Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:25]=1[CH3:26].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: Cc1c(I)cnn1-c1cccs1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4cccs4)c3C)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20 mg, 0.08 mmol), 4-iodo-5-methyl-1-(2-thienyl)-1H-pyrazole (23 mg, 0.08 mmol), copper (I) iodide (4.5 mg, 0.024 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.1 mg, 0.008 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.022 ml, 0.16 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-{[5-methyl-1-(2-thienyl)-1H-pyrazol-4-yl]ethynyl}pyrazolo[1,5-a]pyridine.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[C:8]1([CH:18]=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:18][N:1]2[CH2:7][CH2:6][CH2:5][C@H:2]2[CH2:3][OH:4])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=Cc1cccc2ccccc12
Product: OC[C@@H]1CCCN1Cc1cccc2ccccc12

Procedure:
Using (S)-prolinol ((S)-VIII-1) and α-naphthoaldehyde as the starting materials, a similar operation was carried out to obtain (S)-N-(α-naphthyl)methyl-2-pyrrolidine methanol ((S)-II-2). ##STR317##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([I:10])[C:3]=1[OH:11].[CH:12]1([CH2:15]Br)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([I:10])[C:3]=1[O:11][CH2:15][CH:12]1[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: OCc1cc(I)c(O)c(Cl)n1
Product: OCc1cc(I)c(OCC2CC2)c(Cl)n1

Procedure:
The title compound was synthesized in analogy to Example A, using 6-chloro-5-hydroxy-4-iodo-2-pyridinemethanol and cyclopropylmethyl bromide as starting materials; LC-MS (UV peak area/ESI) 95.8%, 339.9584 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-])=O.Cl.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[N:18]1[CH:19]=[CH:20][C:15]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)=[CH:16][CH:17]=1
Reactant: Clc1ccncc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2c(ccn2-c2ccncc2)c1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
To a solution of 5-nitroindole (7.0 g, 43.2 mmol) and 4-chloropyridine hydrochloride (7.8 g, 51.8 mmol) in DMF (43 mL) was added potassium tert-butoxide (12.1 g, 108.0 mmol), portionwise. The reaction was heated at 100° C. for 48 h. The mixture was allowed to cool to room temperature and poured into water (400 mL). The resulting solid was removed by filtration and dried under vacuum. Desired compound (6.04 g, 25.3 mmol; 58% yield); 1H NMR (DMSO-d6) δ 8.76 (dd, J=1.7, 4.5, 2H), 8.68 (d, J=2.2, 1H), 8.06-8.13 (m, 2H), 7.92 (d, J=9.2, 1 H), 7.75 (dd, J=1.5, 4.6, 2H), 7.07 (dd, J=0.9, 3.5, 1H); ES MS [M+H]+=240. Step 2. Preparation of 1-(4-pyridinyl)-1H-indol-5-amine
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].CCN(CC)CC.[C:20](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21]>C1COCC1.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl) aniline (3a) (0.5 g, 2.55 mmol) in dry THF (8 mL), cooled to 0° C., Et3N (0.4 mL, 2.76 mmol) followed by PivCl (0.34 mL, 2.8 mmol) were added. The reaction mixture was stirred at room temperature for 4 h. After completion of reaction (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with water (30 mL). The organic layer was separated dried over Na2SO4 and concentrated under reduced pressure to give the crude material which was triturated with n-hexane to afford the desired amide 3b (0.45 g, 60%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[CH3:16]O>>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@H:6]1[O:7][CH3:16])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Yield: 25 %

Procedure:
To a solution of N-acetylglucosamine (50 g, 0.22 mmol) in MeOH (50 ml), a catalytic quantity of Amberlite IR-120 H+ resin is added, and the mixture is heated for 2 days. The mixture is filtered, concentrated and purified by silica gel column chromatography (CH2Cl2/MeOH 5:1), obtaining 10 g of the α-anomer methyl 2-acetamido-2-deoxy-α-D-glucopyranoside (25%) anomer and 40 g of the β-anomer that is isomerised to give the α-anomer methyl 2-acetamido-2-deoxy-α-D-glucopyranoside in the same reaction conditions (70% yield).
Reaction SMILES: [CH3:1][CH2:2][C:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=[CH:20]2)=[O:11]>C(O)C.O1CCOCC1.[Pt]=O>[CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[CH:23]=[C:22]([NH2:26])[CH:21]=[CH:20]2)=[O:11]
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc([N+](=O)[O-])ccc3nc2-1
Agent: O=[Pt]
Solvent: CCO
Solvent: C1COCCO1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(N)ccc3nc2-1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
10-Nitrocamptothecin (108 mg, 0.275 m-mol) is dissolved in ethanol (30 ml) and dioxane (20 ml). To this solution is added platinum oxide (20 mg), and the mixture is subjected to catalytic reduction for 30 minutes at room temperature under normal pressure. The catalyst is removed by filtration and the reaction mixture is evaporated under reduced pressure until dryness whereby 96 mg (yield: 96.2% ) of 10-aminocamptothecin is obtained as a yellowish brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>>[CH3:14][C:15]1[C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]=[C:11]([CH3:13])[O:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Product: Cc1nc(-c2ccc(-c3cc(C(=O)Nc4cccc(N5CCOCC5)c4)ccc3C)cc2)no1

