Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10](O)[N:9]=[C:8]([CH3:16])[N:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[CH2:1]([O:3][C:4]([C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([Cl:19])[N:9]=[C:8]([CH3:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCCc1c(O)nc(C)nc1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1c(Cl)nc(C)nc1C(=O)OCC
Temperature: 85 °C

Procedure:
A mixture of 121 (10 mmol) and POCl3 (25 ml) is heated at 85° C. for 4 hours. The solvent is removed in vacuo and EtOAc (40 ml) and water (30 ml) are added to the residue. NaHCO3 is carefully added until the pH of the aqueous layer is greater than 7. The layers are separated and the aqueous layer is extracted with EtOAc (2×30 ml). The combined extracts are washed with brine (50 ml), dried (Na2SO4) and evaporated. Flash column purification of the residue with 3:1 EtOAc, hexane provides the product (122) as a light yellow oil.
Reaction SMILES: [CH2:1]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:11]=2[NH:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH2:33](I)[CH3:34]>>[CH2:1]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:11]=2[N:10]([CH2:33][CH3:34])[C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2
Solvent: CI
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2CC
Yield: 65 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 3-benzyl-8-ethoxy-7-methoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIbb), and methyl iodide by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. F: 228–230° C. 1H-NMR (CDCl3, 300 MHz): d 1.03–1.08 (m, 3H, NCH2CH3), 1.50–1.54 (m, 3H, OCH2CH3), 3.59–3.65 (m, 3H, 1HNCH2+CH2Bn), 3.70 (s, 3H, OCH3), 3.77–3.83 (m, 1H, 1CH), 4.12–4.18 (m, 2H, OCH2), 4.30–4.41 (m, 1H, 1HNCH2), 6.62 (s, 1H Ar), 6.79 (s, 1H Ar), 7.22–7.59 (m, 10H Ar).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:34][CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([OH:43])[C:37]([CH3:45])([CH3:44])[CH2:36]1)(=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([OH:30])[C:24]([CH3:32])([CH3:31])[CH2:23]1)=[O:20]>ClCCl.CO>[C:10]([O:34][CH:35]1[CH2:36][C:37]([CH3:45])([CH3:44])[N:38]([O:43][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:39]([CH3:42])([CH3:41])[CH2:40]1)(=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH:22]1[CH2:23][C:24]([CH3:31])([CH3:32])[N:25]([O:30][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:26]([CH3:28])([CH3:29])[CH2:27]1)=[O:20]
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC(=O)Nc3ccccc3)C(C)(C)C2)CC(C)(C)N1OC(=O)Nc1ccccc1
Yield: 75.8 %

Procedure:
Phenyl isocyanate (9.5 g, 80 mmol) is added over 5 minutes to a suspension of 20.0 g (39 mmol) of di-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate in 125 ml of dichloromethane. The resulting solution is refluxed for 30 minutes and then evaporated to obtain a solid. The crude solid is briefly refluxed in methanol, filtered off, and recrystallized from 2-propanol: dichloromethane to give 22.2g (76% yield) of white solid, m.p. 159-61° C.(dec).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].N([O-])=[O:17].[Na+]>S(=O)(=O)(O)O>[Cl:15][C:14]1[CH:13]=[CH:12][C:4]([C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[OH:17]
Reactant: O=N[O-]
Reactant: Nc1cc(C(=O)CCC(=O)O)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)CCC(=O)c1ccc(Cl)c(O)c1

Procedure:
3-(3-amino-4-chlorobenzoyl)propionic acid was diagotised in sulphuric acid solution with sodium nitrite and the diazonium salt solution was added dropwise to boiling aqueous sulphuric acid to give 3-(4-chloro-3-hydroxybenzoyl)propionic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:24][N:23]=3)[O:19][N:18]=2)[CH:14]=[C:13]([CH3:33])[C:4]=1[O:5][CH2:6][CH2:7]OS(C)(=O)=O)[CH3:2].C[O:35][C:36]([CH:38]1[CH2:41][NH:40][CH2:39]1)=[O:37].C(N(CC)CC)C.Cl>C(O)C.[OH-].[Na+]>[CH2:1]([C:3]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([CH2:29][CH:30]([CH3:31])[CH3:32])=[CH:24][N:23]=3)[O:19][N:18]=2)[CH:14]=[C:13]([CH3:33])[C:4]=1[O:5][CH2:6][CH2:7][N:40]1[CH2:41][CH:38]([C:36]([OH:35])=[O:37])[CH2:39]1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCOS(C)(=O)=O
Reactant: COC(=O)C1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19305.2 %

