Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([OH:25])[C:16]2([C:21]([O:23][CH3:24])=[O:22])[CH2:20][CH2:19][CH2:18][O:17]2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:26]([O:25][CH:15]([C:13]1[CH:12]=[CH:11][N:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:16]1([C:21]([O:23][CH3:24])=[O:22])[CH2:20][CH2:19][CH2:18][O:17]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1(C(O)c2ccnc(OCc3ccccc3)c2)CCCO1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1(C(OC(C)=O)c2ccnc(OCc3ccccc3)c2)CCCO1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4.23 g of methyl 2-[[2-(benzyloxy)-4-pyridyl](hydroxy)methyl]tetrahydro-2-furancarboxylate in 20 ml of dichloromethane were added 5 ml of acetic anhydride, 5 ml of pyridine and 0.43 g of 4-dimethylaminopyridine, and the mixture was stirred at room temperature for 15 hours. 300 ml of ethyl acetate and 100 ml of hydrochloric acid (2N) were added thereto. The organic layer was sequentially washed with 100 ml of water, 100 ml of saturated aqueous sodium hydrogencarbonate and 100 ml of brine, dried over magnesium sulfate and evaporated, to give 4.52 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][C:39]1[NH:40][CH2:41][CH2:42][N:43]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:43]3[CH2:42][CH2:41][N:40]=[C:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC1=NCCN1
Product: CC1=NCCN1c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methyl-4,5-dihydro-1H-imidazole according to conditions described in general procedure C. 1H NMR (400 MHz, CDCl3) δ 1.63-1.70 (m, 9 H), 3.29 (t, J=5.5 Hz, 4H), 3.67 (t, J=8.8 Hz, 2 H), 3.83 (t, J=8.8 Hz, 2 H), 6.25-6.53 (m, 1 H), 6.77 (d, J=11.7 Hz, 1 H), 6.99 (d, J=8.0 Hz, 1 H), 7.25-7.31 (m, 2 H), 7.49-7.60 (m, 2 H), 7.88-7.93 (m, 2 H), 8.01 (d, J=8.0 Hz, 1 H), 8.17 (s, 1 H), 8.34-8.36 (m, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].CCN(C(C)C)C(C)C>CC(C)=O>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:12]([CH3:11])[O:13][CH3:14])[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CON(C)c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,4,6-Trichloro-1,3,5-triazine (XVIII) (30 g, 163 mmol) was dissolved in acetone (300 mL), and N,O-dimethylhydroxylamine hydrochloride (15.8 g, 163 mmol) and DIPEA (42 g, 326 mmol) were added and the mixture then stirred at 0° C. for 1 h. The solution was concentrated and the residue was treated with EtOAc (750 mL), washed with water (100 mL), and the organic layer was dried with Na2SO4. The volatiles were removed in vacuo and the residue was purified by flash column chromatography (pet ether/ethyl acetate=50/1 to 10/1) to yield the desired product, N-(4,6-dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXX), as a white solid (25 g, 73% yield). LCMS (ESI) m/z=210 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1.Br[CH2:18][CH2:19][O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH2:19][O:20][CH3:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: COCCBr
Reactant: N#Cc1nc(N)nc(Nc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN(c1ccccc1)c1nc(N)nc(C#N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-amino-6-phenylamino-[1,3,5]triazine-2-carbonitrile (prepared in an analogous manner to Intermediate 5, 100 mg, 470 μmol), 1-bromo-2-methoxyethane (50 μl, 0.52 mmol) and potassium carbonate 130 mg, 0.94 mmol) in DMF (5 ml) was heated to 100 C and stirred 3 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under vacuum to give the crude product which was used without further purification (400 mg, >100%, contains DMF). Method C HPLC-MS: MH+ requires m/z=271. Found: m/z=271, Rt=1.23 min (52%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](O)=O)=[CH:2]1.[NH2:9][C:10]1[C:11](=[O:24])[N:12]([CH2:21][CH2:22][CH3:23])[C:13](=[O:20])[N:14]([CH2:17][CH2:18][CH3:19])[C:15]=1[NH2:16]>>[CH2:21]([N:12]1[C:11](=[O:24])[C:10]2[NH:9][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[N:16][C:15]=2[N:14]([CH2:17][CH2:18][CH3:19])[C:13]1=[O:20])[CH2:22][CH3:23]
