Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.Cl[C:22]1[N:27]=[C:26]([NH2:28])[N:25]=[C:24]2[NH:29][N:30]=[CH:31][C:23]=12.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH:20][C:22]3[N:27]=[C:26]([NH2:28])[N:25]=[C:24]4[NH:29][N:30]=[CH:31][C:23]=34)[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]ncc12)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 54.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (500 mg, 1.71 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (436 mg, 2.57 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.895 mL, 5.14 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was diluted with MeOH/DMSO and purified by preparative HPLC (basic mode) eluting with 35% ACN in water. The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (360 mg, 54.2%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.83 Hz, 3 H), 3.59-3.68 (m, 3 H), 3.83 (s, 3 H), 5.57 (dd, J=13.42, 6.59 Hz, 3 H), 6.46 (d, J=1.46 Hz, 1 H), 6.61 (d, J=2.93 Hz, 1 H), 7.55 (d, J=1.46 Hz, 1 H), 7.72 (d, J=3.42 Hz, 1 H), 7.89 (s, 1 H), 7.95-8.03 (m, 2 H), 12.33 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H20N10,389; found 389.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=O)[CH:8]=2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[O:16])[CH:8]=2)=[O:4]
Reactant: NCCc1ccccn1
Reactant: COC(=O)c1cc2ccc(C(=O)O)cc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccc(C(=O)NCCc3ccccn3)cc2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 2-(methoxycarbonyl)indole-6-carboxylic acid (290 mg, 1.32 mmol) and 1,1'-carbonyldiimidazole (257 mg, 1.59 mmol) in THF (20 mL) was stirred at reflux for 1 h then cooled and evaporated. A solution of 2-(2-aminoethyl)pyridine (0.19 mL, 1.6 mmol) in DMF (5 mL) was added and the mixture stirred at 80° C. for 2 h, then cooled and evaporated. Trituration with hot EtOAc gave 2-(methoxycarbonyl)-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide as a white solid (360 mg, 84%), mp 191-193° C. 1H NMR [(CD3)2SO] δ12.24 (s, 1H, indole NH), 8.61 (t, J=5.5 Hz, 1H, amide NH), 8.54-8.50 (m, 1H, H-6'), 7.97 (s, 1H, H-3 or H-7), 7.71 (td, J=7.6, 1.8 Hz, 1H, H-4'), 7.70 (d, J=8.6 Hz, 1H, H-4), 7.55 (dd, J=8.6, 1.4 Hz, 1H, H-5), 7.29 (d, J=7.8 Hz, 1H, H-3'), 7.23 (ddd, J=7.4, 4.8, 0.8 Hz, 1H, H-5'), 7.20 (s, 1H, H-3 or H-7), 3.90 (s, 3H, CO2Me), 3.64 (q, J=6.8 Hz, 2H, NHCH2CH2 py), 3.03 (t, J=7.4 Hz, 2H, NHCH2CH2 py); 13C NMR δ166.6 (CONH), 161.5 (CO2Me), 159.2 (C-2'), 136.7, 131.0, 129.1, 128.5 (C-2,6,8,9), 149.0, 136.4, 123.1, 121.6, 121.4, 118.9, 112.2, 107.5 (C-3,4,5,7,3',4',5',6'), 51.9 (OCH3), 39.3, 37.3 (NHCH2CH2 py). Anal. (C18H17N3O3) C,H,N.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22]([O:24]C)=[O:23])[N:4]=[C:3]1[CH3:26].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22]([OH:24])=[O:23])[N:4]=[C:3]1[CH3:26]
Reactant: COC(=O)c1nc(C)n(C)c1C(=O)NCCc1nc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(=O)O)c(C(=O)NCCc2nc3ccccc3n2C)n1C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
To a solution of methyl 1,2-dimethyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-imidazole-4-carboxylate (98 mg, 276 μmol) in THF (2 mL) and MeOH (1 mL) at room temperature was added LiOH (1M, 1.1 mL, 1.1 mmol). The reaction mixture was stirred at r. t. for 6 h. The reaction mixture was acidified with hydrochloric acid (1M, 1.5 mL), all volatiles were removed in vacuo and the residue was suspended in dichloromethane/MeOH (95:5) and filtered. The liquid was evaporated and dried in vacuo to give the product as colorless amorphous material (95 mg, 264 μmol, 95.9%) which was used without any further purification for the next step. MS: M=340.2 (M−H)−
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(=O)(=O)NCCO)cc3)cc2)CC1
Yield: 26.2 %

