Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C@@H:11]3[CH2:28][CH2:29][CH2:30][N:10]3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC>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.CN(C=O)C>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:3]=4)[CH2:9][N:10]4[CH2:30][CH2:29][CH2:28][C@H:11]43)=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Ic1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a high-pressure reaction vial was added cis-6-(3-iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 32, 40.0 mg, 0.08 mmol), trimethylsilylacetylene (9.0 mg, 0.093 mmol), Pd(PPh3)2Cl2 (6.0 mg, 0.008 mmol), CuI (2.0 mg, 0.008 mmol), PPh3 (4.0 mg, 0.016 mmol), Et2NH (0.12 mL, 1.2 mmol), and DMF (0.1 mL). The sealed vial was placed in a 120° C. preheated oil bath for 30 min, cooled to rt, concentrated under a stream of nitrogen, and purified by reverse-phase HPLC to give 27.0 mg (47%) of the desired product as a TFA salt. MS: exact mass calcd for C31H42N2OSi, 486.3; m/z found, 487.6 [M+H]+. 1H NMR (acetone-d6): 7.46 (m, 2H), 7.36 (m, 2H), 6.97 (d, J=2.5, 1H), 6.80 (dd, J=2.6, 8.7, 1H), 6.65 (d, J=8.7, 1H), 4.92 (m, 1H), 4.63 (m, 1H), 4.14 (t, J=6.0, 2H), 3.95 (m, 1H), 3.66 (m, 3H), 3.51 (m, 1H), 3.41 (m, 1H), 3.31 (m, 2H), 2.95 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.50 (m, 1H), 0.22 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].C(Cl)Cl.[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)#[N:11]>CCOCC>[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:1](=[O:5])[C:2]([Cl:4])=[O:3])=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)#[N:11]
Reactant: Cn1ccc2ccc(C#N)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(C#N)cc21
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of oxalyl chloride in CH2Cl2 (2 M, 1.6 mL, 3.2 mmol) was added dropwise to a solution of 6-cyano-1-methyl-1H-indole (360 mg, 2.3 mmol) in ether (5 mL). Stirring was continued for 30 min at 0° C. and the cooling bath was removed. After 2 h, more of the 2 M solution of oxalyl chloride (0.2 mL, 0.4 mmol.) was added. Stirring was continued at room temperature for additional 2 h. The solid was filtered and washed with ether to give (6-cyano-1-methyl-1H-indol-3-yl)glyoxylyl chloride (450 mg, 79%). Ref:: Troxler, F.; Hamisch, A.; Bormann, G.; Seemann, F.; Szabo, L.; Helv. Chim Acta, 1968, 51(1), 1616.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][C:4]=1[CH3:15].COC1C=CC(C(CC)C(O)=O)=CC=1C>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6]([CH2:9][CH2:10][CH2:11][C:12]2=[O:14])=[CH:5][C:4]=1[CH3:15]
Reactant: COc1ccc(CCCC(=O)O)cc1C
Agent: CCC(C(=O)O)c1ccc(OC)c(C)c1
Agent: CS(=O)(=O)O
Product: COc1cc2c(cc1C)CCCC2=O
Yield: 87.5 %

Procedure:
A solution of 4-(4-methoxy-3-methylphenyl)butyric acid (Compound 27, 24.0 g, 115.4 mmol) and 400 mL of methanesulfonic acid was stirred at room temperature under the argon atmosphere for 24 h, then poured into ice, extracted three times with ethyl acetate, washed with NaHCO3 1 N, brine, dried over MgSO4, and filtered. The solvent was removed to give 19.2 g (88%) of the title compound as a dark brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1

