Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[N:13]([O-])=O.[Na+].[OH2:17]>>[CH:2]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=2)[NH:1][N:13]=1)=[O:17]
Reactant: O=N[O-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O
Agent: [Na+]
Product: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 1H-indole-6-carboxylic acid (2.0 g, 12.42 mmol) in water (100 mL) was added NaNO2 (8.56 g, 124.2 mmol). To this suspension was then slowly added dropwise via addition funnel 6N HCL (16 mL). The resulting slurry was allowed to stir at room temperature overnight. The solid precipitate was filtered and washed with water (50 mL) to provide 2.35 g (100%) of 3-formyl-1H-indazole-6-carboxylic acid. 1H NMR (DMSO-d6) δ 14.46 (1H, s), 10.21 (1H, s), 8.26 (1H, s), 8.20 (1H, d, J=8.5Hz), 7.90 (1H, d, J=8.3 Hz). MS (APCI positive) 205 (methyl ester).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[C:8]#[CH:9].CC1C=CC(S(O)(=O)=O)=CC=1.O.CCN(CC)CC>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:7][C:8]#[CH:9]
Reactant: C1=COCCC1
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
At 0° C., 3,4-dihydro-2H-pyran (173 ml, 1.90 mol) is added dropwise over 10 min to a soln. of propargyl alcohol (88.49 g, 1.58 mol) and TsOH.H2O (16.08 g, 84.53 mmol) in CH2Cl2 (880 ml). After stirring for 80 min at 0° C., the mixture is warmed to room temperature, stirred for 3 h, treated with Et3N (12 ml), and evaporated. A vacuum distillation (20 mmHg, 80° C.) gives C (224 g, quant.). Colourless oil. 1H-NMR (400 MHz, CDCl3) δ 1.46-1.70 (m, 4 H), 1.70-1.91 (n, 2 H), 2.41 (t, J=2.2), 3.49-3.58 (m, 1 H), 3.81-3.88 (m, 1 H), 3.49-3.58 (m, 1 H), 4.23 (dd, J=15, 2.2), 4.30 (dd, J=15, 2.2), 4.83 (t, J=3.0).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O>[C:15]([C:12]1[C:11]([O:18][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:10]([CH2:19][CH2:20][CH3:21])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)CCCBr
Reactant: CCCc1c(OCc2ccccc2)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccccc2)ccc(C(C)=O)c1OCCCC(=O)OCC
Temperature: 100 °C
Yield: 52.3 %

Procedure:
A mixture of 4'-benzyloxy-2'-hydroxy-3'-propylacetophenone (3.0 g), anhydrous potassium carbonate (2.9 g), potassium iodide (0.5 g) in N,N-dimethylformamide (40 ml) was stirred at 100° C. To this mixture was added ethyl 4-bromobutyrate (3.1 g) dropwise under stirring and the mixture was stirred for 8 hours. This mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with benzene-ethyl acetate (20:1), to give the title compound (2.2 g, 52.3%) as brown oil.
Reaction SMILES: [CH3:1][CH:2]([C:11](=O)[CH:12]([CH3:21])[CH2:13]C1C=CC(C)=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[NH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[H][H]>O=[Pt]=O.C(O)C>[CH3:21][CH:12]([CH:11]([NH:23][CH:24]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:7]1[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=1)[CH:2]([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[CH3:13]
Reactant: [H][H]
Reactant: NCC1CCNCC1
Reactant: Cc1ccc(CC(C)C(=O)C(C)Cc2ccc(C)cc2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccc(CC(C)C(NC(c2ccc(C)cc2)C2CCNCC2)C(C)C)cc1

Procedure:
A mixture of 2,4-dimethyl-1,5-di-(4-methylphenyl)-3-pentanone (29.4 g., 0.1 mole) and 4-aminomethylpiperidine (34.2 g., 0.3 mole) in 250 ml. ethanol is hydrogenated with PtO2 at room temperature and 40 psi hydrogen pressure. The 2.5 g. platinum catalyst is filtered off and the ethanol removed under reduced pressure. The residual oil is dissolved in ether and the ether solution washed several times with water to remove the excess 4-aminomethylpiperidine. The ether extracts are dried over anhydrous sodium sulfate and concentrated under vacuum to leave 4-[2,4-dimethyl-1,5-di-(4-methylphenyl)-3-pentylaminomethyl]piperidine.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([CH3:24])[C:13]([C:22]#[N:23])=[C:14]2[C:18]=1[O:17][C:16]([CH2:19][O:20][CH3:21])=[N:15]2.O.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:12]([CH3:24])[C:13]([C:22]#[N:23])=[C:14]3[C:18]=2[O:17][C:16]([CH2:19][O:20][CH3:21])=[N:15]3)[CH2:4]1
Reactant: COCc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 90 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (76 μl, 0.60 mmol) was added to a dimethyl sulfoxide (4 ml) solution of 7-fluoro-2-(methoxymethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-59) (58 mg, 0.20 mmol), followed by stirring at 90° C. for 1 hour. After cooling to room temperature, the above brown oily substance and saturated sodium bicarbonate water were added, followed by extraction three times with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform:methanol (50:1) was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration tinder reduced pressure, the entitled compound (39 mg, 17%) was obtained as a brown oily substance.