Procedure:
Example 3 was prepared using 3-(4-bromophenyl)-5-methyl-1,2,4oxadiazole and 4-methyl-N-[3-(4-morpholinyl)phenyl]-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[C:14]2[CH:15]=[CH:16][C:17](I)=[CH:18][C:13]=2[O:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[I:21]C1C=CC2OC=C(CCN)C=2C=1>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[C:14]2[CH:15]=[C:16]([I:21])[CH:17]=[CH:18][C:13]=2[O:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCc1coc2cc(I)ccc12
Reactant: NCCc1coc2ccc(I)cc12
Product: CC(C)(C)OC(=O)NCCc1coc2ccc(I)cc12

Procedure:
Synthesized as described for tert-butyl[2-(6-iodo-1-benzofuran-3-yl)ethyl]carbamate using 2-(5-iodo-1-benzofuran-3-yl)ethanamine. 1H-NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.84 (t, 1H), 3.43 (q, 2H), 4.62 (bs, 1H), 7.25 (d, 1H), 7.43 (s, 1H), 7.56 (dd, 1H), 7.88 (d, 1H).
Reaction SMILES: Cl.C([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH:19]=[O:20])[CH:11]([CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:10]1)C1C=CC=CC=1>[Pd].CO>[CH:19]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:9][CH2:10][CH:11]1[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]
Reactant: O=CN1c2ccccc2N(Cc2ccccc2)CC1CN1CCCC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=CN1c2ccccc2NCC1CN1CCCC1
Reaction time: 2 h
Yield: 98.5 %

Procedure:
10% Pd-C (200 mg) and concentrated hydrochloric acid (0.3 ml) were added to a methanol (25 ml) solution of 4-benzyl-1-formyl-2-(pyrrolidin-1-yl)methyl-1,2,3,4-tetrahydroquinoxaline (500 mg). The reaction mixture was subjected to catalytic hydrogenation at room temperature under 4.5 atmospheric pressure for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated. 10% Aqueous potassium carbonate solution was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated to give 1-formyl-2-(pyrrolidin-1-yl)methyl-1,2,3,4-tetrahydroquinoxaline (360 mg). Oxalyl chloride (0.19 ml) was added to a THF (5 ml) solution of 3-(4-biphenylyl)propionic acid (410 mg) under ice-cooling, to which was added DMF (one drop). The reaction mixture was stirred at room temperature for 30 minutes, which was concentrated. The residue was again dissolved in THF, which was concentrated. The residue was dissolved in THF (7 ml), which was added dropwise to a THF (7 ml) solution of 1-formyl-2-(pyrrolidin-1-yl)methyl-1,2,3,4-tetrahydroquinoxaline (360 mg) and triethylamine (0.31 ml) underice-cooling. The reaction mixture was stirred at the same temperature for one hour. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: hexane to hexane/ethyl acetate=4/1), which was converted into its oxalate. The crystals were washed with IPE to give the entitled compound (350 mg).
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[CH:17]([O-])([O-])[O:18][CH2:19][CH3:20].C(OC(=O)C)(=O)C>>[Cl:1][C:2]([F:15])([F:16])[C:3](=[O:14])[C:4](=[CH:17][O:18][CH2:19][CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(CC(=O)C(F)(F)Cl)c1ccc(Cl)cc1
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Cl)cc1)C(=O)C(F)(F)Cl
Yield: 100.8 %

