Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)(=O)C.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(O)C>[CH3:21][N:22]1[CH2:27][CH2:26][C:25]2([C:16]3=[C:15]4[C:10](=[N:9][C:8]3=[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]3)[NH:1]2)[CH:11]=[CH:12][CH:13]=[CH:14]4)[CH2:24][CH2:23]1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: CN1CCC(=O)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12
Yield: 35.6 %

Procedure:
To a solution prepared from 8 g of 2-(2-aminophenyl)indole, 2.5 ml of acetic acid and 100 ml of ethanol was added 5.15 g of 1-methyl-4-piperidone. The mixture was refluxed for 6 hours. Concentration gave a gum which was triturated with dilute NH4OH and the resultant solid was collected. Flash chromatography using 10% CH3OH/CH2Cl2 as an eluent gave 4.15 g of yellow solid, m.p. 228°-230° dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:10]([C:20]([C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=3[F:30])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([NH2:44])=[O:43]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:38][C:39]3[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=3)[C:42]([NH2:44])=[O:43])[N:10]([C:20](=[O:21])[C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=3[F:30])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c(F)cc(F)cc1F)N1N=C(c2ccc(F)cc2)SC1c1ccccc1O
Reactant: NC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(COc2ccccc2C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To [5-(4-fluoro-phenyl)-2-(2-hydroxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (41 μmol) dissolved in acetonitrile (1 mL) is added K2CO3 (61.5 μmol) and 3-bromomethyl-benzamide (94.2 μmol) and the mixture is heated at 90° C. After 12 hours, the reaction is complete as determined by LC/MS. Purification is accomplished by preparative LC/MS (20-100% MeCN/H2O) to give 3-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-benzamide: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.9 (d, J=7.6 Hz, 1H), 7.7 (s, 1H), 7.6-7.5 (m, 4H) 7.35 (d, J=7.6 Hz, 1H), 7.06 (t, J=8.4 Hz, 1H), 6.99 (t, J=7.6 Hz, 2H), 6.88 (d, J=8 Hz), 6.79 (t, J=8.4 Hz, 2H), 6.26 (bs, 1H), 5.33 (d, J=7.6 Hz); LC/MS (ES+): 566.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:22].[C:23]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)(=[O:25])[CH3:24]>CN1CCCC1=O>[C:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:29]4[CH2:30][CH2:31][CH:27]([NH:26][C:23](=[O:25])[CH3:24])[CH2:28]4)[CH:11]=3)[C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cn(-c2ccccc2)c2cc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC1CCNC1
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccccc2)C1
Temperature: 100 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
To a solution of 1.5 g 7-chloro-1-phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (product of Example 1(d)) in 20 ml of 1-methyl-2-pyrrolidinone at 115° C. is added 3 g of 3-acetamido-pyrrolidine. After stirring at 100° C. for 20 hours, the solvent is removed by reduced pressure to dryness. Ethanol is added to the residue and washed with ether and then diluted cold hydrochloric acid and then water. The solid is dried, yielding 1.60 g 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-acetamido-1-pyrrolidinyl)-quinoline-3-carboxylic acid (9) ##STR43## R-phenyl).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:20]=1)[C:17](Cl)=O.N>>[Br:11][C:12]1[CH:20]=[C:16]([C:17]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:15]=[N:14][CH:13]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Brc1cncc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 5-bromonicotinoyl chloride (Alfa). 1H NMR (300 MHz, DMSO-d6) δ 8.65-8.69 (m, 1H), 8.45-8.49 (m, 1H), 8.79 (t, J=1.7 Hz, 1H), 8.84 (dd, J=1.7, 2.0 Hz, 1H), 9.07 (d, J=2 Hz, 1H), 9.28-9.29 (m, 1H), 9.34 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH:13]1([CH:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>COCCOC>[CH:13]1([CH:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:26])=[CH:23][CH:22]=2)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Nc1ccc(C(=O)Cl)cc1)C1CCCC1
Agent: Cl
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(NC(C)C2CCCC2)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of 4-(1-cyclopentylethylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 4-(1-cyclopentylethylamino)benzoylmalonate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCC1(O)CCOCC1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCOCC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 4-chloro-3-nitro[1,5]naphthyridine (16.6 g, 79.0 mmol) in dichloromethane (250 mL) and triethylamine (14.3 mL, 102.7 mmol) was cooled to 4° C. A solution of 4-aminomethyltetrahydropyran-4-ol (11.4 g, 86.9 mmol) in dichloromethane (70 mL) was added dropwise over a period of 30 minutes. The reaction mixture was allowed to stir at ambient temperature over the weekend and then it was concentrated under reduced pressure. The residue was stirred with water (300 mL). The resulting solid was isolated by filtration, rinsed with water, and dried in a vacuum oven at 50° C. for 4 hours to provide 22.53 g of 4-[(3-nitro[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].N1C(C)=CC=CC=1C>CC#N>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)CCNc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 115 °C
Yield: 71.4 %

