Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH:15]=[CH:14]3)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.CCOC(C)=O.[Pd]>[C:20]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)=[O:8])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1C=Cc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CCc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Reaction time: 16 h
Yield: 100.8 %

Procedure:
A suspension of 8-diphenylphosphinoyl-2-methyl-1,2-dihydroquinoline (5) (11 g, 32 mmol) and Pd/C (1.1 g, 10 wt %) in MeOH (40 mL) was stirred under H2 at 145 psi pressure for 16 hours. The mixture was then diluted with EtOAc (200 mL) and filtered over celite (−25 mL). The filtrate was then evaporated to give compound 6 as a yellow oil (11.2 g, quantitative). 1H NMR (400.13 MHz, CDCl3) δ 7.7-7.6 (m, 4H, Ph-H), 7.6-7.5 (m, 2H, Ph-H), 7.5-7.4 (m, 4H, Ph-H), 7.03 (d, 1H, J=7.2 Hz, C5—H), 6.87 (bs, 1H, N1—H), 6.58 (dd, 1H, J=14.0, 7.2 Hz, C7—H), 6.39 (ddd, 1H, J=10.4, 7.2, 2.8 Hz, C6—H), 3.5-3.4 (m, 1H, C2—H), 2.8-2.7 (m, 2H, C4—H), 1.9-1.8 (m, 1H, C3a—H), 1.6-1.4 (m, 1H, C3b—H), 1.13 (d, 3H, J=6.4 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 148.9, 132.0 (d, J=11.1 Hz), 131.5, 131.0 (d, J=10.1 Hz), 130.7 (d, J=10.1 Hz), 130.6 (d, J=10.1 Hz), 130.4 (d, J=6.1 Hz), 130.3 (d, J=6.1H), 130.1 (d, J=11.1 Hz), 127.0 (d, J=13.1 Hz), 126.9 (d, J=12.1 Hz), 120.4 (d, J=8.1 Hz), 112.5 (d, J=14.1 Hz), 107.9, 106.9, 45.4, 27.4, 25.5, 20.9 ppm; 31P NMR (161.97 MHz, CDCl3) δ 36.4 ppm.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([OH:11])[CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1(=[N:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+]>[C:12]1(=[N:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[C:6]1(=[O:11])[CH2:12][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:12]1(=[O:2])[NH:18][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=S(=O)(O)O
Reactant: CCCCCO
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: ON=C1CCCCC1
Agent: [Na+]
Product: O=C1CCCCC1
Product: O=C1CCCCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Take 200 ml of aqueous solution of 3.0N sulfuric acid in a round bottom flask. Dissolve in this solution 16 grams of sodium dodecyl sulfate (SDS) and 5.3 gm 1-pentanol by mild stirring. A microemulsion is thus formed. Keep the flask in a water bath maintained at temperature of 25° C. To this microemulsion, add 10.0 gm of cyclohexanone oxime and stir the mixture mildly for 2 hours. Remove the flask from the water bath and neutralize the solution using aqueous solution of ammonia. Filter the solution using Whatman No. 1 filter paper. Measure the amount of filtrate and the residue and extract the filtrate with 100 ml of benzene in steps of 50, 25, and 25 ml respectively. Analyze the benzene layer, the aqueous layer and the residue obtained as above by Gas Chromatography for the amount of cyclohexanone oxime, cyclohexanone and caprolactam.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1>N1C=CC=CC=1.CC#N>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]([OH:68])(=[O:69])[CH2:64][CH2:65][C:66]([OH:6])=[O:67]
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Paclitaxel (50 mg, 1 equivalent) was introduced into a 50 ml round bottomed flask and dissolved in pyridine (3 ml). Next, succinic anhydride (30 mg, 5.1 equivalents) was added thereto. After stirring at room temperature for 16 hours, the mixture was diluted with 30% MeCN (30 ml). Then it was filtered and purified by high performance liquid chromatography (HPLC). After freeze-drying, paclitaxel-succinic acid (51.86 mg, yield 92.2%) was obtained.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]4[CH2:25][CH:26]5[NH:30][CH:29]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38]>CO.C(OCC)C>[ClH:38].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2[CH2:25][CH:26]4[NH:30][CH:29]([C:13]3=2)[CH2:28][CH2:27]4)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2-c2ccccc2)CC2CCC1N2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)c1c(n2-c2ccccc2)CC2CCC1N2