Reactant: O=C(O)c1ccoc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(-c3ccoc3)nc2n(CCC)c1=O

Procedure:
The starting 1,3-dipropyl-8-(3-furanyl)xanthine is prepared by a process analogous to that described in Example 2 above using 3-furoic acid and 5,6-diamino-1,3-dipropyluracil, mp 244°-245° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[O:21]=[C:22]1[N:30]([CH2:31][CH2:32][CH3:33])[C:29]2[N:28]=[C:27]([C:34]34[CH2:41][CH2:40][C:37]([CH2:42][CH2:43][C:44]([NH2:46])=O)([CH2:38][CH2:39]3)[CH2:36][CH2:35]4)[NH:26][C:25]=2[C:24](=[O:47])[N:23]1[CH2:48][CH2:49][CH3:50]>C1COCC1>[O:21]=[C:22]1[N:30]([CH2:31][CH2:32][CH3:33])[C:29]2[N:28]=[C:27]([C:34]34[CH2:41][CH2:40][C:37]([CH2:42][CH2:43][C:44]([NH2:46])=[S:2])([CH2:38][CH2:39]3)[CH2:36][CH2:35]4)[NH:26][C:25]=2[C:24](=[O:47])[N:23]1[CH2:48][CH2:49][CH3:50]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(N)=O)(CC3)CC4)nc2n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(N)=S)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 0.33 h

Procedure:
A suspension of P4S10 (23 mg, 53 μmol) and Na2CO3 (4 mg, 53 μmol) in THF (4 ml) was stirred vigorously for 20 min and 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionamide (20 mg, 45 μmol) was added. The resulting pale yellow solution was stirred at rt 1 h, evaporated to dryness and dried in vacuo overnight. The crude material was purified by radial chromatography (1 mm plate) using 2-5% MeOH in CH2Cl2, as eluent to afford a white solid (11 mg, 550). MS: 432 (MH+).
Reaction SMILES: [Br:1]Br.[CH3:3][C@@H:4]1[NH:10][C:9]2[N:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][NH:6][C:5]1=[O:15]>C(O)(=O)C>[Br:1][C:13]1[CH:12]=[N:11][C:9]2[NH:10][C@@H:4]([CH3:3])[C:5](=[O:15])[NH:6][CH2:7][C:8]=2[CH:14]=1
Reactant: BrBr
Reactant: C[C@@H]1Nc2ncccc2CNC1=O
Solvent: CC(=O)O
Product: C[C@@H]1Nc2ncc(Br)cc2CNC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
Bromine (43 ul, 0.84 mmol) was added drop wise to a solution of (S)-2-methyl-1,2,4,5-tetrahydropyrido[2,3-e][1,4]diazepin-3-one (136 mg, 0.77 mmol) in acetic acid (10 mL). The reaction was stirred at room temperature for 3 h. The reaction was quenched with sat. NaHCO3 (10 mL) and extracted with ethyl acetate (3×15 mL), dried over sodium sulfate and concentrated to give the title compound (140 mg, 71%): 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.31 (s, 1H), 7.20 (b, 1H), 5.95 (bs, 1H), 4.97-4.91 (m, 1H), 4.72-4.70 (m, 1H), 3.85-3.79 (m, 1H), 1.47 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:28])[CH2:26]Cl)[N:17]=[CH:16]2)[C@H:6]1[F:29])(=[O:3])[CH3:2].F[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC.[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:28])[CH2:26][N:41]=[N+:42]=[N-:43])[N:17]=[CH:16]2)[C@H:6]1[F:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Compound (38) (60 mg) obtained in item (5) above was dissolved in N,N-dimethylformamide (1.2 ml), to which sodium azide (27 mg) was added and the mixture so obtained was stirred at room temperature for 2 hours. The resulting reaction solution was concentrated and the residue as formed was extracted with chloroform. The solution in chloroform thus formed was washed with water, dried over anhydrous sodium sulfate and then concentrated to afford the titled compound (39) (56 mg) as a syrup. Yield: 92%.
