Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:42]I>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH3:42])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.296 mmol, 0.16 g; Example 43) in DMF (2 mL) at 0° C. was added sodium hydride (80 mg) followed by methyl iodide (0.2 mL) and continued stirring at 0° C. for 30 min. The reaction mixture was diluted with ethyl acetate (10 mL) and quenched excess NaH by drop-wise addition of methanol. This was washed with brine (10 mL), organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluating with 20% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.145 g) as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]1[NH:13][C:12]2[C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=2[N:6]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:31]([O:21][C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:10]1[C:11](=[O:14])[C:12]2[NH:13][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[N:6][C:7]=2[N:8]([CH3:23])[C:9]1=[O:22])(=[O:33])[CH3:32]
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a stirring mixture of (R)-8-(2-chloroethylamino)-1-(5-hydroxyhexyl)-3-methylxanthine (2.2 g, 6.4 mmol), triethylamine (1.94 g, 19.2 mmol) and 4-dimethylaminopyridine (0.39 g, 3.2 mmol) in chloroform (50 ml) at 0-5° C. was added acetic anhydride (1.30 g, 12.8 mmol). The mixture was warmed to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethylacetate-methanol (7:1) to provide (R)-1-(5-acetoxyhexyl)-8-(2-chloroethylamino)-3-methylxanthine (2.2 g, 89% yield) as a white powder.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(C1C(=O)C([Cl:31])=C(Cl)C(=O)C=1C#N)#N.Cl>O1CCOCC1.CC(C)=O>[ClH:31].[N:1]1[C:2]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C1CCc2cc(-c3cn4ccccc4n3)ccc2N1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: O=c1ccc2cc(-c3cn4ccccc4n3)ccc2[nH]1
Temperature: 70 °C
Yield: 42.4 %

Procedure:
To a suspension of 6-(imidazo[1,2-a]pyridine-2-yl)-3,4-dihydrocarbostyril (5 g) in dioxane (50 ml) was added DDQ (6.47 g) with stirring at 70° C. The reaction mixture was heated for 5 hours with stirring. After completion of reaction, the solvent was evaporated. The residue was extracted by the addition of chloroform and 0.5 N sodium hydroxide. The chloroform layer was washed with 0.5 N sodium hydroxide, washed with water and dried. After evaporating chloroform, the residue obtained was isolated and purified using silica gel column chromatography. Oily product obtained was dissolved in acetone and the solution was adjusted to pH of about 1 with concentrated hydrochloric acid. Crystals which formed were collected by filtration. The crude crystals thus obtained were recrystallized from water to give 2.4 g of 6-(imidazo[1,2-a]pyridine-2-yl)carbostyril monohydrochloride.
Reaction SMILES: CN(C1C=CC=CN=1)C.[OH:10][CH:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>N1C=CC=CC=1>[C:31]([O:10][CH:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:33])[CH3:32]
Reactant: CCOC(=O)CCC(C(=O)OCC)C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCC(C(=O)OCC)C(OC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mg of dimethylaminopyridine was added to a mixed solution comprising 500 mg of diethyl 4-hydroxy-4-phenyl-1,3-butanedicarboxylate, 5 ml of pyridine and 1 ml of acetic anhydride, followed by stirring at room temperature overnight. 2N hydrochloric acid was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with 2N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 497 mg of the above-identified compound as colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].[NH:16]1[CH2:25][CH2:24][CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][N:5]1[CH2:4][C:3]2[C:7](=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[N:16]2[CH2:25][CH2:24][CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]2)[C:6]1=[O:14]
Reactant: COC(=O)C1CCNCC1
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 90 °C
Yield: 8.4 %

Procedure:
4-Bromo-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (320.0 mg, 1.180 mmol), methyl isonipecotate (1.595 mL, 11.80 mmol), DIPEA (2.056 mL, 11.80 mmol) and DMF (5 mL) were mixed and heated in sealed tube at 90° C. for 3 days. The crude mixture was purified by MDP under basic conditions to obtain the title compound (33 mg, 8.4% yield). MS (ES+): m/z 334.16 (100) [MH+]; HPLC: tR=0.80 min (UPLC, Analytical).
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:8]=[C:9]([Mg]Br)[CH:10]=[CH:11][CH:12]=1.[CH2:15]([N:22]1[CH2:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Br[Mg]c1cccc(Br)c1
Reactant: COC(=O)C1=CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccccc2)CC1c1cccc(Br)c1
Temperature: 20 °C
Yield: 60.5 %