Reaction time: 2 h

Procedure:
To a solution of the product of step D (70 mg, 0.13 mmol) in methanol was added 2M HCl in diethylether (4 mL). After stirring for 2 h, the solution was concentrated in vacuo, triturated with ethyl acetate, and lyophilized from water to give 2-phenylsulfonyl-5-phenyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (50 mg, 57%, AUC HPLC >99%) as a white solid: mp 195-200° C.; 1H NMR (CD3OD, 300 MHz) δ 8.38 (d, J=1.8 Hz, 1H), 7.95-7.99 (m, 2H), 7.72 (dd, J=8.8, 1.5 Hz, 1H), 7.51-7.64 (m, 6H), 7.39-7.42 (m, 2H), 7.32 (d, J=9.0 Hz, 1H), 5.39-5.40 (m, 1H), 4.49 (br s, 1H), 3.39 (dd, J=8.7, 4.5 Hz, 1H), 2.81 (d, J=17.7 Hz, 1H), 2.37-2.46 (m, 3H), 1.98-2.08 (m, 1H); ESI, m/z 415 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:9][CH:8]=[C:7]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:6]=2.[C:30](Cl)(=O)[CH2:31][CH2:32][CH3:33]>>[CH2:23]([O:22][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:30]([CH2:31][CH2:32][CH3:33])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCCC(=O)Cl
Product: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNS(C)(=O)=O
Yield: 69.3 %

Procedure:
The method described in Part D of Example 45 was used to treat N-[4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide (15.1 g, 36.5 mmol) with butyryl chloride (4.77 mL, 46.2 mmol). The crude product was purified by column chromatography on silica gel (eluting with 96:4 chloroform:methanol containing ammonium hydroxide) to provide 11.8 g of N-[4-(7-benzyloxy-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a tan solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[O:14]([C:21]1[CH:26]=[CH:25][C:24]([C:27](=[C:30]2[S:35][CH2:34][S:33][CH2:32][S:31]2)[CH2:28][CH3:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C([SiH](CC)CC)C>[O:14]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH:30]2[S:31][CH2:32][S:33][CH2:34][S:35]2)[CH2:28][CH3:29])=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCC(=C1SCSCS1)c1ccc(Oc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(c1ccc(Oc2ccccc2)cc1)C1SCSCS1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
In 10 ml of anhydrous dichloromethane were dissolved in 1.0 g of 2-{1-(4-phenoxyphenyl)propan-1-ylidene}-1,3,5-trithiane and 0.67 g of triethylsilane, and a solution prepared by diluting 1 ml of trifluoroacetic acid with 5 ml of dichloromethane was added dropwise at room temperature. The resulting solution was stirred overnight. After sodium carbonate powder was added, the resulting mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation, and then the residue was purified by a silica gel column chromatography (chloroform:hexane=2:1) to give 0.91 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH2:15]([N:23]=[C:24]=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:24]([NH:23][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C=NCCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCCc2ccccc2)cn1
Yield: 29 %

Procedure:
Prepared as in example 9-6b from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine and phenethyl isocyanate. Yield: 29%. 1H NMR (DMSO-d6, 40 MHz): 2.10 (s, 3H), 2.36 (s, 3H), 2.69 (t, J=7.2 Hz, 2H), 3.25 (q, J=7.4 Hz, 2H), 5.02 (s, 2H), 6.00 (t, J=5.8 Hz, 1H), 7.16-7.30 (m, 6H), 7.68 (s, 1H), 8.13 (s, 1H). LC/MS; [M+H] calculated for C18H21N5O2; expected 340.17. found 340.20.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[O-:16][C:17]#[N:18].[K+].[OH-].[Na+]>O.C1COCC1>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:17](=[O:16])[NH:18][C:4]2=[O:5]
Reactant: N#C[O-]
