Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Cl:13]C[C:15]([NH:17]CO)=O.O>C(O)(=O)C.S(=O)(=O)(O)O>[ClH:13].[NH2:17][CH2:15][C:4]1[CH:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=[C:2]([I:1])[C:3]=1[OH:12]
Reactant: O=C(CCl)NCO
Reactant: CC(C)(C)c1ccc(O)c(I)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(I)c(O)c(CN)c1
Product: Cl
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 36.6 %

Procedure:
To a freshly prepared solution of 2-iodo-4-(1,1-dimethylethyl)phenol (5.5 g., 0.02 mole) in a mixture of acetic acid (27 ml.) and sulfuric acid (3 ml.) is added powdered 2-chloro-N-(hydroxymethyl)acetamide (2.5 g., 0.02 mole) with stirring at 20° C. over a 10 minute period. After 2.5 hours the orange solution is poured into water (200 ml.). The 2-chloro-N-[2-hydroxy-3-iodo-5-(1,1-dimethylethyl)benzyl]-acetamide which precipitates is collected, dried by suction and dissolved in ethanol (75 ml.). Concentrated hydrochloric acid (15 ml.) is added and the mixture is refluxed for two hours. The mixture is concentrated to one-half its original volume and allowed to cool. The resulting precipitate (1.4 g.), which is unhydrolyzed 2-chloro-N-[2-hydroxy-3-iodo-5-(1,1-dimethylethyl)benzyl]acetamide, is collected. The filtrate is concentrated to 25 ml. and, upon cooling, crude 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (4 g.) separates which upon crystallization from a mixture of ethanol and ether affords substantially pure 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (2.5 g.), m.p. 200°-201° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].C(OC([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=O)(C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH:21]2[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]2)[C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1c(F)cccc1Cl
Product: Cl
Product: N#Cc1c(Cl)cccc1OC1CCNCC1

Procedure:
2-Chloro-6-(piperidin-4-yloxy)-benzonitrile hydrochloride was prepared in a manner analogous to that described in example 59.2 from 2-chloro-6-fluoro-benzonitrile and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester. White solid. MS (m/z): 237.0 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]1=[O:15].C(N([CH2:25][CH3:26])CC)C.[C:27]1(C)[CH:32]=C[C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl>[C:25]1([CH3:26])[C:30]([S:33]([O:14][CH2:13][C@@H:11]2[O:10][C:9](=[O:15])[N:8]([CH2:7][CH2:6][O:5][C:4]3[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=3[O:2][CH3:1])[CH2:12]2)(=[O:35])=[O:34])=[CH:29][CH:28]=[CH:27][CH:32]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1OCCN1C[C@H](CO)OC1=O
Solvent: ClCCl
Product: COc1ccccc1OCCN1C[C@H](COS(=O)(=O)c2ccccc2C)OC1=O

Procedure:
Using dichloromethane solution of the compound of formula 2 prepared in Example 2 42.7 g (0.16 mol), triethylamine 24.3 g (0.24 mol) and p-toluenesulfonyl chloride 33.6 g (0.176 mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH3:23])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=C(C(C2C=CC(OC)=CC=2)=CC#N)C=CC=1OC>>[CH2:14]([C:16]1[CH:21]=[C:20]([C:6]([C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:7])[CH:19]=[CH:18][C:17]=1[CH2:22][CH3:23])[CH3:15]
Reactant: CCc1ccccc1CC
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1CC
Yield: 41.1 %

