Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([CH:27]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:28][N:29]([CH2:42][CH2:43][CH2:44]O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.OC1C=C(C=CC=1)CC1N(COCC)N=NN=1.BrCCCO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:44][CH2:43][CH2:42][N:29]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[C:32]=3[Cl:41])[CH2:28][CH:27]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)n2)CC1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CCOCn1nnnc1Cc1cccc(O)c1
Agent: OCCCBr
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1
Yield: 52 %

Procedure:
Following the procedure of Example 6(d), except 4-(6-Hydroxy-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester and N-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine were used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole and 3-bromo-propanol in step 6(d), the title compound was synthesized as the free base, 0.46 g (52% yield), as a white solid. MS (ESI) 709.4 (M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH3:14])([CH3:13])[CH:11]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:15][OH:16].N1C=CC=CC=1>C(O)C.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH3:14])([CH3:13])[CH:11]=[N:15][OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NO
Reactant: CC(C)(C=O)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C=NO)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a solution of Compound I (511 mg, 2.66 mmol) in ethanol (1 mL), HCl.NH2OH (277 mg, 4.00 mmol) and pyridine (2.2 mL, 26.58 mmol) were added and it was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness and added 10 mL of ethyl acetate. The organic layer was washed with distilled water, dried over anhydrous sodium sulfate, filtered and evaporated. The crude reaction mixture was purified over silica gel column using 5:1 petroleum ether-ethyl acetate as solvent to afford Compound J (528 mg, 96%) as a white foam.
Reaction SMILES: C1N2CCN(CC2)C1.[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19](Cl)=[C:18]([N+:27]([O-:29])=[O:28])[C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:31]1([C:37]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN1CCCC1=O.O>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([N:34]2[CH2:35][CH2:36][N:31]([C:37]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)=[O:38])[CH2:32][CH2:33]2)=[C:18]([N+:27]([O-:29])=[O:28])[C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: O=c1c([N+](=O)[O-])c(Cl)c2cccnc2n1Cc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1cccs1)N1CCN(c2c([N+](=O)[O-])c(=O)n(Cc3ccccc3)c3ncccc23)CC1
Temperature: 110 °C

