Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].C[O:35][C:36](=O)[CH:37](Cl)[C:38](OC)=[O:39].[BH4-].[Na+]>C(#N)C.CCOC(C)=O.O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH:37]([CH2:38][OH:39])[CH2:36][OH:35])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1O
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OC(CO)CO
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 11 (150 mg, 0.41 mmol) in acetonitrile (10 mL) are added K2CO3 (80 mg, 0.61 mmol) and dimethylchloromalonate (82 mg, 0.49 mmol). The reaction mixture is stirred at 65° C. for 3 h, and is then diluted with EtOAc, washed with water, dried over MgSO4, filtered and evaporated. The residue is purified by prep. TLC (eluting with Heptane/EA 4:1) and is then dissolved in ethanol (10 mL). NaBH4 (60 mg, 1.59 mmol) is added and the reaction mixture is stirred at rt for 3 h. After cooling to 5° C., water is added and the compound is extracted twice with EtOAc. The org. phase is dried over MgSO4, filtered, concentrated and purified by prep. TLC (eluting with Heptane/EA 1:1) to give the title compound as a yellow wax (54 mg); LC-MS: tR=1.06 min; [M+H]+=442.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[C:32]([CH3:34])([CH3:33])[O:31][B:30]([OH:35])[C:29]=2[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCCCCC.CCOC(C)=O>[OH:35][B:30]1[C:29]2[CH:36]=[C:25]([NH:24][C:10](=[O:11])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[CH:26]=[CH:27][C:28]=2[C:32]([CH3:34])([CH3:33])[O:31]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: CC1(C)OB(O)c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of (R)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (LXVI) (1.17 g, 3.5 mmol) and 6-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVIII) (0.62 g, 3.5 mmol) in DCM (35 mL) were added DIPEA (1 mL, 5.3 mmol) and HATU (1.4 g, 3.7 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed sequentially with 1 M aqueous HCl, 1 M aqueous NaOH, and brine, and was dried over MgSO4. The solvent was evaporated and the crude product was purified by flash chromatography using on a first column (DCM/MeOH 500/1→300/1→200/1→100/1), and on a second column (hexane/EtOAc 5/1→4/1→3/1), to give 1.00 g of pure (R)-tert-butyl 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (CLXII) as an off-white solid (1.0 g, 2.03 mmol, 60% yield). 1H NMR (CDCl3) δ ppm 1.40 (s, 9H), 1.50 (s, 6H), 3.13 (dd, J=13 Hz, J=14 Hz, 1H), 3.27 (dd, J=13 Hz, J=13 Hz, 1H), 4.48-4.60 (brs, 1H), 5.13-5.26 (brs, 1H), 7.17 (d, J=8 Hz, 1H), 7.26 (d, J=2 Hz, 1H), 7.36 (d, J=5 Hz, 2H), 7.55 (d, J=5 Hz, 2H), 7.58 (d, J=8 Hz, 1H), 8.11-8.16 (brs, 1H); 19F NMR (CDCl3) δ ppm −61.88 (s, 3F); ESIMS found for C24H28BF3N2O5 m/z 493.6 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CC(=O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (220 g, 2.5 mol), stearyl alcohol (675 g, 2.5 mol) and p-toluenesulfonic acid monohydrate (1.2 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (1 mmHg, 110 to 120° C.) to give stearyl pyruvate (512 g, yield: 80%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.O[C@H:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N(C(OCC)=O)=NC(OCC)=O>[CH2:31]([C@H:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(O[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
Into a solution of tert-butyl 2(4-hydroxybenzoyl)hydrazinecarboxylate (200 mg, 0.79 mmol) and benzyl (R)-(+)-2-hydroxy-3-phenylpropionate (Aldrich) (270 μL, 1.19 mmol) were added triphenylphosphine polymer bound (Fluka, 3 mmol/g, 400 mg) and diethyl azodicarboxylate (190 μL) at 0° C. The resulting mixture was allowed to stir for 2 hr at 0° C. After filtration and rinsing the resin with DCM, the filtrate was evaporated off under vacuo to give a brown residue. Purification by flash chromatography (SiO2, AcOEt/chexanes (2/3)) gave the title compound as a white powder (216 mg, 56%) in 99.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]([F:19])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:10]=2[N:11]=1.[C:20](=O)([O-])O.[Na+].CI>CN(C)C=O.CCOCC>[F:19][C:2]([F:1])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:20])=[O:17])=[CH:12][C:10]=2[N:11]=1
Reactant: O=C(O)c1ccc2oc(SCCC=C(F)F)nc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)c1ccc2oc(SCCC=C(F)F)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
