Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])CCC.C1CCCCC1.CN(C)[CH:29]=[O:30]>O1CCCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:29]=[O:30])[C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)Nc1c(F)cccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N-(2-Bromo-6-fluorophenyl)pivalamide (25.5 mmol, 7.0 g) was dissolved in tetrahydrofuran (200 mL). Mixture was cooled to −78° C. 2M Butyllithium in cyclohexane (62.0 mmol, 31.0 mL) was added to the mixture drop-wise. Reaction mixture was held at −78° C. for 30 minutes. A solution of N,N-dimethylformamide (129 mmol, 10.0 mL) in tetrahydrofuran (30 mL) was added to the reaction mixture drop-wise. Reaction was held at −78° C. for 30 minutes. Reaction was quenched with aqueous ammonium chloride then the mixture was allowed to warm to room temperature. Mixture was extracted 2× ethyl acetate. Combined organic layers were dried (magnesium sulfate), filtered and concentrated. Silica gel chromatography afforded the desired product as white solid in 80% yield. 1H NMR (300 MHz, CDCl3): δ=9.93 (d, J=1.83, 1H), 9.14 (bs, 1H), 7.56-7.50 (m, 1H), 7.42-7.25 (m, 2H), 1.34 (s, 9H). MS m/e (M+H)+=224.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:17])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:17])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1Cc1cccc(Cl)c1O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccccc1Cc1cccc(Cl)c1O
Temperature: 25 °C

Procedure:
(3-Chloro-2-hydroxyphenyl)(2-methoxyphenyl)methane (3.98 g, 16 mmol) was dissolved in 100 ml of methylene chloride and 24 ml of 1M boron tribromide in methylene chloride (24 mmol) was added under nitrogen with stirring at ambient temperature. The mixture was allowed to react for 4 hours and then 100 ml of water was added slowly at ambient temperature. The organic layer was recovered and extracted with 2 N sodium hydroxide. The alkaline extract was acidified with 6 N hydrochloric acid and extracted with ether. The ether extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 2.7 g (72 percent of theory) of the title compound. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[C:11]2[CH2:16][O:15][C:14](=[O:17])[NH:13][C:12]=2[N:18]=1.[ClH:32]>O1CCOCC1>[ClH:32].[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[C:11]2[CH2:16][O:15][C:14](=[O:17])[NH:13][C:12]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc3c2COC(=O)N3)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3ccccc3O)cc(C3CCCNC3)c2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 3-[7-(2-hydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido-[2,3-d][1,3]oxazin-5-yl]-1-piperidinecarboxylate (45 mg, 0.11 mmol) in 1,4-dioxane (1.0 mL) was added 4N HCl in 1,4-dioxane (2.0 mL). The mixture was stirred for 1 hr at room temperature. The resulting solid was collected by filtration, washed with 1,4-dioxane, and dried under reduced pressure to give 7-(2-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride as a white solid. (22.8 mg, yield; 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[C:6]([N:19]=1)=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[N:8]=[N:9][CH:10]=2.[C:21]1([CH3:31])[CH:26]=CC(S(O)(=O)=O)=CC=1>C(NCCC)CC>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:26][CH2:21][CH3:31])[CH2:7][CH2:6][CH3:5])[C:5]2[C:6]([N:19]=1)=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[N:8]=[N:9][CH:10]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(Cl)c2cnnc(-c3ccc(Cl)c(Cl)c3)c2n1
Solvent: CCCNCCC
Product: CCCN(CCC)c1cc(C)nc2c(-c3ccc(Cl)c(Cl)c3)nncc12
Temperature: 25 °C

Procedure:
Heat a mixture of 2-methyl-4-chloro-8-(3,4-dichlorophenyl)pyrido[2,3-d]pyridazine (4) (2.0 g, 6.2 mmol) and p-toluenesulfonic acid (3.2 g) in 10 mL of di-n-propylamine in a sealed tube at 180° C. for 48 hours. Cool the reaction mixture to ambient temperature and partition the reaction mixture between ethyl acetate and water. Wash the organic layer with water and dry over MgSO4. Evaporate the dried solution and purify the product 5 by flash chromatography.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=[O:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:12]([N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccsc12
Yield: 78.6 %