Procedure:
The title compound (25 mg, 26%) was prepared as a white solid from (4-{[(2-hydroxyethyl)amino]sulfonyl}phenyl)boronic acid (49 mg, 0.2 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, 2H, J=8.6 Hz), 7.68 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.9 Hz), 4.98-4.86 (m, 2H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.75-3.69 (m, 2H), 3.19-3.12 (m, 2H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 3H), 1.37-1.27 (m, 2H), 1.25 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 477 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[Br:17]N1C(=O)CCC1=O>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:17])=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1-c1ccccn1
Product: COc1ccc(Br)c(OC)c1-c1ccccn1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 2 using 1,3-Dimethoxy-2-(Pyrid-2-yl) benzene 37 and N-bromosuccinimide to yield 38.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH-:7].[Na+]>>[Si:2]([O:7][Si:2]([O-:4])([O-:3])[O-:1])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: [OH-]
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])O[Si]([O-])([O-])[O-]

Procedure:
400 g of a commercially available water glass solution having an SiO2 :Na2O ratio of 2:1 and a solids content of 45% by weight, prepared by hydrothermal digestion of sand with sodium hydroxide solution, were dehydrated in a laboratory hot-air spray tower (inlet temperature 220° C., outlet gas temperature 120° C.) to give an amorphous sodium disilicate having an ignition loss of 16.8% by weight at 620° C. 8 g of the amorphous sodium disilicate were then heat-treated for 1 h in a muffle furnace at 620° C. and then rapidly cooled. The X-ray reflections (position and intensity) required for the phase calculation are given in Table 1. According to the above formulae, the percentage distribution among the crystalline phases is:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[SnH:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13].Cl[C:23]1[N:28]=[C:27]([Cl:29])[CH:26]=[CH:25][N:24]=1>C1COCC1>[Cl:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([Sn:9]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH3:13])[N:28]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Temperature: -20 °C
Reaction time: 5 h
Yield: 13.7 %

Procedure:
To a solution of LDA (251 ml, 502 mmol) in THF (650 mL) at −20° C. was added SnBu3H (108.5 ml, 402 mmol) dropwise. The mixture was maintained at −20° C. for 15 min, then cooled to −78° C. 2,4-dichloro pyrimidine (50 g, 335 mmol) was added and the reaction was stirred at −78° C. for 5 h. The cooling bath was removed and the reaction was slowly warmed to 0° C. within 30 min. The mixture was poured into 10% NH4Cl at 0° C., and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 1% EtOAc in Hex) to give 4-chloro-2-(tributylstannyl)pyrimidine (18.5 g, 24%) as a pale yellow color syrup. MS (ESI, pos. ion) m/z: 405.1 (M+1); 1H-NMR (400 MHz, CDCl3): δ 8.54 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 1.61-1.54 (m, 6H), 1.37-1.28 (m, 6H), 1.21-1.17 (m, 6H), 0.90 (m, 9H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11]([C:17]([CH3:21])([CH3:20])[CH:18]=[O:19])=[CH:10][C:9]2=[O:22])[CH2:2][CH2:3][CH3:4].[NH2:23][OH:24]>CO.O>[CH2:1]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]3[C:11]([C:17]([CH3:21])([CH3:20])[CH:18]([OH:19])[N+:23]=3[O-:24])=[CH:10][C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCOc1ccc2c(c1)C(=O)C=C(C(C)(C)C=O)C2=O
Solvent: CO
Solvent: O
Product: CCCCOc1ccc2c(c1)C(=O)C=C1C2=[N+]([O-])C(O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-Butoxy-1,4-dioxo-1,4-dihydro-2-naphthalenyl)-2-methylpropanal (compound 5 prepared in step (I) above) (53 mg, 0.18 mmol) in MeOH (5 mL) and water (0.5 mL), 50% NH2OH in water solution (17 μL, 0.28 mmol) was added. The mixture was stirred 3 h at room temp and the solvent was evaporated. The crude product was fairly pure and was taken into the next step without further purification. Yield: 52 mg (92%). 1H NMR (400 MHz, CDCl3) δ 0.99 (tr., 3H), 1.38 (s, 3H), 1.52 (s, 3 H), 1.55 (m, 2 H), 1.84 (quint., 2H), 4.13 (tr., 2H), 5.31 (s, 1 H), 6.43 (s, 1H), 7.24 (d, 1 H), 7.73 (d, 1 H), 9.07 (d, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2=[O:17].S(Cl)([Cl:21])(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:21])[C:11]=1[O:12][CH2:13][CH3:14])[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2=[O:17]
Reactant: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O