Procedure:
A mixture of 49.5 g of 1-choro-4-(4-chlorophenyl)-1,1-difluoro-2,4-butanedione, 41.3 g of ethyl orthoformate and 57 g of acetic anhydride was refluxed under heating for 4 days. The solvent was distilled off to obtain 60.4 g of the crude product, which was used for the next reaction directly.
Reaction SMILES: [C:1]1([CH:7]([O:9][C:10]([C:12]2([C:35]([O:37]C(C3C=CC=CC=3)C)=[O:36])[O:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][C@H:22]([NH:24][CH2:25][C@@H:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[OH:27])[CH3:23])=[CH:20][C:14]=3[O:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.CO>[C:1]1([CH:7]([O:9][C:10]([C:12]2([C:35]([OH:37])=[O:36])[O:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][C@H:22]([NH:24][CH2:25][C@@H:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[OH:27])[CH3:23])=[CH:20][C:14]=3[O:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(OC(=O)C1(C(=O)OC(C)c2ccccc2)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(OC(=O)C1(C(=O)O)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1)c1ccccc1
Yield: 22 %

Procedure:
The title compound was prepared as a tan solid according to the procedure of Example 102 from 5-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-phenylethyl) ester; yield: 22%; Rf =0.39 (9/1 CHCl3 /MeOH; mp 71-79° C.; 1H NMR (300 MHz, DMSO-d6): δ 1.00 (d, 3H), δ 1.5 (br m, 3H), δ 2.4-2.75 (m, 1H), δ 3.15-3.45(br m, 5H), δ 4.90 (br d, 1H), δ 5.20 (br d, 1H), δ 5.90 (q, 1H), δ 6.6 (d, 1H), δ 6.76 (d, 2H), δ 7.21 (br s, 6H), δ 7.36 (m, 3H), δ 7.46 (s, 1H); MS (ES) m/z (relative intensity): 526 (M+, 100).
Reaction SMILES: O1CCCC1.[C:6]([O:11][Si](C)(C)C)(=[O:10])[C:7]([CH3:9])=[CH2:8].[C:16]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])[C:17]([CH3:19])=[CH2:18]>CC1C=CC(C)=CC=1>[C:16]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])[C:17]([CH3:19])=[CH2:18].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)O[Si](C)(C)C
Agent: C=C(C)C(=O)OCCCC
Solvent: Cc1ccc(C)cc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)O
Reaction time: 0 h

Procedure:
A block copolymer of n-butyl methacrylate and methacrylic acid was prepared by adding 3750 grams of tetrahydrofuran and 7.4 grams of p-xylene to a 12-liter flask equipped with a mechanical stirrer, thermometer, nitrogen inlet, drying tube outlet and addition funnels. Feed I, which consisted of 3.0 ml of a 1.0 M solution of tetrabutyl ammonium m-chlorobenzoate catalyst in acetonitrile, was started at 0 minutes and added over 150 minutes and 291.1 gm (1.25 mole) of an initiator, 1,1-bis(trimethylsiloxy-2-methyl propene), was injected. Feed II, which consisted of 1976 gm (12.5 M) trimethylsilyl methacrylate, was started at 0 minutes and added over 35 minutes. One hundred eighty minutes after Feed II was completed (over 99% of the monomers had reacted), Feed III, which consisted of 1772 gm (12.5 M) butyl methacrylate, was started and added over 30 minutes.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)=[CH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].COC1C=C(NC2C=CC=CC=2[N+]([O-])=O)C=CC=1C(C1C=CC=CC=1C)=O>>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:7]2[CH:26]=[CH:27][CH:28]=[CH:29][C:6]=2[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:9])=[CH:11][CH:12]=1
Reactant: CC(C)(C)Oc1ccccc1C(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: COc1cc(Nc2ccccc2[N+](=O)[O-])ccc1C(=O)c1ccccc1C
Product: CC(C)(C)Oc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1

Procedure:
By following the procedure of example 70, but using 2-tert-butoxy-4′-(2-nitrophenylamino)benzophenone (Compound 256) in place of 2-methoxy-2′-methyl-4-(2-nitrophenylamino)benzophenone (Compound 255), the desired compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:18]([CH3:23])=[C:19]([F:22])[C:20]=1[F:21])[C:5]([C:7](=[CH:13][NH:14][CH:15]1[CH2:17][CH2:16]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[H-].[Na+]>>[CH:15]1([N:14]2[C:3]3[C:4](=[C:18]([CH3:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=3[Cl:1])[C:5](=[O:6])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13]2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)c(F)c(F)c(Cl)c1F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c(C)c2c1=O
Yield: 18.1 %