Procedure:
A solution of methanesulfonic acid 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethyl ester (300 mg, 633 μmol), azetidine-3-carboxylic acid methyl ester (218 mg, 1.84 μmol) and triethylamine (129 mg, 1.26 mmol) in ethanol (10 mL) is stirred in a sealed vial at 80° C. for 96 h. The mixture is cooled to rt, diluted with 3 M aq. NaOH and again stirred at rt for 1 h. The mixture is acidified by adding aq. HCl and is then extracted with EA (2×25 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (170 mg) as a colourless oil; LC-MS: tR=0.90 min, [M+H]+=479.10; 1H NMR (CDCl3): δ0.98 (d, J=6.5 Hz, 6H), 1.282 (t, J=7.0 Hz, 3H), 1.93 (hept, J=7.0 Hz, 1H), 2.38 (s, 3H), 2.45 (s, 3H), 2.61 (d, J=7.3 Hz, 2H), 2.73 (q, J=7.3 Hz, 2H), 3.71-3.82 (m, 2H), 3.97-4.08 (m, 1H), 4.19-4.27 (m, 2H), 4.37-4.62 (m, 2H), 4.73-4.97 (m, 2H), 7.87 (s, 1H), 7.89 (s, 1H), 8.07 (s, 1H), 8.53 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:17]([CH3:19])[CH3:18])[C:5]2[CH2:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[OH2:20].OO.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:17]([CH3:19])[CH3:18])[C:5]2[CH2:10][C@H:9]([OH:20])[C@@H:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: O
Reactant: CN(C)c1nc(Cl)nc2c1CC=C2c1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1nc(Cl)nc2c1C[C@H](O)[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-chloro-N,N-dimethyl-7-phenyl-5H-cyclopenta[d]pyrimidin-4-amine (113 mg) in THF (2 mL) at rt was added borane dimethyl sulfide complex in THF (2.0 M solution, 0.41 mL), and the reaction mixture was stirred at rt for 5 h. Water (0.50 mL) was added carefully, followed by 30% H2O2 (0.50 mL) and 1 N NaOH (1 mL). 5 mL EtOAc was added, and the r×n mixture was stirred at rt for 12 h. The crude product was purified by prep. TLC eluting with 50% EtOAc/Hexanes to give the title compound as a yellowish solid (44 mg). LC-MS (M−H2O+H)+=290.05.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16])#[N:2].ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:11]2([CH3:13])[CH2:12][O:27]2)=[O:14])=[CH:5][C:4]=1[C:15]([F:17])([F:16])[F:18])#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Reaction time: 8 h

Procedure:
460 mg of the amide (7) from the Example 1 was dissolved in 30 ml of dichloromethane. 560 mg of m-chloroperbenzoic acid (purity 70–75%) was added. The reaction mixture was stirred overnight at reflux. The reaction was monitored with HPLC. The reaction mixture was washed successively with 2×20 ml of a sodium sulfite solution, 2×20 ml of saturated aqueous NaHCO3 and 20 ml of brine. The organic layer was dried (Na2SO4), filtrated and evaporated under reduced pressure yielding the epoxide (5A) as yellow solid material. Isolated yield: 400 mg (82%). 1H- and 13C-NMR confirmed the expected structure. HPLC: 96% purity.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 4-phenoxy-phenol (169 g, 0.9 mol) in pyridine (500 mL) was treated with acetic anhydride (90 mL). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and 10% HCl solution, and the resulting mixture was stirred for 1 h. The organic phase was washed with 10% HCl and water until pH=7. The organic layer was dried and the solvent was evaporated to afford acetic acid 4-phenoxy-phenyl ester (200 g, 97%). 1H-NMR (CDCl3): 2.21 (s, 3H), 6.94 (m, 6H), 7.04 (m, 1H), 7.28 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][C:7]=2[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=C1CCc2c(F)ccc(O)c21
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1ccc(F)c2c1CCC2
Yield: 85.5 %

Procedure:
4-Fluoro-7-hydroxy-1-indanone (1.0 g) was dissolved in acetic acid (15 ml) and the solution was stirred with 10% palladium-on-carbon (0.5 g) in a hydrogen atmosphere at atmospheric pressure for 12 hours. The catalyst used was removed by filtration using Celite, and the filtrate was concentrated to give 7-fluoro-4-indanol (0.783 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH2:25]([N:27]([CH2:39][CH3:40])[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])[CH3:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([N:27]([CH2:25][CH3:26])[CH2:39][CH3:40])=[O:29])=[CH:31][CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CCN(CC)C(=O)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Temperature: 120 °C
Yield: 27.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(diethylcarbamoyl)phenylboronic acid (23 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydro-spiro[chroman-4,4′-imidazole]-6-yl)-N,N-diethylbenzamide (6.95 mg, 28%). 1H-NMR (MeOD): 1.13 (s, 3H), 1.24 (d, 3H), 2.13 (d, 1H), 2.30 (s, 1H), 3.17 (s, 3H), 3.32 (d, 4H), 5.91 (d, 1H), 7.03 (d, 1H), 7.22 (s, 1H), 7.33 (m, 1H), 7.40 (m, 4H), 7.49 (m, 2H), 7.51 (m, 1H), 7.57 (m, 2H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]#[N:7].Cl.[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>CS(C)=O>[N+:11]([C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:23][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:13])=[O:12]
Reactant: COc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: NCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc([N+](=O)[O-])c(NCCc2ccccc2)c1
Reaction time: 0.33 h
Yield: 51.8 %