Procedure:
4-(3-Nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared from 1-bromo-3-nitro-benzene (3.0 g, 15 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.0 g, 16 mmol) in a manner analogous to Example 2c. Product isolated as a yellow oil (3.95 g, 88%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.23 (s, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 6.20 (br s, 1H), 4.12 (s, 2H), 3.70-3.65 (m, 2H), 2.56 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[C:15]([S:18][CH2:19][CH:20]([CH3:24])[C:21](Cl)=[O:22])(=[O:17])[CH3:16]>O>[C:15]([S:18][CH2:19][CH:20]([CH3:24])[C:21]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:22])(=[O:17])[CH3:16]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)SCC(C)C(=O)N[C@H](C(=O)O)C(C)C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
L-valine (88 g) and sodium carbonate (40 g) are dissolved in water (1 l.) and the solution is chilled in an ice bath with vigorous stirring. 3-Acetylthio-2-methylpropanoyl chloride (135 g) and a solution of sodium carbonate (120 g) in 500 ml of water are added in five equal portions over a 15 minute period. After 1.5 hours, the reaction mixture is extracted with ethyl acetate, the aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated to dryness to yield 190 g of N-(3-acetylthio-2-methylpropanoyl)-L-valine. The named product is obtained by following the procedure of Step (b), Example 49.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C)c3O2)cc1
Yield: 83 %

Procedure:
Treatment of (−)-[7-bromo-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.0 g, 5.22 mmol) with 2-methylphenylboronic acid (1.06 g, 7.83 mmol) generally according to described for Intermediate 37 provided 1.71 g (83%) (−)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. [α]D25=−44.6 (c 10.0 in methanol).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCBr)OCc1ccccc1
Yield: 98.2 %

Procedure:
This compound was prepared from 6-bromohexanoic acid (1.95 g; 10.0 mmol), benzyl alcohol (1.62 g; 15.0 mmol), and p-toluenesulphonic acid (50 mg) in toluene (100 mL) using Procedure B. 2.80 g (98%) product was obtained (clear oil). The product was used in 9b without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:10]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CCCCCBr
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCBr)OCc1ccccc1

Procedure:
A mixture of 6-bromo-hexanoic acid (0.10 mol), benzyl alcohol (0.10 mol), 4-dimethylaminopyridine (1.78·10−2 mol) and dichloromethane (600 ml) is stirred and kept at 0° C. with an ice bath, then added with N,N′-dicyclohexylcarbodiimide (0.13 mol) and left to react for 16 hours. At the end of the reaction, the solution is filtered and the precipitate is discarded, whilst the solution is repeatedly washed with H2O, discarding the precipitate possibly formed. The organic layers are pooled and washed again with a saturated solution of NaHCO3, a solution of HCl 0.1 M and then with water. The solution is dried with MgSO4, filtered, and the solvent is removed by vacuum evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ncc(Br)cc1N
Temperature: 95 °C
Yield: 94.5 %

