Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][C@H:5]([CH3:9])[C:6](Cl)=[O:7].[NH2:15][C:16]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:17]#[N:18].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:17]([C:16]([NH:15][C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=1[Cl:1])[CH3:9])([CH3:22])[CH:19]([CH3:21])[CH3:20])#[N:18]
Reactant: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)Cl
Reactant: CC(C)C(C)(N)C#N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Cl)cc1Cl)C(=O)NC(C)(C#N)C(C)C
Temperature: -5 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A stirred solution of (R)-2-(2,4-dichlorophenoxy)propionyl chloride (380.25 g, 1.5 mol) in toluene is cooled to -10° C. and treated simultaneously, with cooling, with 2-amino-2,3-dimethylbutyronitrile (168.3 g, 1.5 mol) and triethylamine (181.8 g, 1.8 mol) so as to maintain a reaction temperature range of -5° C. to -10° C. When the simultaneous addition of amines is complete, the reaction mixture is stirred at -5° C. for 2 hours, allowed to warm to room temperature in the absence of external heating, and treated with water. The phases are separated. The organic phase is cooled to 0° C., treated with 10% NaOH, and stirred for 1 hour at 0° C. The phases are separated. The organic phase is again washed with fresh 10% NaOH for 1 hour at 0° C., separated and washed a third time at 0° C. for 1 hour with fresh 10% NaOH. The organic phase is then washed sequentially with water, brine and water, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is crystallized in petroleum ether to give the title product as a white solid, 435 g (88% yield) identified by NMR analysis.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.S1C=CC=C1C(Cl)=O.[CH2:31](Cl)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[N:13]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3cccs3)c2CC1
Reactant: ClCc1ccccc1
Agent: O=C(Cl)c1cccs1
Product: c1ccc(Cn2nc(-c3cccs3)c3c2CCNCC3)cc1

Procedure:
The title compound (28 mg) was prepared from 3-thiophen-2-yl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester as described in Example 103, using thiophene-2-carbonyl chloride (5 mmol) in place of 4-chlorobenzoyl chloride, and benzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C18H19N3S, 309.13. found, m/z 310.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.27-7.01 (m, 8H), 5.28 (s, 2H), 3.26-3.24 (br m, 2H), 3.18-3.16 (br m, 2H), 3.11-3.09 (br m, 2H), 2.96-2.94 (br m, 2H).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[CH3:18][C:19]([CH3:21])=O.Cl>CO.O>[CH:19]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1)([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N1CCN(c2ccc(O)cc2)CC1

Procedure:
Sodium cyanoborohydride (3.78 g.) was added to a stirred solution of N-(4-hydroxyphenyl)piperazine (5.35 g.) and acetone (8.7 g.) in a mixture of methanol (100 ml) and water (20 ml.). The pH of the resulting solution was adjusted to pH 7.5 by the addition of a few drops of N hydrochloric acid and stirring was continued at room temperature (~20° C.) for a period of 19 hours. Upon completion of this step, further acetone (8.7 g.) and sodium cyanoborohydride (1.89 g.) were added to the mixture and the pH was again adjusted to a value of 7.5. After a further period of stirring at room temperature for eight hours, water (100 ml.) was added to the reaction mixture and the precipitated solid product was subsequently collected by means of suction filtration and thereafter vacuum dried over phosphorous pentoxide to constant weight. Recrystallization of the crude material so obtained from a mixture of ethanol and methanol then gave pure 1-isopropyl-4-(4-hydroxyphenyl)piperazine in the form of a crystalline solid (yield, 4.78 g.), m.p. 244°-246° C. The yield of pure product amounted to 72% of the theoretical value.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].Br[C:16]([CH3:21])([CH3:20])[C:17](Br)=[O:18]>C(Cl)Cl>[CH3:20][CH:16]1[CH2:21][C:13]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH:14]=2)[C:17]1=[O:18]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)Cc1ccc2c(c1)CC(C)C2=O
Reaction time: 2 h

