Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)[CH3:32]>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:40][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:31]([CH3:32])[CH3:30])=[CH:39][CH:38]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN(C)C)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (87 mg, 0.21 mmol) and 4-dimethylaminomethyl-phenylamine (32 mg, 0.21 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 66 mg of 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.38 (s, 1H), 8.54 (s, 1H), 7.09-7.43 (m, 7H), 4.35-4.42 (m, 2H), 3.57 (s, 2H), 2.90-3.08 (m, 4H), 2.35 (s, 6H), 2.16-2.26 (m, 2H), 1.39 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])=[O:4].[CH2:14]([N:26]([CH2:28][CH2:29]O)[CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:14]([N:26]([CH2:28][CH2:29][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[C:2]([F:12])([F:13])[F:1])[CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(c1ccccc1O)C(F)(F)F
Reactant: CCCCCCCCCCCCN(C)CCO
Product: CCCCCCCCCCCCN(C)CCOc1ccccc1C(=O)C(F)(F)F
Yield: 61.2 %

Procedure:
2-Trifluoroacetylphenol (Matsumoto, S.; Kobayashi, H. and Ueno, K. Bull. Chem. Soc. Jpn. 1969, 42, 960) (490 mg, 2.57 mmol) and 2-[N-dodecyl-N-methylamino] ethanol (627 mg, 2.58 mmol) were reacted by the general procedure as described in example 1 and afforded the title compound (654 mg, 61%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][C:23]([OH:25])=[O:24])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Li].CI.[CH3:29]N(C=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][C:23]([O:25][CH3:29])=[O:24])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2nc(CC(=O)O)sc2-c2ccc(OC)cc2)cc1
Agent: [Li]
Solvent: O
Solvent: CI
Product: COC(=O)Cc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Yield: 37 %

Procedure:
A solution of 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, lithium salt (8.82 g.; 0.024 mole), methyl iodide (17.4 g.; 0.122 mole) and DMF (100 ml.) was stirred at ambient temperature for 16 hours. The mixture was poured into water (1.5 l.) and extracted with methylene chloride (500 ml.). The organic layer was washed with water (3×1.5 l.), saturated sodium bicarbonate (1.0 l.), water (1.5 l.), dried (sodium sulfate), and concentrated in vacuo. The oily residue was dissolved in acetone and applied directly to a Florisil-packed (340 ml.) gravity column (Florisil previously equilibrated with solvent mixture; 500 ml. packing: 100 ml. solvent). The sample was eluted with 5% acetone in hexane. The recovered product was recrystallized from diethyl ether-pentane to afford 3.32 g. (37% yield) of 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, methyl ester; m.p. 79°-81.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]3=[C:5]([C:17]([F:20])([F:19])[F:18])[C:4]=2[CH:3]=1.[Li][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.CN(CCN(C)C)C>[CH2:22]([C:5]1([C:17]([F:18])([F:20])[F:19])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[NH:8][C:7]2[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]1=2)[CH2:23][CH2:24][CH3:25]
Reactant: O=c1[nH]cnc2c(C(F)(F)F)c3cc(Cl)ccc3nc12
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CCCCC1(C(F)(F)F)c2cc(Cl)ccc2Nc2c1nc[nH]c2=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
8-Chloro-10-(trifluoromethyl)pyrimido[5,4-b]quinolin-4(3H)-one (7, 87 mg, 0.290 mmol) was suspended in anhydrous THF-TMEDA (10:1, 2 mL) and cooled to −78° C. under a nitrogen atmosphere. n-BuLi (1.6M 0.73 mL, 4 equiv) was added dropwise over 10 minutes. After the addition was complete, the reaction was stirred for 20 minutes at −78° C. and then warmed to rt over 45 minutes. The reaction was quenched with sat. NH4Cl solution and then partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc (2×) and Et2O (2×). The combined organic phases were dried over Na2SO4 and concentrated. Chromatography (SiO2, 50% EtOAc-hexane) afforded the desired material 8 as a tan solid (35.4 mg, 34%). Rf 0.34 (50% Ethyl acetate-hexane). 1H NMR (CDCl3, 300 MHz) δ 11.42 (br s, NH), 7.78 (s, 1H), 7.30 (m, 1H), 7.18 (dd, J=2.2, 8.5 Hz, 1H), 6.95 (br s, NH), 6.77 (d, J=8.5 Hz, 1H), 2.75 (m, 1H); 2.12 (m, 1H), 1.28 (m, 2H), .0.95 (m, 2H), 0.79 (t, J=7.4 Hz, 3H). ESI-HRMS 358.0935 (M++H, C16H15ClON3F3 requires 358.0934).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:5]=1)[CH3:2].F[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH:16]([CH3:17])[CH3:18])[C:6]=2[CH:5]=1)[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1)[CH3:2]
Reactant: CCNc1ccc2c(c1)C(C(C)C)=CCC2(C)C
Reactant: O=C(O)c1ccc(F)nc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(c1ccc2c(c1)C(C(C)C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 20.4 %