Procedure:
In a 500 mL, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-2-methoxy-3-nitropyridine (15) (20.0 g, 0.086 mol), Fe (20.0 g, 0.36 mol), and NH4Cl (20.0 g, 0.36 mol) in EtOH/H2O (150 mL, 1:1). After heating at 95° C. for 1 h, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give 16.5 g (95%) of 5-bromo-2-methoxypyridin-3-amine (16) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4]([N+:21]([O-])=O)[CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4]([NH2:21])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A solution of 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2-nitropyridine (2.3 g, 7.39 mmol) in MeOH (37 mL) and THF (37 mL) was treated with NH4Cl (11.86 g, 222 mmol) followed by the portion-wise addition of zinc dust (4.83 g, 73.9 mmol) and the mixture stirred at RT overnight. The mixture was diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.4 g, 67%). MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12])[CH3:6]>ClCCl>[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[C:15]=1[OH:16])[CH:11]=[O:12])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C=O)ccc1O
Solvent: ClCCl
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (22.0 mL) was added (rate approx. 1.5 mL/min) to a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (83.0 g) in dichloromethane (400 mL) at 5°-10° C. Thereafter the mixture was stirred for 30 min at 3° C. and then filtered. The product was washed with dichloromethane and water and dried in vacuo at 50° C., yield 77.8 g (73,7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:9][CH:10]=1
Reactant: O=C(CCCCCl)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-(4-chlorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:7][N:6]=1)=N.O.P(=O)(O)(O)[OH:33].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:33])=[N:6][CH:7]=3)=[N:12][C@H:13]3[C@@H:18]2[CH2:17][C@H:16]([OH:30])[CH2:15][CH2:14]3)=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=N)OC)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Analogously as described for Example 35 acidic acid (2R,4aR,10bR)-6-(6-cyano-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (compound 172) is converted in a first step into the corresponding imino ester 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester. In a second step, 443 mg (1.08 mmol) of 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester are dissolved in 3 ml of THF. A solution of 51 mg (2.16 mmol) LICH.H2O is added and the solution stirred at 60° C. for 18 hrs. The pH is adjusted to 5 using phosphoric acid and Disodiumhydrogenphosphate. The solvent is removed and the solid residue extracted with chloroform/methanol. After filtering off and removing the volatiles 350 mg (82%) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Br)c(NC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.4 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (5.0 g, 21.9 mmol), tetrahydro-2H-pyran-4-amine (2.22 g, 21.9 mmol), and N-ethyl-N-isopropylpropan-2-amine (4.25 g, 32.9 mmol) were dissolved in dioxane (50 ml) and the reaction was stirred at room temperature for 12 hours. Ethyl acetate was added to the reaction mixture and the organic layer was washed with water and brine. The organic layer was dried with sodium sulfate. Removal of solvent gave (5-bromo-2-chloro-pyrimidin-4-yl)-(tetrahydro-pyran-4-yl)-amine (32) as a light yellow solid (6.75 g, 99%). 1H NMR (500 MHz, CD3OD) δ ppm 8.04 (1 H, s), 4.14-4.21 (1 H, m), 3.89 (2 H, dd, J=11.4, 4.3 Hz) 3.43 (2 H, td, J=11.9, 2.0 Hz), 1.80 (2 H, ddd, J=12.6, 4.2, 1.8 Hz), 1.63 (2 H, qd, J=12.2, 4.5, Hz); LCMS-ESI (POS), M/Z, M+1: Found 292.0, Calculated 292.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(=O)(O)[O-].[Na+].[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCOCC.C([O-])(=O)C.Cl>CC(C)=O.O>[C:33]1([NH:39][C:40](=[O:41])[NH:1][CH:2]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)[C:3]([NH:5][CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:14]4[NH:18][N:17]=[N:16][N:15]=4)[C:10]([CH3:12])([CH3:13])[S:11][C@H:7]23)=[O:4])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)Nc3ccccc3)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a stirred solution of 0.78 g. (0.002 mole) of 6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 40 ml. of 1:1 acetone-water, the pH of which has been adjusted to 6.0 by the addition of sodium bicarbonate solution, is added 0.238 g. (0.002 mole) of phenyl isocyanate, at ambient temperature. Stirring is continued at ambient temperature for a further 30 minutes, and then 50 ml. of ether acetate is added. The pH of the aqueous phase is lowered to 1.5 with 1 N hydrochloric acid, and then the organic layer is removed, dried and evporated to dryness in vacuo. The residue is re-dissolved in a small volume of ethanol, to which 0.2 ml. of triethylamine is then added. The resulting solution is added dropwise to 200 ml. of ether, with vigorous stirring, and then the solid which precipitates is filtered off. This affords 0.8 g. (66% yield) of 6-(2-[3-phenylureido]-2-[p-hydroxyphenyl] acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its triethylamine salt, m.p. 165°-170° C. (dec.). The infrared spectrum of the product (KBr disc) shows absorptions at 1790 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6 /D2O) shows absorption at 7.60-6.70 ppm (multiplet, 9H, aromatic hydrogens), 5.80-5.50 ppm (multiplet, 3H, C-5 and C-6 hydrogens, and side-chain methine hydrogen), 5.05 ppm (singlet, 1H, C-3 hydrogen), 3.05 ppm (quartet, 6H, N-CH2CH3), 1.55 ppm (singlet, 3H, C-2 methyl hydrogen), 1.10 ppm (triplet, 9H, N-CH2CH3) and 0.95 ppm (singlet, 3H, C-2 methyl hydrogens).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:27]=3)[CH2:15][CH2:16][C:17]3[CH:25]=[C:21]([NH:22][C:23]=1[N:24]=2)[CH:20]=[CH:19][C:18]=3N.N([O-])=O.[Na+].[I-:32].[K+]>S(=O)(=O)(O)O.O>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:27]=3)[CH2:15][CH2:16][C:17]3[CH:25]=[C:21]([NH:22][C:23]=1[N:24]=2)[CH:20]=[CH:19][C:18]=3[I:32]
Reactant: [I-]
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Clc1cnc2nc1Nc1ccc(I)c(c1)CCc1cncc(c1)N2
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine trihydrochloride (161 mg, 0.359 mmol) in 2.0 M of sulfuric acid in water (1.8 mL, 3.59 mmol) was added a solution of sodium nitrite (37.2 mg, 0.539 mmol) in water dropwise at 0° C. The reaction solution was stirred at same temperature for 1 h, then a solution of potassium iodide (89.4 mg, 0.539 mmol) in water was added at 0° C. The reaction solution was stirred at room temperature for 48 h. The precipitate was filtered and washed by water and dried under vacuum to give the desired product (103 mg, 64%). LCMS for C17H14ClIN5(M+H)+: m/z=450.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[N:12]([O-])=[O:13].[Na+].O>CC(O)=O>[CH3:1][O:2][C:3](=[O:11])[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=N[O-]
Reactant: COC(=O)Cc1ccccn1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(=NO)c1ccccn1
Reaction time: 0.67 h
Yield: 9755.6 %