Procedure:
The product of Example 110A (0.137 g, 0.81 mmol) was reacted with benzyl bromide (0.10 mL, 0.85 mmol), and potassium carbonate (0.134 g, 0.97 mmol) in dimethylformamide (5 mL) at ambient temperature for 20 hours. The reaction mixture was diluted with water and the resulting precipitate was collecte by filtration, and dried to give the title compound (0.165 g, 80%). MS (DCI/NH3) m/z 277 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 5.21 (s, 2 H) 7.25 (d, J=5.52 Hz, 1 H) 7.35 (m, 5 H) 8.28 (d, J=5.52 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]([NH2:17])=[S:16]>>[NH2:17][C:15]1[S:16][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)[N:14]=1
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC(N)=S
Product: Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Yield: 94.1 %

Procedure:
Using 3′-(trifluoromethyl)acetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:51]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[CH2:52]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:51]3[CH2:55][CH2:54][CH:53]([N:56]4[CH2:57][CH2:58][O:59][CH2:60][CH2:61]4)[CH2:52]3)=[O:27])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C1CC(N2CCOCC2)CN1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCC(N4CCOCC4)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (55 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added 4-(pyrrolidin-3-yl)morpholine (48 mg, 0.30 mmol) and N,N-diisopropylethylamine (53 μL, 0.30 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-60% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][N:13]=[N:12]1.Cl.[OH:18][CH:19]1[CH2:22][NH:21][CH2:20]1.[CH3:23]CN(C(C)C)C(C)C>CC#N>[OH:18][CH:19]1[CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[N:11]2[C:15](=[O:16])[N:14]([CH3:23])[N:13]=[N:12]2)[CH2:20]1
Reactant: OC1CNC1
Reactant: O=c1[nH]nnn1-c1cc([N+](=O)[O-])ccc1F
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CC#N
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2N2CC(O)C2)c1=O
Yield: 88 %

Procedure:
A mixture of 1-(2-fluoro-5-nitrophenyl)-1H-tetrazol-5(4H)-one (100 mg, 0.42 mmol, 1 equiv.), 3-hydroxyazetidine hydrochloride (55 mg, 0.5 mmol, 1.2 equiv.) and iPr2NEt (0.18 mL, 1.05 mmol, 2.5 equiv.) in 2 mL of CH3CN was refluxed for 3 days. Solvent was removed in vacuo and the residue was taken into EtOAc and washed with water. The organic layer was separated and concentrated. The residue was purified by column chromatography using a mixture of hexane/EtOAc (1:4) as eluent to give 108 mg (Yield=88%) of product as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][C:30](=[O:36])[NH:31]2>>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[CH:15][C:12]1[NH:11][C:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[C:6](=[O:17])[C:7]=3[C:13]=1[CH3:14])[C:30](=[O:36])[NH:31]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 61.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 112 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-dimethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (45 mg, 61.6%) as a yellow solid.
Reaction SMILES: C1CCC(N=C=N[CH:10]2[CH2:15][CH2:14]CCC2)CC1.C(O)[C@H](O)[C@H]1[O:23][C:21](=[O:22])[C:20](O)=[C:19]1O.[CH3:28]N(C=O)C>>[C:21]([O:23][C:15]([CH3:14])([CH3:10])[CH3:28])(=[O:22])[CH2:20][CH3:19]
Reactant: CN(C)C=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCC(=O)OC(C)(C)C

