Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Mix 6-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyridin-2-ylamine (70 mg, 0.235 mmol), triethylamine (68 μL, 0.470 mmol), N,N-dimethylaminopyridine (3 mg, 0.024 mmol), and methanesulfonyl chloride (19 μL, 0.247 mmol) in CH2Cl2 (2 mL). Stir at room temperature overnight and add 150 □L triethylamine and 40 μL methanesulfonyl chloride. Stir at room temperature for 6 h and add 1.00N aqueous HCl (1 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge, then elute, collect, and concentrate 45 mL CH2Cl2. Dissolve crude product in THF (5 mL), add 1.0M tetrabutylammonium fluoride (0.25 mL), and heat to reflux for 1 h. Cool to room temperature and dilute with H2O and brine. Extract into ethyl acetate, dry (MgSO4) and concentrate organics. Chromatograph on silica gel (10 g), eluting with 20% to 35% ethyl acetate/hexanes to afford 61 mg (69%) of the title compound as a yellow oil. MS (ES) 377 (M+H), 375 (M−H); BPLC shows 96% purity.
Reaction SMILES: CCN(CC)CC.[N:8]([C@H:11]1[CH2:15][C@@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@@H:12]1[OH:24])=[N+:9]=[N-:10].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:25][S:26]([O:24][C@@H:12]1[CH2:13][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][C@H:11]1[N:8]=[N+:9]=[N-:10])(=[O:28])=[O:27]
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](OCc2ccccc2)C[C@@H]1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@H](OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a cooled mixture of Et3N (9.49 g, 94.0 mmol) and (1S,2S,4R)-2-azido-4-(benzyloxy)cyclopentanol (18.25 g, 78.3 mmol) in DCM (500 mL) was added dropwise methanesulfonyl chloride (9.87 g, 86.2 mmol) in DCM (50 mL) at 0° C. The mixture was stirred overnight at a temperature of 0° C. to RT. After complete conversion, aq NaHCO3 (5%, 300 mL) was added. The mixture was extracted with DCM, washed with brine, and dried over Na2SO4 to give the title compound as an oil (23.58 g, 75.8 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 1.83-1.89 (m, 1H), 2.06-2.13 (m, 1H), 2.34-2.49 (m, 2H), 3.04 (s, 3H), 3.94-3.99 (m, 1H), 4.08-4.13 (m, 1H), 4.64 (s, 2H), 4.93-4.98 (q, J=5.6/7.0 Hz, 1H), 7.25-7.36 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[H-].[Na+].[CH:14]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O.O>[CH:14]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 50 °C
Yield: 57 %

Procedure:
A stirred solution of 3-hydroxy-4-methoxybenzaldehyde (2.00 g) in dry dimethylformamide (20 mL) is treated portionwise with sodium hydride (60% dispersion in oil; 0.56 g) and the mixture is then heated for 1 hour at 50° C. It is then treated dropwise with cyclopentyl bromide (2.36 g) and is stirred and heated at 50° C. for 22 hours. The solution is diluted with water (100 mL) and extracted with diethyl ether (2×100 mL). The ethereal extracts are combined, dried over magnesium sulfate and concentrated, to give 3-cyclopentyloxy-4-methoxybenzaldehyde (1.65 g) in the form of a golden oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].CC1C=CC(S(O[CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30](/[C:33](/[C:40]3[CH:45]=[CH:44][C:43]([CH2:46][CH3:47])=[C:42]([O:48][CH3:49])[N:41]=3)=[CH:34]\[CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:29][C:28]=2[Cl:50])(=O)=O)=CC=1.O>C(#N)C>[Cl:50][C:28]1[CH:29]=[C:30](/[C:33](/[C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH3:47])=[C:42]([O:48][CH3:49])[N:41]=2)=[CH:34]\[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:31]=[CH:32][C:27]=1[S:26][CH2:25][CH2:24][CH2:23][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8]
Reactant: CCc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCOS(=O)(=O)c3ccc(C)cc3)c(Cl)c2)nc1OC
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCN(CC)CC)c(Cl)c2)nc1OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Potassium carbonate (290 mg) and diethylamine (219 mL) were sequentially added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (120 mg) in acetonitrile (3 mL), and the mixture was stirred at 90° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenyl}sulfanyl)-N,N-diethylpropan-1-amine (110 mg, 80%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][C:4]=1[F:11])#[N:2].[CH3:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH3:12])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1Cc1ccc(C#N)c(F)c1