To a stirred solution of 2-(4,4-difluorobut-3-enylthio)benzoxazole-5-carboxylic acid (400 mg) in dimethylformamide (5 cm3) was added sodium hydrogen carbonate (224 mg) and methyl iodide (284 mg). The reaction mixture was stirred at the ambient temperature for 1 hour. The reaction mixture was filtered through High-flo to remove solid material and the filtrate evaporated to give a yellow oil. This oil was taken up in ether and washed with water. The ether was dried (MgSO4) and evaporated to give a yellow oil when crystallised on standing. Recrystallisation from hexane gave methyl 2-(4,4-difluorobut-3-enylthio)benzoxazole-5-carboxylate as a white solid (31 mg). 1H NMR (CDCl3): δ8.29(1H,d); 8.03(1H,dd); 7.48(1H,d); 4.32(1H,ddt); 3.94(3H,s); 3.36(2H,t); 2.58(2H bq).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.[OH:31][CH:32]1[O:48][C@H:47]([CH2:49][OH:50])[C@@H:37]([O:38][CH2:39][C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)[C@H:35]([OH:36])[C@@H:33]1[OH:34].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:5])[OH:10].[OH:31][CH:32]1[O:48][C@H:47]([CH2:49][OH:50])[C@@H:37]([O:38][CH2:39][C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)[C@H:35]([OH:36])[C@@H:33]1[OH:34]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)C(O)O[C@@H]2CO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of Fmoc-Asp(O-tBu)-Man(4-MBzl) (3.5 g) and 50% TFA in methylene chloride (50 mL) was stirred at room temperature for 45 min. The solvent was evaporated and the product was precipitated by the addition of ether. The solid was collected and air dried to yield a white solid (2.23 g, 70%). mp 155°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:18][CH2:19][CH2:20]CBr>CC(C)=O>[Br:18][CH2:19][CH2:20][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: BrCCCBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 500 mL flask was charged with 4-amino-3-nitrophenol (15.4 g, 100 mmol, commercially available from Aldrich). Acetone (300 mL), cesium carbonate (39.09 g, 120 mmol) and 1,3-dibromopropane (40.84 mL, 400 mmol) were added to the flask and stirred at refluxed temperature. The reaction was monitored by LCMS. After 6 hours, the reaction mixture was cooled to room temperature, filtered and washed with acetone. The organic layer was removed on a rotary evaporator under reduced pressure and the resulting material was purified by silica column chromatography using 40% hexane in dichloromethane as eluant. 20 g of 4-(2-bromoethoxy)-2-nitroaniline was isolated which was used in the next step without any further purification. MS (EI): 275 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=1>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:16]=[CH:17][CH:18]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc(Br)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (6.0 g, 27 mmol, Aldrich, Cat. No. 539112) and tert-butyl (3-aminophenyl)carbamate (6.7 g, 32 mmol, Aldrich, Cat. No. 53175) in N-methylpyrrolidinone (30 mL) was heated at 150° C. overnight. The solution was cooled to room temperature (r.t.) and quenched with NaHCO3 aqueous solution, then extracted with ethyl acetate twice. The combined organic phases were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired compound (10.1 g, 91%). LCMS (M+H)+: m/z=408.0.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]3([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:27][CH2:26][CH2:25]3)C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[N:6][CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:33]1[C:28]([C:24]2([CH2:23][NH:15][C:12]3[N:13]=[N:14][C:9]([C:7]4[S:8][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][N:6]=4)=[CH:10][CH:11]=3)[CH2:25][CH2:26][CH2:27]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(C(N)=O)s2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a crude mixture of t-butyl 6-(5-carbamoylthiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (141 mg, crude) in DCM (6 mL) was added TFA (2 mL) at rt. The reaction mixture was further stirred at rt for 2 hr followed by concentration to dryness. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to provide the title compound as a pale yellow solid (98.5 mg, 99% for 2 steps), LRMS (M+H+) m/z 385.2.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18]C(=O)OC(C)(C)C)=[CH:10][C:5]=2[CH2:4][NH:3]1.Cl.O1CCOCC1>>[NH2:18][C@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][C:9]1[N:8]=[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[C:6]2[C:2](=[O:1])[NH:3][CH2:4][C:5]=2[CH:10]=1
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50.0 mg, 0.111 mmol) and 4N HCl in dioxane (2 mL, 8.00 mmol) was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was purified by reverse phase preparative HPLC. The fractions were collected, concentrated, diluted with EtOAc, and basified with saturated aq NaHCO3 solution. The organic extract was dried and evaporated to give the title compound as a white solid (10 mg, 25.7%). 1H NMR (500 MHz, CDCl3) δ ppm 1.19-1.77 (m, 8H), 2.29 (s, 3H), 3.20 (br s, 1H), 3.99 (br s, 1H), 4.19 (s, 2H), 6.06 (s, 1H), 6.75 (d, J=7.32 Hz, 2H), 7.14 (t, J=7.81 Hz, 1H), 7.48 (d, J=7.32 Hz, 1H), 7.60 (s, 1H), 7.90 (s, 1H), 8.87 (s, 1H). [M+H] calc'd for C20H25N5O, 352. found, 352.
