Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10].[Cl-].[NH4+:23]>C(O)C>[NH:23]=[C:6]1[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:3][CH2:8][NH:7]1
Reactant: [NH4+]
Reactant: COC1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CCO
Product: N=C1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1

Procedure:
The mixture of 5-methoxy-4-p-nitrobenzyloxycarbonyl-1,2,3,6-tetrahydropyrazine (5.7 g) and ammonium chloride (1.6 g) in dry ethanol (100 mL) was heated to reflux for 4 hours. The reaction mixture was then concentrated under reduced pressure. Dichloromethane (100 mL) was added to the residue and extracted with water (3×50 mL) then the combined aqueous layer was washed with dichloromethane. The aqueous layer was neutralized with 10% potassium carbonate aqueous solution and then extracted with dichloromethane (8×50 mL). The combined organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the title compound was obtained as a white solid. Yield: 4.9 g, 91.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClN1C(=O)CCC1=O.[CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])=[CH2:22].C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH2:22][CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])[O:10][N:9]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Reactant: C=CP(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C1CC(c2ccc([N+](=O)[O-])cc2)=NO1

Procedure:
Preparation is carried out in analogy to Example 1 from 19.6 g (0.118 mol) of 4-nitrobenzaldoxime, 17.4 g (0.13 mol) of N-chlorosuccinimide, 16.1 g (0.118 mol) of dimethyl vinylphosphonate and 18.7 ml (0.13 mol) of triethylamine. Crystallization of the crude product from tert.butyl methyl ether provides analytically pure compound of melting point 156° to 158° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](=O)(OC)OC.N1C2C(=CC=CC=2)C(CCC(O)=O)=C1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2)C(CC(O)=O)=C1.N1C2C(=CC=CC=2)C(C(O)=O)=C1>>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)OC
Agent: O=C(O)CCc1c[nH]c2ccccc12
Agent: O=C(O)Cc1c[nH]c2ccccc12
Agent: O=C(O)c1c[nH]c2ccccc12
Product: Cn1ccc2ccccc21
Yield: 45 %

Procedure:
The R group can be at any position of the indole system except position 1. The reaction between indole-3-carboxylic acids and dimethyl carbonate was also investigated. The selectivity between O-methylation and N-methylation was not as high as would be expected. However, as expected, under the reaction conditions, esterfication of a carboxyl group was somewhat faster than N-methylation. For example, the reaction of indole-3-propionic acid with dimethyl carbonate in the presence of potassium carbonate in OMF afforded both an O,N-dimethylated substance in 65% yield after 4 hours at refluxing temperature, together with 30% of the O-methylated product. After the reaction mixture was heated to reflux for another 4 hours, only O,N-dimethylated product was obtained in 93% isolated yield. As demonstrated in Table 2, similar results were observed with indole-3-acetic acid. But when indole-3-carboxylic acid was subjected to the typical reaction conditions, along with 50% of the dimethylated product obtained, 45% of N-methylindole was isolated, formed as a result of decarboxylation of indole-3-carboxylic acid at the reaction temperature (128° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:11][O:12][CH3:13])[CH:10]=1)[C:6]#[N:7].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:33])[CH:22]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)N)=[CH:17][CH:16]=1>CC#N>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[NH:33][C:6]([C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=3)=[N:7][CH:22]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:19][CH:20]=1
Reactant: COCc1cc(C#N)cc(CO)c1
Reactant: NC(c1ccc(Cl)cc1)C(N)c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: COCc1cc(CO)cc(C2=NC(c3ccc([N+](=O)[O-])cc3)C(c3ccc(Cl)cc3)N2)c1

