Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[CH2:19][OH:20])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1>C1COCC1>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([O:20][CH2:19][C:9]2[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][O:12][C:8]=2[C:7]([CH3:22])([CH3:21])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:27][CH:28]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(C)(C)O[SiH2]C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
A solution of [5-(tert-butyl-dimethyl-silanyloxymethyl)-3-phenyl-isoxazol-4-yl]-methanol (4.09 g, 12.8 mmol) in THF (20 mL) was added dropwise to a suspension of sodium hydride (0.73 g of a 55% dispersion in mineral oil, 16.7 mmol). After stirring for 30 min at room temperature, the mixture was cooled in an ice bath and a solution of methyl 6-chloronicotinate (2.20 g, 12.8 mmol) in THF (20 mL) was added dropwise. The ice bath was removed and the reaction mixture was allowed to reach room temperature and was stirred for 2 h. After quenching with water and extractive workup (ethyl acetate/water) the organic phase was dried over sodium sulfate, filtered and concentrated. Chromatographic purification (silica, heptane:ethyl acetate=100:0 to 8:2) afforded the title compound as a colorless oil (2.76 g, 47%). MS: m/e=455.4 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[N:3][C:2]1=[S:6].[H-].[Na+].[N:9]12[CH2:12][CH:11]1[CH2:10]2>O1CCCC1>[NH:9]1[CH2:12][CH:11]([S:6][CH:2]2[NH:3][CH2:4][CH2:5][S:1]2)[CH2:10]1
Reactant: S=C1N=CCS1
Reactant: C1C2CN12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1CSC(SC2CNC2)N1
Reaction time: 1 h

Procedure:
To a 5 ml solution of dried tetrahydrofuran containing 550 mg (4.61 mmol) of 1,3-thiazoline-2-thione which was being cooled with ice, on the other hand, there was added 181 mg (55%) of sodium hydride, and the resulting mixture was stirred for one hour. To the obtained solution, there was added dropwise the above solution of 1-azabicyclo[1.1.0]butane dissolved in tetrahydrofuran at -78° C., and the resulting solution was stirred at a room temperature for 20 hours, and, then, the reaction liquid was subjected to high performance liquid chromatography, and, thus, there was obtained 2-(azetidin-3-ylthio)-1,3-thiazolidine (9).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CCl)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2′-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (203 mg, 0.64 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (761 mg, 6.40 mmol) and the resulting mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted further with CH2Cl2 (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=336 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:31])=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
The above prepared 4-[(6-tert-butoxycarbonylamino-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.720 g, 1.71 mmol) was dissolved in 30 ml of abs. THF and treated at 0° C. with sodium hexamethyldisilazide-solution (1M in THF, 1.05 eq.) and, after 15 Min., 50 eq. of methyl iodide (5.33 ml). The mixture was allowed to react for six days! Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=55/45) yielded eventually 0.497 g of the title compound as white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.O[CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)n2cc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-bromo-1H-pyrazole (200 mg, 1.36 mmol), methyl 4-(1-hydroxyethyl)benzoate (490 mg, 2.72 mmol), and triphenylphosphine (resin bound: 3 mmol/g loading, 907 mg, 2.72 mmol) in THF (5 mL) was stirred for 5 minutes at ambient temperature. Di-tert-butyl azodicarboxylate (627 mg, 2.72 mmol) was added and the reaction mixture was stirred for 24 hours at ambient temperature. The reaction mixture was filtered, and the filtrate was diluted with dichloromethane (25 mL) and TFA (6 mL) and stirred for 30 minutes. The mixture was concentrated under reduced pressure and then diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was separated, washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% diethyl ether/hexanes) to afford methyl 4-(1-(4-bromo-1H-pyrazol-1-yl)ethyl)benzoate. MS ESI calc'd. for C13H14BrN2O2 [M+H]+ 309 and 311. found 309 and 311. 1H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.90 (dd, J=6.5 Hz, 1.5 Hz, 2H), 7.58 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 5.72-5.65 (m, 1H), 3.82 (s, 3H), 1.78 (d, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]([F:8])[F:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Reaction time: 2 h
Yield: 18.9 %

