Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: COc1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 16 h

Procedure:
A solution of 80 mg (0.21 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) of triethylamine and 63.8 mg (0.43 mmol) of 2-methoxyphenyl isocyanate. After 16 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 10 mg (9.6% of theory) of the title compound are obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)Cc1ccc(F)c(F)c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CC1CCCC1)c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 103 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23.0 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-difluoro-phenyl)-acetic acid methyl ester (1.20 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionic acid methyl ester (1.79 g, quant.) as a clear oil: EI-HRMS m/e calcd for C15H18F2O2 (M+) 268.1275, found 268.1278.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([N:20](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:10]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:47]([N:10]1[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=O)OCCOc1nn(Cc2ccccc2)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2c(OCCO)nn(Cc3ccccc3)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a stirring solution of 2-{[1-benzyl-5-(bis{[4-(tert-butyl)phenyl]sulfonyl}amino)-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 40) (1.01 g) in ethanol (20 ml) was slowly added sodium hydroxide solution (2M, 2 ml). The reaction mixture was left stirring at room temperature overnight. The solvent was removed in-vacuo and the residue was taken up in ethyl acetate (30 ml) and washed with water (15 ml) followed by brine (15 ml). It was then dried (MgSO4) and the solvent removed in-vacuo to yield the crude material as a yellow oil (ca.1 g). Purification was achieved using the Biotage™ Flash 40 system (silica, 90 g) with a gradient elution of hexane (75% to 65%) and ethyl acetate (25% to 35%) to yield the title product as a yellow solid (250 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[OH:23].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)SCc1ccccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Yield: 97.4 %

Procedure:
485 mg (1.59 mmole) of 1'-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4'-piperidine] [prepared as described in Preparation 3(b)] were dissolved in 5 ml of anhydrous methylene chloride, and 148 mg (1.76 mmole) of sodium hydrogencarbonate were added, followed by 325 mg (1.88 mmole, content: 85%) of m-chloroperbenzoic acid, whilst ice-cooling. The reaction mixture was stirred whilst ice-cooling, for 30 minutes, after which it was diluted with methylene chloride and then washed, in turn, with water and with a saturated aqueous solution of sodium chloride. The solution was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by thin-layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent, to give 498 mg (yield 98%) of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:27])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([CH:25]=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:27])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([CH2:25][OH:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C=O)ccc1OC2)c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C(=O)c1cc2c(s1)-c1cc(CO)ccc1OC2)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of N-(2,4-difluorophenyl)-8-formyl-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide in ethanol (1 mL) was added sodium borohydride (10 mg, 0.3 mmol, 6 equiv). After 3 hr, excess sodium borohydride was quenched with saturated aqueous ammonium chloride solution (3 mL). The ethanol was removed in vacuo, and the resulting aqueous solution was extracted with ethylacetate (3×3 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (3:2 hexanes/ethylacetate) provided 159bp (5.2 mg, 30%). 1H NMR (500 MHz, CDCl3) δ 7.26 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.86-6.93 (m, 4H), 5.25 (s, 2H), 4.55 (d, J=6.7 Hz, 2H), 4.06 (m, 1H), 3.40 (s, 3H). LCMS (ESI) m/z: 388.1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:41][CH2:40][P:39]([CH3:43])(=[O:42])[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH2:25].Cl>COCCO.C(O)C>[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:37][CH2:38][P:39]([CH3:43])(=[O:42])[CH2:40][CH2:41]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Reactant: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1N
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)cnn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3ccccn3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH:4]([CH2:8][CH3:9])[C:5](Cl)=[O:6].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])#[N:11].C(N(CC)CC)C>C(Cl)Cl>[C:10]([C:12](=[C:5]([OH:6])[CH:4]([CH2:3][S:2][CH3:1])[CH2:8][CH3:9])[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])#[N:11]
Reactant: CCCOC(=O)CC#N
Reactant: CCC(CSC)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)C(C#N)=C(O)C(CC)CSC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At 25° C., 16.7 g (0.1 mol) of 2-[(methylsulfanyl)methyl]butyryl chloride were added to a solution of 12.7 g (0.1 mol) of n-propyl cyanoacetate in CH2Cl2, and the mixture was cooled to 0° C. At 0° C., 20.2 g (0.2 mol) of triethylamine were then added dropwise. After 16 h of stirring at 25° C., the reaction mixture was hydrolyzed and the organic phase was separated off, dried and concentrated. Customary purification gave 15 g (58% of theory) of the title compound as a yellow liquid (b.p. 118 to 120° C./2 mbar).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16](N)=[O:17].C1(O)C=CC=CC=1>>[NH:1]1[C:2]2[C:3](=[CH:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH:11]=2)[C:12](=[O:14])[NH:15][C:16]1=[O:17]
Reactant: NC(N)=O
Reactant: Nc1cc2ccccc2cc1C(=O)O
Solvent: Oc1ccccc1
Product: O=c1[nH]c(=O)c2cc3ccccc3cc2[nH]1
Temperature: 185 °C