Procedure:
To a mixture of 85 mg (0.35 mmol) of ethyl-(8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 168) and 0.10 g (0.71 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. Purification was done using flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (26 mg).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[CH3:21][N:22]([CH3:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[CH3:21][N:22]([CH3:29])[CH:23]1[CH2:28][CH2:27][N:26]([C:15]([CH:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:17])[CH2:25][CH2:24]1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CN(C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)C2c3ccccc3Oc3ccccc32)CC1
Reaction time: 12 h
Yield: 90.4 %

Procedure:
To a stirred solution of 9H-xanthene-9-carboxylic acid (4.4 g, 19.4 mmol) in DCM (200 mL, 3 mol) was added dimethylpiperidin-4-yl-amine (2.5 g, 19.4 mmol). DIPEA (6.8 mL, 38.9 mmol) and HOBt (4.6 g, 34 mmol) were added to the mixture, followed by EDCI (4.5 g, 23.3 mmol). The mixture was stirred for 12 hours, then washed with water (300 mL), NaCl (sat.) (300 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure, and the crude material was purified via silica gel chromatography (10% MeOH/DCM w/1% NH3 (aq)) to yield the title compound (5.9 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.F[C:13](F)(F)[C:14](O)=O.C(Cl)Cl>>[NH2:9][CH2:7][CH2:5][CH2:4][N:9]1[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=[C:10]1[C:14]1[CH:13]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCn1c(-c2ccccc2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
100 mg of resin (7) is suspended in 2 ml of a 50% trifluoroacetic acid/methylen chloride solution and shaken for 1.5 hours at room temperature. Customary working up for solid-phase reactions afforded 3-(3-aminopropyl)-2-phenyl-3H-quinazolin-4-one;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)O)cc2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)COc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2

Procedure:
3 g (0.009 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxycarbonylmethoxy-tetralin, 0.93 ml of N,N-diethylamine (0.009 mole), 4 g (0.009 mole) of BOP and 1.9 ml (0.0135 mole) of triethylamine in 90 ml of anhydrous DMF were stirred at ambient temperature for 6 hours. The solvent was evaporated off and the residue was taken up in ethyl acetate. It was washed with a sodium bicarbonate solution. An emulsion was obtained which was filtered over celite. The filtered solution was washed with acetic acid and then with water. The organic phase was dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The product was purified by flash chromatography, eluting with a 1:1 ethyl acetate/hexane mixture. The product of the heading was obtained in the form of a very dense oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2ocnc2c1
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 16.9 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 10.0 mmol), bromobenzene (471 mg, 3.0 mmol), t-BuOK (224 mg, 2.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 99 mg (51%) of 2-phenylbenzoxazole is obtained. Table I, entry 2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([O:9][C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH3:8]>C(#N)C>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][C:13]([NH:12][C:10](=[O:11])[O:9][CH2:7][CH3:8])=[S:14]
Reactant: CCOC(=O)N=C=S
Reactant: Nc1nncs1
Solvent: CC#N
Product: CCOC(=O)NC(=S)Nc1nncs1
Temperature: 24 °C
Yield: 79.4 %

