Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[N:13][OH:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[S:22]([O:14][N:13]=[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][CH2:8][CH2:7]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: COc1ccc2c(c1)C(=NO)CCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(=NOS(=O)(=O)c1ccc(C)cc1)CCO2
Temperature: 0 °C
Yield: 87.8 %

Procedure:
5.68 g (29.4 mmol) of 6-methoxychroman-4-one oxime were dissolved under argon atmosphere in 30 ml of dry pyridine. At 0° C. 6.05 g (31.8 mmol) of 4-methylbenzene-1-sulfonyl chloride were added in small portions over 40 min. The mixture was stirred at 0° C. for an additional hour and then warmed to room temperature and stirred over night. The mixture was poured onto 260 ml ice water, stirred, and the suspension was filtered. The solid residue was washed with a small amount of cold water (2×) and cold ethanol (1×), and dried to yield 8.96 g (25.8 mmol, 88%) of desired product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([OH:20])=[CH:11][CH:12]=[C:13]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:28]([N:32]=[C:33]=[O:34])([CH3:31])([CH3:30])[CH3:29].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([NH:32][C:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:12]=[CH:11][C:10]=2[OH:20])[CH:6]=[CH:7][CH:8]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 131.8 %

Procedure:
3′-aminomethyl-5-(1H-tetrazol-5-yl)-biphenyl-2-ol (0.31 g, 1.16 mmol) was dissolved in dimethylformamide (10 mL) and the solution was treated with triethylamine (0.8 mL, 5.8 mmol) and tert-butylisocyanate (0.14 mL, 1.27 mmol). The mixture was stirred at room temperature for 2 hours. Workup with ethyl acetate and water, followed by drying afforded 0.56 g (quant.) of the crude 1-tert-butyl-3-[2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[O:32][CH:33]=[CH:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[O:32]1[C:31]2[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[CH2:26][C:27]3[N:28]([CH:35]=[CH:36][CH:37]=3)[CH2:29][C:30]=2[CH:34]=[CH:33]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 1.1 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. To the mixture is added 1.1 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine and the mixture is stirred for 5 hours. The reaction mixture is washed with water, 1N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product as a solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15]OC2=O)=[C:8]([C:17]([O:19]C)=O)[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[Cl-].[Na+]>CN(C)C=O>[C:1]([C:4]1[C:9]2[O:10][C:11]3([C:17](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:16][CH2:15]3)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(C(C)=O)c1OC1CCOC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)c1cccc2c1OC1(CC1)C2=O
Reaction time: 5 h
Yield: 8.6 %