Procedure:
A mixture of 3-amino-2-naphthoic acid (8-1,1.2 g, 6.6 mmol, 1 equiv), urea (2.0 g, 33 mmol, 5.0 equiv) and phenol (7.0 g, 74 mmol, 11 equiv) was heated at 160° C. for 0.5 h an 185° C. for an additional 1.5 h. The reaction was cooled and triturated with methanol (50 mL). The solid precipitate was filtered, washed with methanol, and dried to yield benzo[g]quinazoline-2,4(1H,3H)-dione (1-2) as an orange solid. LRMS m/z (M+H) 213.1 found, 213.1 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[N:17]1([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.CCCCCC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:27][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(CN2CCCC2)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(CN2CCCC2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 106.2 %

Procedure:
To a solution of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, (0.15 g, 0.53 mmol) in N,N′-dimethylformamide is added 4-(pyrrolidinyl-methyl)aniline (0.10 mL, 0.58 mmol). The reaction mixture is heated at 120° C. under N2. Reaction is monitored by mass spectroscopy. After reaction is completed after 1.5 h. After evaporating the solvent, warm ethyl acetate is added to the residue to generate reddish orange residue. It is filtered through a pad of celite to give a yellow solution, which upon addition of hexane generated 0.24 g (62.8% yield) of orange solid: mp 165-166° C., Analysis for C21H20BrN3O2, Calcd: C, 59.17; H, 4.73; N, 9.86. Found: C, 58.77; H, 4.42; N, 9.81.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[F:25][C:26]1[C:31]([F:32])=[C:30](F)[CH:29]=[CH:28][C:27]=1[N+:34]([O-:36])=[O:35]>C(OCC)(=O)C>[F:32][C:31]1[C:26]([F:25])=[C:27]([N+:34]([O-:36])=[O:35])[CH:28]=[CH:29][C:30]=1[O:11][C:8]1[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(F)c2F)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
112 mg of 6-methanesulfonyl-pyridin-3-ol and 100 mg of potassium carbonate were added to an N-methylpyrrolidinone (3 ml) solution of 135 mg of 2,3,4-trifluoro-nitrobenzene, and the reaction liquid was stirred at 50° C. for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[NH:9][C:8]1=[O:16].[OH-].[Na+].[CH3:19]I>CO>[CH3:19][N:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]1=[O:16]
Reactant: CI
Reactant: O=c1[nH]c2cccnc2n1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)n(-c2ccccn2)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A suspension of 10.6 g of the product of Step C and 5 g of sodium hydroxide pastilles in 800 ml of methanol was refluxed for 30 minutes and the mixture was then stirred at room temperature until complete dissolution occured (about 2 hours). 45.6 g of methyl iodide were then added dropwise and the mixture was stirred for another 4 hours at room temperature and then allowed to stand overnight. The mixture was evaporated to dryness and the residue was dissolved in 700 ml of water. The aqueous phase was made alkaline with 30% sodium hydroxide solution and was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and was filtered and the filtrate was evaporated to dryness. The residue was taken up in petroleum ether and the mixture was filtered. The product was crystallized from an xylene-petroleum ether mixture to obtain 7 g (62% yield) of 1-methyl-3-(2-pyridyl)-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one in the form of lightly colored pale yellow crystals melting at 128° -130° C.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C@@H:21]3[CH2:25][C@H:24]([S:26][C:27]4[C@H:28]([CH3:51])[C@@H:29]5[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:30]5[C:31]=4[C:32]([O:34]CC4C=CC([N+]([O-])=O)=CC=4)=[O:33])[CH2:23][N:22]3[CH3:52])=[O:20])[CH2:14][CH2:13]2)=O)=CC=1)([O-])=O.O1CCCC1.[ClH:60]>O>[ClH:60].[N:15]1([C:19]([C@@H:21]2[CH2:25][C@H:24]([S:26][C:27]3[C@H:28]([CH3:51])[C@@H:29]4[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:30]4[C:31]=3[C:32]([OH:34])=[O:33])[CH2:23][N:22]2[CH3:52])=[O:20])[CH2:16][CH2:17][CH2:18][NH:12][CH2:13][CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCCNCC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 1.3 g of 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-[4-(4-nitrobenzyloxycarbonyl)-1-homopiperazinylcarbonyl]-1-methylpyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 2.6 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration, and the filtrate was washed with diethyl ether. The aqueous solution was concentrated by evaporation under reduced pressure, after which the residue was purified by reverse phase column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B), using water as the eluent. Those fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and lyophilized, to give 260 mg of the title compound as a powder.
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=O)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[C:1]1([P:7]([Cl:18])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=P(O)(c1ccccc1)c1ccccc1
Product: O=P(Cl)(c1ccccc1)c1ccccc1