Procedure:
36-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne):tert-butyl propanoate (16) was prepared (57%), as a spongy white solid, from dodecaacid 11 (5.63 g, 4.2 mmol), amine 2 (21.98 g, 52.9 mmol), DCC (10.89 g, 52.9 mmol) 1-HBT (7.14 g, 52.9 mmol), and DMF (250 mL) via Procedure A: 14.55 g; mp 67°-70° C.; 1H NMR δ1.42 (s, CH3, 324H), 1.95, 2.20 (m, CH2CH2CO, 192H), 2.37 (t, J=5.7Hz, OCH2CH2CO, 8H), 3.32 (s, CH2O, 8H), 3.66 (t, J=5.7 Hz, OCH2, 8H), 6.36 (s, NH, 16H); 13C NMR δ28.1 (CH3), 29.7 (CH2CH2CO), 37.4 (OCH2CH2CO), 45.4 (4°CCore), 57.3 (4°CNH), 67.7 (CH2O), 68.9 (OCH2), 80.4 (CMe3), 170.7 (CONH), 172.6 (CO2); IR 3311 (NH), 1730 (ester C=O), 1661 (amide C=O), 1157, (ester C--O) cm-1. Anal. Calcd for C321H556N16O92 : C, 63.08; H, 9.17; N, 3.67. Found: C, 63.18; H, 8.89; N. 3.79.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])=[O:34].ClC(OC(C)C(F)(F)F)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:42])=[O:34])[CH2:20]3)=[CH:13][C:12]2=[O:31])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reactant: O=C(Cl)Oc1ccccc1Cl
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OCC3CCN(C(=O)Oc4ccccc4Cl)C3)cc2=O)cc1

Procedure:
Example 19 was prepared according to procedures described in Example 2, Step A and Step C, substituting tert-butyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)pyrrolidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and 2-chlorophenyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=8.80 Hz, 2 H), 7.61 (d, J=8.80 Hz, 2 H), 7.43 (d, J=8.25 Hz, 1 H), 7.23-7.31 (m, 3 H), 7.14-7.19 (m, 1 H), 6.10-6.21 (m, 2 H), 3.38-4.14 (m, 6 H), 3.10 (s, 3 H), 2.77-2.93 (m, 1 H), 2.15-2.32 (m, 1 H), 1.83-2.00 (m, 1 H). MS (ESI) 503 (M+H).
Reaction SMILES: [N:1](=[C:3]([CH:6]([CH3:8])[CH3:7])[C:4]#N)[OH:2].[OH-:9].[Na+].[OH2:11]>>[N:1](=[C:3]([CH:6]([CH3:8])[CH3:7])[C:4]([OH:11])=[O:9])[OH:2]
Reactant: [OH-]
Reactant: O
Reactant: CC(C)C(C#N)=NO
Agent: [Na+]
Product: CC(C)C(=NO)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 3.36 g of 2-oximino-3-methylbutyronitrile, 7 ml of 50% NaOH and 3 ml of water is refluxed under a slow stream of nitrogen for several hours. This is allowed to cool to RT. The mixture is then diluted with water and washed with ether to remove the neutrals. The aqueous layer is acidified and extracted into ether to give 2-oximino-3-methylbutanoic acid, m.p. =153° (dec).
Reaction SMILES: C(=O)([O-])[O-:2].[Cs+].[Cs+].[C:7]1([C:13]2[C:14](=[O:18])[O:15][CH2:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:20][N:21]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([O:36][CH3:37])=[CH:28][C:29]=2[CH:33]([CH3:35])[CH3:34])[S:22]1(=[O:24])=[O:23]>CO.CN(C)C=O>[O:18]=[C:14]1[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:17]([O:2][CH2:20][N:21]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[CH:28][C:29]=3[CH:33]([CH3:35])[CH3:34])[S:22]2(=[O:24])=[O:23])[CH2:16][O:15]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: O=C1OCC=C1c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC1=C(c3ccccc3)C(=O)OC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
Cesium carbonate (0.82 g) was added to a solution of 3-phenyl-2(5H)-furanone (0.88 g) in methanol (15 mL) and the mixture was stirred at room temperature for one hour and stripped of methanol. 2-Chloromethyl-4-isopropyl-6-methoxysaccharin (1.52 g) was added to a solution of the residue in dimethylformamide (15 mL) and the mixture was stirred at room temperature for two days. Silica gel (4.4 g) was added, volatiles were removed under vacuum, and the solid was subjected to flash chromatography on silica gel using ethyl acetate-hexane (3:7) as eluant. Recrystallization of the product from ethanol-ether gave 2-(2,5-dihydro-2-oxo-3-phenylfuran-4-yl)oxymethyl-4-isopropyl-6-methoxysaccharin as a colorless solid (0.45 g, 20% yield, m.r. 180°-182° C. ).
Reaction SMILES: [C-:1]1([C:6]#[C:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](C#C[C-]3C=CC=C3)[CH:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].[CH-]1C=CC=C1.[Fe+2].C([C-]1C=CC=C1)#C.[CH-]1C=CC=C1.[Fe+2].[I:46]C1C=CC=C(I)C=1>>[C-:1]1([C:6]#[C:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:46])[CH:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: Ic1cccc(I)c1
Reactant: C(#C[c-]1cccc1)c1cccc(C#C[c-]2cccc2)c1
Agent: [Fe+2]
Agent: C#C[c-]1cccc1
Agent: c1cc[cH-]c1
Product: Ic1cccc(C#C[c-]2cccc2)c1