Procedure:
A neat solution of 8.82 g (30.39 mmol) of 3-(3,4-dichloro-phenylamino)-propionic acid tert-butyl ester, 13.97 ml (151.97 mmol) of methyl bromoacetate and 17.64 ml (151.97 mmol) of 2,6-lutidine was stirred 14 h at 60° C., diluted with 20 ml of CH3CN and heated at 115° C. for 6 h. The reaction was then partitioned between aq. 10% KHSO4 solution and EtOAc (3×). The organic phases were washed with aq. 10% NaCl solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 95:5 to 9:1) to yield 7.86 g (71%) of the title compound as an yellow oil. MS: 362.0 (MH+, 2Cl).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.I[CH:18]([CH3:22])[CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:22][O:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Reactant: CC(I)CCCl
Product: CCCCCCCCC1(C)SC(=O)C=C1OCCCCCl
Yield: 76.8 %

Procedure:
From 32 (47 mg, 0.18 mmol) and 3-iodo-1-chlorobutane (40 μL, 0.36 mmol) following general procedure H was obtained 41 (46 mg, 85%) after flash chromatography (20% EtOAc/Hexanes). 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J=7 Hz, 3H), 1.07-1.27 (m, 1H), 1.24 (s, 10H) 1.48-1.51 (m, 1H), 1.62 (s, 3H), 1.75-1.82 (m, 2H), 1.89-1.98 (m, 4H), 3.59 (t, J=5.9 Hz, 2H), 3.95-3.98 (m, 2H), 5.28 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 25.1, 26.0, 26.5, 29.0, 29.2, 29.3, 29.5, 29.7, 31.8, 44.1, 59.6, 71.7, 101.6, 186.1, 193.8. Analysis Calculated for C17H29C2S: C, 61.3; H, 8.78, Found: C, 61.9; H, 9.01.
Reaction SMILES: [CH2:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.C=CCCCC>C1(C)C=CC=CC=1>[CH3:10][C:9](=[O:11])[CH2:8][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C=CCCCC
Product: CCCCCCC(C)=O

