Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.CN(C=O)C.Br[CH2:33][CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Cl:36][CH2:35][CH2:34][CH2:33][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([C:15]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=34)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: ClCCCBr
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-ol in a solution of DMF and MeOH is treated with 1-bromo-3-chloropropane (3 equiv) and cesium carbonate (2 equiv). The reaction is heated to 60° C. and stirred overnight. The reaction is then purified on silica gel column (see Prep. 77) chromatography to afford the desired product.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I>CN(C=O)C>[Cl:14][CH2:15][CH2:16][CH2:17][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCc2ccccc2N1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1CCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A 50 mL flask was charged with 3,4-dihydro-1H-quinolin-2-one (2.00 g, 13.6 mmol) and sodium hydride (60% in oil, 0.712 g, 16.3 mmol) in DMF (50 mL, dry) and stirred at 0° C. for 1 h, followed by addition of 1-chloro-3-iodo-propane (2.77 g, 13.6 mmol) and stirring at rt for 20 h. The reaction mixture was quenched with water (10 mL), and the product was extracted into EtOEt (3×25 mL). The combined organic layers were dried (Na2SO4), evaporated and purified by flash CC (SiO2; EtOAc/heptane 1:4) to give the crude title compound (85LM31) (2.25 g). 1H NMR (CDCl3) δ 7.29-7.22 (m, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.08-6.98 (m, 2H), 4.10 (t, J=7.3 Hz, CH2), 3.62 (t, J=5.9 Hz, CH2), 2.88 (t, J=7.3 Hz, CH2), 2.63 (t, J=7.3 Hz, CH2), 2.19-2.10 (m, 2H); 13C NMR (CDCl3) δ 170.5, 140.0, 128.2, 127.8, 126.3, 123.2, 115.0, 43.3, 40.2, 32.2, 30.5, 26.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:28])[N:12]=2)[CH3:10])[C:3]=1I.[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:28])[N:12]=2)[CH3:10])[C:3]=1[C:37]#[C:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](Nc1ncnc(N)c1I)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[C@H](Nc1ncnc(N)c1C#Cc1ccccc1)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (58 mg, 0.11 mmol) (prepared according to the procedure in Example 5A) in THF (5 mL) was added Pd(PPh3)2Cl2 (2 mg, 2.5%), CuI (1 mg, 5%), TEA (0.1 mL, 0.16 mmol), and phenylacetylene (20 mg 0.16 mmol). After stirring at 70° C. for 2 hours, the solvent was stripped. The residue was purified on silica with 0 to 10% MeOH in DCM to give material that required further purification. Purification on silica with 0 to 100% EtOAc in hexanes gave (S)-2-(1-(6-amino-5-(phenylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one. 1H NMR (400 MHz, DMSO-D6) δ7.88 (s, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.88 (dt, J=6.8, 1.6 Hz, 2H), 7.59-7.41 (m, 10H), 6.92 (d, J=7.0 Hz, 1H), 6.75 (bs, 2H), 4.73 (p, J=6.8 Hz, 1H), 1.35 (d, J=6.7 Hz, 3H). ES/MS m/z=493.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1Br.C([Mg]Cl)(C)C.CN([CH:19]=[O:20])C.Cl>CCCCCCC.CCOCC.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:19]=[O:20]
Reactant: Fc1cc(Cl)cc(Br)c1Br
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Cl)cc1Br
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
To a solution of 1,2-dibromo-5-chloro-3-fluoro-benzene (10 g, 34.68 mmol) in heptane (27 ml) was added THF (44 ml) and the mixture was cooled to −45° C. Then iPrMgCl (38.14 ml, 38.14 mmol, 1M solution in THF) was added dropwise to the reaction mixture maintaining the temperature between −40° C. to −45° C. The mixture was stirred for 30 minutes at −40° C. before DMF (13.4 ml, 173.4 mmol) was added dropwise to the reaction mixture maintaining the temperature between −45° C. to −20° C. After stirring for another 15 minutes at −20° C., the reaction mixture was poured into a mixture of 2N HCl (20 ml) and ether (50 ml) at 0° C. The organic layer was separated and the aqueous layer was extracted two times with ether. The combined organic layers were dried with Na2SO4 and evaporated in vacuo to obtain the title compound as yellow solid (7.8 g, 95%).
Reaction SMILES: [P:1]([O:13]C[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].P(O[CH2:42][C@H:43]1[O:47][C@@H:46]([N:48]2[C:58]3[N:57]=[C:55]([NH2:56])[NH:54][C:52](=O)[C:51]=3[N:50]=[CH:49]2)[CH2:45][C@@H:44]1[OH:59])(OP(OP(O)(O)=O)(O)=O)(=O)O.OP(=O)(OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)OP(=O)(OP(=O)(O)O)O>>[CH:55]1[N:57]=[C:58]2[N:48]([C@@H:46]3[O:47][C@H:43]([CH2:42][O:12][P:9]([O:8][P:5]([O:4][P:1]([OH:13])([OH:3])=[O:2])([OH:7])=[O:6])([OH:11])=[O:10])[C@@H:44]([OH:59])[CH2:45]3)[CH:49]=[N:50][C:51]2=[C:52]([NH2:54])[N:56]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1