Procedure:
The titled product was prepared from the product of Step B and 2-methylimidazole using the same procedure described in Step B of Example 1.
Reaction SMILES: I[C:2]1[C:3]2([CH2:8][CH2:9][CH2:10][CH:11]=1)[O:7][CH2:6][CH2:5][O:4]2.C([Li])CCC.[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20](OC(C)C)[O:19]1.O>C1COCC1>[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:2]2[C:3]3([CH2:8][CH2:9][CH2:10][CH:11]=2)[O:7][CH2:6][CH2:5][O:4]3)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: IC1=CCCCC12OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(C2=CCCCC23OCCO3)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 6-iodo-1,4-dioxaspiro[4.5]dec-6-ene (Synlett, 2008, 1086-1090; 2.70 g, 10.2 mmol) in THF (30 mL), butyl lithium (1.65 M solution in hexane; 6.7 mL, 11.1 mmol) was added at −78° C. The reaction solution was stirred at −78° C. for 1 hour. Then, 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (4.0 mL, 19.8 mmol) was added thereto, and the mixture was stirred at −78° C. for 2 hours. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=9:1) to yield the title compound (1.52 g, 56%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.[Na].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([N+:22]([O-:24])=[O:23])=[C:16]([O:21][CH2:31][C:32]([F:35])([F:34])[F:33])[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: Cc1nc(OCC(F)(F)F)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 9, the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) was treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate, sodium and potassium carbonate in acetone at room temperature to yield the 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-6-(2,2,2-trifluoro-ethoxy)-pyrimidine as a light brown solid; m.p. 92-95° C.; MS: [M+H]+=416; and the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one as yellow amorphous solid;
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:9][C:8]=1[O:19][CH3:20])C.[NH3:22]>>[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH2:22])=[O:3])=[C:8]([O:19][CH3:20])[CH:9]=1
Reactant: N
Reactant: CCOC(=O)COc1ccc(Cc2ncc[nH]2)cc1OC
Product: COc1cc(Cc2ncc[nH]2)ccc1OCC(N)=O

Procedure:
Treatment of 4-(1-imidazolylmethyl)-2-methoxyphenoxyacetic acid ethyl ester with ammonia as described in Example 8 gave 4-(1-imidazolylmethyl)-2-methoxyphenoxyacetamide, m.p. 124°-125° C. (from chloroform/petrol). Found: C, 59.39, H, 5.83, N, 16.07. C13H15N3O3 requires: C, 59.75, H, 5.78, N, 16.08%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27].O>CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCN(CCCCl)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 10.65 g of 4-(4-fluorobenzamido)piperidine (preparation 2) and potassium carbonate (9.93 g) in 160 ml of dry dimethylformamide was cooled to 0° C. and a solution of 1-bromo-3-chloropropane (5.68 ml) in 5.68 ml of dry dimethylformamide added dropwise thereto. After 3 hours at room temperature the reaction mixture was poured into 1600 ml of water and stirred for one hour. The solid which precipitated was recovered by filtration (7.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[N:3][C:2]([C:32]2[CH:33]=[C:28]([Cl:27])[C:29]([OH:44])=[C:30]([Cl:43])[CH:31]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, {6-chloro-4-[trans-4-(dimethylamino)cyclohexyl-amino]-1,5-naphthyridin-3-yl}(cyclopropyl)methanone (50 mg, 0.13 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (65 mg, 84%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.43 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.11 (s, 2H), 5.64-5.54 (m, 1H), 3.51-3.44 (m, 1H), 2.91 (s, 6H), 2.93-2.89 (m, 1H), 2.63-2.56 (m, 2H), 2.32-2.24 (m, 2H), 1.87-1.68 (m, 4H), 1.33-1.18 (m, 4H); ESI MS m/z 499 [M+H]+; HPLC>99% (AUC), tR=10.12 min.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.80 min, m/z=473.1-474.1 [M+H]+, m/z=472.2-471.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.61 (m, 1H) 1.78-1.88 (m, 1H) 2.17-2.25 (m, 1H) 2.53 (s, 3H) 2.99 (dd, J=11.00, 6.85 Hz, 1H) 3.11-3.19 (m, 2H) 3.22-3.30 (m, 2H) 3.33-3.37 (m, 1H) 4.60 (t, J=4.89 Hz, 1H) 7.34 (dd, J=8.31, 3.42 Hz, 3H) 7.69 (dd, J=7.95, 2.32 Hz, 1H) 7.83-7.88 (m, 2H) 7.98 (d, J=2.45 Hz, 1H) 8.49 (d, J=2.20 Hz, 1H) 8.74 (d, J=2.45 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])=[C:6]([O:13][CH3:17])[CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(O)c(CC=C(C)C)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C)=O)c(O)c1CC=C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Then, 19.00 g of 2',4'-dihydroxy-3'-(3-methyl-2-butenyl)acetophenone was dissolved in 160 ml of acetone, and 14.29 g of anhydrous potassium carbonate and 6.2 ml of methyl iodide were added to the solution and the mixture was stirred at room temperature in a nitrogen current overnight. After the reaction, the solvent was removed by distillation and the obtained residue was extracted with ether, the extract was washed with water, dried with anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation to obtain 20.02 g (yield=99.1%) of 2'-hydroxy-4'-methoxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH:19](O)=[O:20].C(OCC)(=O)C>C(OC(=O)C)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:19]=[O:20])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1