Reaction SMILES: [H][H].[O:3]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH:13]([OH:16])[C:14]#[CH:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1>[O:3]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH:13]([OH:16])[CH:14]=[CH2:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: C1COCCO1
Product: C=CC(O)c1cccc(Oc2ccccc2)c1

Procedure:
With stirring, at room temperature and under normal pressure, hydrogen was introduced (3.37 l H2 ; 0° C./760 mm Hg) in a solution of 33.7 3-phenoxy-α-ethynylbenzylalcohol in 340 ml dioxan and 1.7 g Lindlar catalysator.
Reaction SMILES: [C:1](=[C:4]([C:7]#[N:8])[C:5]#[N:6])([CH3:3])[CH3:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>[Zn].C1COCC1>[C:5]([CH:4]([C:7]#[N:8])[C:1]([CH3:3])([CH3:2])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:6]
Reactant: CC(C)=C(C#N)C#N
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)C(C#N)C#N
Reaction time: 1 h

Procedure:
Zinc powder (1.23 g, 18.85 mmol) was added to a THF (20 mL) solution of isopropylidenemalononitrile (1.0 g, 9.42 mmol), ethyl bromoacetate (3.15 g, 18.85 mmol) and titanium bis(cyclopentadienyl)dichloride (235 mg, 0.94 mmol). After stirring for 1 hour the solution was partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with water, brine, dried over MgSO4 and filtered. The solution was concentrated and the crude residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CD3CN): δ 4.55 (s, 1H); 4.10 (q, J=7.2 Hz, 2H); 2.48 (s, 2H); 1.24 (s, 6H); 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1>[Pd].C(O)C>[CH3:1][N:2]([CH3:23])[C:3](=[O:22])[CH2:4][O:5][CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: CN(C)C(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)COC1CCNCC1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
Benzyl 4-(2-(dimethylamino)-2-oxoethoxy)piperidine-1-carboxylate (81) (3.0 g, 9.36 mmol) and palladium on carbon (0.100 g, 0.94 mmol) were added to ethanol (40 mL). This was stirred for 3 hours under an atmosphere of hydrogen. The reaction was filtered and the solvent evaporated to afford a viscous clear oil. The crude product was purified by distillation at 0.5 mBar, collecting fractions that distilled at 90° C. to afford the desired material as a colourless oil (1.000 g, 57.3% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.51-1.42 (2H, m), 1.98-1.92 (2H, m), 2.63-2.57 (2H, m), 2.95 (3H, s), 3.10-3.05 (5H, m), 3.51-3.44 (1H, m), 4.17 (2H, s) NH proton missing.