Reaction SMILES: C(OC(N1CCNCC1)=O)(C)(C)C.[Cl:14]CC(Cl)=O.[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][O:26][CH3:27].[ClH:28].Cl.COCC(N[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)C>>[ClH:14].[ClH:28].[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][O:26][CH3:27])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1
Reactant: COCCNCCOC
Reactant: COCC(C)NC(=O)CN1CCNCC1
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Product: COCCN(CCOC)C(=O)CN1CCNCC1

Procedure:
N,N-Bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N,N-bis-(2-methoxy-ethyl)amine in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:48]([NH:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(CC)CC>>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:17]([NH:56][NH:55][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:19])[C:13]([CH3:14])([CH3:15])[CH3:16])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccccc1
Yield: 67 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using Cbz-(L)-tert-leucine (2.00 g, 4.48 mmol), EDAC (0.969 g, 5.05 mmol), HOBT (0.669 g, 4.95 mmol), NMM (0.542 mL, 4.93 mmol), benzylhydrazine×2HCl (0.962 g, 4.93 mmol) and Et3N (1.38 mL, 9.85 mmol) which gave the title compound (1.11 g, 67%) as a low melting solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[NH:15][N:14]=[CH:13]2)(=[O:9])=[O:8].CCCCP(CCCC)CCCC.O[C@H:47]([C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]2)[CH3:48]>C1COCC1>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]([C@@H:47]([C:49]1[CH:50]=[CH:51][CH:52]=[C:53]3[C:58]=1[CH2:57][N:56]([C:59]([O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[O:60])[CH2:55][CH2:54]3)[CH3:48])[N:14]=[CH:13]2)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2cccc(F)n2)S(=O)(=O)c2cc3cn[nH]c3cc2C)c(OC)c1
Reactant: C[C@H](O)c1cccc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cccc(F)n2)S(=O)(=O)c2cc3cnn([C@H](C)c4cccc5c4CN(C(=O)OC(C)(C)C)CC5)c3cc2C)c(OC)c1
Reaction time: 0.83 h

Procedure:
To a 100 mL RB flask containing THF (4381 μl) at 0° C. was added sequentially N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)-6-methyl-1H-indazole-5-sulfonamide (4-5, 200 mg, 0.438 mmol), TRI-N-BUTYLPHOSPHINE (216 μl, 0.876 mmol), DTBAD (202 mg, 0.876 mmol) and (S)-tert-butyl 8-(1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (243 mg, 0.876 mmol). After 50 min at 0° C., concentrated in vacuo. Purified by normal-phase ISCO (40 g column, 0-40% EtOAc:Hex) to give an off-white solid
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C.CO>[N:15]1([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.0 g (9.28 mmol) product from Step A and 1.6 mL (18.6 mmol) morpholine in 20 mL DMF was heated to 90° C. for 6 hours. After the mixture had cooled to room temperature, the DMF was stripped off in vacuo. The crude material was then redissolved in methanol and stirred with 20 g Amberlyst-A26® for about 20 minutes. The mixture was then stripped of solvent and used without further purification in the next step. Rf 0.20 in 40% EtOAc/hexane, visualized by UV and visible light.