Procedure:
dCTP, dGTP, dTTP
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:16]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:30]1[CH:50]=[N:49][C:33]2[NH:34][C:35](=[O:48])[CH2:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:38][C:32]=2[CH:31]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]1[C:16]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]([CH3:12])[C:8](=[O:11])/[CH:9]=[CH:10]/[C:30]1[CH:50]=[N:49][C:33]2[NH:34][C:35](=[O:48])[CH2:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:38][C:32]=2[CH:31]=1)[CH3:2]
Reactant: C=CC(=O)N(C)Cc1cccc(C(C)C)c1OCC
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(Cc2ccc(OC)cc2)CC(=O)N3)cccc1C(C)C
Yield: 44.5 %

Procedure:
A solution of N-(2-ethoxy-3-isopropylbenzyl)-N-methylacrylamide (0.281 g, 1.07 mmol) in propionitrile (4 mL) and DMF (0.8 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.30 mL, 1.73 mmol) and 7-bromo-4-(4-methoxy-benzyl)-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 0.828 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.018 g, 0.082 mmol) and P(o-tol)3 (0.050 g, 0.16 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 1.5 h, then allowed to cool. The mixture was diluted with H2O (100 mL) and then was washed with EtOAc (3×50 mL). The organic layer was washed with brine (2×100 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, CH2Cl2 to CH2Cl2/MeOH, 100 to 99.5:0.5) gave the title compound (0.20 g, 44%) as a light yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.43-10.41 (m, 1H), 8.55-8.49 (m, 1H), 8.10-8.01 (m, 1H), 7.55-7.50 (m, 1H), 7.35-7.17 (m, 4H), 7.12-7.04 (m, 1H), 6.91-6.85 (m, 3H), 4.80-4.66 (m, 2H), 3.83-3.70 (m, 7H), 3.65-3.62 (m, 2H), 3.41-3.38 (m, 2H), 3.29-3.90 (m, 1H), 2.56-2.51 (m, 3H), 1.39-1.37 (m, 3H), 1.25-1.11 (m, 6H); MS (ESI) m/e 543 (M+H)+.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][CH2:8]C(Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N-:12]=[N+]=[N-].[Na+].C[C:17](C)=[O:18]>O>[CH:2]1([CH2:7][CH2:8][N:12]=[C:17]=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C=NCCC1CCCC1
Reaction time: 1 h