Procedure:
2-(2,2-difluoroethoxy)ethanol (0.13 g, 1.0 mmol), p-toluenesulfonyl chloride (0.19 g, 1.0 mmol), and DMAP (0.12 g, 1.0 mmol) were dissolved in dichloromethane (2 ml) at 0° C. and stirred for 2 h at this temperature. The reaction mixture was loaded onto a small column, which was eluted with dichloromethane to yield the title compound as a clear oil (53 mg, 19%). It was observed that the size of the column affects reaction yield, with a smaller column giving a better yield. 1H NMR (CDCl3, 300 MHz): δ 7.78 (d, 2H, J=11.2 Hz), 7.34 (d, 2H, J=11.2 Hz), 5.76 (tt, 1H, J1=5.6 Hz, J2=73.6 Hz), 4.17 (t, 2H, J=6.0 Hz), 3.75 (t, 2H, J=6.0 Hz), 3.64 (td, 2H, J1=6.0 Hz, J2=20 Hz), 2.45 (br s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16].[C:17](Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1C=CC=CC=1>CCCCCC>[C:17]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[CH:15][S:14][CH:13]=[C:5]12)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)Cl
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCCCCC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 7 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.6 g. (4.8 ml.) of hexanoyl chloride in 70 ml. of benzene is heated with stirring under reflux for 3 hours. The reaction mixture is stirred with cooling in an ice bath for 2 hours, 150 ml. of hexane is added and the mixture is placed in a chill room. The solvents are removed in vacuo on a steam bath. A 10 ml. portion of ether is added to the residue and the mixture is returned to the chill room. The tan crystals are collected by filtration, washed with ether and dried. The ether is concentrated giving a green oil which is triturated twice with hexane and once with a mixture of hexane and ether, giving crystals which are collected, washed with ether and dried. The two crops of crystals are combined, dissolved with warming in 75 ml. of ether and filtered. The filtrate is concentrated to 35 ml. and stored in a cold room for 4 hours. The solid is collected, washed with ether then hexane and dried, giving the desired product, mp. 76°-77° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21].N1C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 8-(tert-butoxycarbonylamino)-2-naphthol, as described in Example 9, Step A, (8.00 g, 30.9 mmol), triisopropylsilyl chloride (7.92 mL, 37.0 mmol), and imidazole (4.20 g, 61.7 mmol) in DMF (75 mL) was stirred at ambient temperature for 18 hours, then poured into 10% aqueous citric acid (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—50% hexane to yield the desired product.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[O:30]1[CH2:34][CH2:33][CH2:32][NH:31]1>>[O:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:19]([C:14]1[N:15]([CH3:18])[N:16]=[CH:17][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[N:25][CH:24]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1)=[O:11])=[O:21]
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: C1CNOC1
Agent: Cl
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)N1CCCO1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 131 μmol; example 236, step 3) and isoxazolidine hydrochloride (17 mg, 145 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (9 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[F:21][C:22]([F:27])([F:26])[CH2:23][CH2:24]I>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:24][CH2:23][C:22]([F:27])([F:26])[F:21])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: FC(F)(F)CCI
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(CCC(F)(F)F)c3c(Cl)cccc23)cc1
Yield: 5.6 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.108 g, 0.4 mmol), sodium hydride (60% in oil, 0.016 g, 0.4 mmol) and 3,3,3-trifluoropropyliodide (0.047 mL, 0.4 mmol) to give the title compound (0.008 g).
Reaction SMILES: B.O1CCCC1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](O)=[O:14])([O-:9])=[O:8]>O1CCCC1>[N+:7]([C:10]1[CH:11]=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])([O-:9])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 800 mL, 800 mmol) was added at −20° C. over 45 min to a solution of 3,4-dinitrobenzoic acid (93.5 g, 441 mmol) in tetrahydrofuran (300 mL). The resulting mixture was stirred at −20° C. for 1 h and then warmed to room temperature and stirred overnight. It was quenched by the addition of 32 mL of 1:1 acetic acid/water. Solvents were removed in vacuo and the residue was poured into an ice-cold 1000 mL of sat. sodium bicarbonate with vigorous stirring over 15 min. The mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with sat. sodium bicarbonate, brine and dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a light yellow solid (100%). 1H-NMR (CDCl3, 500 MHz) δ 7.91 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.71 (dd, J=8.5, 1.0 Hz, 1H), 4.87 (s, 2H), 2.30 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[C:5]([NH2:15])[NH:4][N:3]=1.[C:16]1([C:22](=O)[CH2:23][C:24](OCC)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][C:24](=[O:25])[NH:15][C:5]=23)=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1ccc(-c2c(C)n[nH]c2N)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2c(C)nn3c(-c4ccccc4)cc(=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
3-Methyl-4-(4-methoxyphenyl)-1H-pyrazol-5-amine (200 mg) and ethyl 3-phenyl-3-oxopropanoate (227 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and 270 mg of the target compound is yielded by column chromatography.
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].C[Si]([C:18]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19]1)(C)C.O>O1CCCC1>[CH3:3][Si:2]([CH2:3][Si:2]([CH:21]1[CH:20]=[CH:19][CH:18]=[CH:22]1)([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:4])([CH3:5])[CH3:4]
Reactant: [Li]C1([Si](C)(C)C)C=CC=C1
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C[Si](C)(C1=Cc2ccccc2C1)C1C=CC=C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 54.6 %

