Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH3:12]
Reactant: CCN
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CCNc1ccc(C(=O)O)cn1

Procedure:
This intermediate is prepared from 6-chloronicotinic acid and ethylamine by the same procedure as described for Example 35 step a). 1-Butanol was substituted for ethyl acetate for the extraction. Recrystallization (MeOH—CHCl3) yielded 0.53 g (50%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([O:27][CH2:28][CH2:29][CH2:30]Br)[CH3:26].C([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[CH2:25]([O:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)[CH3:26]
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: CCOCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOCCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
11 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine and 5.7 g of 3-ethoxypropyl bromide are suspended in 150 ml of isopropanol and dissolved at 100°. 9.4 g of potash are added thereto, and the mixture is boiled under reflux for 20 hours. Concentration by evaporation and chromatography over silica gel yield an oil, which is crystallised from methylene chloride and petroleum ether, yielding 1-[4-(3-ethoxypropylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 87°-89°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCc1cncc(Br)c1
Yield: 90.1 %

Procedure:
To a stirred solution of 5-bromonicotinaldehyde (5 g, 26.9 mmol) in ethanol (Volume: 100 mL) was added sodium borohydride (0.610 g, 16.13 mmol) slowly over five min at ambient temperature. A half hour later, the reaction mixture was placed in an ice bath then slowly added 50 mL saturated ammonium chloride and stirred for 5 min. After that the reaction mixture was concentrated in vacuo to provide a white solid to which was partitioned between water and ether. The ethereal layer was dried over magnesium sulfate, and concentrated to give a clear liquid of (5-bromopyridin-3-yl)methanol (4.8 g, 24.25 mmol, 90% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.59 (d, J=2.1 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.01-7.93 (m, 1H), 5.46 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.5 Hz, 2H), Mass spec.: 188.0 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[N:7]([N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]1.C(Br)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:23]([N:20]1[CH2:19][CH2:18][CH:17]([CH2:16][N:3]2[CH2:4][CH2:5][CH2:6][N:7]3[N:8]=[C:9]4[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]4)=[C:15]3[C:2]2=[O:1])[CH2:22][CH2:21]1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCCn3nc4ccccc4c3C2=O)CC1
Product: O=C1c2c3ccccc3nn2CCCN1CC1CCN(CCc2ccccc2)CC1

Procedure:
The product was prepared using the method described in example 2e), using tert-butyl 4-[(1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-b]indazol-2(3H)-yl)methyl]piperidine-1-carboxylate (example 16a) and phenethyl bromide as reagents. The product was purified by flash chromatography on silica gel, using the mixture chloroform:methanol in a ratio of 95:5 as eluent. Thus, 223 mg of 2-[(1-phenethylpiperidin-4-yl)methyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-b]indazol-1-one were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([F:31])[C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[C:24]([F:31])=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ncc(Cl)cc1F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(Cl)cc3F)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-chloro-3-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=445.2 [M+H]+, 447.2 [M+2+H]+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1>CN(C=O)C.C(N(CC)CC)C>[C:1]([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A solution of benzoic acid (0.123 g) in DMF (5 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.231 g), HOBT (0.163 g) and triethylamine (0.56 ml) and stirred at room temperature for 1 h. A solution of 3-amino-1-N-Boc-piperidine (0.3 g) in DMF (1 ml) was then added and stirring continued for 18 h. The solution was concentrated under reduced pressure to give an oil which was partitioned between ethyl acetate and water. The separated organic extracts were washed with water, hydrochloric acid (2N), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.120 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([N:8]([CH3:16])[C:9](=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1>CC(O)=O.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]([CH3:16])[C:6]=2[CH:7]=1
Reactant: CN(C(=O)CC(C)(C)C)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1c(CC(C)(C)C)nc2ccc(Br)cc21
Temperature: 90 °C
Yield: 78 %

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)-N,3,3-trimethylbutanamide (300 mg) in AcOH (5 ml) was added zinc (596 mg) at room temperature. Then the mixture was heated at 90° C. for 2 h. The inorganic material was removed by filtration, and the filtrate was concentrated. The residue was poured into a mixture of EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4, concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (200 mg) as a white solid.
Reaction SMILES: N#N.[NH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][C:4]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCCc2ccccc2N1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCCCN2
Yield: 92 %