Procedure:
3,4-Dimethoxybenzoyl chloride (4.01 g, 20 mmol), 1,2-diethylbenzene (2.68 g, 20 mmol), and aluminum chloride (2.93 g, 22 mmol) were treated in the same manner as described above for the synthesis of 3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (10% EtOAc in hexane gradient to 20% EtOAc in hexane in 40 min.) to give (3,4-diethyl-phenyl)-(3,4-dimethoxy-phenyl)-methanone as an orange oil (2.45 g, 41%). The product was carried over without further purification to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[N:13]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([Cl:22])=[O:18])[N:13]=1
Reactant: O=C(O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a suspension of (E)-3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acrylic acid (5.7 g, 19 mmol) in DCM (20 mL) was added oxalyl chloride (4.8 g, 38 mmol) and 2 drops of DMF. The resulting mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure to give the crude desired product (6.0 g, 99% yield), which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:23]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCCCCCCCCCBr
Solvent: CCO
Product: CCCCCCCCCCCCN1C(C)(C)CC(O)CC1(C)C

Procedure:
A mixture of 15.7 parts of 2,2,6,6-tetramethylpiperidin-4-ol and 12.5 parts of n-dodecyl bromide in 50 parts of ethyl alcohol was heated under reflux conditions for 72 hours. The cooled reaction mixture was filtered to remove 2,2,6,6-tetramethylpiperidin-4-ol hydrobromide formed during the reaction and the ethyl alcohol solvent was removed by distillation under reduced pressure. The residue was treated with petroleum under (b.p. 40°-60°C) and filtered to remove the unreacted 2,2,6,6-tetramethylpiperidin-4-ol and the petroleum ether solvent was removed by distillation under reduced pressure. Fractional distillation of the residue gave 1-n-dodecyl-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 41°-2°C and the following elemental analysis by weight:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O>Cl>[Cl:13][CH2:14][C:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:12])[NH:10]2)=[O:16]
Reactant: O=c1ccc2cccc(O)c2[nH]1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of 8-hydroxycarbostyril (27 g) and chloroacetyl chloride (37 ml) in ntirobenzene (250 ml) was added aluminum chloride (85 g) portionwise and the mixture was stirred at 70° C. for 20 hours. After adding 10% hydrochloric acid (500 ml), nitrobenzene was removed by steam distillation. After cooling, crystals which formed were collected by filtration, washed with 300 ml of hot water and recrystallized from methanol to give 4.0 g of 5-chloroacetyl-8-hydroxycarbostyril.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([NH2:9])=[C:7]([S:10][CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1.Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>O1CCOCC1>[CH3:1][S:2][C:3]1[C:8]([N:9]=[C:14]=[O:15])=[C:7]([S:10][CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CSc1cc(C)nc(SC)c1N=C=O
Yield: 140.2 %

Procedure:
A solution of 800 mg (4 mmol) 2,4-bis(methylthio)-3-amino-6-methylpyridine and 0.4 ml (2.3 mmol) trichloromethyl chloroformate in 20 ml anhydrous dioxane was refluxed under nitrogen overnight. The reaction mixture was cooled and filtered and the filtrate was concentrated to dryness in vacuo yielding 730 mg of the title compound (81% yield) as a tan colored solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1Cl
Reactant: C1COCCN1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(N2CCOCC2)ccc1Cl
Temperature: 160 °C
Yield: 16.1 %

Procedure:
To a microwave vial was added 2 ml of a solution of 3,6-dichloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (306 mg, 0.71 mmol) in DMSO (6 ml). Morpholine (0.022 ml, 0.25 mmol) and DIPEA (0.129 ml) were added and the mixture was heated at 160° C. for 3 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified by Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to afford the title compound (19 mg).
Reaction SMILES: CC1(C)C([C:7]2[CH:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C@H:21]([CH2:26][O:27][CH3:28])CC(O)=O)[CH:18]=[CH:19][CH:20]=3)[CH:10]=[CH:9][C:8]=2C2C=C(OC)C=CC=2F)=CCC1.CC1(C)C(C2C=C(C[O:52]C3C=C([C@@H](COC)CC(O)=O)C=CC=3)C=CC=2C2C=C(OC)C=CC=2F)=CCC1>>[CH2:13]([O:14][C:15]1[CH:16]=[C:17]([C:21](=[O:52])[CH2:26][O:27][CH3:28])[CH:18]=[CH:19][CH:20]=1)[C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:12]=1
Reactant: COC[C@@H](CC(=O)O)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(C3=CCCC3(C)C)c2)c1
Reactant: COC[C@H](CC(=O)O)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(C3=CCCC3(C)C)c2)c1
Product: COCC(=O)c1cccc(OCc2ccccc2)c1