Reaction SMILES: C(#N)C.[CH2:4]([CH:6]([CH2:23][CH3:24])[C@H:7]([NH:10][S:11]([C:14]1[S:15][C:16]([Sn](C)(C)C)=[CH:17][CH:18]=1)(=[O:13])=[O:12])[CH2:8][OH:9])[CH3:5].[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(OCC)(=O)C>[CH2:23]([CH:6]([CH2:4][CH3:5])[C@H:7]([NH:10][S:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:13])[CH2:8][OH:9])[CH3:24]
Reactant: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc([Sn](C)(C)C)s1
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1cccs1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of anhydrous acetonitrile (6 mL) and N-[(1S)-2-ethyl-1-(hydroxymethyl)butyl]-5-(trimethylstannyl)thiophene-2-sulfonamide (0.24 g, 0.56 mmol) was added Selectfluor (Aldrich) (0.204 g, 0.57 mmol) all at once. The mixture was heated to 75° C. under a nitrogen atmosphere, stirred 16 h and then cooled to 25° C. and filtered. Evaporation of the solvent produced a crude solid that was taken up in ethyl acetate and again filtered to remove insoluble solids. Evaporation of the remaining solvent produced an oil that was purified by flash chromatography using hexane-ethyl acetate 2-1 as eluant, producing the title compound as the major product (0.051 g, 33%). MS (−ESI) 276.20 ([M−H]−).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][Si:7]([CH3:10])([CH3:9])Cl>C(N(CC)CC)C>[CH3:6][Si:7]([C:3]([Si:7]([CH3:10])([CH3:9])[CH3:6])=[CH:2][C:1]([NH2:5])=[O:4])([CH3:10])[CH3:9]
Reactant: C=CC(N)=O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C(=CC(N)=O)[Si](C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
71 g (1 mol) of acrylic acid amide are dissolved in 750 ml of anhydrous triethylamine in a 6 liter three-necked flask equipped with a stirrer and a reflux condenser. 270 g (2.5 mols) of trimethylchlorosilane are then added dropwise over the course of 2 hours at room temperature (approximately 25° C). The temperature is then slowly raised to 60° C and the reaction mixture is stirred for about 16 hours at this temperature. The triethylamine hydrochloride which has precipitated is filtered off under protective gas and the filter cake obtained is rinsed with 200 ml of triethylamine. The triethylamine is then distilled off under a slight vacuum at 40°-45° C. The resulting concentrated filtrate is subjected to a purification distillation with addition of a little sulphur as a polymerisation inhibitor. 149 g (69% of theory) of bis-trimethylsilylacrylic acid amide, boiling at 71° C/20 mm Hg, are obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:26])([CH3:25])[C:23]#[CH:24]>>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:26])([CH3:25])[C:23]#[CH:24])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C#CC(C)(O)CCCCCl
Product: C#CC(C)(O)CCCCn1c(=O)c2c(ncn2COCC)n(C)c1=O

Procedure:
44.84 g (0.2 mol) of 7-ethoxymethyl-3-methylxanthine were reacted with 32.13 g (0.2 mol) of 1-chloro-5-hydroxy-5-methyl-6-heptyne from Example 1B1), and worked up in analogy to Example 1B2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[N:23]1(C(OC(C)(C)C)=O)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[N:23]1([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:5])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Yield: 68 %

Procedure:
The synthesis was carried out according to the method described in (a) above using 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (B) and tert-butyl 1-homopiperazinecarboxylate to yield 4-[3-([1,4]diazepane-1-carbonyl)benzyl]-2H-phthalazin-1-one (4) as a yellow crystalline solid (5.3 g, 68%); m/z [M+1]+ 381 (97% purity); δH 2.6-3.8 (10H, m), 4.4 (2H, s), 7.2-7.5 (3H, m), 7.7-8.0 (3H, m), 8.2-8.3 (1H, m), 12.6 (1H, s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=3)[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:24]4[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=4)[CH:15]=3)[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCN(CCN3CCCC3)CC2)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(CCN4CCCC4)CC3)ncn2)s1

Procedure:
6-[4-(2-Pyrrolidin-1-ylethyl)piperazin-1-yl]pyrimidin-4-amine 11-2 (0.35 g, 1.27 mmol), sodium hydride (0.101 g, 2.53 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.183 g, 1.27 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column and isolated via lyophilization. Hi-Res MS: calc: 385.1921 found: 385.1918. 1NMR (DMSO): 12.1 ppm (s, 1H); 8.46 ppm (s, 1H); 8.27 ppm (s, 1H); 6.27 ppm (s, 1H); 3.63 ppm (m, 6H); 3.35 ppm (m, 4H); 2.76 ppm (m, 6H); 1.96 ppm (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Cc1cccc(O)c1
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(C)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and m-cresol: 1H-NMR (CDCl3) δ 7.89 (1H, d, J=2.8 Hz), 7.40 (1H, dd, J=8.8, 2.8 Hz), 7.21 (1H, t, J=7.9 Hz), 6.96–6.87 (2H, m), 6.81–6.72 (2H, m), 3.83 (3H, s), 2.83 (3H, s).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:18])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>>[CH:21]1([CH2:20][N:6]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])[C:7]2=[O:18])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: COc1ccccc1-n1cc(CC(C)C)[nH]c1=O
Product: COc1ccccc1-n1cc(CC(C)C)n(CC2CC2)c1=O

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-methoxy-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 42, 150 mg) by alkylation with bromomethylcyclopropane (90 mg). 3-Cyclopropylmethyl-4-isobutyl-1-(2-methoxy-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a colorless oil (52 mg). MS (ESI): 301.2 (MH+).