Procedure:
{3-[5-(4-Chloro-phenyl)-4-(4-nitro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-5-methoxymethyl-phenyl}-methanol was prepared from 3-hydroxymethyl-5-methoxymethyl-benzonitrile and 1-(4-chloro-phenyl)-2-(4-nitro-phenyl)-ethane-1,2-diamine in an analogous manner as described in example 35. LR-MS (ES): 452 [(M+H)+], 493 [(M+H+CH3CN)+].
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:23])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH3:26][C:27]1[O:28][C:29]([C:35]2[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=2)=[C:30]([C:32](Cl)=[O:33])[N:31]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:23])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[CH3:20])[O:13][CH:14]=1)[C:32]([C:30]1[N:31]=[C:27]([CH3:26])[O:28][C:29]=1[C:35]1[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1)=[O:33])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)Cl)c1
Reactant: CC(F)(F)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2oc(C)nc2C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)(F)F)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5,5-difluoro-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (74 mg, 0.24 mL) in THF (2.0 mL) was added to a suspension of NaH (26 mg, 0.60 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-methyl-5-m-tolyl-oxazole-4-carbonyl chloride in THF (1.5 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 2 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a colorless oil. TLC: rf (7:3 hept-EA)=0.18. LC-MS-conditions 02: tR=1.17 min, [M+H]+=504.17.
Reaction SMILES: [C:1]([S:5]([NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1)[C:9]1[N:10]=[N:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])[CH:13]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:33]>C1(C)C=CC=CC=1.CO>[C:1]([S:5]([NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[CH:22][N:21]=1)[C:9]1[N:10]=[N:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH3:33])=[O:16])[CH:13]=1)=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C(=O)O)n1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)n1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of 0.30 g (0.65 mmol) 2-(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic acid in 2.5 ml toluene and 0.81 ml MeOH at rt was added 1.3 ml (2.6 mmol) 2.0 M TMS-diazomethane in hexanes. After 4 h at room temperature, the reaction mixture was concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-15% MeOH in CH2Cl2) afforded 0.12 g (38%) methyl 2-(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoate. ES-MS [M+1]+=478.2. 1H NMR (CDCl3, 400 MHz) δ 8.29 (d, J=2.75 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J=8.70 Hz, 1H), 7.24 (m, 1H); 5.87 (d, J=5.31 Hz, 1H,), 5.33 (d, J=5.31 Hz, 1H), 4.38 (q, J=7.70, 2H), 3.71 (d, J=0.82 Hz, 1H); 1.92 (d, J=1.65 Hz, 6H); 1.27 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].N1C=CC=CC=1.[CH3:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](Cl)=[O:42]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:41]([C:40]4[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=4[CH3:38])=[O:42])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)c2ccccc2C)cc1OC
Reaction time: 16 h

Procedure:
0.46 g of the compound prepared in Example 5 step B), 20 ml of DCM and 0.5 g of pyridine were mixed at 20° C. and 0.18 g of 2-methylbenzoyl chloride in 10 ml of DCM was then added. The reaction mixture was stirred for 16 hours and then concentrated under vacuum. The residue was washed with water, with 1N hydrochloric acid, with 10% sodium carbonate and then with water. It was dried over sodium sulfate and the solvent was then evaporated off to dryness to give the expected product in the form of a white solid, which crystallized from isopropyl ether. m=0.3 g. M.p.=180° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:11][CH2:12][NH:14][CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1ccc(OC)cc1)c1ccc2cc[nH]c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccc(OC)cc1)c1ccc2cc[nH]c2c1

Procedure:
[3-(1H-Indol-6-yl)-3-(4-methoxy-phenyl)-propyl]-methyl-amine XXXVI was prepared as a hydrochloride salt (220 mg, 61%) from 3-(1H-indol-6-yl)-3-(4-methoxy-phenyl)-N-methyl-propionamide using the procedure described above for preparation of [3-(1H-indol-7-yl)-3-phenyl-propyl]-methyl-amine XX. MS (M+H)=295.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[C:5]([NH:7][C:8]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:9]=1[C:10]([O:12]C(C)(C)C)=[O:11])=[O:6]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[C:5]([NH:7][C:8]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COc1ccccc1C(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2-methoxybenzamido)-4-phenoxybenzoate and stirred at room temperature for 3 minutes. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 52 mg of 2-(2-methoxybenzamido)-4-phenoxybenzoic acid as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:25]4[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: C1CNCCNC1
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCCNCC4)c(F)cc3cc2c1=O
Yield: 80.8 %