Reaction SMILES: [CH2:1]([CH:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH:5]([CH3:8])[CH2:6][CH3:7])[CH3:2].Br[CH2:17][CH2:18][CH3:19]>>[CH2:1]([CH:3]([N:9]([CH2:17][CH2:18][CH3:19])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][CH:5]([CH3:8])[CH2:6][CH3:7])[CH3:2]
Reactant: CCCBr
Reactant: CCC(C)CC(CC)Nc1ccccc1
Product: CCCN(c1ccccc1)C(CC)CC(C)CC

Procedure:
N-(1-Ethyl-3-methylpentyl)-N-propylaniline was prepared from N-(1-ethyl-3-methylpentyl)aniline and 1-bromopropane using the same method as in Example 2ii).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:16])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14]Cl)[N:13]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[C:2]([O:6][C:7](=[O:16])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][O:27][CH2:26][CH2:25][O:24][CH3:23])[N:13]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: COCCOCc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of the chloride (Intermediate II, 420 mg, 1.69 mmol) and potassium carbonate (818 mg, 5.92 mmol) in 2-methoxyethanol (12 ml) was stirred for 2 hours at 90° C. TLC indicated complete conversion. The mixture was filtered through a pad of celite and the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel, ethyl acetate/heptane, 25-70% gradient) to give 46% (225 mg, 781 μmol) of title compound as pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9H), 3.39 (s, 3H), 3.54-3.58 (m, 2H), 3.64-3.69 (m, 2H), 4.58 (s, 2H), 6.82 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.[NH2:15][NH2:16]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:16][N:15]=[C:3]([OH:2])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: NN
Product: Oc1cc(-c2ccc(F)cc2)[nH]n1
Yield: 84.4 %

Procedure:
5-(4-Fluoro-phenyl)-1H-pyrazol-3-ol (7.67 g, 84%) was prepared as a white solid from 3-(4-Fluoro-phenyl)-3-oxo-propionic acid methyl ester (10.0 g, 51.0 mmol) and hydrazine (4.76 mL, 153 mmol) by a procedure analogous to Example 22. C9H7FN2O: 1H NMR (d6-DMSO): δ 7.66 (dd, 2H, JCH—CF=11.7 Hz, JCH—CH=8.7 Hz), 7.21 (d, 2H, J=8.7 Hz), 5.83 (s, 1H) ppm.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.C(OCC)C>[C:1]1([CH2:7][CH2:8][CH:9]=[CH:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCc1ccccc1
Reactant: CCCCCC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCC(=O)C=CCCc1ccccc1

Procedure:
A mixture of 3-phenylpropanol (2.68 g., 20 mmole), triphenyl-(2-keto-n-heptyl)phosphonium chloride (8.22 g., 20 mmole), sodium carbonate (2.36 g., 22.3 mmole) and water (20 ml.) in tetrahydrofuran (70 ml.) is refluxed for 6 hours under an atmosphere of argon. The cooled mixture is diluted with ethyl ether and the layers separate. The organic phase is washed with saturated sodium chloride solution, dried over Na2SO4 and evaporated. The residue is taken up in hexane and insoluble triphenyl phosphine oxide is filtered off. The residue obtained on evaporation of the hexane is purified by flash chromatography on silica gel (120 g.) eluting with ethyl ether/hexane (1:30) to give two isomers of 1-phenyl-3-decen-5-one; 2.93 g. Rf (ethyl ether/hexane 1:4) 0.73 and 0.42 g. Rf (ethyl ether/hexane 1:4) 0.85.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][NH:6][C:7](=[O:20])[NH:8][C:9]1[S:10][C:11]([F:19])=[C:12]([CH2:14][N:15](OC)[CH3:16])[N:13]=1>C(O)(=O)C.O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][NH:6][C:7](=[O:20])[NH:8][C:9]1[S:10][C:11]([F:19])=[C:12]([CH2:14][NH:15][CH3:16])[N:13]=1
Reactant: CON(C)Cc1nc(NC(=O)NCc2cccc(F)c2)sc1F
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CNCc1nc(NC(=O)NCc2cccc(F)c2)sc1F
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