Procedure:
DABCO (6.26 g, 55 mmol) was added to a solution of 1-benzyl-4-chloro-3-nitro-1,8-naphthyridin-2(1H)-one (126) (8.81 g, 28 mmol) and piperazine-1-yl-thiophene-2-yl-methanone (6.57 g, 33 mmol) in N-methylpyrrolidone at room temperature. The solution was heated at 110° C. for 2 h. The solution was cooled and poured into ice cold 10% ammonium chloride solution in water. The solids formed were filtered, washed by water, and dried to yield yellow solid. Yield 11 g (83%), mp 255° C. 1H-NMR (DMSO-d6): δ 3.26 (m, 4H), 3.90 (m, 4H), 5.61 (s, 2H), 7.15 (m, 1H), 7.25 (m, 5H), 7.47 (m, 2H), 7.80 (d, J=5.2 Hz, 1H), 8.43 (d, J=7.6 Hz, 1H), 8.76 (d, J=4.4 Hz, 1H); EIMS m/z 476 (M+1).
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:27]#[N:28])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24]C3)[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:29])(OC)=O.CS(C)=O.[Cl-].[Na+]>O>[C:27]([C:9]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:26]3[CH2:24][CH2:25]3)[CH:12]=2)[CH2:10][CH2:5][C:6](=[O:29])[CH2:7][CH2:8]1)#[N:28]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(OC(F)F)c(OCC3CC3)c2)CCC(=O)CC1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one (0.5 g, 1.27 mmole), dimethyl sulfoxide (10 mL), water (1 mL) and sodium chloride (0.5 g) under an argon atmosphere was heated at 145°-150° C. for 4.5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water, extracted twice with ethyl acetate, the organic layer was washed twice with water and once with brine, was dried (sodium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 20-25% ethyl acetate/hexanes, and the resultant solid was triturated with ether/hexane and then with cold ether to provide a solid (0.22 g, 51.6%): m.p. 85.5°-86.5° C. Analysis Calc. for C18H19F2NO3 : C 64.47, H 5.71, N 4.18; found: C 64.28, H 5.63, N 4.20.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:9])=[C:6]([S:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)O)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step G, using equimolar amounts of 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylthio)benzoic acid, 4-nitrophenol, and dicyclohexylcarbodiimide in methylene chloride, yielding 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylthio)benzoate.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=2)[N:15]=[CH:14][C:13]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)OCC)C.[C:32]([O:36][C:37](=[O:48])[NH:38][C@H:39]1[CH2:44][CH2:43][C@H:42]([CH2:45][CH:46]=O)[CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33].C(OCC)(=O)C>O1CCCC1>[C:32]([O:36][C:37](=[O:48])[NH:38][C@H:39]1[CH2:40][CH2:41][C@H:42]([CH2:45][CH:46]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][C:13]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:43][CH2:44]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: CCOP(=O)(Cc1c(OCc2ccccc2)cnc2ccc(OC)nc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(OCc3ccccc3)c(C=CC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sodium hydride (86 mg, 1.91 mmol, 2.3 eq) is added at 0° C. to a stirred solution of (3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-ylmethyl)-phosphonic acid diethyl ester (350 mg, 0.83 mmol, 1.0 eq) in tetrahydrofuran (30 mL) and the resulting mixture is stirred at 0° C. for 1 hour before the addition of a solution of [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (200 mg, 0.83 mmol, 1.0 eq) in tetrahydrofuran (5 mL). After 15 hours stirring at room temperature, the reaction mixture is quenched with ammonium chloride aqueous solution (20 mL), tetrahydrofuran is removed and the resulting residue is extracted with ethyl acetate (3×50 mL) and brine (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 6:1, v/v) to afford {trans-4-[3-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-allyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (548 mg, 55% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:26]([C:25]2[CH:28]=[CH:29][C:22]([S:21][CH3:20])=[CH:23][CH:24]=2)=[NH:27])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CSc1ccc(C#N)cc1
Reactant: Cc1ccc(N)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(C(=N)Nc2ccc(C)c(C)c2)cc1
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
To a solution of 3,4-dimethylaniline (10 g, 83 mmol) in THF (10 ml), lithium bis(trimethylsilyl)amide (20% in THF, 93 ml, 99 mmol) was added under stirring in nitrogen blanket for a period of 20 minutes followed by 4-methylthiobenzonitrile (12.31 g, 83 mmol) over a period of 10 min. After 1 hour the reaction mixture was poured over ammonium chloride solution (30%, 100 ml). The resultant mixture was extracted with ethyl acetate and washed with water, dried over anhydrous sodium sulphate. The ethyl acetate extract was concentrated to yield the title compound (19 g, yield 85.1%, mp 111-113° C., purity 99.1% by HPLC). 1H-NMR (CDCl3):δ 2.23-2.24 (d, 6H), 2.51 (s, 3H), 4.81 (bs, 2H, D2O exchangeable), 6.70-6.72 (m, 1H), 6.77 (s, 1H), 7.08-7.1 (d, 1H), 7.25-7.27 (d, 2H), 7.76-7.78 (d, 2H). MS m/z: 271.3 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2[N:20](COCC[Si](C)(C)C)[N:21]=[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:20][N:21]=[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:26][CH2:25]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(F)ccc3c21
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(F)ccc23)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 8 %

Procedure:
A round-bottomed flask equipped with a septum having a top-mounted argon intake is charged with 95 mg of 5-(2,6-difluorophenyl)-7-fluoro-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}1-([2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline in 10 ml of DCM. After cooling to 0° C. using an ice bath, 0.173 ml of TFA are added and the mixture is stirred at RT for 20 h. It is concentrated under RP and the solid obtained is taken up in 30 ml of water and 2 ml of 0.75M aqueous ammonia solution. The product is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. It is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and methanol (95/05 by vol.), to give 6 mg of 5-(2,6-difluorophenyl)-7-fluoro-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline (yellow solid). MS (E/I): m/z=475 (M+); 1H NMR: 1.67 (m, 2 H) 2.10 (m, 2 H) 2.87 (s, 3 H) 2.90 (m, 2 H) 3.56 (m, 2 H) 3.79 (m, 1H) 6.08 (d, J=8.3 Hz, 1 H) 7.29 (m, 1 H) 7.33 (t, J=7.8 Hz, 2 H) 7.68 (m, 1 H) 7.88 (broad t, J=9.3 Hz, 1 H) 8.50 (dd, J=9.3, 5.4 Hz, 1 H) 12.80 (s, 1 H)*.
Reaction SMILES: O[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH2:7](N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.N>>[CH2:18]([NH:6][C:4](=[O:5])[CH:3]=[CH2:2])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: NC(=O)CCO
Reactant: CCCCCCCCCCCCN
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: N
Product: C=CC(=O)NCCCCCCCCCCCC
Temperature: 160 °C