Procedure:
The 3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(perhydro-1,4-diazepin-1-yl)-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 3, but starting from 2 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 2 g of hexahydro-1,4-diazepine. 2 g of 3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(perhydro-1,4-diazepin-1-yl)-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 226° C.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][S:12]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[CH:19][CH:18]=1)(=[O:14])=[O:13])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.O1CCCC1>[C:4]([O:8][C:9]([NH:11][S:12]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[CH:21][CH:22]=1)(=[O:14])=[O:13])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
Lithium hydroxide monohydrate (826 mg, 19.68 mmol) in water (10 mL) was added to a solution of ethyl 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoate (3.8 g, 9.84 mmol) in tetrahydrofuran (30 mL) at 0° C. and stirred at room temperature for 18 h. The volatiles were evaporated; the residue diluted with water (50 mL) and extracted with diethyl ether (2×20 mL). The aqueous layer was acidified (pH ˜5) with acetic acid at 0° C., precipitated solid was filtered and dried under reduced pressure to afford 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoic acid (2.3 g, 56%) as white solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.[SH:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[OH-].[K+]>CC(O)C>[NH:8]1[CH:9]=[C:5]([CH2:4][CH2:3][S:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[N:6]=[CH:7]1
Reactant: ClCCc1c[nH]cn1
Reactant: Sc1ncc[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1c[nH]c(SCCc2c[nH]cn2)n1

Procedure:
183 mg (1.1 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride, 110 mg (1 mmol) of 2-mercapto-1H-imidazole and 200 mg (3.26 mmol) of solid potassium hydroxide are brought to reflux in 10ml of 2-propanol for 4 h. The mixture is then evaporated and the semi-solid residue is chromatographed through silica gel, using a chloroform/methanol (5/1) mixture. The resulting product is treated with oxalic acid in ethanol to provide the title compound in the form of an oxalate salt, M.p.: 224-°226° C.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][N:27]1[CH:31]=[N:30][N:29]=[C:28]1[SH:32]>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:32][C:28]3[N:27]([CH3:26])[CH:31]=[N:30][N:29]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cn1cnnc1S
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nncn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70) where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4-methyl-4H-1,2,4-triazole-3-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:31][CH2:32][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:34][CH2:35]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)CCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCC(C)(C)C)s4)cc23)CC1
Yield: 5 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (3,3-dimethylbutyl)amine (32 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 4.5 mg of the title compound (5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6][C@@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([F:17])[CH:15]=3)[CH:10]=[C:9]2[C:21]([CH3:33])([CH3:32])[C:22](OCC2C=CC=CC=2)=[O:23])[CH2:4][O:3]1.CC1(C)O[C@@H](CN2C3C(=CC([N+]([O-])=O)=C(F)C=3)C=C2C(C)(C)C(OC[C@H]2COC(C)(C)O2)=O)CO1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH3:34])[O:6][C@@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([F:17])[CH:15]=3)[CH:10]=[C:9]2[C:21]([CH3:33])([CH3:32])[CH2:22][OH:23])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](Cn2c(C(C)(C)C(=O)OCc3ccccc3)cc3cc([N+](=O)[O-])c(F)cc32)O1
Agent: CC1(C)OC[C@H](Cn2c(C(C)(C)C(=O)OC[C@H]3COC(C)(C)O3)cc3cc([N+](=O)[O-])c(F)cc32)O1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc([N+](=O)[O-])c(F)cc32)O1
Reaction time: 0.08 h
Yield: 49 %