Procedure:
Under the same reaction procedure and conditions as in Example 2 (2-amino-3-pycoline 20 mol %, 150° C., 48 hours), benzyl acetone 32 mg (0.22 mmol) and 1-hexene 182 mg (2.16 were reacted in toluene 100 mg in the presence of various metal catalysts (10 mol % based on benzyl acetone). A measurement was made of the yields of 2-octanone and the results are given in Table 7, below.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:14][NH2:15].O>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:15][CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a chilled (0° C.) stirred solution of 4-(bromomethyl)-benzenesulfonylchloride (3.0 g, 11 mmol) in DCM (100 mL) was added methylamine hydrochloride (1.2 g, 12 mmol). After 30 minutes, water (100 mL) was added. The organic layer was separated, washed with brine (30 mL), and dried over sodium sulfate and concentrated in vauco to afford 4-bromomethyl-N-methyl-benzenesulfonamide.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16]Br)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCc1sc2c(c1CCBr)CCN(C(C)=O)C2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: CCc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C(C)=O)C2
Yield: 62 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.5 g of 6-acetyl-3-(2-bromoethyl)-2-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 2.2 g of 6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 191°-201° C. as oxalate 1/2hydrate thereof.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1(C)C=CC=CC=1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH2:23][CH2:24][CH:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCCCC1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCC1CC=C(c2ccc(Br)cc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
236 Grams (1 mol) of p-dibromobenzene and 1 l of dry toluene were introduced into a three-neck flask in dry nitrogen atmosphere to carry out dissolution with stirring at 50° C. To the resulting solution was dropwise added 525 ml of a hexane solution of 1.67 N commercial n-butyllithium (0.88 mol), over 30 minutes. After dropping, the temperature was maintained at 50° C. further for 30 minutes, and then lowered down to 25° C. To this solution was dropwise added a solution obtained by dissolving 135 g (0.8 mol) of 4-n-pentylcyclohexanone in 125 ml of toluene, over 30 minutes, followed by continuing stirring for 30 minutes at 30° C., and then 250 ml of 6 N hydrochloric acid was added dropwise while maintaining the temperature at 30° C. or lower (the first step). The resulting organic layer was separated, 25 g of potassium hydrogen sulfate was added thereto, and after hexane was distilled off with stirring, the resulting residue was concentrated until the liquid temperature reached 110° C. to complete the dehydration reaction (the second step). The resulting concentrate was distilled under a reduced pressure to take a fraction of 160°~170° C./1 mm Hg, whereby there was obtained 160 g of 1-(p-bromophenyl)-4-n-pentylcyclohexene (R=n-C5H11 and n=1 in said formula (B)) (yield: 62.4%), which was then twice recrystallized from ethanol to give a crystal having a melting point of 67°~68° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)nc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nccc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.06 mmol, Step-1, single enantiomer) and propionyl chloride (8 mg, 0.09 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4](Cl)[N:3]=1.[C:20]1([CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]3[NH:32][CH:33]=[N:34][C:30]=3[CH:29]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC1C=CC=CC=1)C1C=CC=CC=1.N1C2C=CC=CC=2NC=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([N:34]2[C:30]3[CH:29]=[C:28]([O:27][CH2:26][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:36]=[CH:35][C:31]=3[N:32]=[CH:33]2)[N:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Reactant: c1ccc(COc2ccc3[nH]cnc3c2)cc1
Agent: c1ccc2[nH]cnc2c1
Solvent: CCCCO
Solvent: c1ccc(COCc2ccccc2)cc1
Product: C[Si](C)(C)CCOCn1cnc2c(-n3cnc4ccc(OCc5ccccc5)cc43)nc(Cl)nc21
Temperature: 120 °C
Yield: 48.8 %

Procedure:
860 mg of product obtained in stage 1 above are mixed with 605 mg of 5-(phenylmethoxy)-1H-benzimidazole (benzyl ether in the 5-position of benzimidazole) and 15 ml of butanol. The mixture is heated at 120° C. for 24 hours. Partial drying, washing with H2O and then drying under vacuum at 50° C. are carried out. 667 mg of 2-chloro-6-[6-(phenylmethoxy)-1H-benzimidazol-1-yl]-9-[[2-(trimethylsilyl)ethoxy]methyl]-9H-purine are obtained, in the form of beige-colored crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](O)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[N:35]1([CH:41]([CH3:44])[CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[N:35]1([CH:41]([CH3:44])[CH2:42][NH:43][C:13]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[O:4][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([CH3:1])[C:11]3=[O:12])=[O:14])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Reactant: CC(CN)N1CCCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCC(C)N3CCCCC3)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 4.00 g of 3-methylflavone-8-carboxylic acid and 1.98 ml of triethylamine in 74 ml of anhydrous tetrahydrofuran was added a solution of 1.50 ml of ethyl chlorocarbonate in 15 ml of anhydrous tetrahydrofuran under ice-cooling and the mixture was stirred for 1 hour. To the mixture, a solution of 2.03 g of 2-piperidinopropylamine in 20 ml of anhydrous tetrahydrofuran was added and the mixture was stirred for 1.5 hours under ice-cooling and further at room temperature for 16 hours. The reaction mixture was treated by the same procedure as in Examples 3(b) to give 4.15 g of colorless crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 106.5°-108.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12](I)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1([CH3:34])[C:31]([CH3:33])([CH3:32])[O:30][BH:29][O:28]1>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([B:29]2[O:30][C:31]([CH3:33])([CH3:32])[C:27]([CH3:34])([CH3:26])[O:28]2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1ccc(COCC(=O)OC(C)(C)C)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(COCC(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1

