Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]1
Reactant: CCOC(=O)c1n[nH]cc1C
Reactant: COc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nn(-c2ccccc2OC)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
Ethyl 4-methyl-1H-pyrazole-3-carboxylate (4.0 g) was dissolved in N,N-dimethylacetamide (30 mL), 2-methoxyphenylboronic acid (7.9 g), copper acetate (9.5 g) and pyridine (8.4 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.6 g, 25%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13]>C(O)C>[F:13][C:12]([F:15])([F:14])[C:11]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:10]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1nc(C(F)(F)F)cs1

Procedure:
A solution of ethyl amino(thioxo)acetate (4 g) and 3-bromo-1,1,1-trifluoroacetone (3.1 ml) in ethanol (150 ml) was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (3.56 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][N:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][C:29](=[O:36])[N:28]([C:37]2[CH:38]=[CH:39][C:40]3[S:44][N:43]=[C:42]([CH:45]=O)[C:41]=3[CH:47]=2)[C:27]1=[O:48]>C(Cl)Cl>[Br:21][C:20]([Br:24])=[CH:45][C:42]1[C:41]2[CH:47]=[C:37]([N:28]3[C:29](=[O:36])[CH:30]=[C:31]([C:32]([F:35])([F:34])[F:33])[N:26]([CH3:25])[C:27]3=[O:48])[CH:38]=[CH:39][C:40]=2[S:44][N:43]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=C(Br)Br)c3c2)c1=O
Yield: 83.4 %

Procedure:
Triphenylphosphine (0.354 g, 0.00138 mol) is added to a solution of carbon tetrabromide (0.223 g, 0.000676 mol) in methylene chloride. The resultant mixture is stirred at room temperature for 10 minutes and treated dropwise with a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (0.200 g, 0.000563 mol) in methylene chloride. The resultant mixture is stirred 20 minutes and concentrated in vacuo. The resultant residue is purified by flash column chromatography using silica gel and 10:1 methylene chloride/ethyl acetate to give the title product as a white solid (0.240 g, 83.6%, mp 260-262° C.) which is identified by NMR and IR spectral analyses.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[N:20][N:21]=3)[CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1>>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:24])[CH3:25])=[N:20][N:21]=4)[CH:18]=3)[CH2:4][CH2:3]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)C(C)C
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Product: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12)C(C)C

Procedure:
The title compound was prepared starting from Intermediate 103c and Intermediate 95c using analogous procedures to those described in Intermediate 95d. LCMS (Method 4): Rt 3.92 min, m/z 765 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:29]([O:42][C:43]([NH:45][C:46]1[NH:47][C:48](=[O:59])[C:49]2[N:50]=[CH:51][N:52]([CH2:55][C:56](O)=[O:57])[C:53]=2[N:54]=1)=[O:44])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:56](=[O:57])[CH2:55][N:52]1[CH:51]=[N:50][C:49]2[C:48](=[O:59])[NH:47][C:46]([NH:45][C:43]([O:42][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:44])=[N:54][C:53]1=2)[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 11.65 (brs, 1H), 11.25 (s, 0.45H), 11.23 (s, 0.55H), 9.20 (brs, 1H), 8.39 (s, 1H), 8.03–7.91 (m, 2H), 7.82 (s, 0.55H), 7.80 (s, 0.45H), 7.46 (d, 4H), 7.38 (t, 4H), 7.30 (dt, 2H), 6.87 (s, 1H), 5.15 (s, 1.1H), 4.96 (s, 0.9H), 4.47 (s, 0.9H), 4.22 (q, 0.9H), 4.10 (s, 1.1H), 4.09 (q, 1.1H), 3.69 (t, 1.1H), 3.52 (t, 0.9H), 3.45 (t, 1.1H), 3.29 (t, 0.9H), 1.26 (t, 1.35H), 1.16 (t, 1.65H).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([N:29]1[C:38]2[C:33](=[CH:34][C:35]([CH:39]=[CH:40][C:41]([O:43][CH3:44])=[O:42])=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O1CCCC1>[CH2:1]([N:8]([C@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C@@H:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:30][CH2:31][CH2:32]2)[CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Reactant: COC(=O)C=Cc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C[C@H](c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
A solution of (S)-N-benzyl-α-methylbenzylamine (2.6 ml) in anhydrous tetrahydrofuran (50 ml), cooled to −70° C. and under nitrogen, was treated dropwise with a solution of butyllithium in hexanes (5 ml, 2.5M) over about 5 minutes to give a red solution. After stirring at −70° C. for a further 40 minutes the mixture was treated dropwise with a solution of methyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)acrylate [2.0 g, Reference Example 7(d)] in tetrahydrofuran (20 ml) over about 10 minutes. Stirring was continued at low temperature for a further 20 minutes and then the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ether and water, the layers separated, and the organic layer washed with water then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9 and then 15:85, v/v) to give the title compound as a viscous, colourless oil, 1.5 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][OH:10]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([OH:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:9]=[O:10]
Reactant: Oc1ccccc1Br
Reactant: CO
Solvent: Cc1ccccc1
Product: O=Cc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Over 0.25 hours 2-bromophenol (22.38 g, 129 mmol) was added to a solution of Mg(OMe)2 in methanol (111.9 ml, 8% w/w) and toluene (35 ml). The reaction was heated to reflux and maintained at reflux for 1 hour, then toluene (118 ml) was added. The solvent was distilled off until the temperature reached 92-94° C. A solution of paraformaldehyde in toluene was added portionwise over 1 hour at 80-90° C. and the reaction mixture heated to reflux and maintained at reflux for 3 hours. The reaction mixture was then allowed to cool to ambient temperature and left to stand overnight. Toluene (140 ml) was added to the reaction mixture, which was then washed with 2M H2SO4 (140 ml). The organic phase was dried and evaporated and the crude material used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccnc(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(OC)ccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottomed flask 2-bromo-4-methoxypyridine (315 mg, 1.68 mmol) was dissolved in THF (6 mL). The solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.35 mL, 1.76 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min then at room temperature for 1.5 h. An additional portion of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 0.15 mL, 0.20 mmol) was added and stirring was continued at room temperature for 30 min. Tributyltin chloride (0.50 mL, 1.84 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give 4-methoxy-2-tributylstannanyl-pyridine as a white paste which was used without further purification.
Reaction SMILES: [O:1]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1>[OH-].[Na+]>[O:1]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccc(NC(=O)C(=O)OCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)Nc1ccc(Oc2ccc(NC(=O)C(=O)O)cc2)cc1