Procedure:
Example 11 describes the procedure for producing 1,3-bis(ferrocenylethynyl)benzene 516. Ethynylferrocene 500 was reacted with 1,3-diiodobenzene 502 to form 1-(ferrocenylethynyl)-3-iodobenzene 504. Sufficient ethynylferrocene 500 was present such that the second step of the reaction immediately proceeded. 1-(Ferrocenylethynyl)-3-iodobenzene 504 reacted with ethynylferrocene 514 to form 1,3-bis(ferrocenylethynyl)benzene 516. The reaction procedure is shown in FIG. 5.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:11]1)=[O:7])(C)(C)C.[CH2:22]([N:25]=[C:26]=[O:27])[CH2:23][CH3:24].[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:26]([NH:25][CH2:22][CH2:23][CH3:24])=[O:27])[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(CCCCCCN)C1
Reactant: CCCN=C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CCCNC(=O)NCCCCCCN1CC[C@@H](CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
6-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)hexylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-propyl isocyanate (0.33 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.67 g) to give 4-amino-5-chloro-2-methoxy-N-((3S)-1-(6-(3-n-propylureido)hexyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:25]=1[NH2:26]>C(OCCO)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([C:14]#[N:15])=[C:2]2[NH:26][C:25]1[C:24]([F:23])=[CH:30][C:29]([F:31])=[CH:28][C:27]=1[F:32]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3c(F)cc(F)cc3F)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 200.0 mg (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 105.7 mg (0.92 mmol) of pyridine hydrochloride and 148.6 mg (1.0 mmol) of 2,4,6-trifluoro-aniline in 10 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 112.6 mg (37.4%) of the product as a yellow solid, m.p. 297° C. (dec.), mass spectrum (electrospray, m/e): M+H 330.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[N:3]=1.[F:21][CH:22]([F:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C.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>[F:21][CH:22]([F:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[N:3]=1
Reactant: CC1(C)OB(c2ccccc2C(F)F)OC1(C)C
Reactant: CC(C)COC(=O)N1CCN(c2nccc(Cl)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)N1CCN(c2nccc(-c3ccccc3C(F)F)n2)CC1
Temperature: 120 °C