Procedure:
82 g of β-hydroxypropionamide and 195 g of dodecylamine were heated with 50 mg of 2,6-di-t-butyl-p-cresol for 4 hours in a temperature range of 130° C. to 190° C. unitl the evolution of ammonia was complete. After adding 5 g of polyphosphoric acid the reaction mixture was maintained at 160° C. for 1 hour and then distilled in an oil pump vacuum. The main run was taken off between 148° C. and 168° C. at 0.3 bar and crystallized in the receiver.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.C(O)(=O)C.CO>[Zn].C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[CH:19][CH:20]=1
Reactant: CSc1nc2ccc(CNc3ccc(F)cc3[N+](=O)[O-])cc2s1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3ccc(F)cc3N)cc2s1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a stirred mixture of 4-fluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (1.18 g, 3.3 mmol) from the previous step, acetic acid (3 mL), MeOH (3 mL) and DCM (20 mL) at −10° C. was added portionwise zinc dust (1.7 g, 26 mmol). The reaction mixture was stirred at −10° C. for 0.5 h. The mixture was poured into ice-water and extracted with EtOAc (100 mL×3). The combined organic layers were washed sequentially with water, saturated aq NaHCO3 (100 mL×2), and brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-fluoro-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (0.93 g, yield 87%) as a yellow solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.42 (dd, J=8.4, 1.8 Hz, 1H), 6.42-6.56 (m, 3H), 4.35 (s, 2H), 3.60 (br s, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 320 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[C@H:13]1[CH2:17][C:16](=[O:18])[C:15]([CH2:19][CH:20]=[CH2:21])=[C:14]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[C@@H:13]([O:2][N+:1]([O-:4])=[O:3])[CH2:17][C:16](=[O:18])[C:15]=1[CH2:19][CH:20]=[CH2:21]
Reactant: O=[N+]([O-])O
Reactant: C=CCC1=C(C)[C@@H](O)CC1=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: C=CCC1=C(C)[C@@H](O[N+](=O)[O-])CC1=O
Yield: 97.2 %

Procedure:
Into a mixed solution of 8 g of fuming nitric acid and 24 g of acetic anhydride, kept at a temperature of -5° to 10° C., was added dropwise 6 g of (S)-4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one ([α]D23 : +10.3° (C=1.17, in chloroform), (R)-isomer/(S)-isomer=15.7/84.3). Thereafter, with the same operations as in Example 1, 7.56 g of crude (S)-3-methyl-4-nitroxy-2-(2-propenyl)-2-cyclopenten-1-one was obtained.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>C1(C)C=CC=CC=1>[C:1]1([S:7][CH2:8][C:9]([Cl:15])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CSc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)CSc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5.0 g of (phenylthio)acetic acid in 20 ml of toluene under nitrogen was added 5.2 ml of oxalyl chloride in four portions. The solution was stirred at room temperature for about twenty hours and then concentrated in vacuo to the oily title compound, which was used in subsequent reactions without further purificaton or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)CCNCCOc2ccc(C(=O)O)cc2OC)ccc1NC(=O)Nc1ccccc1C
Yield: 34.7 %

Procedure:
To a solution of ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate (550 mg, 0.98 mmol) in THF (15 mL) was added 0.25 N NaOH (15 mL). The resulting mixture was then heated under reflux for 2 days. The mixture was poured into 1 N HCl and the solid was collected. The crude solid was recrystallized from EtOH—CHCl3 to give 182 mg (35%) 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoic acid 256 as a white crystalline powder. mp 115-118° C.; IR (KBr) 1707 cm−1; 1H-NMR (DMSO-d6) d 1.02-1.12 (m, 3 H), 2.25 (s, 3 H), 2.50 (s, 2 H), 335-3.89 (m, 10 H), 4.11-4.16 (m, 2 H), 6.71-8.56 (series of m, total 12H), 12.65 (br s, 1H); MS NAB) m/z 536 (M++1); Anal. Calcd. for C29H33N3O7.3/4H2O: C, 63.43; H, 6.33; N, 7.65. Found: 63.34; H, 6.28; N, 7.28.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[CH:30]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:27][C:25]([CH3:28])([CH3:26])[CH2:24][O:23][C:5]1[C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:10]=[CH:11]/[C:12]1[N:13]=[C:14]2[N:18]([C:19]=1[C:20]([NH:38][C:35]1[S:36][CH:37]=[C:33]([CH:30]([CH3:32])[CH3:31])[N:34]=1)=[O:21])[CH:17]=[CH:16][S:15]2
Reactant: CC(C)c1csc(N)n1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1csc(NC(=O)c2c(/C=C/c3cccc(OC(F)F)c3OCC(C)(C)C)nc3sccn23)n1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 4-(isopropyl)-1,3-thiazol-2-amine (41 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (26 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 60 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 1.26 (d, J=6.9 Hz, 6H), 2.92-2.98 (m, 1H), 3.57 (s, 2H), 6.64 (s, 1H), 7.18 (t, J=74.7 Hz, 1H), 7.20-7.30 (m, 2H), 7.42 (s, 1H), 7.64-7.70 (m, 1H), 7.83 (d, J=15.6 Hz, 1H), 8.12-8.18 (m, 1H), 8.60-8.70 (m, 1H), 12.86 (br s, 1H); APCI-MS (m/z) 547.26 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7]([Br:14])=[C:6]([OH:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][C:3]1=2.[CH3:20][O:21][CH2:22]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:14][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:19])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[C:6]=1[O:15][CH2:20][O:21][CH3:22]
Reactant: COCCl
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C
Temperature: 45 °C