Procedure:
17.3 g (125 mmol) of AlCl3 were added to a solution of 6.71 g (50 mmol) of isobutylbenzene in 30 ml of analytical grade methylene chloride, while cooling with ice. 11.9 g (52 mmol) of 2-bromoisobutyryl bromide were then added rapidly, and stirring was continued at 0° C. for 1 hour and at room temperature for 2 hours. The mixture was heated under reflux for a further 15 hours and then worked up analogously to Example A. The crude product was chromatographed on 100 g of silica gel (hexane/methylene chloride 1:1). The yield was 8.42 g (83%).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17](F)=[CH:16][N:15]=[C:14]([NH:19][C:20]4C=CC=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[Br:27]C1C(NC2C=CC=C(O)C=2)=NC(Cl)=NC=1.C(N)C=C>>[CH2:20]([NH:19][C:14]1[N:13]=[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[C:17]([Br:27])=[CH:16][N:15]=1)[CH:21]=[CH2:22]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2Br)c1
Solvent: C=CCN
Product: C=CCNc1ncc(Br)c(Nc2cccc(O)c2)n1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 5-bromo-2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and allylamine were reacted to yield N2-allyl-5-bromo-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.08 (s, 1H), 7.21 (t, 1H, J=8.1 Hz), 7.02-6.97 (m, 2H), 6.71 (dd, 1H, J=2.4 and 8.7 Hz), 5.91-5.77 (m, 1H), 5.19-5.09 (m, 2H), 3.94-3.89 (m, 2H); LCMS: ret. time: 18.33 min.; purity: 99%; MS (m/e): 322 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:30]C=2C=1.N>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([NH2:30])=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of N-t-butoxycarbonyl-5-carboxyisoindoline (D13) (240 mg), EDC (350 mg), HOBT (140 mg), triethylamine (0.32 ml) and 0.880 ammonia solution (1 ml) in DMF (10 ml) was stirred overnight at rt and then evaporated. The residue was partitioned between EtOAc (10 ml) and 5% citric acid (10 ml). The organic layer was collected, washed with water (10 ml), saturated NaHCO3 solution (10 ml), water (10 ml), brine (10 ml), dried (MgSO4) and evaporated to give the title compound (D14) (154 mg). MS electrospray (+ion) 263 (MH+). 1H NMR δ (CDCl3), 7.73 (2H, m), 7.26 (1H, m), 6.88 (2H, m), 4.72 (2H, s), 4.69 (2H, s),1.52 (9H, s).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:20]=[CH:19][C:18]2[C:17](SC)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=1.O>C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:20]=[CH:19][C:18]2[C:17]([NH:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H](Nc1ncnc2cc(N)ncc12)c1ccccc1
Temperature: 180 °C
Yield: 10.9 %

Procedure:
A mixture of [R]-1-phenylethylamine (0.072 mL, 0.55 mmol) and 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (97 mg, 0.5 mmol) (described in a previous experimental) is heated at 180° C. under N2 for 1.5 hr. The reaction is then cooled to room temperature producing a precipitate. The mixture is added to water and CHCl3, sonicated and filtered. The phases are separated and the aqueous phase is extracted with CHCl3. The combined extracts are washed with water, saturated brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue purified by using preparative tlc (5% MeOH/CHCl3) and recrystallization from CHCl3 to give 7-amino-4-([R]-1-phenylethylamino)pyrido[4,3-d]pyrimidine (14.5 mg, 11), mp 231.8-232.1° C. 1H NMR (DMSO) δ 9.23 (1H, s), 8.50 (1H, d, J=8.0 Hz), 8.19 (1H, s), 7.41 (2H, d, J=7.0 Hz), 7.31 (2H, t, J=8.0 Hz, 7.21 (1H, tt, J=7.4, 1.2 Hz), 6.45 (2H, s), 6.33 (1H, s), 5.56 (1H, p, J=7.2 Hz), 1.55 (3H, d, J=7.0 Hz).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[Cl:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>CC(C)=O>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:20][C:19]=1[Cl:25])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccc(OCc3ccccc3)c(Cl)c2)n1
Temperature: 2.5 °C

Procedure:
To cyanuric chloride (1.208 g, 6.4 mmol) dissolved in acetone (10 mL) stirring at 0-5° C., was added a solution of 160a (1.505 g, 6.4 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (2.6 mL, 6.4 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 h under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 5% NaOH. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a light beige solid (160b, 1.46 g, 60%), mp 145° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 111.2 min, 97.1% purity.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7]#[N:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: N#CCc1cccs1
Product: N#CC(=C1CCCCC1)c1cccs1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 2-thienylacetonitrile and cyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=O)=[CH:7][C:6]=2[CH:12]=1.[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].CCCCCCC.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:15]/[CH:13]=[O:14])=[CH:7][C:6]=2[CH:12]=1
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C/C=C/c1cc2cc(Cl)ccc2o1
Yield: 68.9 %