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH:17]([CH2:18][OH:19])[CH2:16][N:15]3[N:20]=[C:21]([I:26])[C:22]([C:23](O)=[O:24])=[C:14]3[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].C[N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH:17]([CH2:18][OH:19])[CH2:16][N:15]3[N:20]=[C:21]([I:26])[C:22]([C:23]([NH2:28])=[O:24])=[C:14]3[CH2:13]2)=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(NC(=O)N2Cc3c(C(=O)O)c(I)nn3CC2CO)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)N2Cc3c(C(N)=O)c(I)nn3CC2CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of Intermediate 351F (0.12 g, 0.257 mmol) in dry DMF (3 mL) was added HATU (0.195 g, 0.512 mmol), diisopropylethylamine (224 μL, 1.128 mmol) and ammonium chloride (0.0687 g, 1.128 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated completely to dryness and the crude was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 3-5% methanol in chloroform). Fractions containing the product were combined to afford Intermediate 351G (0.08 g, 67%) as an off-white solid. MS(ES): m/z=467 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (s, 1H), 7.69-7.74 (m, 2H), 7.63-7.69 (m, 2H), 7.37-7.48 (m, 1H), 6.93 (br. s., 1H), 5.22 (d, J=18.07 Hz, 1H), 5.13 (t, J=5.27 Hz, 1H), 4.72 (d, J=4.52 Hz, 1H), 4.51 (d, J=18.57 Hz, 1H), 4.31-4.38 (m, 1H), 4.20-4.28 (m, 1H), 3.43 (t, J=6.02 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.C([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])C.[C:18]([O-])(=O)C.[NH4+]>Cl>[CH3:18][C:17]1[CH:16]=[N:13][C:14]2[CH2:15][C:2]([CH3:9])([CH3:1])[CH2:3][C:4](=[O:5])[C:6]=2[CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: Cc1cnc2c(c1)C(=O)CC(C)(C)C2
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 3-amino-2-methacrolein (8.5 g., 0.1 mol.) and dimedone (14 g., 0.1 mol.) was treated with triethylamine (5 ml.) and ammonium acetate (0.1 g.) and heated in an oil bath at 120° C with stirring for 20 hours. The cooled reaction mixture was diluted with 2N HCl (50 ml.) and extracted with ethyl acetate (2 × 50 ml.) and the extracts discarded. The aqueous solution was adjusted to pH 10.0 with sodium bicarbonate and extracted with ethyl acetate (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed to give a residual oil which was distilled to give the title compound as a colorless oil (7.8 g., 40% b.p. 80°/0.2 mm Hg. (RT = 2 min. 2% OV17, T=150°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7](N1CCCC1)[CH2:6][CH2:5]2.C([O-])(=[O:20])C.[Na+].C(O)(=O)C.O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[C:7](=[O:20])[CH2:6][CH2:5]2
Reactant: CC1=C(N2CCCC2)CCc2cc(F)ccc21
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1C(=O)CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To the 6-fluoro 1-methyl-2-pyrrolidinyl-3,4-dihydronaphthalene afforded above in Step B in 1700 ml of ethyl acetate was added sodium acetate (10.2 g; 124.4 mmol), acetic acid (10.2 ml; 178.2 mmol) and 102 ml of water. The reaction mixture was stirred at room temperature for 4 hours. The layers were separated and the organic layer was washed with brine, 5% NaHCO3, and brine. The organic layer was dried over MgSO4 and was concentrated to afford 7.9 g of the subtitle compound as a dark orange-red oil (60% yield).