Procedure:
(3R)-3-(3-(((2-(5,5-Dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)-4-(methyloxy)butanoic acid or (3S)-3-(3-(((2-(5,5-dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)-4-(methyloxy)butanoic acid (74). Compound 74.2 was obtained from compound 74.1 by a method analogous to that used for the preparation of compound 5.7 as described in Example 5 using a Peterson olefination followed by hydrogenation and final chiral separation. Coupling with 14.5 and hydrolysis was carried out according to the methods described herein. 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (dd, 1H), 7.33 (d, 1H), 7.28 (d, 1H), 7.24 (t, 1H), 6.96 (t, 1H), 6.88 (m, 2H), 6.84 (bd, 1H), 6.79 (m, 2H), 5.52 (bt, 1H), 5.08 (s, 2H), 3.75 (s, 3H), 3.56 (dd, 1H), 3.48 (t, 1H), 3.40 (m, 1H), 3.33 (s, 3H), 2.88 (dd, 1H), 2.65 (dd, 1H), 2.24 (dt, 2H), 1.65 (t, 2H), 0.85 (s, 6H).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(N(CC)CC)C>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][N:10]1[C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=[CH:9]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: BrCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CCCBr)n(C)c1=O
Reaction time: 24 h
Yield: 76.6 %

Procedure:
A solution of theophylline (10.0 g, 0.0555 mol), 1,3-dibromopropane (11.6 ml, 23.1 g, 0.114 mol) and triethylamine (10.5 ml, 7.62 g, 0.0753 mol) in N,N-dimethylformamide (250 ml) was stirred at 60° C. overnight. The stirring was continued one day at room temperature. The solvent was evaporated under reduced pressure. The residue was suspended in CH2Cl2 and water. An emulsion was caused by a fine solid suspended in the mixture. The solid was filtered out and discarded. The aqueous layer was extracted three times with CHCl3. The combined organic layers were dried with MgSO4. Evaporation of the solvent under reduced pressure gave 7-(3-bromopropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione (12.8 g, 77% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.S(Cl)(Cl)=O.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[O:7]=[C:5]([C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1)[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:8]
Reactant: CC(C)CCC(=O)O
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CC(C)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 82 h

Procedure:
A mixture of 25 g (0.215 mol) of 4-methyl valeric acid and 29.35 g (0.247 mol) of thionyl chloride was heated at reflux for 1.5 hour. The excess thionyl chloride was removed under reduced pressure using a cryogenic trap. The residue was taken up with 120 g (0.764 mol) of bromobenzene (Compound 27) and the mixture was cooled in an ice-bath and then treated with 23 g (0.172 mol) of anhydrous aluminum chloride through a powder addition funnel. The mixture was stirred at room temperature for 82 h and then quenched by the addition of 50 ml of an ice/water mixture, followed by 30 ml of conc. HCl. The organic layer was separated and the aqueous layer extracted with 2×50 ml of ether. The organic extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in-vacuo and the residue purified by distillation (~80 degrees C./0.01 mm) to give the title compound as a colorless solid. PMR (CDCl3): & 0.94 (6 H, d, J~6.0 Hz), 1.53-1.68 (3H, m), 2.85-2.97 (2H, m)., 7.60 (2H, d, J~8.4 Hz), 7.83 (2H, d, J~8.4 Hz).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[S:8][C:9]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1>N1C=CC=CC=1.C(OCC)(=O)C>[O:16]=[C:15]1[C:9]2[S:8][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[N:11][C:10]=2[CH2:12][CH2:13][CH2:14]1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 50 °C
Reaction time: 15 h