Procedure:
3-Acetoxymethyl-7β-aminoceph-3-em-4-carboxylic acid (50.0 g) was dissolved in acetic anhydride (75 ml.) and formic acid (400 ml.) with stirring at 20° C. When complete solution was obtained (~ 5 min.) the solvents were evaporated (rotary evaporator, oil-pump), leaving a gum which was shaken with ethyl acetate (250 ml.). The insoluble material was removed by filtration and the filtrate was evaporated to dryness leaving a gum which was triturated under ether and petroleum-ether (b.p. 40°-60°), giving 3-acetoxymethyl-7β-formamidoceph-3-em-4-carboxylic acid as a pale yellow powder (43.6 g.), TLC RF 0.19, [α]D20 + 113.5° (c 1.00, dioxan), λ max (pH6 buffer) 259 nm. (ε 8,400), νmax (Nujol) 1772 (β-lactam) 1748 (acetate), 1708 (carboxylic acid), 1654, 1548 cm.-1 (amide), τ (D2O with NaHCO3)1.67 (0.9-proton singlet: CHO), 1.75 (0.1-proton singlet: CHO), 4.20 (1-proton doublet, J 4.5 Hz.: C-7 H), 4.80 (1-proton doublet, J4.5 Hz.: C-6 H), 5.00, 5.26 [two 1-proton doublets (branches of a quartet), J 13 Hz: C-3 CH2 ], 6.24 6.64 [two 1-proton doublets (branches of a quartet), J 18 Hz.: C-2 H2 ] 7.86 (3-proton singlet: CH3CO) (there is evidence for "cis" and "trans" forms in the secondary amide part).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][O:10][CH2:11][CH2:12][NH2:13]>C(O)C>[C:1]([CH2:3][C:4]([NH:13][CH2:12][CH2:11][O:10][CH3:9])=[O:6])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: COCCN
Solvent: CCO
Product: COCCNC(=O)CC#N
Temperature: 25 °C

Procedure:
0.5 g (4.42 mmol) Ethyl cyanoacetate and 0.37 g (4.86 mmol) 2-methoxyethylamine are dissolved in 10 ml ethanol and stirred at reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the product is crystallised from ethanol/diethylether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1.[C-:14]#[N:15].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:14]#[N:15])=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 15 in dimethylformamide (0.3 M) at room temperature under nitrogen was added potassium cyanide (1.2 eq). The reaction was stirred at room temperature overnight. The reaction was diluted with H2O then extracted with ethyl acetate (3×). The organic phases were combined, washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (26%) 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 4H), 3.74 (s, 2H), 3.70 (s, 3H) 3.64 (s, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:4].[ClH:13].Cl.[CH2:15]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:13].[ClH:1].[CH2:15]([N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[O:4])[CH2:26][CH2:25]1)[C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17]
Reactant: O=C(CCl)NCc1ccccn1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(CC(=O)c2ccccc2)CC1)NCc1ccccn1