Procedure:
Under anhydrous conditions and N2 atmosphere, 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 mg) in THF (5 ml) was treated with LiAlH4 (0.65 ml @ 1.0M in THF). The resulting solution was heated at reflux for 1 hr. The reaction was quenched by addition to a small amount of ice. The resulting mixture was diluted with a large excess of CH3CN (˜50:1) and filtered. The filtrate was concentrated in vacuo to give 84 mg of the titled product. 1H NMR (300 MHz, CDCl3) 1.69 (m, 2H), 1.86 (m, 2H), 2.82 (m, 2H), 3.10 (m, 2H), 3.6 (bs, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.88 (t, J=7.3 Hz, 1H), 7.09 (dt, J=7.6 Hz, J=1.4 Hz, 1H), 7.15 (d, J=7.4 Hz, 1H).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([C:14]2[N:15]=[C:16]([CH:25]3[NH:29][C:28](=[O:30])[CH2:27][CH2:26]3)[O:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>Cl>[C:8]1([C:14]2[N:15]=[C:16]([CH:25]3[CH2:26][CH2:27][C:28](=[O:30])[N:29]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[O:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CCCCCCCBr
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCN1C(=O)CCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
NaH (820 mg of a 50% dispersion, 17 mmol) was covered with DMF (80 mL) and 5-(4,5-diphenyl-2-oxazolyl)-2-pyrrolidinone (4.00 g, 13 mmol) added. The mixture was stirred at about 120° C. for about 15 minutes, cooled to room temperature and methyl 8-bromooctanoate (3.42 g, 14.5 mmol) added. The mixture was heated at about 110° C. for about 1 hour, cooled, diluted with 1N HCl and extracted with Et2O (3 times). The combined extracts were washed with H2O (3 times), dried over Na2SO4 and the solvent evaporated. The residual oil was chromatographed on a column of silica gel using Et2O as eluent to afford methyl 2-(4,5-Diphenyl-2-oxazolyl)-5-oxo-l-pyrrolidineoctanoate (4.85 g, 80%) as an oil. IR (Film) 1740 (CO2CH3), 1695 (N.CO) cm-1 ; 1H NMR (CDCl3) δ1.18-1.60 (10H, m, CH2), 2.20 (2H, t, J=7 Hz, CH2CO2CH3), 2.30-2.55 (3H, m, CH2 of ring), 2.73 (1H, m, CH2 of ring), 3.00 (2H, m, NCH2 of side chain), 3.61 (3H, s, CO2CH3), 4.86 (1H, m, CHN of ring), 7.25-7.40 (6H, m, aromatic H) , 7.50-7.70 (4H, m, aromatic H), MS m/z 461 (MH+).
Reaction SMILES: O=O.C(NC(C)C)(C)C.C([Li])CCC.CN1CCCN(C)C1=O.[CH3:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1.Cl[C:39]([O:41][CH3:42])=[O:40].[Cl-].[NH4+]>C1COCC1.O>[CH3:42][O:41][C:39](=[O:40])[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: COC(=O)Cl
Agent: O=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
With exclusion of oxygen, 11.79 ml (84.11 mmol) of diisopropylamine are introduced into 40 ml of THF and cooled to −78° C., and 52.57 ml (84.11 mmol) of n-butyllithium (1.6 M solution in hexane) are slowly added dropwise. The mixture is stirred at −78° C. for 10 minutes and then 10.17 ml (84.11 mmol) of 1,3-dimethyltetrahydro-2-(1H)-pyrimidinone are added. After 15 minutes, 7.7 g (40.05 mmol) of tert-butyl 4-methylbenzoate, dissolved in 40 ml of THF, are added dropwise, and the mixture is stirred for a further 15 minutes. 3.25 ml (42.05 mmol) of methyl chloroformate are separately dissolved in 20 ml of THF, cooled to −70° C. and then rapidly added to the reaction mixture. After a further 15 minutes, ammonium chloride solution is added to the reaction mixture, which is warmed to room temperature. It is diluted with water, and the phases are separated. The aqueous phase is extracted twice with diethyl ether. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 50:1). 4.2 g (16.78 mmol, 40% yield) of the title compound are obtained as a colourless oil.
Reaction SMILES: Br[C:2]1[C:3]([N+:11]([O-])=O)=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[OH-].[Na+].O>C(=O)([O-])[O-].[Na+].[Na+].[Cu].C(OCC)C>[NH2:11][C:3]1[C:2]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:7](=[O:9])[C:6]=2[N:5]([CH3:10])[N:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cn1nc([N+](=O)[O-])c(Br)c1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc2[nH]c3c(N)nn(C)c3c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A suspension of 4-bromo-1-methyl-3-nitro-1H-pyrazole-5-carboxylic acid ((Y. A. Manaev et al., J. Gen. Chem. USSR. (Engl. Transl.), 1982, 52, 2991), 11.0 g, 43.9 mmol), p-toluidine (23.5 g, 219 mmol), and copper powder (4.0 g, 63.0 mmol) in 5% aqueous sodium carbonate (200 ml) was stirring at 100° C. for 3 h by mechanical stirrer. After cooling to room temperature, 2N sodium hydroxide (50 ml), water (100 ml), and diethyl ether (300 ml) were added to the mixture. The separated aqueous layer was washed with ether (200 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (300 ml×2). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. To the residue (9.46 g) was added phosphorus oxychloride (90 ml), and the stirring mixture was refluxed for 1 h. After cooling to room temperature, the excess phosphorus oxychloride was removed in vacuo. To the black oily residue (ca. 10 g) was added 50% acetic acid (100 ml) at 0° C., and the mixture was refluxed with stirring for 3 h. After cooling to room temperature, the solvent was removed in vacuo, and the residue was suspended with methanol. The formed solid was collected by filtration to give 5.39 g (48%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=[O:3])[CH3:2].[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-benzoic acid prepared in Example 68-(b)-[1] (0.3 g), 4-dimethylaminopyridine (0.01 g) and benzyl alcohol (0.1 g) are dissolved in dichloromethane (25 ml), and thereto is added EDC.HCl (0.18 g), and the mixture is stirred at room temperature three nights. The reaction mixture is washed with saturated aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by a silica gel column chromatography (eluant, chloroform) to give the title compound (0.26 g).
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](OCC3C=CC=CC=3)[CH:18]=2)[NH:13][CH:12]=1)C1C=CC=CC=1.C(N)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N1(C(=O)C2N(CCCBr)C=NC=2N(C)C1=O)C.C(=O)([O-])[O-].[K+].[K+]>>[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: c1ccc(CNCCc2c[nH]c3ccc(OCc4ccccc4)cc23)cc1
Agent: Cn1c(=O)c2c(ncn2CCCBr)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: NCc1ccccc1
Product: NCCc1c[nH]c2ccccc12