Procedure:
Employing ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-cyclopropylaminoacrylate (410 mg) and 60% sodium hydride (35 mg), the procedure of Reference Example 22 is repeated to give ethyl 1-cyclopropyl-6,7-difluoro-8-chloro-5-methyl-1,4-dihydro-4 -oxoquinoline-3-carboxylate (70 mg), as pale yellow powder (recrystallized from dichloromethane --n-haxane), m.p. 153°-154° C.
Reaction SMILES: [NH:1]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:2]([C:6]([N:8]1[CH2:37][CH2:36][CH2:35][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:18][CH:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:22])[OH:21])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].FC(F)(F)C(O[C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=O>N1C=CC=CC=1>[NH:1]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[C@H:2]([C:6]([N:8]1[CH2:37][CH2:36][CH2:35][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:28]([NH:30][CH2:31][C:32]([O:34][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:33])=[O:29])[CH2:18][CH:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:21])[OH:22])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(OC(C)(C)C)C(=O)O)C(=O)NCC(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(OC(C)(C)C)C(=O)O)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
XIX (1.32 g, 2.15 mmol) and p-nitrophenyl trifluoroacetate (0.607 g, 2.58 mmol) were reacted in pyridine (10 ml) in the same manner as described for the preparation of X in part (b). The resulting oil was triturated with ether and petroleum ether. The solid obtained was composed of one major component (Rf1 0.44) and one minor component (Rf1 0.33). Repeated recrystallization from chloroform-petroleum ether and further purifications using several organic solvents were attempted, but these attempts were only of limited effect in fractionating the major component as pure XX. The component (1.13 g, Rf1 0.44) containing only traces of the component (Rf1 0.33) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C@:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:31]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[Si:24]([O:23][CH2:22][C@:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:31][CH3:32])[CH:37]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
The compound (600 mg, 1.18 mmol) obtained in Example 52-1), 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (314 mg, 1.42 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (93 mg, 0.12 mmol), and potassium carbonate (489 mg, 3.54 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (2 mL), and the mixture was stirred at 90° C. for 5 h. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60 to 100:0) to obtain the title compound (551 mg, 89%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>>[O:30]1[CH2:29][CH:28]1[CH2:26][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:4]([CH2:3][CH2:2][OH:1])[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[N:6]=2)=[CH:14][CH:15]=1
Reactant: OCCn1cc(C(F)(F)F)nc1-c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCn1cc(C(F)(F)F)nc1-c1ccc(OCC2CO2)cc1
Reaction time: 1 h

Procedure:
A suspension of 3.26 g of 1-(2-hydroxyethyl)-2-(4-hydroxyphenyl)-4-(trifluoromethyl)-1H-imidazole and 9.26 g of anhydrous potassium carbonate in 95 ml of epichlorohydrin is heated under reflux, while stirring, for 1 hour. The mixture is subsequently cooled in an ice bath, filtered and the filtrate freed of solvent in a rotary evaporator. The oil that remains behind is chromatographed on silica gel with ethyl acetate. The main fractions are combined and are caused to crystallise by the addition of hexane, yielding 2-[4-(2,3-epoxypropoxy)-phenyl]-1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-imidazole having a melting point of 110°-112°.
Reaction SMILES: Br[C:2]1[O:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)#[CH:18]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:7]([C:4]1[O:3][C:2]([C:18]#[C:17][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:6][CH:5]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(Br)o1
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C#Cc2ccc([N+](=O)[O-])o2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-nitrofuran (1.65 g) and triethylamine (34 ml) in anhydrous acetonitrile (55 ml) under nitrogen was added bis(triphenylphosphine)palladium dichloride (130 mg) and cuprous iodide (35 mg). 4-Ethynylbenzonitrile (1.09 g) was added and the reaction mixture was stirred under nitrogen overnight. The mixture was evaporated to dryness and the residue was dissolved in dichloromethane (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (ethyl acetate/hexane 1:10) and triturated with ethyl acetate/hexane (1:3) to give 4-[(5-nitro-2-furyl)-ethynyl]benzonitrile.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[C:32]([C:39]([NH:41][C:42]1[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][C:43]=1[O:57][CH3:58])=[O:40])[N:33]2[CH3:38]>>[C:24]([N:21]1[CH2:22][CH2:23][N:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([C:4]3[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]4=[C:2]([C:45]4[CH:46]=[CH:47][C:42]([NH:41][C:39]([C:32]5[N:33]([CH3:38])[C:34]6[C:30]([CH:31]=5)=[C:29]([O:28][CH3:27])[CH:37]=[CH:36][CH:35]=6)=[O:40])=[C:43]([O:57][CH3:58])[CH:44]=4)[N:3]=3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Reactant: CC(=O)N1CCN([C@H]2CC[C@H](c3nc(Br)c4c(C)nccn43)CC2)CC1
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C(C)=O)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C

Procedure:
Using the procedure described in example 1 step 1f 1-(4-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)piperazin-1-yl)ethanone (0.059 mmol, 25 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (0.059 mmol, 26 mg) gave after purification on prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid) 11 mg of the title compound.