Procedure:
A 0.5 M THF solution of (3-bromophenyl)magnesium bromide (20 mL, 10 mmol) was cooled to −15° C., and methyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1.05 g, 4.3 mmol) in toluene (3.0 mL) was slowly added for 3 h at −15° C. The reaction mixture was warmed to 20° C. and quenched by addition of saturated NH4Cl aqueous solution followed by extraction with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give methyl 1-benzyl-3-(3-bromophenyl)piperidine-4-carboxylate (1.0 g, 2.6 mmol).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][C:31]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1ccc(Oc2ccccc2)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ccccc2)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (3.30 g), 2-chloro-4-phenoxybenzonitrile (2.30 g), anhydrous iron (III) chloride (1.60 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.15 g of desired compound (melting point: 135.0°-140.0° C.).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl-:5].[CH3:6][P+:7]1([CH2:12][CH2:13]O)[CH2:11][CH2:10][CH2:9][CH2:8]1.Cl.C>C(Cl)(Cl)Cl.CN(C)C=O>[Cl-:3].[CH3:6][P+:7]1([CH2:12][CH2:13][Cl:5])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: C[P+]1(CCO)CCCC1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C[P+]1(CCCl)CCCC1

Procedure:
27.3 g (0.23 mole) of thionyl chloride were added dropwise, whilst stirring, to a solution of 36.5 g (0.2 mole) of 1-methyl-1(2-hydroxyethyl)-phospholanium chloride in 200 ml of chloroform and a small amount of dimethylformamide at 65° C. When the evolution of hydrogen chloride had subsided, the reaction mixture was concentrated under reduced pressure and the residue which remained was taken up in water. The solution thereby produced was treated with active charcoal and then filtered. Concentration of the filtrate under reduced pressure gave 1-methyl-1-(2-chloroethyl)-phospholanium chloride in the form of a crystal hydrate from which water was eliminated on warming at 70° C. The substance which remained melted above 250° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[C:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].N1CCCC1>CO>[C:19]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:2][C:1](=[O:3])[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:11]4[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=4)[C:17]#[N:18])[CH:5]=3)[O:10]2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cc(-c2cccc(C#N)c2)ccc1O
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: CC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 3′-acetyl-4′-hydroxybiphenyl-3-carbonitrile (0.802 g, 3.38 mmol) and 1-acetylpiperidin-4-one (0.477 g, 3.38 mmol) in MeOH (50 mL) was added pyrrolidine (0.4 mL). The resulting solution was heated to reflux for 1.5 h. The reaction mixture was cool down to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with aqueous 1 M HCl, aqueous 1 M NaOH, and brine successively. Solvent was removed under reduced pressure after dried over anhydrous Na2SO4, to yield 0.768 g of 3-(1′-acetyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)benzonitrile as a light brown solid. It was used for next step without further purification. MS ESI +ve m/z 361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:4][C:5]([O:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][C:7]=1[NH2:8].[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=O)[CH:26]=1>C1COCC1>[N:19]1([C:3]2[N:4]=[C:5]([O:9][CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:6]=[C:7]3[C:2]=2[N:1]=[C:32]([NH:31][C:27]2[CH:26]=[C:25]([CH3:34])[CH:30]=[CH:29][CH:28]=2)[NH:8]3)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: Nc1nc(OCCOc2ccccn2)nc(N2CCOCC2)c1N
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(Nc2nc3c(N4CCOCC4)nc(OCCOc4ccccn4)nc3[nH]2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 21.2 %

Procedure:
5,6-Diamino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine (0.332 g, 1.00 mmol, 1.00 equiv.) and m-tolyl isocyanate (0.133 g, 1.00 mmol, 1.00 equiv.) were mixed in 10 mL THF and stirred at room temperature for 15 hours. THF was removed, and the residue was treated with POCl3 in 2 mL CH3NO2 at 100° C. for 30 minutes. The reaction mixture was neutralized with 2N NaOH solution at 0° C., and subjected to EtOAc extraction. The organic solution was dried over MgSO4, filtered through a plug of silica gel, concentrated to around 2 mL, and cooled to 0° C., resulting in formation of the titled compound as off-white crystal which was collected by filtration, washed with EtOAc, and dried (0.095 g, 0.212 mmol, 21.2% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]([CH3:21])([CH3:20])[CH2:7][CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:2].O.NN>C(O)C>[CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]([CH3:21])([CH3:20])[CH2:7][CH2:8][NH2:9])[CH3:2]
Reactant: CCOC(=O)NC(C)(C)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)NC(C)(C)CCN
Yield: 95.5 %