A solution of 2-(3-(3-fluorobenzyl)ureido)-4-(N-methoxy-N-methyl-aminomethyl)-5-fluorothiazole (2.05 g, 6 mmol) in glacial acetic acid (30 mL) was treated with micronized zinc dust (12 g) and stirred at 60 C for 1-2 hours. The mixture was diluted with water (30 mL) and filtered on Celite. The filter cake was washed with 1:1 HOAc:water (3×20 mL) and the combined filtrate were brought to pH 10 with ammonium hydroxide (−82 mL). The resulting mixture was stirred in ice and the crude product was collected by filtration and washed with water (4 mL). The crude product was further purified by silica gel chromatography (5:94:1 MeOH:DCM:NH4OH) to afford Intermediate 40 as a white solid (1.25 g, 67% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1>O1CCOCC1.[OH-].[Na+].O.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCc1ccc(N)c(=O)[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (1.8 ml, 12.6 mmol) was added to a solution of 3-amino-6-propyl-2-pyridinone (1.63 g, 10.8 mmol) in a mixture of dioxane (25 ml) and 1N NaOH at 0° C. Within minutes a white precipitate formed. The reaction mixture was stirred at the same temperature for 1 h then at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate then methylene chloride. Each extract was washed with brine then combined and dried over magnesium sulfate. Removal of the solvents in vacuo gave a yellow semi-solid which was a mixture of starting material and product. This was redissolved in a mixture of dioxane (24 ml) and 10% aqueous sodium carbonate (12 ml) and cooled to 0° C. Benzyl chloroformate (1.5 ml, 10.5 mmol) was once again added and after stirring for 0.5 h, the reaction mixture was allowed to stir at room temperature for 3 h. After dilution with water, the precipitate was filtered off and washed thoroughly, first with water and then with ether. Drying gave the title compound as a white powder: 1H NMR (CDCl3) d 0.96 (t, J=7.3 Hz, 3 H), 1.68 (m, 2 H), 2.52 (t, J=7.5 Hz, 2 H), 5.22 (s, 2 H), 6.07 (d, J=7.5 Hz, 1 H), 7.34-7.43 (m, 4 H), 7.68 (s, 1 H), 8.05 (br d, J=5.3 Hz, 1 H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:13]1[CH:18]=[C:17](C=O)[C:16]([CH:21]=O)=[CH:15][CH:14]=1.C(Cl)Cl>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:21][C:16]3[C:15](=[CH:14][CH:13]=[CH:18][CH:17]=3)[C:11]2=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: O=Cc1ccccc1C=O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 42.6 %

Procedure:
A mixture of 4-acetylphenylisocyanate (27.5 g, 0.17 mol) and o-phthalicdicarboxaldehyde (25.0 g, 0.186 mol) is heated in an oil bath at 170°-175° C. for 4.0 hours under nitrogen atmosphere. On cooling the melt solidified which is pulverized and refluxed with CH2Cl2 and CH3OH and filtered to give 18.2 g (41.4%) of the desired 2-(4-acetylphenyl)-2,3-dihydro-1H-isoindole-1-one, mp 235°-237° C. The residue is recrystallized from DMF (1800 ml). Yield 13.0 g (29.6%), mp 236°-239° C. (Jap. patent J5 7050-960; mp 243°-244° C. for the nonsolvated compound, prepared by a different route).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:45][N:46]([CH3:63])[NH:47][C:48]([C:50]1([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([N:53]1[CH2:54][CH2:55][C:50]([CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:48]([NH:47][N:46]([CH3:63])[CH3:45])=[O:49])[CH2:51][CH2:52]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-(1H-indole-3-yl)propionic acid (0.37 g, 1.2 mmol) in methylene chloride (15 ml) and dimethylformamid (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.16 mg, 1.20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 9, 1.20 mmol) and the mixture was stirred for 30 min. Then 4-benzylpiperidine-4-carboxylic acid N′,N′-dimethylhydrazide (0.26g, 1.0 mmol) and diisopropylethylamine (0.69 ml, 4.0 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chloride/(10% ammonia in methanol) (9:1) to give 0.43 g of (2-(4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indole-3-ylmethyl)-2-oxoethyl)carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:24]=[CH:23][C:10](/[CH:11]=[N:12]/[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][O:16][C:17]3=[O:22])=[CH:9][CH:8]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1.