Procedure:
Thirteen grams (0.064 m) of diphenylphosphinic acid was combined with 50 ml of thionyl chloride and the mixture heated at reflux for 2.5 hours. The diphenylphosphinic chloride was purified by distillation, bp 140° C. at 0.1 torr.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.O>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][C:21]4[NH:25][N:24]=[N:23][N:22]=4)[CH:17]=[CH:18][CH:19]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1cccc(OCc2csc(-c3ccccc3)n2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(-c2nc(COc3cccc(Cc4nnn[nH]4)c3)cs2)cc1
Temperature: 135 °C
Yield: 28.6 %

Procedure:
To a solution of 9.0 g (0.03 mol) of 3-(2-phenyl-4-thiazolylmethoxy)benzenacetonitrile in 200 ml of dimethylformamide are added 9.5 g (0.15 mol) of sodium azide and 7.9 g (0.15 mol) of ammonium chloride, and the slurry is heated to 135° C. for 72 hours. The mixture is allowed to cool to room temperature, diluted with 200 ml of water, and extracted four times with 200 ml of ethyl acetate. The combined ethyl acetate solution is washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil, which is subjected to high pressure liquid chromatography (ethyl acetate/hexane as eluent). Fraction 2 is concentrated to obtain 3.0 g (29%) of crystals, m.p. 160°-161° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH2:36][CH:37]([NH2:39])[CH3:38].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH2:36][CH:37]([NH:39][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:38]
Reactant: CN(C)CCN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: CC(N)Cc1cc(F)ccc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 85.2 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.59 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.44 g, 2.59 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (10 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 1.15 g, 85.2% yield. MS: 521.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.43 (s, 1H), 11.31 (d, 1H, J=6.0 Hz), 10.98 (d, 1H, J=7.5 Hz), 8.16 (s, 1H), 8.01 (s, 1H), 7.42-7.35 (m, 2H), 7.20-7.13 (m, 1H), 7.10-7.02 (m, 1H), 6.18 (d, 1H, J=7.2 Hz), 4.16 (m, 1H), 3.95 (t, 2H, J=6.0 Hz), 3.33 (m, 2H), 3.10-2.96 (m, 2H), 2.81 (s, 6H), 1.33 (d, 3H, J=6.3 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:16]=2[C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)CCc3ccccc32)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2c(-c3ccccc3)ccc3ccccc23)cc1

Procedure:
To 30 ml. of dioxane were added 1.90 grams (5.58 mmoles) of 3-phenyl-4-(4-methoxybenzoyl)-1,2-dihydronaphthalene (prepared as in Example 3) and 2.00 grams (8.81 mmoles) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The resulting mixture was heated at reflux for twelve hours in a nitrogen atmosphere. The mixture then was cooled and evaporated to dryness. Water and ether were added to the residue. The ether layer was separated and washed 5 times with 20 ml. portions of 5 N sodium hydroxide and then with aqueous sodium chloride. The mixture then was dried over magnesium sulfate and evaporated to give 1.9 grams of substantially pure 1-(4-methoxybenzoyl)-2-phenylnaphthalene as a green oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH2:27]([NH2:31])[CH2:28][CH2:29][NH2:30].[BH4-].[Na+]>C1COCC1.CO>[NH2:30][CH2:29][CH2:28][CH2:27][NH:31][CH2:16][C:13]1[C:14]([F:15])=[C:2]([F:1])[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: NCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NCCCNCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 was reacted with propane-1,3-diamine in THF. The thus-obtained imine was reduced with sodium borohydride in methanol to give the title compound.