Procedure:
Following General Procedure B, 6-bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 2.8 g, 9.33 mmol) and sulfuryl chloride (1.51 g, 11.2 mmol) in dichloromethane were reacted to yield the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C(Cl)=O.O[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[C:27]([O:33][CH3:34])[CH:26]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[C:27]([O:33][CH3:34])[CH:26]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: COc1cc(O)ccc1C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)c(OC)c2)cc1
Reaction time: 2 h
Yield: 15.3 %

Procedure:
Prepared using General Procedure 2: To a stirred solution of 4-(heptyloxy)benzoic acid (1.41 g, 5.98 mmol) in DCM (10 mL) was added DMF (3 drops) and oxalyl chloride (0.589 mL, 6.87 mmol). After stirring for 2 h, the reaction mixture was added to a solution of 4-hydroxy-2-methoxybenzaldehyde (1 g, 6.57 mmol) and TEA (1.25 mL, 8.96 mmol) in DCM (10 mL) and stirred for 18 h. The reaction mixture was diluted with DCM (100 mL) and was washed with NaHCO3 (100 mL). The organic layer was pre-absorbed onto silica gel and purified by chromatography (EA/isohexanes) to afford 340 mg (15%) 4-formyl-3-methoxyphenyl 4-(heptyloxy)benzoate INT-25 as a white solid. LCMS-ESI (m/z) calculated for C22H26O5: 370; found 371 [M+H]+, tR=3.17 min (Method 10).
Reaction SMILES: C[O-:2].[Na+].C([C@@H]1CC[C@@H](C)C[C@H]1OC([N:17]1[CH:22]=[CH:21][CH2:20][C:19](=O)[C@H:18]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH3:31])=O)(C)C>CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C@H:18]2[CH2:19][C:20](=[O:2])[CH:21]=[CH:22][NH:17]2)=[C:25]([CH3:31])[CH:26]=1
Reactant: C[O-]
Reactant: Cc1cc(F)ccc1[C@@H]1C(=O)CC=CN1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: [Na+]
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1CC(=O)C=CN1
Yield: 161 %

Procedure:
Sodium methoxide (100 mg) was added to a solution of intermediate 6b (170 mg) in MeOH (15 mL) under a nitrogen atmosphere. The mixture was refluxed for two hours, and the solvent was removed in vacuo. The residue was partitioned between water (10 mL) and AcOEt (15 mL). The layers were separated, and the aqueous phase was extracted with further AcOEt (4×10 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give the title compound (145 mg) as a light yellow oil.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.I[CH2:23][C:24]([NH2:26])=[O:25].[H-].[Na+]>CN(C=O)C>[NH2:26][C:24](=[O:25])[CH2:23][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(N)=O)c3ccccc23)CC1
Reaction time: 16 h
Yield: 19.5 %