Procedure:
5.12 g of ethyl[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,1-dimethylpropyl]-carbamate are put into solution in 47 mL of ethanol. 4 mL of hydrazine hydrate are added and the mixture is refluxed for 30 minutes with heating. After returning to RT, the reaction medium is filtered and the solvent is then evaporated. 2.8 g (yield=88%) of ethyl(3-amino-1,1-dimethylpropyl)carbamate are obtained as a brown gum used as such.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:9][C:4]2[C:5]([Br:8])=[CH:6][CH:7]=[CH:2][N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc(Br)nc1
Product: Brc1cccnc1Nc1ccccc1
Yield: 67 %

Procedure:
A mixture of 2,5-dibromopyridine (10.2 g, 43 mmole) in aniline (25 mL) was stirred and heated at reflux for 3 h. The reaction was cooled to RT and most of the aniline was distilled off under vacuum. The remaining residue was taken up in ethyl acetate and the solution was washed with 1.0 N Na2CO3 then with brine, dried (Na2SO4), and concentrated under vacuum. Trituration with petroleum ether, filtration and drying under vacuum gave the title compound (7.20 g, 67%) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.4 Hz, 1H), 7.58 (dd, 1H), 7.31-7.39 (m, 4H), 7.11 (m, 1H), 6.79 (br s, 1H); MS (ES) m/e 249.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[CH:21]([NH:23][C@@H:24]1[C:35](=[O:36])[N:26]2[C:27]([C:32]([OH:34])=[O:33])=[C:28]([CH3:31])[CH2:29][S:30][C@H:25]12)=[O:22]>O1CCCC1>[CH:21]([NH:23][C@@H:24]1[C:35](=[O:36])[N:26]2[C:27]([C:32]([O:34][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:33])=[C:28]([CH3:31])[CH2:29][S:30][C@H:25]12)=[O:22]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A solution of diphenyldiazomethane in ether (prepared from benzophenone hydrazone [21 g, 41.8 mmole]) was added to a solution of 7β-formamido-3-methylceph-3-em-4-carboxylic acid (9.7 g, 40.2 mmole) in tetrahydrofuran (150 ml) and the mixture was stirred overnight in the absence of light. The solvents were removed in vacuo and the residual oil was dissolved in methylene chloride (200 ml). The solution was washed with 3%-sodium hydrogen carbonate solution (2 × 100 ml), dried, and evaporated to a yellow oil which was triturated with ethyl acetate-ether to give the title ester as a white crystalline solid (8.15 g, 49.5%), m.p. 136° to 140°, [α]D23 + 38° (c 0.94; Me2SO), λmax. (EtOH) 258 nm (ε 6,800), νmax. (Nujol) 3330 (NH), 1771 (azetidin-2-one), 1707 (CO2R) and 1655 and 1523 cm-1 (CONH), τ (Me2SO-d6) 1.91 (1H, d, J 9.5 Hz; NH), 1.89 (1H, s; CHO), 2.4 to 2.8 (10H, m; (C6H5)2CH), 3.07 (1H, s; (C6H5)2CH), 3.19 (1H,dd, J 9.5 and 5 Hz; C7 --H), 4.83 (1H,d, 5 Hz; C6 --H), 6.33 and 6.57 (2H, AB-q, 18 Hz; C2 --H2), 7.95 (3H, S; C3 --CH2) (Found: C, 64.55; H, 4.9; N, 6.7; S, 7.7. C22H20N2O4S (408.5) requires C, 64.7; H, 4.9; N, 6.9; S, 7.85%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]=[C:16]1[NH:20][CH2:19][C:18](=[O:21])[N:17]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[C:18](=[O:21])[CH2:19][NH:20][C:16]3=[O:15])=[CH:30][CH:29]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(CN2C(=O)CNC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4C(=O)CNC4=O)cc3)nc2c1
Temperature: 115 °C
Reaction time: 17 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.19 g, 0.98 mmol) in N,N-dimethylacetamide (4 mL) were added 4-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzaldehyde (0.19 g, 0.89 mmol), sodium hydrogen sulfite (58.5 wt %, 0.24 g, 1.30 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) and the reaction mixture was stirred at 115° C. for 17 hours under nitrogen, then cooled to room temperature. The precipitate was filtered, washed with methanol, water, then methanol, and dried in air. The solid was suspended in hot DMSO (approximately 3 mL); saturated aqueous NaHCO3 (approximately 3 mL) and water were added. The solid was filtered, washed with water, then methanol, and air dried to give the title compound as a light yellow solid. Yield: 0.16 g (46%). MP 317-318° C. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.17 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.74 (d, J=2.0 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 4.61 (s, 2H), 4.02 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H). MS (ES+) m/z: 395.09 (M+1).