Procedure:
Diethyl N,N'-(oxydi-p-phenylene)dioxamate (2.0 gm.) is stirred at room temperature for 3 hours in 1.0 N sodium hydroxide (50 ml.). The solid is collected by filtration and dissolved in water. The pH is adjusted to pH=3 with concentrated hydrochloric acid and the desired product collected by filtration (1.6 gm., mp >320°). The ir spectrum is consistent with the assigned structure.
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[C:6]([CH2:8]P(=O)([O-])[O-])[N:7]=1)[CH3:2].[H-].[Na+].[CH3:15][O:16][CH2:17][O:18][C:19]1[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1.O>O1CCCC1>[CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:24]\[C:23]2[C:19]([O:18][CH2:17][O:16][CH3:15])=[N:20][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(CP(=O)([O-])[O-])co1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCOC)co1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of diethyl ([(2-ethyl-1,3-oxazol-4-yl)methyl]phosphonate (2.97 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.32 g) was added to the reaction mixture and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-3:7, v/v) to give 2-ethyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.24 g, yield 7.4%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1Cl>>[O:23]=[C:21]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=1)[CH2:22][O:3][C:1](=[O:4])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1ccccc1
Yield: 33 %

Procedure:
This crude material was reacted with acetic acid (1.42 mL, 1.49 g, 24.8 mmol) and triethylamine (3.46 mL, 2.51 g, 24.8 mmol), as described above for the synthesis of 3-(3,4-dichlorophenyl)propan-2-one. Flash chromatography over silica gel (10-30% ethyl acetate in hexanes) gave pure product (0.83 g, 33% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.08 (s, 3H) 3.80 (s, 2H) 4.85 (s, 2H) 7.17-7.36 (m, 5H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[N:12]=[C:13]([CH3:16])[NH:14][CH:15]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:12]1[C:11]([CH:9]=[O:10])=[CH:15][N:14]=[C:13]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(C=O)n1Cc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (21.4 ml, 0.18 mol) was added carefully to a mixture of 4-formyl-2-methylimidazole (18.1 g, 0.16 mol) and potassium carbonate (45.0 g, 0.33 mol) in DMF (100 ml) at 0° C. and the reaction mixture allowed to warm to ambient temperature. The mixture was then partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution, the organic phase separated and dried. The volatiles were removed by evaporation to give the title compound as crude mixture of regioisomers 32.0 g, (99%). M/z: 201.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([CH3:21])[NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][N:34]=[C:35]=[O:36]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:20][C:35]([NH:34][CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:36])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccco1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: ClCCl
Product: C[C@H](NC(=O)NCc1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.7 %

Procedure:
(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (100 mg, 0.28 mmol), as described in Example 1, is dissolved in 1.77 mL dichloromethane and furylmethylisocyanate (34.1 mg, 0.28 mmol) is dropwise added. After stirring for 45 min at r.t. the solvent is removed and the residue purified by chromatography (silicagel, eluents: hexane/ethylacetate). 116.2 mg (86.7%) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]3)[CH:8]=2)[N:3]=1.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3([C:27]([NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:25][CH2:26]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C3(C(=O)O)CCC3)ccc2n1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CCC1