Procedure:
A solution of 5-chlorobenzofuran-2-carboxaldehyde (813 mg, 4.50 mmol) and formylmethylene triphenylphosphorane (1.37 g, 4.50 mmol) in CH2Cl2 (40 ml) was treated as sen in preparation 1. After a chromatography on silicagel (n-heptane/EtOAc 4/1) pure title compound (640 mg, 3.10 mmol, yield 68.8%) as yellow crystals was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][CH3:17])[N:15]=2)=[CH:7][C:6]=1[CH2:18][CH2:19][CH3:20].[CH2:21]([O:23][C:24](=[O:36])[CH2:25][C@H:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)[CH3:22].O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:36])[CH2:25][C@H:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]4[S:12][CH:13]=[C:14]([CH2:16][CH3:17])[N:15]=4)=[CH:7][C:6]=3[CH2:18][CH2:19][CH3:20])=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)[CH3:22]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCBr
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
To a mixture of 2-[4-(2-bromoethoxy)-3-propylphenyl]-4-ethyl-1,3-thiazole (105 mg 0.30 mmol) (Example 34) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (65 mg, 0.30 mmol) (Example 6) in DMF (4 mL, containing 1% v/v of water), was added Cs2CO3 (145 mg, 0.44 mmol), and the mixture was stirred for 24 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in EtOAc and filtered. The filtrate was concentrated and purified by silica gel chromatography (gradient: 100% hexane to 1:9 (v/v) EtOAc/hexane) to give 66 mg (41%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 7.72-7.58 (m, 3H), 6.98 (d, 1H), 6.86-6.60 (m, 3H), 4.33-4.28 (br, 2H), 4.28-4.20 (br, 1H), 4.10 (q, 2H), 3.52-3.40 (m, 1H), 2.84 (m, 4H), 2.64 (dd, 1H), 2.58-2.50 (m, 3H), 2.40-2.24 (m, 2H), 1.72-1.50 (m, 3H), 1.26 (t, 3H), 1.20 (t, 3H), 0.84 (t, 3H).
Reaction SMILES: [C:1]1([CH3:30])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]2[C:11](=[O:29])[N:12]([CH2:18][C:19]([O:21]CC3C=CC=CC=3)=[O:20])[C:13]([CH3:17])=[C:14](Cl)[N:15]=2)=[CH:3][CH:2]=1.[OH-].[K+].O>[Pd].O1CCCC1.CO>[C:1]1([CH3:30])[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:9][C:10]2[C:11](=[O:29])[N:12]([CH2:18][C:19]([OH:21])=[O:20])[C:13]([CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)cc1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CCNc2ncc(C)n(CC(=O)O)c2=O)cc1
Reaction time: 72 h
Yield: 22.7 %

Procedure:
A mixture of 3-(2-4-tolylethylamino)-5-chloro-6-methyl-1-(benzyloxycarbonylmethyl)pyrazinone (854 mg, 2.00 mmol), as prepared in the preceding step, potassium hydroxide (452 mg, 8.00 mmol), 10% palladium on carbon (254 mg) in tetrahydrofuran (20 mL), methanol (30 mL), and water (7 mL) was stirred under hydrogen balloon for three days. The mixture was filtered through Celite. The filtrate was adjusted to pH 2–4 with 10% HCl and concentrated to about 2 mL under reduced pressure. The white solid which precipitated from the solution was filtered, washed with a small amount of water, and dried to give the title compound (137 mg, 22.7%). 1H NMR (CDCl3) δ 7.20 (d, 2 H, J=7.5 Hz), 7.10 (d, 2 H, J=7.8 Hz), 6.70 (s, 1 H), 4.71 (s, 2 H), 2.87 (m, 2 H), 2.50 (m, 2 H), 2.26 (s, 3 H), 2.15 (s, 3 H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([O:26]C)=[O:25])=[CH:14][CH:13]=2)[C:9](=[O:28])[C:8]([CH2:29][C:30]#[N:31])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:32].[K+].Cl>>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([OH:26])=[O:25])=[CH:14][CH:13]=2)[C:9](=[O:28])[C:8]([CH2:29][C:30](=[O:32])[NH2:31])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CC#N)c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CCCCc1ccc(CC(N)=O)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 3 h

Procedure:
A mixture of 400 mg of 6-butyl-3-cyanomethyl-1-(2'-methoxycarbonylbiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine and 2.2 ml of 1N aqueous KOH solution is boiled for 3 hours, cooled and acidified with hydrochloric acid. 6-Butyl-3-carbamoylmethyl-1-(2'-carboxybiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine is obtained after conventional working-up.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:7]([CH2:23][C@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([CH2:42][OH:43])[CH2:25]2)[CH2:6]1)(=O)C.[OH-:44].[Na+].Cl.[Cl-].[Na+].O(P(O[C:66]1[C@H:67]([CH3:90])[C@H:68]2[C@@H:85]([C@H:86](O)[CH3:87])[C:84](=[O:89])[N:69]2[C:70]=1[C:71]([O:73][CH2:74][C:75]1[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=1)=[O:72])(OC1C=CC=CC=1)=O)C1C=CC=CC=1>C(Cl)Cl.CO>[OH:44][C@@H:86]([C@H:85]1[C:84](=[O:89])[N:69]2[C:70]([C:71]([O:73][CH2:74][C:75]3[CH:76]=[CH:77][C:78]([N+:81]([O-:83])=[O:82])=[CH:79][CH:80]=3)=[O:72])=[C:66]([S:4][C@@H:5]3[CH2:9][NH:8][C@H:7]([CH2:23][C@H:24]4[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]5[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=5)=[O:30])[C@H:26]([CH2:42][OH:43])[CH2:25]4)[CH2:6]3)[C@H:67]([CH3:90])[C@H:68]12)[CH3:87]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: [OH-]
Reactant: CC(=O)S[C@H]1C[C@@H](C[C@@H]2C[C@@H](CO)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CN[C@H](C[C@@H]4C[C@@H](CO)N(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)C3)[C@H](C)[C@H]12
Reaction time: 0.33 h
Yield: 79.3 %