Procedure:
To a solution of the isobutyl 4-(4-chloropyrimidin-2-yl)piperazine -1-carboxylate 8 and 2-(2-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 11 (1.2 eq) in acetonitrile was added Pd(PPh3)4 (0.10 eq), K2CO3 (2 eq) and water. The vial was sealed and heated by microwave irradiation at 120° C. for 15 minutes. The solvent was evaporated and the residue was dissolved in DMF and purified by reverse phase HPLC. m/z 391.1 (M+1), r.t: 3.59.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:21])[C:12]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=3[F:20])[C:6]=2[CH:5]=[CH:4][N:3]1[CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[C:29]([C:31]([OH:33])=O)[CH:28]=[CH:27][N:26]2[CH:34]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:49][NH:50][CH3:51]>CN(C=O)C.CC#N>[CH3:49][N:50]([CH3:51])[C:31]([C:29]1[CH:28]=[CH:27][N:26]2[CH:34]=[C:23]([CH2:22][N:3]3[CH:4]=[CH:5][C:6]4[C:10]([C:11](=[O:21])[C:12]5[C:13]([F:20])=[CH:14][C:15]([F:19])=[CH:16][C:17]=5[F:18])=[CH:9][NH:8][C:7]=4[C:2]3=[O:1])[N:24]=[C:25]2[CH:30]=1)=[O:33]
Reactant: O=C(O)c1ccn2cc(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccn2cc(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To the product obtained in Example 23 (4.7 mg, 0.010 mmol) in DMF were added EDC (2.51 mg, 0.013 mmol), HOBt (2.06 mg, 0.013 mmol) and dimethylamine (3.83 μL, 0.030 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with 3:2 MeCN:H2O (2 mL) and purified by reverse phase HPLC (C-18 column) to give the title compound (3.1 mg). LC/MS: m/z 494(M+H). 1H-NMR (500 MHz, d6-DMSO): δ 2.92 (s, 3H), 2.99 (s, 3H), 5.43 (s, 2H), 6.99 (d, 1H), 7.15 (d, 1H), 7.33 (t, 2H), 7.58 (d, 1H), 7.73 (s, 1H), 7.89 (d, 1H), 8.03 (s, 1H), 8.66 (d, 1H), 13.1 (d, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([O:15][C:20]2[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([O:17][CH3:16])[N:19]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(NC(C)=O)ccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(NC(C)=O)ccc1Oc1nc(OC)cc(OC)n1
Yield: 70 %

Procedure:
0.78 g (3.7 mmol) of the obtained methyl 6-acetylamino-3-hydroxypicolinate, 0.81 g (3.7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.51 g (3.7 mmol) of potassium carbonate were added to 50 ml of DMF, and the mixture was reacted at 80° C. for two hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and concentrated. The oily product thereby obtained was purified by column chromatography to obtain methyl 6-acetylamino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[CH2:21][C:22]([O-:24])=[O:23])=[CH:9][C:8]([O:25][CH3:26])=[CH:7][CH:6]=2.[C:27](=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][S:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1.O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:34][CH2:35][S:36][C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH2:17][CH:16]1[CH2:21][C:22]([O:24][CH3:27])=[O:23])=[CH:9][C:8]([O:25][CH3:26])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCCC3CCNCC3CC(=O)[O-])c2c1
Reactant: BrCCSc1cccs1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1CN(CCSc2cccs2)CCC1CCCc1c(F)cnc2ccc(OC)cc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension composed of 0.95 g of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro-6-methoxy-quinolin-4-yl)propyl]piperidine-3-acetate, 0.7 g of potassium carbonate, 0.68 g of 2-(2-bromoethylthio)-thiophene in 40 cm3 of dimethylformamide was stirred for 16 hours at a temperature in the region of 60° C. under an inert atmosphere. After cooling to about 20° C., the reaction mixture was poured over 200 cm3 of water and 200 cm3 of ethyl acetate. The organic phase was separated after settling out and then washed 5 times with 100 cm3 of water and then with 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue obtained was purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 μ; diameter 2 cm; height 40 cm), eluting with a cyclohexane-ethyl acetate (68/32 by volume) mixture. 15-cm3 fractions were collected. Fractions 15 to 21 were concentrated. 480 mg of methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-acetate were obtained in the form of an orange-colored oil.