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0994 g, 0.347) and iodoacetamide (0.0704 g, 0.381 mmol, 1.10 equiv.) was dissolved in DMF (1 mL) at rt under N2. NaH (0.033 g, 0.825 mmol, 2.38 equiv., 60% dispersion) was added, and the reaction mixture was stirred for 16 h. Additional NaH (0.039 g) was added and the reaction mixture was stirred for 1.5 h. The reaction mixture was poured over ice, and the resulting mixture was extracted with EtOAc. The organic extracts was washed with water and then with brine. The organic extracts was dried over MgSO4, filtered, and concentrated. The crude product (0.124 g) was purified by PTLC (2×1 mm×20 cm×20 cm SiO2 plates, developed with 3:1 EtOAc:hexane, eluted with 10% MeOH in CH2Cl2) to give tert-butyl 6-(2-amino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0233 g) in 19% yield. 1H NMR (300 MHz, CDCl3) δ 1.50, 2.93-3.07, 3.68-3.79, 4.71, 5.33, 5.90-5.94, 7.15-7.24, 7.50-7.54; MS (ESI+) for C19H25N3O3 m/z 344.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4]1.Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>CN(C=O)C>[CH3:15][O:14][C:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]([CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:13]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60% dispersion in mineral oil, 86 mg, 2.14 mmol) is added to a solution of methyl indole-4-carboxylate (250 mg, 1.427 mmol) in DMF (20 ml) and the resulting suspension is stirred at room temperature for 30 minutes. After this time (2-(2-bromoethoxy)tetrahydro-2H-pyran (388 mg, 1.86 mmol) is added and the reaction is stirred at room temperature for 22 hours. Dilution with EtOAc (50 ml), washing with water (25 ml×3), saturated NaHCO3 (25 ml×2) and brine (25 ml), drying over MgSO4, concentration in vacuo and purification by chromatography (SiO2, DCM/MeOH) affords 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 304
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)[CH3:19].[Na]>C(O)C>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH:28]=[CH:1][C:3]2[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=2)=[O:29])=[CH:23][CH:22]=1)[CH3:19]
Reactant: CCOc1ccc(C(C)=O)cc1
Reactant: CCC(C)(Oc1ccc(C=O)cc1)C(=O)OC
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc(C(=O)C=Cc2ccc(OC(C)(CC)C(=O)OC)cc2)cc1

Procedure:
Following the procedure in Example 1 using 7.1 parts of methyl 2-(4-formylphenoxy)-2-methyl-2-ethylacetate and 4.9 parts of p-ethoxyacetophenone in 10 parts by volume of ethanol containing 0.1 part of sodium metal provides methyl 2-[4-(2-p-ethoxybenzoylethenyl)phenoxy]-2-methyl-2 ethylacetate. This compound has the following structural formula. ##SPC11##
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]Br.Cl.Cl.[CH3:12][NH:13][NH:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH3:12][N:13]1[CH2:2][C:3]2[N:4]=[CH:5][S:6][C:7]=2[CH2:8][N:14]1[CH3:15]
Reactant: BrCc1ncsc1CBr
Reactant: CNNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1Cc2ncsc2CN1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under ice cooling, 4,5-bis(bromomethyl)thiazole (600 mg) and 1,2-dimethylhydrazine dihydrochloride (294 mg) were suspended in ethanol (20 ml). Triethylamine (1.23 ml) was added in one portion to the reaction mixture, followed by stirring at room temperature for 30 minutes and then, at 50° C. for 30 minutes. The solvent was distilled off and the residue was purified by chromatography on a silica gel column (5% methanol—methylene chloride), whereby the title compound (90 mg, 24%) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[NH2:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH2:25]Br)=[C:19]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[CH:18]=2)[CH:10]=[CH:9][C:8]=1[N+:36]([O-:38])=[O:37]>CC#N>[NH2:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH2:25][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[C:19]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[CH:18]=2)[CH:10]=[CH:9][C:8]=1[N+:36]([O-:38])=[O:37]
Reactant: Nc1nc(NCCNc2ccc(NC(=O)CBr)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Reactant: CNCCO
Solvent: CC#N
Product: CN(CCO)CC(=O)Nc1ccc(NCCNc2ccc([N+](=O)[O-])c(N)n2)cc1-c1ccc(Cl)cc1Cl
Reaction time: 12 h
Yield: 21 %