Procedure:
572 μl of methyl chloroformate (7.3 mmol) are added to a solution of 500 mg of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (2.4 mmol) in 5 ml of pyridine. The reaction mixture is stirred at 50° C. for 15 h and then diluted with ethyl acetate; the mixture is then extracted by shaking, in each case 2×, with water and cold 1 N hydrochloric acid. The organic phase is dried and evaporated. Yield: 290 mg
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1.[CH:15](OCC)=[O:16].[H-].[Na+]>C(COC)OC>[OH:16][CH2:15][CH:8]([CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC=O
Reactant: CCOC(=O)CC(C)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(CO)C(C)c1cccnc1

Procedure:
Treatment of ethyl 3-(3-pyridyl)butyrate with ethyl formate and sodium hydride in glyme, followed by acidification gave ethyl 2-(hydroxymethyl)-3-(3-pyridyl)butyrate, m.p. 128°-131°.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[S:24][C:23]([S:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[N:22][N:21]=1.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[S:24][C:23]([S:25][CH2:26][C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:28])=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(CSc1nnc(S)s1)N1CCOCC1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(SCC(=O)N4CCOCC4)s3)CS[C@H]12

Procedure:
While utilizing 0.680 g of 7-ACA, 0.900 g of 5-mercapto-2-morpholinocarbonylmethylthio-1,3,4-thiadiazole, 4.0 ml of acetonitrile and 2.70 g of DCPA, the procedure was carried out in accordance with Example 5, and there was obtained 1.02 g (83.3% of yield) of red brown powder of 7-amino-3-[(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[N:16][CH:15]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:20]1([CH3:33])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([O:31][NH2:32])(=[O:30])=[O:29]>ClCCl>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH3:33])[C:21]=1[S:28]([O-:31])(=[O:30])=[O:29].[NH2:32][N+:17]1[CH:18]=[CH:19][C:14]([C:10]2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:2][CH3:1])=[CH:12][C:11]=2[CH3:13])=[CH:15][N:16]=1
Reactant: COC(=O)c1cc(-c2ccnnc2)c(C)cc1OC
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cc[n+](N)nc2)c(C)cc1OC
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 0 °C

Procedure:
Methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-2-(4-fluorophenyl)pyrazolo[1,5-h]pyridazin-5-yl)-2-methoxy-4-methylbenzoate and methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-2-(4-fluorophenyl)pyrazolo[1,5-h]pyridazin-4-yl)-2-methoxy-4-methylbenzoate. Part A: To a cooled solution (0° C., ice bath) containing methyl 2-methoxy-4-methyl-5-(pyridazin-4-yl)benzoate (0.16 g, 0.66 mmol) and dichloromethane (3 mL) was added O-(mesitylsulfonyl)hydroxylamine (0.32 g, 0.90 mmol) in dichloromethane (3 mL) quickly, dropwise. The solution was maintained at 0° C. for 5 min, removed from the cooling bath and maintained at ambient temperature for 5 h. The solution was concentrated to afford 1-amino-4-(4-methoxy-5-(methoxycarbonyl)-2-methylphenyl)pyridazin-1-ium 2,4,6-trimethylbenzenesulfonate as a foam (274 MH+). Part B: The product thus obtained in part A was suspended in THF (2.0 mL). tert-butyl 3-(4-fluorophenyl)propioloyl(methyl)carbamate (0.17 g, 0.60 mmol) was added and the suspension cooled to −78° C. (dry Ice/acetone bath). DBU (0.27 g, 1.8 mmol) in THF (1.0 mL) was added dropwise over 2 min. The mixture was left in the cooling bath for 20 min, then removed from cooling and allowed to proceed for 20 h at ambient temperature. The mixture was filtered and concentrated. Purification on silica gel (20-80% ethyl acetate/hexanes, 60 min gradient) afforded methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-2-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-5-yl)-2-methoxy-4-methylbenzoate and methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-2-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-4-yl)-2-methoxy-4-methylbenzoate as separate regioisomers.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:31]1([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:39][CH2:38][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-[(1S,2R,3S,4R)-4-(2,6-Dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (160) mg, 0.44 mmol) is dissolved in THF (5 ml) under an atmosphere of argon. Diisopropylamine (69 mg, 0.53 mmol) is added followed by 2,2-diphenylethylamine (96 mg, 0.49 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA).). 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.15(m, 10H), 4.75(m, 1H), 4.60(m, 1H), 4.50(m, 1H), 4.20(m, 3H), 3.95(m, 1H), 2.85(m, 1H), 2.40(q, 2H), 2.10(m, 1H), 1.20(t, 3H), MS (ES+) m/e 521 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:13][S:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:29]([CH2:26][CH2:27][CH3:28])[N:30]=[C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:13][S:12][CH2:11][CH:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccc(Cl)c(Cl)c2)CSCC1=Cc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccc(Cl)c(Cl)c3)CSCC2C1c1ccc(Cl)c(Cl)c1