Procedure:
A mixture comprising 3-methoxy-4-nitrobenzonitrile (1 g, 5.6 mmol), phenethylamine hydrochloride (1.8 g, 11.2 mmol), 50% sodium hydroxide (0.9 g, 11.2 mmol) and DMSO (3 mL) was heated at 100° C. for 3.5 hours, cooled and poured into a solution of 1N hydrochloric acid (200 mL, 0° C.). The mixture was stirred for 20 minutes to give a precipitate. The precipitate was collected and recrystallized from hot ethanol to provide 4-nitro-3-phenethylaminobenzonitrile (0.78 g, 2.9 mmol) as orange crystals. MS (CI), Calculated for C15H13N3O2, 267.3, Found (MH+): 282. A mixture comprising 4-nitro-3-phenethylaminobenzonitrile (0.75 g, 2.8 mmol), palladium on carbon (100 mg) and 1:1 methanol/THF (100 mL) was hydrogenated under 1 atm for 3 hours, filtered and concentrated under reduced pressure to provide 4-amino-3-phenethylaminobenzonitrile (0.68 g, 2.8 mmol) as a tan solid.
Reaction SMILES: C(O[K])(C)(C)C.[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CC1C=CC(S([CH2:30][N+:31]#[C-])(=O)=O)=CC=1>COCCOC.CCO>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:30]#[N:31])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
tBuOK (2.29 g, 20.45 mmol, 2.5 eq) was added in portions at −5° C. to a solution of 1-(pyridin-4-yl)piperidin-4-one (1.44 g, 8.18 mmol, 1 eq) and TOSMIC (1.91 g, 9.81 mmol, 1.2 eq) in DME (20 ml) and EtOH (0.5 ml), and then stirring was carried out for 2 h at RT. The reaction mixture was hydrolyzed with ice-water (50 ml), extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 4% MeOH in dichloromethane), the desired product was obtained in the form of a brown solid. Yield: 34% (530 mg, 2.83 mmol).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][O:12][N:13]=[CH:14][C:15]([NH:17][C@H:18]2[C@@H:21]([S:22][CH2:23][CH2:24][OH:25])[NH:20][C:19]2=[O:26])=[O:16])[N:10]=1)=[O:4].[CH2:27]1[O:30][CH:28]1C.C(Cl)(=O)C>CC(N(C)C)=O>[C:28]([O:25][CH2:24][CH2:23][S:22][C@H:21]1[NH:20][C:19](=[O:26])[C@H:18]1[NH:17][C:15](=[O:16])[CH:14]=[N:13][O:12][CH2:11][C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])[S:7][CH:8]=1)(=[O:30])[CH3:27]
Reactant: O=C(C=NOCc1csc(NC(=O)CCl)n1)N[C@@H]1C(=O)N[C@@H]1SCCO
Reactant: CC1CO1
Solvent: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)OCCS[C@H]1NC(=O)[C@H]1NC(=O)C=NOCc1csc(NC(=O)CCl)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 0.65 g of (3R,4R)-3-[[[(2-chloroacetylamino-4-thiazolyl)(methoxyimino)]acetyl]amino]-4-[[2-(hydroxy)ethyl]thio]-2-azetidinone in 5 ml of dimethylacetamide are added 1 ml of propylene oxide and 0.36 g of acetyl chloride, and the mixture is stirred at 0° C. for 3 hours. After further addition of 0.36 g of acetyl chloride, the mixture is stirred for additional 3 hours. The solvent is then distilled off under reduced pressure to give crystals, which are collected by filtration and washed with methylene chloride. The above procedure gives 0.558 g of (3R,4R)-4-[[2-(acetoxy)ethyl]thio]-3-[[[(2-chloroacetylamino-4-thiazolyl)(methoxyimino)]acetyl]amino]-2-azetidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([Cl:18])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Cl)cc1OC
Temperature: 50 °C