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2cc(I)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a mixture of 25.36 g of 2-amino-5-iodobenzoic acid in 250 ml of water and 90 mL of THF was added 7.40 g of glacial acetic acid and stirred at room temperature. Then was added 7.82 g of potassium cyanate in water dropwise. Left to overnight. Added another 5.47 g of potassium cyanate. Stirred overnight. A total of 160 g of NaOH pellets were added portionwise, keeping the mixture cool in ice-water bath. The mixture was stirred at room temperature overnight. The mixture was cooled in a refrigerator and the precipitate filtered through a sintered glass funnel. The precipitate was then dissolved in water and acidified with 4N HCl. The precipitate was collected by filtration. The solid was dried in a vacuum oven to yield 25.44 g of the title compound.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:38])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:38])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:26]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)C1CN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccc3c(I)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate (410 mg, 1 mmol) and NIS (247 mg, 1.1 mmol, 2.0 eq.) were dissolved in CH3CN (5 mL). Then CF3COOH (35 mg, 0.3 mmol, 0.3 eq.) was added to the mixture dropwise at 0° C. The mixture was warmed to r.t. and stirred for another 1.5 h. Then the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using PE/EA (1/1) as eluent to give product the title compound as a slight red solid (300 mg, 56%). ESI-MS (M+H+): 536.2. 1H NMR (400 MHz, CDCl3) δ: 8.19 (d, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.22 (d, 1H), 4.34-4.28 (m, 4H), 3.91-3.67 (m, 1H), 3.80-3.78 (m, 3H), 3.75 (s, 3H), 2.24-2.21 (m, 2H), 1.90-1.88 (m, 2H), 1.62-1.58 (m, 2H), 1.15-1.12 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([CH3:23])([CH3:22])[C:15](OC(C)(C)C)=[O:16])=[CH:10][CH:9]=1.CCOC(C)=O>C1COCC1>[F:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([CH3:23])([CH3:22])[CH2:15][OH:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)c1ccc(F)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Lithium aluminum hydride (1.0M in THF) (Aldrich, St. Louis, Mo.; 12.98 mL, 12.98 mmol) was added to a solution of tert-butyl 2-(6-fluoropyridin-3-yl)-2-methylpropanoate (2.07 g, 8.65 mmol) in THF (34 mL) at 0° C. (gas evolution), and the resulting solution was stirred at 0° C. for 5 min. EtOAc (15 mL) was then added at 0° C. to quench excess lithium aluminum hydride, followed by 10% aqueous Na/K tartrate (150 mL). The resulting mixture was stirred at 25° C. for 10 min and then partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organic extracts were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-(6-fluoropyridin-3-yl)-2-methylpropan-1-ol (1.46 g, 8.63 mmol, 100% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.22 (br. s., 1H), 7.78-7.84 (m, 1H), 6.89 (dd, J=8.6, 3.1 Hz, 1H), 3.63 (s, 2H), 1.36 (s, 6H). 19F NMR (377 MHz, CDCl3) δ −72.21 (br. s., 1 F). m/z (ESI, +ve) 170.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2cc(Br)ccc2n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2cc(Br)ccc2n1
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Crude 2,4-Dichloro-6-bromoquinazoline (18.8 g.) was dissolved in dichloromethane (500 mL) and chilled in a dry ice bath. To the solution was added morpholine (11.6 g.) and it was stirred for two hours. The organic layer was washed with saturated ammonium chloride solution (2×200 mL), dried with sodium sulfate, and evaporated. The resulting solid was washed with ether, and dried to give 2-chloro-4-morpholino-6-bromoquinazoline (15.0 g.).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:2]3[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1cc[nH]n1
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C1CCCC2=C1C(c1ccc(Cl)c([N+](=O)[O-])c1)n1nccc1N2

Procedure:
1,3-Cyclohexanedione, 4-chloro-3-nitrobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH2:12][CH3:13].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH2:14][CH2:15][CH2:16][CH2:17][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH2:32][CH2:31]1)[CH2:12][CH3:13]
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(F)cc21