Reaction SMILES: C(=O)(O[CH:5]1[CH:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6]1)OC.[C:28]1([S:34]([CH2:37][N+:38]([O-:40])=[O:39])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:38]([CH:37]([CH:5]1[CH:9]([CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:8]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=[CH:6]1)[S:34]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:36])=[O:35])([O-:40])=[O:39]
Reactant: COC(=O)OC1C=CC(OCc2ccccc2)C1COCc1ccccc1
Reactant: O=[N+]([O-])CS(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C(C1C=CC(OCc2ccccc2)C1COCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
To a round bottomed flask equipped with an argon inlet, a magnetic stirrer and a cooling bath was dissolved crude 10 (9.8 g, 26.5 mmol), phenylsulfonylnitromethane (5.4 g, 26.8 mmol) and tetrakis(triphenylphosphine)palladium (0.6 g, 0.52 mmol) in THF (80 mL) at 0° C. The reaction mixture was degassed using argon for a few minutes. Triethylamine (8.4 g, 11.1 mL, 79.5 mmol) was added to the reaction mixture over the course of 10 minutes at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then quenched with 2 N HCl at 0° C. (100 mL) and extracted with hexane/ethyl acetate (1:1; 2×30 mL). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated in vacuo to afford a red-colored oily residue. Silica pad filtration was conducted using ethyl acetate to remove the baseline materials and give the title compound (14.2 g crude, >100%) as a light brown oil which was used in the next step without any further purification.
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][N:16]3[C:21]=2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.[OH-].[Na+]>ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([Br:22])[N:16]3[C:21]=2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[C@@H](NC(=O)c1ccn2c1CCCC2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cc(Br)n2c1CCCC2)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide (9i) (9.7 g, 34.35 mmol) in dry dichloromethane (200 ml) at −78° C. was added N-bromo-succinimide (6.11 g, 34.35 mmol) in several portions (over 2 min) and the mixture was stirred for 1 h min at −78° C., 1 h at 0° C. and 30 min at 25° C. Then 500 ml aqueous 2% sodium hydroxide was added, and the mixture was extracted 3 times with dichloromethane, the combined organic layers were dried over sodium sulfate, evaporated and the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 5.24 g (42%) of 3-bromo-5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide. LC/MS (method 4): Rt=1.33 min; m/z=361.21 (M+H+).
Reaction SMILES: N1C=CC=CC=1OC(=S)OC1C=CC=CN=1.Cl[CH2:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[NH:30][CH2:29][CH:28]([N:32]([CH3:34])[CH3:33])[CH2:27]2)=[O:20]>CN(C=O)C>[CH3:33][N:32]([CH3:34])[CH:28]1[CH2:29][N:30]2[CH2:18][C:19](=[O:20])[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:31]=32)[CH2:27]1
Reactant: CN(C)C1CNc2c(cccc2NC(=O)CCl)C1
Agent: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: CN(C)C=O
Product: CN(C)C1Cc2cccc3c2N(CC(=O)N3)C1

Procedure:
This compound was prepared using the procedure of Example 66, but substituting chloroacetic anhydride for di (2-pyridyl)thiocarbonate and cyclizing the initially formed N8 -(chloroacetyl)-1,2,3,4-tetrahydro-N3,N3 -dimethyl-3,8-quinolinediamine by heating at 150° C. in DMF.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[C-:22]#[N:23].[Na+]>>[CH:19]1([C:4]2[C:3]([CH2:2][C:22]#[N:23])=[CH:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=3)[N:5]=2)[CH2:20][CH2:21]1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: [Na+]
Product: N#CCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 8 b], 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 3 d]) was reacted with sodium cyanide to give the title compound as white crystals.