Procedure:
To a solution of 4-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound M), 233 mg, 0.71 mmol) in 6 ml of CH2Cl2 was added chloromethyl methyl ether (0.162 ml, 2.1 mmol), diisopropylethyl amine (0.764 ml, 4.2 mmol) and a catalytic amount of tetrabutylammonium bromide. The reaction mixture was heated to 45° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane 1/9) to yield the methoxymethyl ester of the title compound as a white solid (200 mg). This white solid was further dissolved in 20 ml of EtOH. An aqueous solution of NaOH (0.5 ml, 1M) was added. The reaction mixture was stirred at room temperature for over night. The EtOH was removed and the residue was added 2 ml of ethyl acetate and 3 ml of water. This mixture was very slowly acidified with 10% HCl to PH=7. The ethyl acetate layer was separated and washed with brine, dried over Na2SO4. After filtration of the drying agent and removal of solvent, the reaction yielded the title compound as a white solid (155 mg). 1H NMR d 7.99 (s, 1H), 5.20 (s, 2H), 3.66 (s, 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(N2CCCC2)cc1N
Yield: 90 %

Procedure:
To a solution of tert-butyl 2-nitro-4-pyrrolidin-1-ylphenylcarbamate obtained in step VI above (1.0 eq) in MeOH was hydrogenated using Pd/C under H2 atmosphere. After completion of the reaction, reaction mixture was filtered through celite and evaporated to dryness to get desired tert-butyl 2-amino-4-pyrrolidin-1-ylphenylcarbamate. (Yield=90%)
Reaction SMILES: [CH:1]([C@@H:4]1[NH:23][C:22](=[O:24])[C@H:21]([NH:25]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH2:20][C:19]2=[CH:43][CH:44]=[C:16]([CH:17]=[CH:18]2)[O:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2].N1CCCCC1>CO.[Pd]>[NH2:25][C@@H:21]1[CH2:20][C:19]2=[CH:18][CH:17]=[C:16]([CH:44]=[CH:43]2)[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C@H:4]([CH:1]([CH3:2])[CH3:3])[NH:23][C:22]1=[O:24]
Reactant: CC(C)[C@H]1COCCCCCC=CCOc2ccc(cc2)C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Agent: [Pd]
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)[C@H]1COCCCCCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.87 (1.46 mmol) of 9H-fluoren-9-yl-methyl ((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),4,18(22),19-tetraen-16-yl)-carbamate and 0.16 g of 10% Pd/C in 100 ml of methanol was stirred under a hydrogen atmosphere at RT. After stirring overnight and addition of 0.5 ml of piperidine, stirring was continued for 2 h, and the mixture was filtered and freed of solvent. The residue was separated by preparative HPLC. The required fractions were combined and freeze dried. 0.18 g of the title compound was obtained as trifluoroacetate.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[CH:15]([C:21]([O:23][CH3:24])=[O:22])[C:16]([CH3:20])(I)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>C(#N)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([CH3:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)I
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C1=C(C)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Yield: 27.1 %

Procedure:
A mixture of methyl 7-(2-phenoxyacetamido)-3-methyl-3-iodocepham-4-carboxylate (0.25 g.) in dry acetonitrile (10 cc) and sodium acetate (45 mg.) was heated under reflux for 4 hours and concentrated. The residue was mixed with water and extracted with chloroform. The chloroform layer was washed with an aqueous sodium thiosulfate solution and then with water, dried and concentrated. The residue was subjected to chromatography on silica gel and eluated with chloroform to yield crystals (50 mg.) of methyl 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 124°-125° C.