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2c(Cl)cc(F)cc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 7-chloro-3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)-piperazine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1.CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[C:3]([CH3:10])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(B(O)O)c(C)c1
Temperature: -62.5 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A solution of 4-bromo-3-methylanisole (7, 92 g, 0.457 mol) in anhydrous THF (400 ml) was treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexane, 201 mL, 0.503 mol, 1.1 equiv) in hexane at −60-−65° C. under N2. The resulting reaction mixture was stired at −60-−65° C. for an additional 30 min before being treated dropwise with B(OiPr)3 (94.56 g, 116 mL, 0.503 mol, 1.1 equiv) at −60-−65° C. The reaction mixture was stirred at −60-−65° C. for an additional 1 h. The reaction was then quenched with saturated NH4Cl aqueous solution (400 mL) at −60-−65° C., and the resulting mixture was gradually warmed to 0° C. for 1 h and subsequently to room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc/THF (1:1, 200 mL). The combined organic extracts were then washed with H2O (200 mL), and saturated NaCl aqueous solution (200 mL), dried over MgSO4, and concentrated in vacuo. The residual white solids were then suspended in heptane (400 mL), and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with heptane (2×100 mL), dried in vacuo at 40-45° C. for overnight. The crude product (8, 57.9 g, 75.86 g theoretical, 76.3%) was obtained as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH:29]1([CH:35]=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=CC1CCCCC1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(NCCCCNCC1CCCCC1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with cyclohexane carboxaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0240 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg) of the subject compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][CH3:9].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][CH2:23][CH2:24]Cl>CS(C)=O.O>[CH2:7]([NH:10][CH2:24][CH2:23][CH2:22][O:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCN
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCNCCCOc1ccc2ccccc2c1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-propylamine (0.28 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 8 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-propyl-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 112° C., (yield 0.51 gm, 91.2%).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:16][CH2:15]1.[CH:28](=[O:37])[C:29]1[C:30]([O:35][CH3:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.Cl>C1COCC1.C(O)(C)C.O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[C:27]([CH:28]([OH:37])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:16][CH2:15]1
Reactant: COc1ccccc1N1CCN(CCc2ccccn2)CC1
Reactant: COc1ccccc1C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(O)c1cccnc1CCN1CCN(c2ccccc2OC)CC1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
n-Butyl-lithium (1.6M solution in hexane) (7.0 ml, 11.2 mmol, 1.1 equiv.) was added dropwise at below -60° C. to a solution of 1-(2-methoxyphenyl)-4-(2-pyridylethyl)piperazine base (3.00 g, 10.1 mmol) in anhydrous THF (20 ml). The resulting orange-red solution was stirred for a further 0.25 h at -70° C. then quenched with a solution of ortho-anisaldehyde (1.5 g, 11.0 mmol) in anhydrous THF (2 ml). The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (2×75 ml). The organic extract was washed (brine), dried (Na2SO4) and concentrated in vacuo. The residue was subjected to chromatography (SiO2 :Et2O) to give the first Rf diastereoisomer as a white foam which was dissolved in isopropanol (20 ml) and acidified with ethanolic hydrogen chloride to afford the first diastereoisomer of the title compound as the trihydrochloride (227 mg), m.p. 140°-145° C. (Found: C,57.7;H,6.5;N,7.8 C26H31N3O3.3HCl requires C,57.5;H,6.3;N,7.7%).