Procedure:
The procedure is an adaptation of procedure in Org. Syn. Col. Vol II, p 846, Col. VI, p 95. A solution of 0.65 g of 3-cyclopentylpropionyl chloride (Example 253) in 10 ml of acetone is added dropwise to a 0° C. solution of 0.46 g of sodium azide in 5 ml of water When the addition is complete, stirring is continued for 1 hour. The mixture is extracted wink toluene, dried over anhydrous sodium sulfate and filtered. The toluene solution is added dropwise to 25 ml of toluene which is heated at reflux temperature. When the addition is complete, the reaction is refluxed until nitrogen evolution has ceased (ca 1 hour). The reaction is cooled and the resulting toluene solution of the corresponding isocyanate is then used a% in Example 124, 119, 99, and all new examples.
Reaction SMILES: [Si](=O)=O.Br[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-:19].[Na+].[Na+].Cl>CC(C)=O.O.N1C=CC=CC=1>[OH:19][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=[Si]=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-[N-(3-triethoxysilyl)propyl]-carbamoyl-2-nitrobenzyl isonicotinate (TCNI) which binds to silicon dioxide through the ethoxysilyl groups, and has a pyridine metal binding group and a nitrobenzyl radiation sensitive group was prepared according to the synthetic procedure represented in Scheme 2. 4-Bromomethyl-3-nitrobenzoic acid (A) was refluxed overnight with sodium carbonate in acetone/water (1:1). After cooling to room temperature, the reaction mixture was made acidic with 1 N hydrochloric acid and the product was extracted into ethyl acetate, dried over magnesium sulfate and rotary evaporated to yield 4-hydroxymethyl-3-nitrobenzoic acid. The 4-hydroxymethyl-3-nitrobenzoic acid (B) was dissolved in pyridine and reacted with isonicotinoyl chloride hydrochloride at room temperature for 2 days. The resultant solution was poured onto ice, stirred overnight at room temperature and extracted with ethyl acetate. The organics were dried over magnesium sulfate and rotary evaporated to remove the solvents. Residual pyridine was removed by the addition of toluene followed by rotary evaporation. The resultant solid was slurried in ethanol at room temperature and the product, 4-carboxy-2-nitrobenzyl isonicotinate, was isolated by filtration and dried under vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH2:30]([O:37][C:38]([NH:40][NH:41][CH3:42])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.O>[CH2:30]([O:37][C:38]([NH:40][N:41]([C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[CH3:42])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CNNC(=O)OCc1ccccc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(=O)N(C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
2.1 g of (tert-butoxycarbonyl-methyl-amino)-acetic acid was dissolved in 150 mL of tetrahydrofuran, and 4.64 mL of triethylamine and 1.51 mL of isobutyl chloroformate were added under stirring at ice-cooling. After stirring at room temperature for 10 minutes, N′-methyl-hydrazine carboxylic acid benzyl ester hydrochloride was added and stirred at room temperature for 50 minutes. The reaction solution was added with water, extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, followed by purification by silica gel column chromatography (ethyl acetate:n-hexane=1:1), to afford 3.2 g of N′-[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-N′-methyl-hydrazine carboxylic acid benzyl ester. Subsequently, by conducting catalytic hydrogen reduction in accordance with Production example 365, 1.9 g of the title compound was obtained.
Reaction SMILES: CO[C:3](=[O:26])[CH2:4][NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O.[NH2:28][NH2:29]>CO>[C:18]([O:17][C:15]([NH:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH2:4][C:3]([NH:28][NH2:29])=[O:26])=[O:25])[CH3:24])=[O:23])=[O:22])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: NN
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)NN
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cooled (ice bath), stirred solution of Boc-Gly-Gly-Ala-Gly-OMe (2.5 g, 6.7 mmoles, described in Example 4) in methanol (50 ml) is added hydrazine hydrate (2.5 ml). The solution is stirred at 0° C for 3 hr and at room temperature overnight. The precipitate is separated by filtration, washed with methanol and dried to yield the title compound; amino acid analysis: Gly 3, Ala 0.99.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=2)[O:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>CC#N>[OH:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[OH:2])=[CH:12][O:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)c(O)c1
Yield: 49.9 %