Procedure:
N-Benzyl-5-benzyloxytryptamine, which can be prepared by the procedure of Speeter and Anthony, J.A.C.S., 76, 6208 (1954) by reacting 5-benzyloxy-3-indol-glyoxylyl chloride with benzylamine and reducing the product with lithium aluminium hydride, is reacted with 3-(theophyllin-7-yl)propyl bromide in the presence of a weak base such as potassium carbonate to yield N-benzyl-5-benzyloxy-N-[3-theophyllin-7-yl)propyl]tryptamine. Debenzylation by hydrogenation in the presence of a platinum catalyst gives the desired compound. By starting from 5-acetoxy-3-indolglyoxylyl chloride instead of 5-benzylox-3-indol-glyoxylyl chloride and proceeding in analogous manner 5-acetoxy-N-[3-(theophyllin-7-yl)propyl]tryptamine is prepared. Treatment of this compound with ammonia solution to remove the acetyl group gives the desired compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25]
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCOCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (90 mg, 0.30 mmol, 1.00 equiv) in DMF (10 mL) was added 2-chloro-1-(morpholin-4-yl)ethan-1-one (73.35 mg, 0.45 mmol, 1.50 equiv) and potassium carbonate (83 mg, 0.60 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 19 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(morpholin-4-yl)ethan-1-one (30.8 mg) as a white solid. MS (ES, m/z): 430 (M+H+). 1H NMR (400 MHz, CD3OD-d6): δ 8.23 (s, 1H), 4.05-4.08 (m, 1H), 3.67-3.68 (m, 6H), 3.59-3.60 (m, 2H), 3.40 (s, 2H), 3.08 (t, 2H), 3.01 (t, 2H), 2.52-2.59 (m, 3H), 2.34 (s, 3H), 2.16-2.19 (m, 2H), 1.93-1.96 (m, 2H), 1.45-1.57 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)O)=[C:4]([O:15][CH3:16])[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]2[S:14][CH:13]=[N:12][CH:11]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(O)c1cncs1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)ccc1Cc1cncs1
Yield: 56.3 %