Procedure:
N-Methyl ethanolamine (2 eq) was added to a stirred solution N-[4-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-2-(2,4-dichlorophenyl)phenyl]-2-bromoacetamide (8.65 eq) in CH3CN at room temperature. The reaction was monitored by LC/MS and was determined to be complete after 12 hours. The reaction was concentrated and purified by silica column chromatography eluting with MeOH in CH2Cl2 (5:95, v/v). After collecting the purified fractions and concentrating, N-[4-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-2-(2,4-dichlorophenyl)phenyl]-2-[(2-hydroxyethyl)methylamino]acetamide was obtained as a light yellow glass (21% yield, LC/MS m/z 549.4 MH+) in 95% purity.
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:15](=[O:16])[C:14]2[CH:13]=[C:12]3[CH:11]=[C:10]([F:27])[C:9]([F:28])=[CH:8][C:7]3=[N:6][C:5]=2[N:24]([CH2:25][CH3:1])[CH:23]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CCN
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3cc(F)c(F)cc3cc2c1=O
Reaction time: 0.67 h
Yield: 90.7 %

Procedure:
A solution, at about 2° C., of 14.6 g of ethylamine in 200 cm3 of ethanol is added in the course of 10 minutes, at between 2° and 5° C., with stirring, to a suspension of 20 g of ethyl 2-(2-chloro-6,7-difluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 200 cm3 of ethanol at about 2° C., the mixture is stirred for a further 40 minutes at between 2° and 5° C. and the temperature is then allowed to rise to about 20° C. in the course of 2 hours. After 24 hours at about 20° C., the insoluble matter is drained and washed with 2 times 30 cm3 of ethanol and 2 times 50 cm3 of diisopropyl ether. 16.35 g of 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthridine are obtained in the form of a beige solid melting at 290° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:12][CH2:13][N:14]1[C:22]2[C:21]([O:23][CH3:24])=[N:20][CH:19]=[N:18][C:17]=2[C:16]([CH:25]=O)=[CH:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:27][C:28]([CH2:33][OH:34])([CH2:31][OH:32])[CH2:29][OH:30]>CO>[CH2:5]([O:12][CH2:13][N:14]1[C:22]2[C:21]([O:23][CH3:24])=[N:20][CH:19]=[N:18][C:17]=2[C:16]([CH2:25][NH:27][C:28]([CH2:33][OH:34])([CH2:31][OH:32])[CH2:29][OH:30])=[CH:15]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(CO)(CO)CO
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ncnc2c(CNC(CO)(CO)CO)cn(COCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
Sodium cyanoborohydride was added to a suspension of 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (50 mg, 168 μmol) and 2-amino-2-(hydroxymethyl)propane-1,3-diol (20.37 mg, 168 μmol) in methanol (5 mL) and stirred overnight at r.t. The crude reaction was absorbed onto silica and eluted with 20% MeOH/EtOAc to afford 2-((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(hydroxymethyl)propane-1,3-diol (24 mg, 59.6 μmol, 35.5% yield) as a syrup. 1H NMR (d4-MeOH) 8.42 (s, 1H), 7.65 (s, 1H), 7.23 (m, 5H), 5.74 (s, 2H), 4.51 (s, 2H), 4.11 (s, 3H), 4.04 (s, 2H), 3.68 (s, 6H). 13C NMR (d4-MeOH) 158.4, 151.2, 150.9, 139.1, 134.4, 129.7, 129.2, 129.0, 117.5, 116.4, 78.9, 71.9, 62.9, 62.6, 54.8, 36.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:22]([NH2:24])=[O:23])[N:12]3[C:17](S(C)=O)=[CH:16][C:15]([CH3:21])=[N:14][C:13]=23)=[C:4]([CH3:25])[CH:3]=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28].C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:22]([NH2:24])=[O:23])[N:12]3[C:17]([N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])=[CH:16][C:15]([CH3:21])=[N:14][C:13]=23)=[C:4]([CH3:25])[CH:3]=1
Reactant: CCCNCCC
Reactant: Cc1cc(S(C)=O)n2c(C(N)=O)cc(-c3c(C)cc(Br)cc3C)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)c1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A mixture of 8-(4-bromo-2,6-dimethyl-phenyl)-4-methanesulfinyl-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (100 mg), N,N-dipropylamine (48 mg) in ethanol (1 mL) was heated at reflux for 1 h. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=1:1) to give a solid. The solid was washed with a mixture of diisopropylether and ethyl acetate to give the title compound (50 mg).