yl)pyridine (commerically available at Array Biopharma, 0.040 g, 0.270 mmol), and triethylamine (commerically available at Sigma Aldrich, 0.038 ml, 0.270 mmol) in DMSO (Solvent Volume: 0.449 ml) and the reaction was stirred at 110° C. overnight. Upon completion, the reaction was filtered into a 24 well plate and purified by reverse phase purification using the following conditions: (Instrumentation: MS—Waters SQ; UV—Waters 2487 or Waters PD; Solvents: A: Water w/0.1% NH4OH B: Acetonitrile w/0.1% NH4OH; Column: Phenomenex Gemini-NX C18 110A 5 um 21×100; Flow Rate: 44 mL/min. 10 min Method, variable gradient over 8 mins.)
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:22][N:23]=[C:24]=[O:25]>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:22][NH:23][C:24]([NH:16][C:13]1[S:14][CH:15]=[C:11]([CH2:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[N:12]=1)=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cc2csc(N)n2)cc1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Cc2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)cc1
Temperature: 150 °C
Yield: 66 %

Procedure:
4-(Toluene-4-sulfonylmethyl)-thiazol-2-ylamine (0.5 mmol) was dissolved in THF (3 ml) and 3,4-dichlorobenzylisocyanate (1.2 eq., 0.6 mmol) was added. The reaction was heated by microwave for 30 min. at 150° C. Solvent was removed in vacuo. The crude product was purified by column chromatography eluting with a gradient of 0-20% EtOAc (with 10% MeOH) in hexanes to give the title compound as a white solid in 66% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.3 %

Procedure:
To a solution of 4-chlorobenzylamine (859 mg, 6.07 mmol) in 1,2-dichloroethane (20 mL) was added t-butyl-4-oxo-piperidine-1-carboxylate (1.451 g, 7.282 mmol), acetic acid (400 uL), and sodium triacetoxyborohydride (1.800 g, 8.497 mmol). The mixture was stirred at rt under nitrogen for 2 h, diluted with ethyl acetate, washed thrice with saturated sodium bicarbonate solution and dried over magnesium sulfate. The extracts were filtered and concentrated to afford 4-(4-chloro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.49 g, >100%) as a yellow oil, which was of sufficient purity by H-NMR to use without further purification.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2]2.[FH:15].F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].C(Cl)Cl>ClCCCl>[F:15][C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][C@H:1]1[OH:7]
Reactant: F
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](O)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A mixture of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.46 g, 27.4 mmol) and triethylamine trihydrofluoride (4.42 g, 27.4 mmol) in DCE (4 mL) was stirred at 80° C. (bath) for 18 hours. After cooling to room temperature, saturated sodium bicarbonate (20 mL) and DCM (30 mL) were added. The organic phase was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (hexane:ethyl acetate 1:1) to give trans-tert-butyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (3.5 g, 58%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Br[CH2:40][CH2:41][OH:42]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:40][CH2:41][OH:42])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(CCO)CC1
Temperature: 70 °C

Procedure:
5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 7, 0.087 mmol) is dissolved in anhydrous DMF (1 mL). TEA (0.04 mL, 0.262 mmol, 3 equiv.) is added followed by 2-bromo-ethanol (0.019 mL, 0.262 mmol, 3 equiv.) dissolved in anhydrous DMF (0.7 mL). The reaction vessel is sealed and heated at 70° C. for 12 h. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (5×), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product is purified using preparative RP LC-MS to give 2-[4-(4-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidin-1-yl]ethanol (72) as a yellow powder: ESMS m/z 602.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzaldehyde (12.13 ml, 110 mmol, Aldrich) and pinacolone (12.48 ml, 100 mmol, Aldrich) in absolute ethanol (120 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 3.72 ml, 10 mmol). The clear yellow reaction mixture was stirred at room temperature under argon for 24 hours. The reaction mixture was concentrated to 1/3volume and partitioned between 50% saturated NH4Cl and EtOAc. The layers were separated and the organic layer was washed twice with H2O and brine, then dried (Na2SO4) and concentrated under reduced pressure. The oily residue was purified by flash chromatography (Merck Silica gel, 10% EtOAc/hexane), yielding the title compound as a colorless oil that slowly solidified. The white solid was recrystallized from hexane, yielding the title compound as white crystals (13.9 g, 67.5%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH3:9].[Ca]>>[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: N
Reactant: O=C(O)CCC(=O)O
Agent: [Ca]
Product: O=C([O-])CCC(=O)[O-]
Product: [NH4+]