Procedure:
A suspension of 6.5g of tetrahydro-3,5-bis-[(3,4-dichlorophenyl)methylene]-4H-thiopyran-4-one and 1.1g of n-propyl hydrazine in 250ml of methanol/chloroform (1:1) is heated at reflux temperature for about 16 hours. The reaction mixture is allowed to cool slightly. Unreacted starting material precipitates out and is removed by filtration. The filtrate is concentrated in vacuo, added to chloroform and washed with dilute hydrochloric acid and water. The organic layer is dried with magnesium sulfate and concentrated in vacuo to 5g of a semi-solid material. This is applied to a wet-packed (hexane) neutral alumina column (Activity I) and eluted with 0-100% ether/hexane. Elution with 10-40% ether/hexane yields the product as an oil.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][C:23]2[NH:2][C:4]3[C:18]([C:22]=2[CH2:21]1)=[C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: CN1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1

Procedure:
The compound is formed analogously to that described in Example 5, from 14 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride and 6.2 g of 1-methyl-4-piperidone. Melting point: >250° C. (decomposition)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(O[C:27](=[O:29])[CH3:28])(=O)C>>[C:17]([N:1]([C:27](=[O:29])[CH3:28])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[CH2:22])[N:10]([C:16](=[O:21])[CH3:15])[N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Product: C=C1Cc2cc3c(cc2C(c2ccc(N(C(C)=O)C(C)=O)cc2)=NN1C(C)=O)OCO3
Yield: 34.4 %

Procedure:
2.93 g (0.01 mol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were refluxed with 20 ml of acetic anhydride for 6 hours. The solution was evaporated at reduced pressure, the residue was taken up in 2×20 ml of anhydrous ethanol, the solution was repeatedly evaporated and the resulting residue of 4.55 g was submitted to column chromatography (adsorbent: Kieselgel 60, eluant: ethyl acetate - benzene 4:1). The raw produce was triturated with 20 ml of hot isopropanol to yield 1.44 g (34.4%) of the aimed product, m.p. 240°-245° C. (slight decomp.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.[CH3:10][CH2:11][CH2:12][CH2:13]C(O)=O>>[CH2:10]([C:2]1[NH:1][CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CCCCC(=O)O
Product: CCCCc1nc(C(=O)OC)c[nH]1

Procedure:
The title compound was prepared using the procedure described in Example 55(a) starting from methyl 1H-imidazole-4-carboxylate (5 g, 39.7 mmol) and n-valeric acid (13 ml, 119 mmol). Yield: 1.2 g. 1H-NMR (400 MHz; CDCl3): δ 0.92 (t, 3H), 1.24-1.29 (m, 2H), 1.68-1.76 (m, 2H), 2.76 (t, 2H), 3.87 (s, 3H), 7.62 (s, 1H), 9.92 (bs, 1H).