Procedure:
A mixture of Example 679A (204 mg, 0.8 mmol), trifluoroacetic acid (0.87 mL, 8 mmol), and triethylsilane (1.27 mL, 8 mmol) in methylene chloride was stirred at room temperature for 5 days. The solution was concentrated under vacuum, diluted with methylene chloride, and poured into 2M NaOH. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was then purified by flash column chromatography on silica gel with 1:1 hexanes/methylene chloride to provide 108 mg (57%) of the title compound. MS (ESI) m/e 240 (M+H)+, 1H NMR (DMSO-d6, 300 MHz): □ 8.88 (s, 1H), 7.67 (s, 1H), 7.21 (d, J=7.80 Hz, 1H), 7.07 (d, J=2.03 Hz, 1H), 6.96 (dd, J=7.80, 2.03 Hz, 1H), 4.10 (s, 2H), 3.84 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[NH:9]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([N:8]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)N(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N(N)Cc1ccccc1
Yield: 91.6 %

Procedure:
##STR187## A solution of of 2-benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide (2.8 g, 9.6 mmol) in 50% trifluoroacetic acid in dichloromethane (10 ml) was stirred for 10 min at room temperature. Then saturated sodium bicarbonate was added until pH >7 and the aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The obtained oil was chromatographed on silica (100 g) with ethyl acetate as eluent to give 1.7 g of 2-benzyl-4-ethylsemicarbazide.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([O:17][C@H:18]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]3[CH2:43][CH2:42]3)[CH:30]=2)[CH2:19][C:20]2[C:25]([Cl:26])=[CH:24][N+:23]([O-:27])=[CH:22][C:21]=2[Cl:28])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:28][C:21]1[CH:22]=[N+:23]([O-:27])[CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][C@@H:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:17][C:15](=[O:16])[CH2:14][NH:13][S:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12]
Reactant: O=C(CNS(=O)(=O)c1ccc(C(=O)O)cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNS(=O)(=O)c1ccc(C(=O)N2CCOCC2)cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
(S)-4-(2-(2-(4-carboxyphenylsulfonamido)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (30 mg, 0.045 mmol), morpholine (19.76 mg, 0.227 mmol), DMAP (11.08 mg, 0.091 mmol) and EDC (43.5 mg, 0.227 mmol) were dissolved in DMF (1.5 ml). The reaction was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(morpholine-4-carbonyl)phenylsulfonamido)-acetoxy)ethyl)pyridine 1-oxide (15 mg, 0.021 mmol, 45.3% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][N:26]([C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1)C(=O)OC(C)(C)C>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:37]4[CH:36]=[N:35][C:34]([NH:26][CH3:25])=[CH:39][CH:38]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CNc1ccc(-c2ccc3c(c2)-c2nc(C(=O)N(CCO)C(C)C)sc2CCO3)cn1
Yield: 2.5 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.9 mg, 0.129 mmol) and tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)carbamate (51.6 mg, 0.154 mmol) were reacted to give 282, purified by HPLC (1.4 mg, 2.5% yield, M+1 439.1).