Procedure:
To a stirred solution of 19.2 g (190 mM) of 2-amino-1,3,4-thiadiazole in 200 ml of acetonitrile were added in one portion 25 g (190 mM) of ethoxycarbonyl isothiocyanate. The reaction mixture was stirred at 24° C for sixteen hours. The precipitate was collected by filtration, washed three times with ethyl acetate and dried to provide 35 g (80% yield) of [(1,3,4-thiadiazol-2-ylamino)thioxomethyl]carbamic acid, ethyl ester.
Reaction SMILES: [CH3:1][N:2]([O:27][CH3:28])[C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:6][C:5]=1[NH:15]C(OCC1C=CC=CC=1)=O>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:1][N:2]([O:27][CH3:28])[C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:6][C:5]=1[NH2:15]
Reactant: CON(C)C(=O)c1cc(OCC(C)C)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CON(C)C(=O)c1cc(OCC(C)C)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methyl-N-methyloxy-2-benzyloxycarbonylamino-5-isobutyloxybenzamide (1.0 g) was dissolved in a mixture of ethyl acetate (10 ml) and methanol (10 ml). To the solution was added 10% palladium-carbon (0.2 g). The mixture was stirred for two hours at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration. From the filtrate, the solvent was distilled off to leave N-methyl-N-methyloxy-2-amino-5-isobutyloxybenzamide as a yellow oily product (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13](C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.O.[NH2:21]N>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][NH:13][N:21]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c[nH]nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1.41 g of ethyl 2-(2-chlorobenzoyl)-3-(N,N-dimethylamino)acrylate (a compound described in JP-A 7-101940), 0.30 g of hydrazine monohydrate and 5 ml of acetic acid was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure. Water was poured into the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ethyl 3-(2-chlorophenyl)-1H-pyrazole-4-carboxylate of the formula:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>CN(C)C=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]2[CH2:10][CH2:11][N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:8]2=[O:12])=[CH:25][CH:26]=1
Reactant: O=C1NCCN1c1ccncc1
Reactant: Clc1ccc(OCCCCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCCOc2ccc(Cl)cc2)CCN1c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-pyridyl)-2-imidazolidinone (0.10 g, 0.62 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 27.2 mg, 0.68 mmol). The mixture was stirred at room temperature for 30 minutes then cooled in ice bath again. 1-Bromo-7-(4-chlorophenoxy)heptane (0.19 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvent was removed under reduced pressure. 5 mL of saturated aqueous NH4Cl solution and 10 mL dichloromethane were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 2) as a white solid (0.15 g, 62%).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:15](=[O:30])[NH:14]2)=O)=CC=1)([O-])=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35][NH2:36]>CCO>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35][NH:36][C:11]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15](=[O:30])[NH:14]1)=[O:10]
Reactant: O=C1NN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(c2ccccc2)C1c1ccccc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: O=C1NN(C(=O)NCc2ccc(Cl)c(Cl)c2)C(c2ccccc2)C1c1ccccc1
Yield: 23 %

Procedure:
A solution of 1-[(4-nitrophenyl)oxycarbonyl]4,5-diphenyl-3-pyrazolidinone (1.00 g, 2.48 mmol) and 3,4-dichlorobenzylamine (5 mL) in 50 mL abs. EtOH was heated to reflux for 8 hours. Solvent was removed in vacuo, the residue taken up in CH2Cl2, washed twice with 1N HCl and once with pH 7 buffer, and dried over Na2SO4. After removal of solvent in vacuo, the product was purified by chromatography (0-35% EtOAc:hexane gradient) to give 250 mg (23%) solid:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([Cl:15])[C:3]=1[N+:16]([O-:18])=[O:17].[NH2:19][C:20]1[C:21]([Cl:28])=[N:22][C:23]([CH3:27])=[N:24][C:25]=1[Cl:26].CC([O-])(C)C.[K+]>O1CCCC1>[Cl:15][C:4]1[C:3]([N+:16]([O-:18])=[O:17])=[C:2]([N:24]2[C:25]([Cl:26])=[C:20]([NH2:19])[C:21]([Cl:28])=[N:22][CH:23]2[CH3:27])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1N=C(Cl)C(N)=C(Cl)N1c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 1 h
Yield: 117 %