Procedure:
Chloro-2-indenyldimethylsilane (5.15 g, 0.025 mol.) according to Example 1 was dissolved in 10 ml of tetrahydrofuran. The solution was cooled to 0° C. and a solution of trimethylsilylcyclopentadienyllithium (3.60 g, 0.025 mol.) in 20 ml of tetrahydrofuran was added. Stirring was carried out for 15 hours at 25° C. 50 ml of water were then added, and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the yellowish oil that remained was purified by means of column chromatography. The solvents were removed to yield 2.12 g (34%) of trimethylsilylcyclopentadienyl-2-indenyl-dimethylsilane in the form of a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[N:18]=1
Reactant: CCc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(-c2nc(Cl)c3ccccc3n2)cc1

Procedure:
A mixture of 7.43 g of 2-(4-ethylphenyl)quinazolin-4(3H)-one and 50 ml of thionyl chloride was treated with 2.17 g of dimethylformamide as described in Example I. The solid was recrystallized twice from petroleum ether (60°-110° fraction) to give 4.23 g of light-colored 4-chloro-2-(4-ethylphenyl)quinazoline, m.p. 75.5°-76.5°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(O)C.[CH2:15]([NH:17]CC)C.[CH3:20][CH2:21][CH2:22][CH2:23]CC.C(O)C>>[CH:8]1([N:3]2[CH2:4][CH2:5][CH2:15][NH:17][CH2:2][CH2:1]2)[C:7]2[C:20](=[CH:21][CH:22]=[CH:23][CH:6]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CCNCC
Reactant: CCCCCC
Solvent: CCO
Product: c1ccc2c(c1)CCCC2N1CCCNCC1

Procedure:
R(−) N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine was obtained as the second material to elute on subjecting racemic material (5.3 g), prepared as in Example 2, to preparative Chiral Pak AD HPLC resolution using a hexane/ethanol mixture with modification with diethylamine. The enantiomeric purity was determined on an analytical scale using hexane:ethanol:diethylamine (90:5:.05, v/v) and detection at 220 nm. The solution containing this enantiomer was concentrated using a rotary evaporator to give the title compound (2.65 g), [α]D22−94° (c=0.64, methanol); 98.5% ee.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH2:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH2:20][C:21]2[C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=2)[CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3c(c2)CCNC3)cc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3c(c2)CCN(Cc2c[nH]c4ncccc24)C3)cc1
Yield: 17 %