Reaction SMILES: [CH2:1](O)[C:2]#[CH:3].S(=O)(=O)(O)O.[CH3:10][C:11]1[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[CH3:32])[N:12]=1>>[CH3:10][C:11]1[C:15]([CH2:16][C:17]([O:19][CH2:3][C:2]#[CH:1])=[O:18])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[CH3:32])[N:12]=1
Reactant: C#CCO
Reactant: Cc1ccncc1-n1nc(C)c(CC(=O)O)c1-c1ccccc1
Agent: O=S(=O)(O)O
Product: C#CCOC(=O)Cc1c(C)nn(-c2cnccc2C)c1-c1ccccc1

Procedure:
0.445 g (6.345 mmol) of prop-2-yn-1-ol and a drop of concentrated sulfuric acid were added to 0.130 g (0.423 mmol) of [3-methyl-1-(4-methylpyridin-3-yl)-5-phenyl-1H-pyrazol-4-yl]acetic acid, and the mixture was stirred under reflux for 4 h. The solvent was removed under reduced pressure, a mixture of 10 ml of dichloromethane, 1.5 ml of diisopropylethylamine and 10 ml of water was added to the residue and the aqueous phase was extracted with 15 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.083 g (57% of theory) of a light-beige solid of melting point 106° C.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH:28]([CH3:32])[NH:27]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:30]3[CH2:29][C@@H:28]([CH3:32])[NH:27][C@@H:26]([CH3:25])[CH2:31]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC1CNCC(C)N1
Solvent: CCCCO
Product: Cc1nc(N2C[C@@H](C)N[C@@H](C)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=O)[NH2:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.P(Cl)(Cl)(OCC)=O.[NH4+].[Cl-]>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]#[N:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(N)=O)CC1
Agent: CCOP(=O)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C#N)CC1
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl((trans-4-carbamoylcyclohexyl)methyl)carbamate (1.7 g, 6.6 mmol) in CH2Cl2 (33 mL) was added DBU (3 g, 19.8 mmol) at room temperature. After stirring for 10 min, ethyl dichlorophosphate (2.2 g, 13.2 mmol) was added. The mixture was stirred at room temperature for 50 min. TLC (CH2Cl2:MeOH=10:1) showed the reaction was complete. The mixture was poured into sat. NH4Cl (aq., 150 mL) and extracted with CH2Cl2 (100 mL*2). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by combi flash to give tert-butyl((trans-4-cyanocyclohexyl)methyl)carbamate (1.4 g, 88%) as a white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([OH:24])[CH2:11][P:12]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:16])[O:13]CC)=O)(C)(C)C.C[Si](C)(C)[Br:34].O>ClCCl.CO>[BrH:34].[NH2:8][CH2:9][C:10]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([OH:24])[CH2:11][P:12]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:13])[OH:16]
Reactant: C[Si](C)(C)Br
Reactant: CCOC(OCC)P(=O)(CC(O)(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1)OCC
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Br
Product: CCOC(OCC)P(=O)(O)CC(O)(CN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.48 g of ethyl 3-(N-tert.-butoxycarbonylamino)-2-(4-chlorophenyl)-2-hydroxy-propyl(diethoxymethyl)phosphinate in 10 ml of anhydrous dichloromethane is treated with 0.76 g of trimethylbromosilane and the resulting colourless solution stirred for 24 hours at room temperature under an inert atmosphere. The volatile materials are removed under reduced pressure to give a foam which is redisslued in 5 ml of methanol containing 1% of water and the solution stirred for 20 hours at room temperature. After this time evaporation of the solvent in vacuo followed by chromatography of the residue on reverse-phase silicagel and drying of the off white solid thus obtained in high vacuum gives 3-amino-2-(4-chlorophenyl)-2-hydroxypropyl(diethoxymethyl)phosphinic acid hydrobromide salt. Dissolution of the salt in the methanol and treatment with propylene oxide gives 3-amino-2-(4-chlorophenyl)-2-hydroxy-propyl(diethoxymethyl)phosphinic acid; 1H-NMR (D2O): δ(ppm)=7.39 (4H, m, Ph), 4.75 (1H, d, CH--P), 3.67-3.23 (6H, m, 2×CH2CO+CH 2 N), 2.38-1.97 (2H, ABq, CH2P), 1.23-1.04 (6H, t, 2×CH3).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:54](=[O:55])[N:6]2[C:7]([C:41]([O:43]CC3C=CC([N+]([O-])=O)=CC=3)=[O:42])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15]([CH3:17])[C@H:14]([C:18]([N:20]4[CH2:23][CH:22]([N:24](C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[C:25](=[NH:27])[CH3:26])[CH2:21]4)=[O:19])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:25]([NH:24][CH:22]1[CH2:21][N:20]([C:18]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:54](=[O:55])[N:6]4[C:7]=3[C:41]([OH:43])=[O:42])[CH2:16][N:15]2[CH3:17])=[O:19])[CH2:23]1)(=[NH:27])[CH3:26]
Reactant: CC(=N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CC(=N)NC1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)C1
Yield: 61.4 %

Procedure:
453 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-{3-[N-(4-nitrobenzyloxycarbonyl)-N-acetimidoylamino]azetidin-1-ylcarbonyl}pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 21 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and 500 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated at room temperature for 1.5 hours in an atmosphere of hydrogen. The catalyst was then removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure. The residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 40 ml). Of the fractions obtained by elution with 8% by volume aqueous acetonitrile, the one containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to give 166 mg of the title compound as a powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:32]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)c3cccs3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 11 mL (0.11 mmol) 2-thiophenecarbonyl chloride. NMR was consistent with the proposed compound.