Procedure:
To a suspension of 3-(3,4-dimethoxyphenyl)acrylic acid (416 mg 2 mmol) in toluene (10 mL) was added thionyl chloride (1.45 mL, 20 mmol). The solution was heated at 50° C. for 1 hour and then the solvent was removed under reduced pressure to give (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride, which was used directly in the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.C(O)(C(F)(F)F)=O>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C=O)cc1F
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1F
Yield: 58.5 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.80 g, 30.0 mmol), 3-fluoro-4-methoxybenzaldehyde (4.86 g, 1.05 equiv.) and TFA (4.6 mL, 2 equiv.) to give the title compound (5.2 g, 59%) as white crystals. MP: 68° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[O:10]=[C:11]1[CH2:16][C:15](=O)[CH2:14][CH2:13][NH:12]1>C(O)C>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:15]1[CH2:14][CH2:13][NH:12][C:11](=[O:10])[CH:16]=1
Reactant: Nc1cc(F)ccc1F
Reactant: O=C1CCNC(=O)C1
Solvent: CCO
Product: O=C1C=C(Nc2cc(F)ccc2F)CCN1
Yield: 20.5 %

Procedure:
A mixture of 2,5-difluoroaniline (6.45 g) and 2,4-dioxopiperidine (5.66 g) was heated under nitrogen for 6 h. The reaction mixture was then dissolved in ethanol (50 ml), adsorbed onto silica, and purified by FCC eluting with System A (150:8:1) to give the title compound (2.3 g), m.p. 252°-255°.
Reaction SMILES: [CH2:1]([S:7](Cl)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>CO>[CH2:1]([S:7]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:21][CH:22]=1)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCS(=O)(=O)Cl
Reactant: N#CCC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCCS(=O)(=O)Nc1ccc(C(=O)CC#N)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 3.7 grams (0.02 Mol) hexane sulfonyl chloride, 3.2 grams (0.02 Mol) 4-aminobenzoylacetonitrile and 5 mL of pyridine was stirred at 0° C. for 1.5 hours. The resulting very thick brown solution was dissolved in 15 mL of methanol and dropwise added to 100 mL of 2N hydrochloric acid at 0° C. A tan precipitate formed which was stirred for 30 minutes, then filtered and washed with water and dried for 2 hours at 50° C./10 mm Hg to give 6.9 grams of crude product. This was recrystallized from aqueous ethanol to give 4.2 grams (13.6 mMol, 68% yield) of pure product, m.p.=125°-127° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(OCC)(=O)C>[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][C:3]([N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[C:9](=[O:16])[NH:8][C:7]4[CH:17]=[CH:18][CH:19]=[CH:20][C:6]3=4)=[O:4])[CH2:29]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Reactant: C1CCN(CC2CCCNC2)CC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCC(CN3CCCCC3)C2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 35 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 3-[(1-piperidinyl)methyl]piperidine to give colorless crystals, mp. 150°-152° C. (ethyl acetate).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:4]1)[CH3:2].[C:15]([NH:22][C@H:23]([C:31](O)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(Cl)CCl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([N:3]1[C:7]([NH:8][C:31](=[O:32])[C@@H:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccncc2)cc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a 25 ml flask was added 1-ethyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine 20.2.0 (283 mg, 1.50 mmole), Boc-L-phenylalanine (439 mg, 1.65 mmole), EDC (375 mg, 1.95 mmole), 4-dimethylaminopyridine (202 mg, 1.65 mmole) and 5 ml of dichloromethane. The reaction was stirred at room temperature for 4 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 101.1.A (568 mg, 87% yield) as colorless amorphous. 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (brs, 1H), 8.56 (d, J=5.8 Hz, 2H), 7.64 (d, J=6.2 Hz, 2H), 7.65-7.63 (m, 5H), 6.68 (s, 1H), 5.32 (brs, 1H), 4.52 (dd, J=14.6, 7.3 Hz, 1H), 3.95 (q, J=7.2 Hz, 2H), 3.25-3.14 (m, 2H), 1.52 (s, 9H), 1.37 (t, J=7.4 Hz, 3H)
Reaction SMILES: C([O:3][P:4]([C:9]([C:12]1[C:21]([Br:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:23]#[N:24])=[CH:17][CH:18]=2)[CH:13]=1)([F:11])[F:10])(=[O:8])[O:5]CC)C>ClCCl.C[Si](Br)(C)C>[Br:22][C:21]1[C:12]([C:9]([P:4](=[O:3])([OH:8])[OH:5])([F:10])[F:11])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:23]#[N:24])[CH:15]=2
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2cc(C#N)ccc2cc1Br
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: N#Cc1ccc2cc(Br)c(C(F)(F)P(=O)(O)O)cc2c1

Procedure:
A solution of diethyl[(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonate (2.2 g) in dichloromethane (5 mL) and TMSBr (7 mL) was stirred overnight and concentrated. The residue was co-evaporated with dichloromethane (2×), ethanol/water (2×) and then dissolved in 20 mL of methanol. Ammonia (30%) was then added with vigorous stirring and the mixture was concentrated and co-evaporated with methanol (3×). The solid residue was washed with ether to give the desired product as a white powder. MS (−ESI): m/z 360.0 and 361.9 (M−1)−.