Procedure:
2.24 kg of the slurry solution obtained in the above salt substitution reaction was separated into the filtrate and precipitate by a Nutsche funnel filtration. Finally, 1.82 kg of the solution and 0.42 kg of the precipitates were obtained. The molar ratio of the succinic acid in the solution was 1.92 to ammonia and 0.13 to calcium, respectively. It was found that 91% of calcium was removed as precipitates by the salt substitution reaction, and an ammonium succinate solution was obtained. Calcium in the removed precipitates was 32.2% of the total solid matter, and succinic acid was less than 8.0%.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](F)=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=1)[CH2:2][CH2:3][CH3:4].O[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C(=O)N(C)C>[CH2:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Oc1cccnc1
Reactant: CCCCOC(=O)c1ccc(F)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C(=O)N(C)C
Product: CCCCOC(=O)c1ccc(-c2cccnc2)c(C(C)=O)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
1.5 g of 3-acetyl-4-fluoro-benzoic acid n-butylester, 0.6 g of 3-hydroxypyridine and 4.1 g of Cs2CO3 are stirred in 20 ml of tetramethylurea for 2 h at 110° C. After cooling to RT the mixture is poured into 200 ml EE and the mixture is washed 3 times with 100 ml brine. Drying takes place over Na2SO4 and the solvent is distilled off in vacuo. Chromatography over silica gel with MTB furnishes 1.3 g of a pale yellow oil. Rf (MTB)=0.30 MS (DCl): 314 (M+H)+
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([OH:11])(=[O:10])[CH:8]=[CH2:9]>C=CC1C=CN=CC=1.Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:7]([O:11][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)(=[O:10])[CH:8]=[CH2:9]
Reactant: C1=COCCC1
Reactant: C=CC(=O)O
Agent: C=Cc1ccncc1
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)OC1CCCCO1
Temperature: 65 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 310 mL (2.75 mol) of 3,4-dihydro-2H-pyran, 99.1 g (94 mL, 1.38 mol) of acrylic acid, 5 g of crosslinked poly(4-vinylpyridine hydrochloride) (Fluka Chemical Corp., catalog number 82803, 6 meq/g), and 0.5 g of phenothiazine was warmed until an exothermic reaction caused the temperature to rise to 99° C. An ice bath was used to cool the mixture to 65° C., and the mixture was stirred at 65° C. for 18 hours. After cooling to room temperature, the mixture was filtered to remove the catalyst. NMR analysis of the filtrate showed the presence of 2-tetrahydropyranyl acrylate and 3,4-dihydro-2H-pyran with little or no acrylic acid. The mixture was stirred with anhydrous sodium carbonate and calcium hydride for 1 hour. After removal of excess 3,4-dihydro-2H-pyran in a rotary evaporator, distillation over calcium hydride, anhydrous sodium carbonate, and phenothiazine gave 136.6 g of 2-tetrahydropyranyl acrylate, b.p. 66°-70° C. (3.2 mm).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH:17]=[CH:16]1>C1(C)C=CC=CC=1>[C:8]1([S:14][CH:17]2[CH2:16][C:15](=[O:21])[O:20][C:18]2=[O:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CC(Sc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.5 %

Procedure:
Triethylamine (0.8 ml) was added dropwise to a solution of benzenethiol (9.3 ml, 91 mmol) and maleic anhydride (8.9 g, 91 mmol) in toluene (125 ml). After stirring at room temperature for 12 hr the solvent was evaporated to leave 20 g of crude 3-phenylsulfanyl-dihydro-furan-2,5-dione as a brown oil. 1H NMR (CDCl3) δ 7.20-7.70 (5H, m), 4.20 (1H, dd), 3.40 (1H, dd), 2.90 (1H, dd).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)[CH:13]=2)[CH:8]=1)(=O)=O.CN(C=O)C.[CH3:32][C:33]#[CH:34].Cl>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[F:24][C:19]1[CH:18]=[C:17]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:32]#[C:33][CH3:34])[CH:8]=3)[CH:13]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: O=S(=O)(Oc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1)C(F)(F)F
Reactant: C#CC
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#Cc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Reaction time: 2 h