[CH3:34][CH2:35][O-:36].[Na+]>C(OCC)(=O)CC.CCO>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[C:35](=[O:36])[C:34]3[C:18]([C:17]([O:16][CH2:15][CH3:14])=[O:22])=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12][CH:11]2[C:10]2[CH:23]=[CH:24][C:7]([CH:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[CH:8][CH:9]=2)=[CH:28][CH:27]=1
Reactant: CN1CCCC1c1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCO
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1ccc(C3CCCN3C)cc1)N2
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A mixture of (E)-4-(4-(1-methylpyrrolidin-2-yl)benzylideneamino)isobenzofuran-1(3H)-one (0.32 g, 1 mmol), 4-fluorobenzenaldehyde (0.248 g, 2 mmol) was dissolved in dry ethyl propionate (5 mL), EtONa (0.136 g, 2 mmol) in EtOH (5 mL) was added to this solution and the mixture was stirred at room temperature until the starting material was disappeared as monitored by TLC. The reaction was quenched with 0.5 mL of water, the resulting mixture was concentrated in vacuo, and the residue was purified by column chromatography (MeOH:DCM=1:20) to give the title compound (200 mg, yield 42%) as a pale yellow solid. LC-MS (ESI) m/z: 472 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C>C1COCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)Cc2ccc(C)nc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(NCCc2ccc(C)nc2)cc1
Temperature: 0 °C
Yield: 28.1 %

Procedure:
2-(6-Methyl-pyridin-3-yl)-N-p-tolyl-acetamide (0.960 g, 4 mmol) was dissolved in dry THF (20 cm3), and cooled to 0° C. LiAlH4 (5.0 eq., 20 mmol, 10 ml of a 2.0 M solution in THF) was added dropwise at first, until no more gas evolution was observed (˜0.5 ml), and then the remaining LiAlH4 solution was added in one portion. The resulting solution was heated to reflux for 16 hours with stirring. Wet diethyl ether was then added until no further gas evolution was observed, the resulting medium filtered, and the residue washed with ether (˜50 cm3). The filtrate was dried (MgSO4), and the solvent removed to yield a crude yellow oil. The oil was purified by flash chromatography, eluting with 1:1 petrol (40-60)/EtOAc. The product was collected as the fraction with Rf=0.294. The product was obtained as a pale yellow oil (254 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH2:11][CH2:12][CH2:13][Cl:14])=[C:6]([NH:8]N)[CH:7]=1.O.[NH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.Cl>CCO>[Br:1][C:2]1[C:7]2[C:18]3[CH2:17][NH:16][CH2:21][CH2:20][C:19]=3[NH:8][C:6]=2[C:5]([S:10][CH2:11][CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1
Reactant: NNc1cc(Br)ccc1SCCCCl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: ClCCCSc1ccc(Br)c2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 58 %

Procedure:
1-{5-Bromo-2-[(3-chloropropyl)sulfanyl]phenyl}hydrazine hydrochloroide (784 mg, 2.4 mmol) and 4-piperidone monohydrate.HCl (398 mg, 2.6) were dissolved in EtOH (5mL). Conc. Hcl (0.2 mL, 2.4 mmol) were added. The reaction was refluxed for 18 hrs and then cooled to rt. The ppt was collected by filtration and the residue was washed with EtOH (3mL). 9-bromo-6-[(3-chloropropyl)sulfanyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloroide (500.4 mg, 58%) was isolated as a white powder. 1H NMR (CD3OD, 300 Mhz) δ7.18 (d, 1H, 8.0 Hz), 7.12 (d, 1H, 8.0 Hz), 4.73 (s, 2H), 3.64 (t, 2H, 6.6 Hz), 3.58 (t, 2H, 6.3 Hz), 3.16 (t, 2H, 6.3 Hz), 3.02 (t, 2H, 6.6 Hz), 1.87-1.96 (m, 2H) ppm.