Procedure:
A mixture of 2-chloro-N-(pyridin-2-ylmethyl)acetamide (1.3 mmol), N-phenacyl piperazine dihydrochloride (1 mmol), and K2CO3 (8.75 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-31), 0.7 g (60.45%), M+ 381.
Reaction SMILES: [C:1]([C@@:3]1([CH:32]2[CH2:34][CH2:33]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:23][N:22]([C:24](OC(C)(C)C)=[O:25])[CH2:21]4)[CH:19]=3)[N:9]=2)[C:4]1=[O:31])#[N:2].Cl.O.C(#N)C.[C:40]([O:43][CH2:44]C)(=O)C>>[CH:32]1([C@:3]2([C:1]#[N:2])[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:23][N:22]([C:24](=[O:25])[CH2:40][O:43][CH3:44])[CH2:21]5)[CH:19]=4)[N:9]=3)[C:4]2=[O:31])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(Nc3nccc(N4CC[C@@](C#N)(C5CC5)C4=O)n3)cn2)C1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COCC(=O)N1CC(n2cc(Nc3nccc(N4CC[C@@](C#N)(C5CC5)C4=O)n3)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-(4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate (300 mg) obtained in Step C of Example 131 in ethyl acetate (5 mL) was added a solution of 4 M hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, to a suspension of the reaction mixture in tetrahydrofuran (10 mL) were added triethylamine (1.3 g) and methoxyacetyl chloride (77 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the reaction mixture was poured into water, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol). The obtained crude product was subjected to HPLC (C18, mobile phase: water/acetonitrile (containing 10 mM NH4HCO3)), and the obtained fraction was concentrated under reduced pressure. The residue was recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([CH2:26][C:4]([C:3]2[CH:8]=[C:9]([NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18])[CH:10]=[CH:11][C:2]=2[F:1])=[O:6])[CH:23]=[CH:22][N:21]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)OC)c1
Reactant: Cc1ccnc(Cl)n1
Product: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1
Yield: 69.9 %

Procedure:
Using multiple iterations of a procedure analogous to the procedure described in Intermediate 11 using methyl 2-fluoro-5-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (104 g, 411 mmol) and 2-chloro-4-methylpyrimidine (59 g, 493 mmol), the title compound of Step B was obtained (100 g, 69.9% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.67-13.75 (br, 1H), 8.50-8.53 (m, 0.3H), 8.31-8.38 (m, 1H), 7.50-7.82 (m, 2.6H), 6.56-7.20 (m, 3.5H), 6.20-6.25 (m, 1H), 5.82-6.01 (1.3H), 5.20-5.40 (m, 2.6H), 4.50-4.61 (m, 2.6H), 4.31-4.41 (m, 0.9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH:19]1([C:22]#[CH:23])[CH2:21][CH2:20]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C(NC(C)C)(C)C.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.[Cu]I>[CH:19]1([C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCc1cccc(C#CC2CC2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a degassed solution of tert-butyl 3-(3-bromophenyl)propylcarbamate (57) (1.0 g, 3.1 mmol) and cyclopropyl acetylene (2.9 mL, 3.4 mmol, 70% soln in toluene) in diisopropylamine (4 mL) was added PdCl2(PPh3)2 (0.120 g, 0.17 mmol), tri-o-tolylphosphine (0.048 g, 0.16 mmol) and CuI (0.026 g, 0.16 mmol). The resulting mixture was degassed and stirred under nitrogen at 90° C. for overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography (10-40% ethyl acetate-hexane gradient) gave tert-butyl 3-(3-(cyclopropylethynyl)phenyl)propylcarbamate. Yield (0.756 g, 79%). This alkyne was used for deprotection without further purification.