Procedure:
11.4 g of 6-(3,4-difluorophenyl)-2-naphthyl trifluoromethanesulfonate and 60 ml of DMF were dissolved in 20 ml of triethylamine. To the solution were then added 0.4 g of tetrakis(triphenylphosphine)palladium (0) and 0.1 g of copper iodide (I). Methyl acetylene was then introduced into the reaction mixture at ordinary temperature and pressure. The reaction mixture was then stirred for 2 hours. The reaction solution was neutralized with a 10% hydrochloric acid, extracted with 100 ml of toluene, and then washed with water and saturated brine. The solvent was then distilled off. The residue was then purified through silica gel column chromatography (hexane) to obtain 7.4 g of 2-(3,4-difluorophenyl)-6-(1-propinyl)naphthalene.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH2:12][O:13][C:14]([CH3:16])=[O:15].[N+:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][CH:27]=[O:28])[N:21]=1)([O-:19])=[O:18].O>C1COCC1>[OH:28][CH:27]([CH2:26][CH2:25][N:22]1[CH:23]=[CH:24][C:20]([N+:17]([O-:19])=[O:18])=[N:21]1)[CH2:16][C:14]([O:13][CH2:12][CH3:11])=[O:15]
Reactant: CCOC(C)=O
Reactant: O=CCCn1ccc([N+](=O)[O-])n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)CCn1ccc([N+](=O)[O-])n1
Reaction time: 0.25 h

Procedure:
Lithium bis(trimethylsilyl)amide (10 ml. of a 1M solution in THF) was cooled to -75° under argon and freshly distilled EtOAc (0.88 g.) was added over 5 minutes. Crude 3-(3-nitropyrazol-1-yl)propionaldehyde (1.75 g.) in dry THF (10 ml.) was added at -75° over 10 minutes and the mixture was kept at -75° for a further 15 minutes then allowed to warm to 20° . Water (200 ml.) was added and the mixture was extracted with EtOAc (3×60 ml.). The extracts were dried (MgSO4) and evaporated in vacuo to give crude ethyl 3-hydroxy-5-(3-nitropyrazol-1-yl)valerate as an oil (2.41 g.) which was used in the next stage without further purification. The n.m.r. spectrum in CD3OD included the following resonances: 7.76 (d, 1H): 6.86 (d, 1H); 4.36 (t, 2H); 4.1 (q, 2H); 3.9 (m, 1H); 2.47 (d, 2H); 2.1 (m, 2H); 1.24 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#N.C[Li].[OH2:36].[CH2:37](OCC)C>>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)(=[O:36])[CH3:37]
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(C#N)c2)c1)C(=O)OC(C)(C)C
Reactant: CCOCC
Reactant: O
Agent: [Li]C
Product: CC(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of tert-butyl ({1-[(3-cyanophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (431 mg) in diethyl ether (4 mL) was added a 1.0 mol/L solution (2.4 mL) of methyllithium in diethyl ether at −78° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a brown oil (yield 110 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19](CCl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27].[CH3:31]N(C)C=O>>[C:26]([NH:30][C:19]1[O:18][N:17]([CH3:31])[CH:16]([C:15]2[N:14]=[CH:13][N:12]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=4[C:8](=[O:25])[N:9]4[CH2:24][CH2:23][C@H:10]4[C:11]=23)[N:20]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CN(C)C=O
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CC(C)(C)N
Product: CN1OC(NC(C)(C)C)=NC1c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Yield: 88 %