Procedure:
(Preparation by reaction of 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylic acid [“A61”] with tert-butylamine)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:20][O:21]S(C)(=O)=O)([CH2:14][O:15]S(C)(=O)=O)[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@@H:10]1OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[OH:21][CH2:20][C@:13]12[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:10]([O:15][CH2:14]1)[C@H:11]([N:26]1[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]1=[O:28])[O:12]2
Reactant: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cn([C@@H]2O[C@]3(CO)CO[C@H]2[C@H]3OCc2ccccc2)c(=O)[nH]c1=O
Temperature: 80 °C
Yield: 43.7 %

Procedure:
To a solution of nucleoside 11 (329 mg, 0.54 mmol) in ethanol/water (10 cm3, 1:1, v/v) was added 6M NaOH (aq) (0.9 ml, 5.4 mmol). The mixture was refluxed at 80° C. for 43 h followed by evaporation to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (2.4% methanol, v/v) as eluent to afford nucleoside 12 (85 mg, 44%). δC ((CD3)2SO) 163.8, 150.3, 138.0, 135.8, 128.3, 127.7, 127.5, 108.0, 90.2, 86.5, 86.4, 79.3, 76.5, 72.5, 71.2, 57.2, 40.2, 40.0, 39.8. 39.6, 39.4, 39.2, 39.0, 12.3.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O.N1CCCCC1>C(O)(=O)C>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[CH:11][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=C2Cc3ccccc3C2=O)cc1

Procedure:
A mixture of indan-1-one (3.3 g), methyl 4-formylbenzoate (5.0 g), piperidine (0.6 ml) and glacial acetic acid (0.5 ml) was heated on a steam bath for 3 hours. The solid mass obtained was boiled up in industrial methylated spirits (200 ml) and then hot filtered. The solid residue obtained was washed with industrial methylated spirits and dried to give methyl 4-(1-oxoindan-2-ylidenemethyl)benzoate, m.p. 194-198° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:19])[CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[S:8][C:9]([S:10]([CH3:11])=[O:26])=[C:5]2[C:4](=[O:19])[CH2:3]1
Reactant: CSc1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6,6-Dimethyl-3-methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (200 mg, 0.66 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to −78° C. Meta-chloroperoxybenzoic acid (82 mg of 70% (w/w); 0.66 mmol) was dissolved in CH2Cl2 (5 mL) and added dropwise to the solution, which was allowed to stir at −50° C. for 1 h, then warmed to room temperature. The mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine. After drying (Na2SO4), the solution was evaporated to dryness and the residue was purified by chromatography on silica gel, eluting with ethyl acetate:hexane (1:1). The title compound was isolated as a white solid (160 mg, 79%). 1HNMR (360 MHz, CDCl3)δ 1.08 (3H, s), 1.11 (3H, s), 2.43 (1H, d, J=18 Hz), 2.53 (1H, d, J=18 Hz), 3.00 (3H, s), 3.03 (2H, s), 7.24-7.28 (1H, m), 7.52-7.54 (1H, m), 7.76-7.80 (1H, m), 8.64-8.66 (1H, m). MS (ES+) 320 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:17][CH3:18])=[N:4][N:5]2[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([C:13](=[O:16])[CH2:14][CH3:15])[C:6]=12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:17][CH3:18])=[N:4][N:5]2[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([C:13](=[O:16])[CH:14]([CH3:15])[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:6]=12
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCC(=O)c1ccc(OC)n2nc(CC)c(Cl)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nn2c(OC)ccc(C(=O)C(C)CC(=O)OC(C)(C)C)c2c1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The compound of Example 145 (280 mg) was dissolved in tetrahydrofuran (12 mL) in an argon atmosphere. While the solution was kept at −78° C., 1 mol/L lithium bis(trimethylsilyl)amide/tetrahydrofuran solution (1.23 mL) was added and the mixture was stirred at −78° C. to room temperature for 30 min. t-butyl bromoacetate (181.6 μL) was then added at −78° C. and the mixture was stirred at room temperature for 7 hours. Subsequently, the reaction was terminated by adding a saturated aqueous solution of ammonium chloride and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=1:1) afforded the title compound as a green powder (237.1 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:2]1([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccccc1
Product: c1ccc(Nc2ccccc2)cc1
Reaction time: 4 h
Yield: 98.1 %

Procedure:
According to general procedure B, chlorobenzene (57 mg, 0.50 mmol) reacted with aniline (48 mg, 0.50 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (59 mg, 0.60 mmol) in toluene at 70° C. to give the title compound (73 mg, 86%) as a white solid. The coupling reaction of bromobenzene (158 mg, 1.00 mmol) with aniline (93 mg, 1.00mmol) occurred at room temperature over 4 h using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 to give the title compound (166 mg, 98%): 1H-NMR (400 MHz, CDCl3): δ 7.34 (t, 4H, J=7.8 Hz and 7.5 Hz), 7.14 (d, 4H, J=8.7 Hz), 7.00 (t, 2H, J=7.2 and 7.5 Hz), 5.74 (bs, 1H). 13C{1H}-NMR (100 MHz, CDCl3): δ 143.09, 129.32, 120.97, 117.78. GC/MS(EI): m/z 169 (M+).