Procedure:
The procedure used in Example 3: step b was followed using (3-iodo-4-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 300: step a) 600 mg, 1.65 mmol), PdCl2(PPh3)2 (58 mg, 0.08 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography yielded the title compound contaminated with the product resulting from halide reduction (569 mg, 95%). The material was used without further purification. 1H-NMR (CDCl3): δ 7.73 (d, 1H, J=1.9 Hz), 7.38 (dd, 1H, J=2.1, 7.9 Hz), 7.18 (d, 1H, J=7.9 Hz), 4.61 (s, 2H), 3.97 (s, 2H), 2.55 (s, 3H), 1.50 (s, 9H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:4].Br[CH2:19][C:20]1[O:21][C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1>C1COCC1.[NH4+].[Cl-].CCOCC>[C:25]1([C:23]2[N:24]=[C:20]([CH2:19][N:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]3[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=3)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:21][C:22]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)COc1cccc(NC(=O)OC)c1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(N(Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
NaH (0.34 g of a 50% dispersion in mineral oil, 3.5 mmol) was washed twice with hexanes and covered with dry THF (10 mL). A solution of methyl [3-[(methoxycarbonyl)amino]phenoxy]acetate (0.75 g, 3 mmol) in dry THF (10 mL) was added and the mixture stirred at room temperature. After about 30 minutes, a solution of 2-bromomethyl-4,5-diphenyl-oxazole (0.99 g, 3 mmol) in THF (7 mL) was added and the mixture stirred overnight at room temperature. The mixture was diluted with saturated NH4Cl solution and Et2O, the organic phase separated, washed with H2O and saturated NaCl solution and dried over MgSO4. The solvent was evaporated and the residue chromatographed on a column of silica gel using a mixture of hexanes and EtOAc (4:1) as eluent to give methyl [3-[[(4,5-diphenyl-2-oxazolyl)methyl](methoxycarbonyl) amino]phenoxy]acetate (0.71 g, 48%). IR (film) 1760, (CO2CH3), 1715 (NCO2CH3) cm-1 ; 1H NMR (CDCl3) δ3.73 (6H, s, CO2CH3), 4.58 (2H, s, OCH2CO2CH3), 4.99 (2H, s, CH2 -oxazole), 6.79 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 7.02 (2H, m, aromatic H), 7.20 to 7.45 (7H, m, aromatic H), 7.50 to 7.65 (4H, m, aromatic H); MS m/z 473 (MH+).
Reaction SMILES: [C:1]1([NH:11][C:12]([CH2:14][C:15]([O:17]CC)=O)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:20][OH:21].Cl.NO.[Na]>CO>[C:1]1([NH:11][C:12]([CH2:14][C:15]([NH:20][OH:21])=[O:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)Nc1cccc2ccccc12
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(CC(=O)Nc1cccc2ccccc12)NO

Procedure:
19.3 g (0.075 mol) of ethyl α-naphthylcarbamoylacetate are treated with a solution of hydroxylamine, prepared from 5.6 g (0.08 mol) of hydroxylamine hydrochloride and 3.68 g of sodium in 250 ml of methanol. After leaving the reactants in contact for 5 hours, the mixture is evaporated to dryness in vacuo, the residue is taken up in 400 ml of cold water, the solution is filtered over charcoal, and the product is precipitated cold with 3N HCl, filtered off and washed with water. CRL 40,518 is obtained by recrystallisation from ethanol.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:31]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)C4CCCCC4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of cyclohexanesulfonyl chloride (0.161 g, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then re-cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was then stirred at RT for 45 min before the addition of cyclohexanesulfonyl chloride (0.064 g, 0.352 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL) and the combined organic extracts dried over a phase separating column and concentrated. The residue was then purified by MDAP (basic conditions), to afford the title compound (22 mg). LCMS (A) m/z: 431 [M+1]+, Rt 1.16 min (basic).