Procedure:
0.94 g (2.5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was stirred at room temperature overnight with 2 g (27 mmol) of tert.-butylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there was obtained 0.91 g (88%) of (S)-1-(5-tert.-butylamino-methyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=4)[C:19]#[N:20])[N:8]3[N:7]=2)[CH2:5][CH2:4]1.[CH3:25]S(Cl)(=O)=O.CCN([CH:36]([CH3:38])[CH3:37])C(C)C>C(Cl)Cl>[CH2:37]([O:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=4)[C:19]#[N:20])[N:8]3[N:7]=2)[CH2:4][CH2:5]1)[CH:36]([CH3:38])[CH3:25]
Reactant: COc1ccc(-c2cncc(C#N)c2)n2nc(C3(CO)CC3)nc12
Reactant: CS(=O)(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cncc(C#N)c2)n2nc(C3(COCC(C)C)CC3)nc12
Reaction time: 0.5 h

Procedure:
Compound 248 (0.02 g, 0.06 mmol) was dissolved in DCM (2 mL). TEA (0.035 mL, 0.25 mmol) and methanesulfonyl chloride (0.007 mL, 0.09 mmol) were added and stirred under argon for 30 min. The reaction mixture was washed with H2O and the organic phase was filtered through a phase separation cartridge (chromabond PTS). The solvent was concentrated and the crude product was suspended in iso-butanol (6 mL) under an argon atmosphere. DIPEA (0.05 mL, 0.31 mmol) was added and the mixture was stirred at 60° C. for 18 h. Iso-butanol was evaporated and the crude product was purified by preparative HPLC/MS to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1)=[C:20]=[S:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:19][C:20]([NH:14][C:13]2[C:8]([O:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][CH:10]=[CH:11][CH:12]=2)=[S:21])=[CH:23][CH:24]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1ccc(N=C=S)cc1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=S)Nc2cccnc2Oc2ccccc2C(C)(C)C)cc1
Yield: 19.7 %

Procedure:
127.15 mg (0.525 mmol) of 1b were mixed with 92.16 mg (0.525 mmol) of 1-(4-isothiocyanatophenyl)ethanone, 5 mL of CH2Cl2 and 6.61 mg (0.052 mmol) of DMAP and refluxed under Argon for 72 h. 225a was filtered and purified by crystallization in MeOH to yield 43.3 mg of an off-white solid used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=O>CN(C)C=O>[Br:14][C:15]1[C:16]2[CH:17]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[S:3][C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Br)cccc2s1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Methyl thioglycolate (42.35 g) was added under nitrogen at 80° C. to a solution of triethylamine (109 ml) in dimethylformamide (290 ml), the mixture was stirred at 100° C. for 15 minutes, then a solution of 2-bromo-6-fluorobenzaldehyde (81.35 g; prepared in a manner similar to that described above) in dimethylformamide (70 ml) was added. The mixture was stirred at 130° C. for 5 hours, then it was cooled to ambient temperature and poured into ice-water (3000 ml). The resulting solid was collected by filtration, washed with water (2×250 ml) and dried in air to give methyl 4-bromobenzo[b]thiophene-2-carboxylate (101 g) as a yellow solid which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][C:13]1([CH2:26][OH:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[Cl:11][CH2:12][C:13]1([CH:26]=[O:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CCl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)(CCl)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a −78° C. solution of oxalyl chloride (5.1 mL, 57 mmol) in dichloromethane (100 mL) in an oven-dried round-bottomed flask was added dimethylsulfoxide (8.2 mL, 114 mmol) in dichloromethane (17 mL). The mixture was stirred for 2 minutes and tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (13.7 g, 52 mmol) in dichloromethane (50 mL) was added over 10 minutes. The solution was stirred for 15 minutes at −78° C. and triethylamine (36 mL, 260 mmol) was added. The mixture was stirred at −78° C. for 15 minutes and was warmed to room temperature. The mixture was stirred for 15 minutes at room temperature and was quenched with saturated aqueous NaHCO3 (200 mL). The aqueous solution was washed with Et2O (2×300 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow oil that solidified upon standing under nitrogen atmosphere at room temperature (13.7 g, 99%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.60 (m, 2H), 2.00-2.07 (m, 2H), 3.07 (t, 2H), 3.57 (s, 2H), 3.69-3.79 (m, 2H), 9.55 (s, 1H).