Procedure:
To a solution of pyridin-2-yl-acetic acid methyl ester (8.9 ml, 0.66 mmol) in AcOH (16 mL) at 0° C. with stirring, an aqueous solution of sodium nitrite (4.67 g, 0.66 mmol in 14 mL) was added portion wise. After addition was completed stirring was continued for 40 min at room temperature. Water (30 mL) was added and the mixture was stirred for additional 1 h. The mixture was concentrated to remove most of the AcOH and basidified to pH 8˜9 with Na2CO3 aq. extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Drying in a vacuum oven affords Hydroxyimino-pyridin-2-yl-acetic acid methyl ester (11.6 g, 97%) as an off-white solid, m/z 181.6 [M+1]+
Reaction SMILES: Cl.[SH:2][CH:3]1[CH2:6][N:5]([C:7]2[S:8][CH2:9][CH2:10][N:11]=2)[CH2:4]1.O.C1(P(O[C:28]2[C@H:29]([CH3:52])[C@@H:30]3[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]3[C:32]=2[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[O:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(OC(=O)C)C.C(Cl)(Cl)Cl.C(#N)C>[S:8]1[CH2:9][CH2:10][N:11]=[C:7]1[N:5]1[CH2:6][CH:3]([S:2][C:28]2[C@H:29]([CH3:52])[C@@H:30]3[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]3[C:32]=2[C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=2)=[O:34])[CH2:4]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: SC1CN(C2=NCCS2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(C4=NCCS4)C3)[C@H](C)[C@H]12
Reaction time: 2 h
Yield: 87.1 %

Procedure:
There was dissolved 700 mg of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride (8), which was obtained in the above Example 6, in 15 ml of a mixed solvent composed of water, acetonitrile and chloroform, and, to the resulting solution, there was added 1668 mg of p-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate (14). To the obtained solution which was being cooled with ice, there was added 2.8 ml of diisopropylethylamine in the stream nitrogen, and the resulting mixture was stirred at the same temperature for two hours. To the reaction liquid, there was added ethylacetate, and the resulting solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, and, then, the solvent was evaporated in a vacuum, and the obtained residue was subjected to silica gel column chromatography (eluent: chloroform-acetone), and, thus, there was produced 1339 mg (yield: 92%) of p-nitrobenzyl (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate (15).