Procedure:
(2R, 4S)-4-acetylthio-2-[(2S,4R)-2-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylmethyl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (150 mg, 0.24 mmol) was dissolved in a solution comprising methylene chloride (0.5 ml) and methanol (1.5 ml). A 2N sodium hydroxide aqueous solution (0.18 ml, 0.36 mmol) was dropwise added under cooling with ice in a nitrogen stream, and the reaction mixture solution was stirred for 20 minutes. After a 6N hydrochloric acid (0.06 ml, 0.36 mmol) was added to the reaction solution, the solution was poured into a saturated sodium chloride aqueous solution, then extracted with methylene chloride, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By using the compound thus obtained and p-nitrobenzyl (1R, 5S, 6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (130 mg, 0.22 mmol), the same procedure as in Example 1-1) was carried out to obtain p-nitrobenzyl (1R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-2-[(2R, 4S)-2-[(2S, 4R)-2-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (129 mg, yield: 58%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2].[Cl-:15]>C(O)(=O)C>[Cl:14][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][Cl:15])[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=1
Reactant: [Cl-]
Reactant: COC(=O)c1cc(Cl)cc(C(C)=O)n1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(C(=O)CCl)n1

Procedure:
A solution of methyl 6-acetyl-4-chloro-2-pyridinecarboxylate (6.55 g) and surfuryl chloride (2,73 ml) in acetic acid (33 ml) was stirred at ambient temperature for 14 hours and further at 50° C. for three hours, The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and washed with water to give methyl 4-chloro-6-chloroacetyl-2-pyridinecarboxylate (6.75 g).
Reaction SMILES: [Cl:1][C:2]([Cl:22])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([OH:5])=[O:4].[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[Cl:1][C:2]([Cl:22])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: O=C(O)C(Cl)(Cl)CCCCCCCCC=Cc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCc1ccccc1
Yield: 86.5 %

Procedure:
1.09 g (3.18 mmol) 13 was dissolved in 300 ml THF and hydrogenated for 40 minutes at -40° C. at a hydrogen overpressure of 42 mbar after addition of 200 mg 10% Pd/BaSO4. The catalyst is sucked off and 0.95 g (90%) 14 was obtained as a colourless oil after evaporating the remaining solution. 100 mg (0.29 mmol) 14 was dissolved in 1 ml ethanol, cooled in an ice-bath and admixed with a solution of 12 mg (0.29 mmol) sodium hydroxide in 1 ml ethanol. The sodium salt was precipitated by addition of ether and it was allowed to stand for 12 hours in a refrigerator. The precipitate was suction filtered, washed with cold ether and dried in a vacuum. 100 mg (94%) sodium salt of 14, melting point 157-159° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[S:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH3:38]I>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH3:38])[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(Cc3ccc(Cl)cc3)sc2n1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(c1ccc(Cl)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-chlorophenylmethyl)thiazolo[5,4-d]pyrimidine (53 mg, 0.1 mmol) in DMF (2 ml) was added 1N NaOH (150 μl, 0.15 mmol) and MeI (7 μl, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (40 mg, 74%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.FC(F)(F)C(O)=O.[CH3:45][C:46]1[S:50][C:49]([C:51]([N:53]2[CH2:58][C:57]3([CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[O:56][CH2:55][CH2:54]2)=[O:52])=[CH:48][CH:47]=1.C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:61]2[CH2:62][CH2:63][C:57]3([O:56][CH2:55][CH2:54][N:53]([C:51]([C:49]4[S:50][C:46]([CH3:45])=[CH:47][CH:48]=4)=[O:52])[CH2:58]3)[CH2:59][CH2:60]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.426 g) in MeCN (2 mL) was added dropwise to a solution of (5-methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.154 g) and triethylamine (0.15 mL) in MeCN (5 mL) at RT under argon. The resulting mixture was stirred at 60° C. under argon for 16 h, and then at 80° C. for an additional 3 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine and water (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The brown solid was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as a yellow solid. Yield 0.246 g.