Procedure:
The mixture of crude reaction mixture of (S)-benzyl 2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate and ((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate was dissolved in THF (15 mL) and cooled in an ice-water bath. LiAlH4 (2.8 mL of 1 M solution, 2.8 mmol) was added dropwise. After addition was complete the reaction was stirred for 5 minutes. The reaction was quenched by adding water (0.5 mL), 15% NaOH solution (0.5 mL) and then water (1.5 mL). The mixture was filtered over Celite, and the solids were washed with THF and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate-hexanes) to obtain the product as a brown oil (505 mg, 49% over 2 steps). ESI-MS m/z calc. 366.4, found 367.3 (M+1)+. Retention time 1.68 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J=7.6 Hz, 1H), 7.65 (d, J=13.5 Hz, 1H), 6.57 (s, 1H), 4.94 (t, J=5.4 Hz, 1H), 4.64-4.60 (m, 1H), 4.52-4.42 (m, 2H), 4.14 (dd, J=6.2, 8.4 Hz, 1H), 3.74 (dd, J=7.0, 8.3 Hz, 1H), 3.63-3.53 (m, 2H), 1.42 (s, 3H), 1.37 (m, 6H) and 1.19 (s, 3H) ppm.
Reaction SMILES: C[O-].[Na+].C([O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)(=O)C>CO>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][OH:7])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCc1ccc(CCOC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCc1ccc(CCO)cc1

Procedure:
Sodium methoxide (22.6 g) and methanol (450 mL) are charged into a 1 liter single neck round bottom flask equipped with a guard tube and stirred for few minutes to form a clear solution. A mixture of 4-octylphenethyl acetate (58 g) and methanol (50 mL) is added and the mass is stirred for 3 hours at room temperature. Methanol is evaporated and the residue is diluted with water (300 mL) and extracted with ethyl acetate (2×300 mL). The extracts are combined, dried with sodium sulphate and concentrated under vacuum to give crude as yellow color liquid. The crude is purified is by a silica gel column using 30% ethyl acetate/hexane as the eluent to yield the title compound. Yield: 56 g.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][O:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N+]=[N-]>[Pd].C(O)(C)C>[NH2:1][C@@H:4]1[CH2:9][O:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@H]1C[C@H](NC(=O)OC(C)(C)C)[C@H](N=[N+]=[N-])CO1
Agent: [Pd]
Solvent: CC(C)O
Product: C[C@H]1C[C@H](NC(=O)OC(C)(C)C)[C@H](N)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A mixture of tert-butyl (2S,4S,5S)-5-azido-2-methyltetrahydro-2H-pyran-4-ylcarbamate (1.8 g, 3.6 mmol) and 10% palladium on carbon (50 mg) in isopropanol (10 mL) was stirred at room temperature under hydrogenation overnight. After that, the mixture was filtered through a pad of celite. Concentrated to get the title compound (150 mg, crude) as a yellow oil, which was used directly for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20]([O:22]CC)=O)=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20]([NH2:25])=[O:22])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1nn(CCO)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Product: CCc1c(Sc2cc(Cl)cc(Cl)c2)c(C(N)=O)nn1CCO

Procedure:
A mixture of Example 46 (407 mg, 1.05 mmol) and 0.880 ammonia solution was heated at 90° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. The precipitate was filtered off and washed with water (5 ml) to afford the title compound (273 mg) as a white solid, m.p. 214-216° C.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)C=CC=CC=1>CO.C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(OCc3ccccc3)c2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Reaction time: 48 h
Yield: 93.1 %

Procedure:
A slurry of palladium hydroxide on carbon (330 mg) in methanol (10 mL) was added to a solution of 1,1-dimethylethyl 4-[3-(phenylmethoxy)phenyl]-1-piperazinecarboxylate (Description 20, 3.25 g, 8.8 mmol) in ethyl acetate/methanol (1:9) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 48 h. The mixture was filtered through celite and the solvent was evaporated under reduced pressure to give the title compound (2.28 g, 93%). 1H NMR (360 MHz, CDCl3) δ1.48 (9H, s), 3.10-3.13 (4H, m), 3.54-3.57 (4H, m), 6.34 (1H, dd, J 7.9, 2.2 Hz), 6.41 (1H, t, J 2.0 Hz), 6.34 (1H, dd, J 8.3, 2.2 Hz), and 7.11 (1H, t, J 7.9 Hz).