Procedure:
A mixture of α-[(6-acetyl-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone (3.5 g), 1,8-diazabicyclo[5,4,0]-7-undecene (0.14 g) and sodium chloride (1.1 g) in N,N-dimethylformamide (66.5 ml) was stirred at 150°-160° C. for 5 hours. The solvent was distilled off under reduced pressure and the residue was subjected to chromatography on silica gel. The fraction eluted with dichloromethane was recrystallized from CHCl3 -hexane to give 7-acetylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (0.22 g) as colorless needles melting at 114°-115° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C(O)(=O)C.[CH2:13]([NH:15][C:16](=[O:18])[O-:17])[CH3:14].[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[CH:25]([CH3:33])[CH:26]3[CH2:30][NH:29][CH2:28][CH:27]3[C:31]=2[CH:32]=1>ClCCCl.C(Cl)Cl>[CH2:13]([NH:15][C:16](=[O:17])[O-:18])[CH3:14].[CH3:19][O:20][C:21]1[C:22]([Cl:1])=[CH:23][C:24]2[CH:25]([CH3:33])[CH:26]3[CH2:30][NH:29][CH2:28][CH:27]3[C:31]=2[CH:32]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: CCNC(=O)[O-]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)C(C)C1CNCC21
Temperature: 60 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
N-chlorosuccinimide (0.22 g, 1.6 mmol) and acetic acid (8 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.45 g, 1.6 mmol) in DCE (8 mL), and stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL), and washed with H2O (50 mL). The organic extract was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 250 mg (51%) of the subtitle compound. MS calculated for C16H20ClNO3+H, 310, observed: 310.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:15]([NH2:16])=[CH:14][C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12]2)[CH:6]=1)C.CCN(CC)CC.[BH4-].[Na+]>CCO.O>[NH2:16][C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][CH:8]=2)[N:12]=[C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cccc(CO)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
To a solution of Intermediate 29a (1.00 g, 3.48 mmol) and Et3N (265 μL, 1.91 mmol) in EtOH (35 mL) was added NaBH4 (198 mg, 5.23 mmol) and the suspension stirred at RT for 1.5 h. NaBH4 (198 mg, 5.23 mmol) was added and the suspension stirred for a further 19 h. NaBH4 (1.31 g, 34.8 mmol) was added and the suspension stirred for a further 24 h, then diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound as a white solid (740 mg, 87%). LCMS (Method 3): Rt 2.05 min, m/z 246 [MH+].
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.[N:29]1([C:35]2[N:36]=[C:37]([CH2:42][C:43]([O-])=[O:44])[NH:38][C:39](=[O:41])[CH:40]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Na+]>CN(C)C=O.ClCCl.C(OCC)C.CO>[CH3:19][N:20]([CH3:28])[C:21]1[CH:22]=[C:23]([NH:27][C:43](=[O:44])[CH2:42][C:37]2[NH:38][C:39](=[O:41])[CH:40]=[C:35]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:36]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CN(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CN(C)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
0.160 ml of pyridine, 240 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 400 mg of N, N-dimethyl-m-phenylenediamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 in 4 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature overnight and is then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, rinsed with ethyl ether and dried in a rotary evaporator. After purification by silica column chromatography as a solid deposit, eluent: dichloromethanemethanol 95/05, a solid is obtained which is taken up in a mixture of dichloromethane, methanol and ethyl ether. The solid is filtered off and dried. 30 mg of N-[3-(dimethylamino)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12]([CH3:17])=[N:13][NH:14][C:15]=1[CH3:16].[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:15]([CH3:16])=[N:14][N:13]([CH2:26][CH3:27])[C:12]=1[CH3:17]
Reactant: COc1ccc(OCCCCCCc2c(C)n[nH]c2C)c(Cl)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(C)c(CCCCCCOc2ccc(OC)cc2Cl)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a solution of 6.8 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-dimethyl-1H-pyrazole (Example 7) in 100 ml of dimethylformamide was added 1.13 g of sodium hydride. The mixture was stirred one hour at room temperature, and then 3.8 g of ethyl iodide was added and the reaction mixture stirred for six hours longer. The reaction mixture was concentrated to remove the solvent, the residue partitioned between dilute hydrochloric acid and methylene dichloride, and the organic layer washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica with hexane:ethyl acetate:acetonitrile 4:2:1 to give 2.6 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-1-ethyl-3,5-dimethyl-1H-pyrazole as a pale yellow oil; MIC=0.7-1.5 microg/ml (herpes 1 and 2).
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][C:10]2[N:9]=[C:8]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:7]=[C:6]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[C:4]1[C:5]=23)[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[CH2:12][CH2:11][C:10]2[N:9]=[C:8]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:7]=[C:6]3[NH:25][N:26]=[C:4]1[C:5]=23)[CH3:2]
Reactant: CCN1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3[nH]nc1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-1-(3-ethyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea (27 mg, 0.045 mmol) was taken in TFA (0.1 mL) and stirred at room temperature for 30 minutes. To the reaction was added triethylsilane (21 uL, 0.128 mmol) and the mixture was stirred for 15 minutes at room temperature before it was heated at 80° C. for 30 minutes. The reaction mixture was concentrated, taken in DCM and washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave (R)-1-(3-ethyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C19H22N6O [M+H]+ 351. found 351. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 7.32 (dd, J=3.4, 7.9, 4H), 7.24-7.14 (m, 1H), 6.40 (s, 1H), 4.90-4.79 (m, 1H), 4.02-3.89 (m, 2H), 3.40 (m, 2H), 3.01 (m, 2H), 1.40 (d, J=6.9, 3H), 1.24 (t, J=9.4, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH3:22][C:23]1[N:28]([C:29](O)=[O:30])[C:27](=[O:32])[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:8][C:7]1[C:2]([NH:1][C:29]([N:28]2[C:23]([CH3:22])=[CH:24][CH:25]=[CH:26][C:27]2=[O:32])=[O:30])=[CH:3][CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)[N:6]=1
Reactant: Cc1cccc(=O)n1C(=O)O
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(=O)n1C(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a vial were added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (100 μmol), 6-methyl-2-oxopyridine-1(2H)-carboxylic acid and N,N-dimethylformamide (1.5 mL) followed by O-(7-Azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) (200 μmol) and triethylamine (250 μmol). The vial was shaken for 16 h at room temperature. The mixture was concentrated via Speedvac. The residue was partitioned between dichloromethane and water. The organics were evaporated under vacuum to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-methyl-2-oxopyridine-1(2H)-carboxamide which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:6]([C:7]([OH:9])=[O:8])[N:5]2[C:10](=[O:22])[C@@H:11]([NH:12][C:13](=[O:21])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:4]2[S@:3]1=O.ClC(Cl)(Cl)COP([O-])([O-])=O.N1C=CC=CC=1>O1CCOCC1>[CH3:1][C:2]1[CH2:24][S:3][C@@H:4]2[C@H:11]([NH:12][C:13](=[O:21])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:22])[N:5]2[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC1(C)C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[S@]1=O
Agent: O=P([O-])([O-])OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 244.6 %