Procedure:
A mixture of 6-phenyl-1,2,3,4-tetrahydroisoquinoline (prepared by the method of L. N. Pridgen, J. Heterocyclic Chem. 1980, 17, 1289) (0.5 g, 2.38 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.4 g, 2.28 mmol) in toluene (5 ml) was heated at reflux under nitrogen for 18 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from ethyl acetate afforded the title compound (0.13 g, 17%), m.p. 211°-213° C.; (Found: C, 80.15; H, 6.30; N, 12.32. C23H21N3.0.3H2O requires C, 80.11; H, 6.31; N, 12.18%); δH (DMSO-d6) 2.73 (2H, br s, CH2CH2Ph), 2.87 (2H, br s, NCH2CH2), 3.61 (2H, s, ArCH2N), 3.83 (2H, s, NCH2Ph), 7.02 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.18 (1H, d, J 3.2 Hz, 2-H), 7.30-7.45 (6H, m, ArH), 7.60 (2H, d, J 7.6 Hz, ArH), 8.05 (1H, d, J 7.6 Hz, 4-H), 8.20 (1H, dd, J 6.1, 1.4 Hz, 6-H), and 11.48 (1H, br s, NH); m/z (CI+, NH3) 340 (M+1)+.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>O.C(O)(=O)C>[N:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:2]([NH2:3])=[O:1])=[CH:11][CH:10]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: N#C[O-]
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A solution of sodium cyanate (0.26 g) in water (30 ml) was added over 10 minutes to a stirred solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.50 g) in a mixture of acetic acid (20 ml) and water (30 ml). The solution was stirred for 2 hours, allowed to stand for 18 hours and then evaporated. The residue was triturated with water and filtered. The solid was crystallised from N,N-dimethylformamide to give the title compound (0.27 g), m.p. above 250° C. Found: C,64.17; H,6.42; N,23.32. C16H19N5O requires: C,64.62; H,6.44; N,23.55%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11](=O)[CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:4][C:3]=1[CH:19]([CH3:21])[CH3:20].[H][H].[OH-].[K+]>C(O)C.[Pd]>[OH:1][C:2]1[C:3]([CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)CCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(CCCC(=O)O)cc(C(C)C)c1O
Yield: 91.7 %

Procedure:
Keto-ester 6 (1.0 g, 3.4 mmol) was dissolved in ethanol (50 mL) and palladium catalyst on charcoal (10%, 50 mg) was added. Hydrogenation was performed with 45 psi of hydrogen gas for 20 h. The catalyst was then filtered off and potassium hydroxide (909 mg, 16.2 mmol) was added, and the reaction mixture was refluxed for 1 h. The solvents were evaporated, and aqueous HCl (50 mL, 4.0 M) was added. The acidic aqueous phase was extracted with methylene chloride (3×30 mL), the combined organic extracts were dried over anhydrous magnesium sulfate and evaporated, giving 8 as white crystals (824 mg, 91%). 1H NMR (300 MHz, CDCl3): δ 6.89 (s, 2H), 3.18 (septet, J=6.9 Hz, 2H), 2.64 (t, J=7.7 Hz, 2H), 2.43 (t, J=7.4 Hz, 2H), 1.98 (q, J=7.7 Hz, 2H), 1.29 (d, J=6.9 Hz, 12H). 13C NMR (90.55 MHz, CDCl3): δ 180.51, 149.56, 134.07, 133.52, 123.83, 35.28, 33.98, 27.60, 27.09, 23.21. HRMS (m/z): [M+H]+ calcd. for C16H24O3 263.1653. found 263.1664.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=1[CH:12]=O>CO>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[CH:12][C:11]2[C:10]([F:9])=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1c(F)cccc1F
Solvent: CO
Product: Fc1cccc(F)c1C=Nc1ccc(Cl)cc1

Procedure:
A mixture of 4-chloroaniline (1.84 g, 14.1 mmol) and 2,6-difluorobenzaldehyde 115 (1.55 mL, 14.1 mmol) in methanol (MeOH, 30 mL) was allowed to react for 18 hours at room temperature. The mixture was evaporated giving 4-chloro-N-(2,6-difluorobenzylidene)aniline 116 as a yellow solid.