Procedure:
6.71 g (0.022 mole) of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene and 3.56 g (0.020 mole) of 5-amino-4,6-dichloro-2-methylpyrimidine are dissolved in 50 ml of tetrahydrofuran. The solution is cooled to -30° C. and, at this temperature, a solution of 4.6 g (0.041 mole) of potassium tert-butylate in 50 ml of tetrahydrofuran is added dropwise. After 1 hour at -30° to 0° C., the mixture is extracted with water and ethyl acetate while adding 10 ml of acetic acid. The extracts are dried over sodium sulfate and concentrated, affording 10.5 g of an oil as crude product. This product is purified by chromatography through a column of silica gel using a mixture of 3 parts of petroleum ether and 1 part of ethyl acetate. The solvent is removed by rotary evaporation, affording 8.3 g of product as residue. Recrystallisation from a mixture of toluene and cyclohexane yields 6.80 g (69.2% of theory) of yellow crystals with a melting point of 134°-136° C.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=O)[C:20]12[O:31]CCCO1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]1([C:40]#[N:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:33][C:34]4([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:40][N:41]=[C:21]3[C:20](=[O:31])[C:19]=2[CH:18]=1)(=[O:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(CCl)CCCCC1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C12OCCCO2
Product: O=C1C2=NCC3(CCCCC3)CN2c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21

Procedure:
The title compound was prepared as a yellow foam from 5′-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclohexanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 492 [M−H]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH-:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH3:27])[N:17]=[CH:16][N:15]=1>CN(C=O)C>[CH2:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=1)[CH3:27]
Reactant: [NH-]S(=O)(=O)Cc1cccc(N)c1
Reactant: CCc1ccccc1-c1cc(Cl)ncn1
Solvent: CN(C)C=O
Product: CCc1ccccc1-c1cc(Nc2cccc(CS(N)(=O)=O)c2)ncn1
Temperature: 80 °C

Procedure:
A mixture of (3-aminophenyl)methanesulfonyl amide (0.112 g, 0.60 mmol) and 4-chloro-6-(2-ethylphenyl)-pyrimidine (0.131 g, 0.60 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control), then concentrated in vacuo, and the residue was recrystallized from isopropanol to give {3-[6-(2-ethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 26)
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([O:18]C)=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C(O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:21][NH2:22])=[O:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 133.5 %

Procedure:
To a room temperature solution of methyl 2-(4-cyclohexylphenyl)cyclopropanecarboxylate (150 mg, 0.58 mmol) in ethanol (40 mL) was added hydrazine hydrate (293 mg, 5.85 mmol). The reaction mixture was then heated at 80° C. for 16 h, concentrated in vacuo and the residue dissolved in DCM (50 mL). The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(4-cyclohexylphenyl)cyclopropanecarbohydrazide (200 mg) which was taken on to the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH:17]=1.[C:45]([C:47]1([OH:52])[CH2:51][CH2:50][CH2:49][CH2:48]1)#[CH:46]>C(#N)C.[Cu]I>[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30]([C:46]#[C:45][C:47]4([OH:52])[CH2:51][CH2:50][CH2:49][CH2:48]4)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH:17]=1
Reactant: C#CC1(O)CCCC1
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Temperature: 160 °C
Yield: 33.6 %

Procedure:
Triethylamine (0.078 mL, 0.560 mmol), tetrakistriphenylphosphine palladium (43.0 mg, 0.036 mmol) and copper (I) iodide (7.0 mg, 0.037 mmol) were added to a solution of (5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2); 0.1 g, 0.186 mmol) and 1-ethynyl-cyclopentanol (61.6 mg, 0.56 mmol) in acetonitrile (0.9 mL), and the mixture was stirred with microwave heating at 160° C. for three minutes. The reaction solution was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (31.0 mg, 33%).
Reaction SMILES: [S:1]1[CH:6]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)[S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH3:29])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12>>[S:1]1[CH:6]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]4[N:28]([CH3:29])[N:27]=[N:26][N:25]=4)[CH2:20][S:21][C@H:16]23)=[O:10])[S:4][CH2:3][CH2:2]1
Reactant: CON=C(C(=O)O)C1=CSCCS1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)C1=CSCCS1

Procedure:
2-(2,3-Dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 1.2 g.) was allowed to react with 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.65 g.) in a similar manner to that of Example 1 to give the captioned compound (2.1 g.), pale yellowish white powder.