Procedure:
The polymer ester of (1S, 5R, 6R)-2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid 1-oxide[45.60g, 0.05 mole, from example 29(a)] was refluxed for 24 hours in dioxan (500 ml.) with trichloroethylphosphate (1.15g, 5.0 m.mole) and pyridine (0.41 ml., 0.40g, 0.0051 mole) as in example 16 above to give the polymer ester of (6R, 7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid (40.65g). The IR and NMR spectra were identical with the product obtained in example 8 above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH2:9])=[CH:4][C:3]=1[CH3:15].[O-:16][C:17]#[N:18].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:18][C:17]([NH:9][N:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:15])[CH:4]=1)=[O:16]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1ccc(F)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(NC(N)=O)c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl [1-(4-fluoro-3-methylphenyl)hydrazino]acetate (Intermediate 64, 0.8, 38 mml), sodium cyanate (0.84 g, 0.0129 mol) and trifluoroacetic acid (0.95 ml, 0.0114 mol) in toluene (15 ml) was stirred under nitrogen at room temperature for 24 hours. The mixture was poured into 8% sodium bicarbonate solution (40 ml) and extracted with ethyl acetate (2×30 ml). The organic extract was dried (MgSO4) and evaporated to give a red oil. This was crystallised by trituration with ether to give a white solid (Intermediate 65, 228 mg; 24%), m.p. 132°-133° C.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]1[S:11][C:10]2=[CH:12][C:13]3[S:14][C:15]([CH3:18])=[CH:16][C:17]=3[C:9]2=[CH:8]1.[CH2:19]([O:22][C:23]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:26]([CH3:33])=[CH:25][C:24]=1[Si:34](Cl)([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:20]=[CH2:21]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][C:23]1[C:28]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:27][C:26]([CH3:33])=[CH:25][C:24]=1[Si:34]([C:12]1[C:13]2[S:14][C:15]([CH3:18])=[CH:16][C:17]=2[C:9]2[C:10]=1[S:11][CH:7]([CH3:6])[CH:8]=2)([CH2:35][CH3:36])[CH2:37][CH3:38])[CH:20]=[CH2:21]
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](Cl)(CC)CC
Reactant: Cc1cc2c(s1)C=C1SC(C)C=C12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](CC)(CC)C1=C2SC(C)C=C2c2cc(C)sc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At −78° C., n-butyllithium (1.56 M, 1.69 mL, 2.64 mmol) was added dropwise to a solution of 2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen (0.50 g, 2.42 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was cooled to −78° C., a solution of (2-allyloxy-3-tert-buyl-5-methylphenyl)chlorodiethylsilane (0.72 g, 2.20 mmol) in toluene (3 mL) was added dropwise thereto. The resulting reaction mixture was warmed to room temperature and stirred for 2 hours. After the solvent was distilled off under reduced pressure, toluene was added and the mixture was filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure to quantitatively obtain (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)diethylsilane.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:21]=3[CH3:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: Cc1ccncc1B(O)O
Product: Cc1ccncc1-c1c(F)ccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 61.8 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 4-methylpyridine-3-boronic acid (150 mg, 0.96 mmol) were reacted. After purification the title compound (100 mg, 62% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=5.1 Hz, 1 H), 8.47 (s, 1H), 8.46 (bm, 1H), 7.99 (a dd, J=5.2, 9.2 Hz, 1H), 7.58 (t, J=8.7 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 2.96 (m, 1H), 2.11 (s, 3H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=338, HPLC 1.68 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH:22]([CH3:23])[CH3:21])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC(C)NCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CC(C)NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 88.5 %