Procedure:
Compound 3-(2,4-dimethoxy-phenyl)-7-hydroxy-chromen-4-one (2 gm, 6.7 mmol) was dissolved in CH3CN (25 ml) and AlCl3 (2.6 gm, 20 mmol) was added to the solution at 0° C. The reaction was then refluxed for 10 hours. The mixture was cooled and then poured ice-cooled water. The precipitated solid were filtered, washed with water and purified by silica gel column chromatography using chloroform-methanol as the eluent to give 7-hydroxy-3-(2-hydroxy-4-methoxy-phenyl)-chromen-4-one (0.95 gm, 50%) as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:8]=1.Cl.Cl.N1C2C(=NC=CC=2OC2C=CC(N[C:43]([NH:45][C:46](=[O:56])[CH2:47][C:48]3[C:53](Cl)=[CH:52][CH:51]=[CH:50][C:49]=3Cl)=[S:44])=CC=2F)C=C1.ClC1C=CC=C(Cl)C=1CC(N=C=S)=O.[N-]=C=S>>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:43]([NH:45][C:46](=[O:56])[CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[S:44])=[CH:19][CH:18]=2)[CH:8]=1
Reactant: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reactant: Cn1ccnc1-c1cc2nccc(Nc3ccc(N)cc3)c2s1
Agent: Cl
Agent: O=C(Cc1c(Cl)cccc1Cl)N=C=S
Agent: [N-]=C=S
Product: Cn1ccnc1-c1cc2nccc(Nc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)c2s1
Yield: 12 %

Procedure:
Starting from the compound 301, following the procedures described above for the synthesis of compound 269b (scheme 61, example 222) but replacing 2-(2,6-dichlorophenyl)acetyl isothiocyanate with 2-phenylacethyl isothiocyanate, title compound 302 was obtained in 12% yield, as a yellow solid. 1H NMR (d-DMSO) δ (ppm): 12.47(s, 1H), 11.76(s, 1H), 10.83(s, 1H), 8.41(d, 1H, J=6.9 Hz), 7.84(s, 1H), 7.80(s, 1H), 7.78(s, 1H), 7.55(s, 1H), 7.46(s, 1H), 7.43(s, 1H), 7.32(m, 4H), 7.28-7.20(m, 1H), 7.20(s, 1H), 6.94(d, 1H, J=6.8 Hz), 3.98(s, 3H), 3.81(s, 2H). MS (m/z): 499.1(M+H) (found).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:23][CH2:24][CH2:25][Cl:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(F)c(Cl)c2)C1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(CCCCl)c2ccc(F)c(Cl)c2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 9.5 mmol), 1-bromo-3-chloropropane (4.7 ml, 48 mmol) and potassium carbonate (1.97 g, 14.3 mmol) were suspended in N-methylpyrrolidone (NMP, 15 ml), followed by stirring at 100° C. for 8 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. After drying the organic layer over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), and the purified product was concentrated under reduced pressure to thereby obtain 1.0 g of oily colorless 3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: O.[CH3:2][O:3][C:4]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1)=[O:5].[CH2:12](O)[CH2:13][OH:14].C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[CH3:2][O:3][C:4]([CH:6]1[CH2:7][CH2:8][CH2:9][C:10]21[O:14][CH2:13][CH2:12][O:11]2)=[O:5]
Reactant: OCCO
Reactant: COC(=O)C1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)C1CCCC12OCCO2
Yield: 70.3 %