Procedure:
A suspension of 1.1 g (3.9 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.4 g (10 mmole) of N-(2-propyl)-3-pyrrolidinemethanamine and 50 ml of acetonitrile was refluxed for 2 hours. The precipitate was removed by filtration, washed with acetonitrile, ether, and dried in vacuo to give 1.4 g of the title compound, mp 218°-221° C.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=[O:37])[CH:27]([OH:36])[C:28]2[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=[O:37])[C:27]([C:28]2[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=2)=[O:36])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CSc1ccc(C(O)C(=O)c2ccc(Cl)c(Cl)c2)cc1
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CSc1ccc(C(=O)C(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
Dimethyl sulfoxide (16.3 mmol, 1.20 ml) was added to methylene chloride (70 ml) and the solution was cooled to −65° C. Trifluoroacetic acid anhydride (13.1 mmol, 1.84 ml) was added over 2 minutes and the cold solution was stirred an additional 10 minutes. A solution of 1-(3,4-dichlorophenyl)-2-hydroxy-2-[4-(methylthio)phenyl]ethanone from step 2 (7.10 mmol, 2.32 g) in methylene chloride (ca. 10 ml) was introduced and after 30 minutes, triethylamine (32.6 mmol, 4.53 ml) was added. The mixture was warmed to 0° C. over 30 minutes, diluted with water (60 ml) and extracted with ethyl acetate (200 ml). The organic phase was separated, dried over magnesium sulfate, filtered through silica gel, and concentrated in vacuo. The residue was subjected to chromatography on silica gel using mixtures of hexane and ethyl acetate as eluents, affording the title compound as a yellow solid (2.035 g, 88%). Step 4 Preparation of 5-(3,4-Dichlorophenyl)-4-[4-(methylthio)phenyl]-2-(trifluoromethyl)-1H-imidazole
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:32]1([C:35]2[N:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=2)[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[N:36]=[N:37][N:38]([CH2:40][C:41]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:14]5[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=5[N:12]([C:20]([CH3:30])([CH3:31])[CH2:21][OH:22])[CH:11]=4)=[O:9])[CH:3]=3)=[O:42])[CH:39]=2)[CH2:34][CH2:33]1
Reactant: O=C(O)Cn1cc(C2CC2)nn1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C4CC4)nn3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method 1 (Example 19) followed by Method Y (Example 1) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29) and (4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetic acid (Preparation 94).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])[CH3:2].[NH2:23][N:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:23][N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)[CH3:21])[N:15]=1)[CH3:13])[CH3:2]
Reactant: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=O)n1
Reactant: Nn1cccc1
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=Nn2cccc2)n1
Reaction time: 16 h

Procedure:
Monoimine 2-[1-(2,6-diethylphenylimino)ethyl]-6-acetylpyridine (8, 1.5 g, 5.1 mmol) and 1-aminopyrrole (460 mg, 5.6 mmol) were dissolved in 25 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 16 hours the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 845 mg (46%) of mixed diimine 13.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)CCC>[CH2:20]([NH:27][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccccc1Nc1nc(Cl)nc2ccccc12
Reactant: NCc1ccccc1
Solvent: CCCCO
Product: Cc1ccccc1Nc1nc(NCc2ccccc2)nc2ccccc12
Yield: 55.2 %

Procedure:
2-Chloro-4-(2-methylphenylamino)quinazoline (2.7 g, 0.01 mol) and benzylamine (2.4 g, 0.022 mol) were dissolved in n-butanol (20 ml) and heated under reflux for 5 hours. The solution was cooled, excess solvent removed in vacuo and the residue treated with water, filtered and crystallised from ethanol/water. The compound was then chromatographed (silica gel, 0.5% methanolic ammonia/chloroform) to afford an oil, which on trituration with ether gave crystals of 2-benzylamino-4-(2-methylphenylamino)quinazoline (1.88 g, 55%), m.p. 127°-130°.