Procedure:
A reflux condenser equipped with a Dean-Stark water separator was attached to a round bottom flask containing methyl 2-cyclopentanonecarboxylate (2 ml, 16.2 mmol), ethylene glycol (994 μl, 17.8 mmol), p-toluenesulfonic acid monohydrate (139 mg, 0.73 mmol), and benzene (30 ml). The mixture was heated under reflux for 2 hours. To the reaction mixture, triethylamine (0.22 ml) was added and the mixture was concentrated and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane=1/9, 1/1) to obtain the title compound (2.12 g, yield 70.3%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH3:19])[C:14]=1[OH:15])[CH:10]=O)([CH3:6])[CH2:3][CH2:4][CH3:5].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23]C(O)=O.N1CCCCC1.Cl>O.N1C=CC=CC=1>[CH3:20][C:16]([C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][CH3:5])[C:14]=1[OH:15])[CH:10]=[CH:23][C:22]([O:28][CH2:29][CH3:30])=[O:27])([CH3:21])[CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)CC(=O)O
Reactant: CCCC(C)(C)c1cc(C=O)cc(C(C)(C)CCC)c1O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCCC(C)(C)c1cc(C=CC(=O)OCC)cc(C(C)(C)CCC)c1O

Procedure:
Ethyl 3,5-bis(1,1-dimethylbutyl)-4-hydroxycinnamate was prepared by heating a mixture of 29 grams of 3,5-bis(1,1-dimethylbutyl)-4-hydroxybenzaldehyde, 40 grams of ethyl hydrogen malonate, 50 milliliters pyridine and 3 milliliters of piperidine at 90° to 95° C. for 7 hours. The reaction mixture was poured into a solution of 50 milliliters of concentrated hydrochloric acid in 100 milliliters of water. The oil which precipitated was separated by extraction with petroleum ether and the extract was stripped under vacuum to a pot temperature of 50°C./14 mm. The viscous residue weighed 39 grams.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[CH:15]1([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCCl>[CH:15]1([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:8]3[CH2:9][C:10]4[N:4]([CH:3]=[CH:2][CH:1]=4)[CH2:5][C:6]4[N:14]=[CH:13][CH:12]=[CH:11][C:7]3=4)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: c1cnc2c(c1)NCc1cccn1C2
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ncccc21
Yield: 39.4 %

Procedure:
A mixture of the 9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (4.67 mmol), 4-cyclohexylbenzoyl chloride (4.90 mmol) and triethylamine (5.1 mmol) in 1,2-dichloroethane was refluxed for three days under nitrogen. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with a solvent gradient from 5 to 20% of ethyl acetate in hexane to provide the title compound as a tan solid (0.684 g), m.p. 150-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:19][OH:20])[C:8]2[CH:9]([OH:18])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:19][O:20][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)[C:8]2[CH:9]([OH:18])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)c1cc(CO)c2c(c1)-c1ccccc1C2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(COC2CCCCO2)c2c(c1)-c1ccccc1C2O

Procedure:
3-Methoxycarbonyl-1-hydroxymethyl-9-fluorenol (0.96 g) was treated with dihydropyran (0.43 ml) and p-toluenesulfonic acid (20 mg) in CH2Cl2 (20 ml) for 0.5 hour. The reaction mixture was washed once with NaHCO3 (10% soln) then dried and evaporated to give a mixture of products. Chromatography on silica gel using EtOAc/hexane 1:1 as eluant gave the product (403 mg).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8](=[CH:14][NH:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](Cl)[CH:3]=1.C(OCC)(=O)C.CCCCCC>CS(C)=O>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CNCC1CCCO1)C(=O)c1ccc(Br)cc1Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cn(CC2CCCO2)c2cc(Br)ccc2c1=O
Yield: 75.2 %

Procedure:
500 mg of ethyl 2-(4-bromo-2-chloro-benzoyl)-3-[(tetrahydro-furan-2-ylmethyl)-amino]- acrylate and 148 mg of potassium t-butylate are held at 60° in 20 ml of DMSO for 30 mins. After chromatography on silica gel with ethyl acetate/hexane 1:1 343 mg of ethyl 7-bromo-4-oxo-1-(tetrahydro-furan-2-ylmethyl)-1,4-dihydro-quinoline-3-carboxylate are isolated as a yellowish oil. Yield: 75%. Mass spectrum: peaks inter alia at m/e: 380 (M++H, 100%).