Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[N:6]1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1
Reactant: [H][H]
Reactant: COC(C)(C)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: COC(C)(C)Cn1ccc(N)n1
Yield: 70.9 %

Procedure:
In a Parr shaker bottle was placed 1-(2-methoxy-2-methyl-propyl)-3-nitro-1H-pyrazole (1.33 g, 6.68 mmol), 10% palladium on activated carbon (135 mg) and ethanol (50 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 2 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentration in vacuo with silica gel (3 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 5% methanol/ethyl acetate) to afford 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (802 mg, 71%) as a colorless oil: ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2208; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 6H, 2×CH3), 3.13 (s, 3H, OCH3), 3.80 (s, 2H, NCH2), 4.48 (brs, 2H, NH2), 5.38 (d, J=2.3 Hz, 1H, Ar), 7.21 (d, J=2.3 Hz, 1H, Ar).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:29])=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>O1CCCC1>[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:13]=[CH:12][C:11]=3[CH3:29])=[O:8])=[CH:5][CH:4]=2)[CH2:41][CH2:40]1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Reactant: CN1CCCNCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CN2CCCN(C)CC2)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1.5 g, 3.49 mmol) was dissolved in tetrahydrofuran (30 ml), pyridine (560 μl, 6.98 mmol) was added, and the mixture was stirred for 30 minutes. N-methylhomopiperazine (660 μl, 5.23 mmol) was added thereto, and the resulting mixture was refluxed for 12 hours and then filtered. The filtrate was concentrated and crystallized from dimethylether to give 4-(4-methylhomopiperazin-1-ylmethyl)-N-[2-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made in the following manner: 2 g of 4-Bromobenzyl bromide and 1 equ. piperazine in acetonitrile would be stirred at room temperature and 1.1 g of potassium carbonate would be added. The reaction would be stirred at room temperature overnight. The solution would then be filtered through Celite and concentrated in vacuo to afford the crude product. Purification would be done by flash chromatography using a methylene chloride/methanol gradient.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:16]2[N:12]([C:13](=[O:17])[NH:14][CH2:15]2)[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1.[H-].[Na+].I[CH3:27]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C@H:16]2[N:12]([C:13](=[O:17])[N:14]([CH3:27])[CH2:15]2)[C@H:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1
Reactant: CI
Reactant: O=C1NCC2C(c3cc(F)ccc3F)=CC(c3ccccc3)N12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C[C@H]2C(c3cc(F)ccc3F)=C[C@@H](c3ccccc3)N2C1=O

Procedure:
A solution of 2-4a (0.02 g, 0.06 mmol), sodium hydride (5 mg), and iodomethane (0.004 mL, 0.03 mmol) in THF (1.0 mL) was stirred at rt for 1 h. The reaction was quenched with water (2.0 mL) and extracted with EtOAc (20 mL). The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The remaining oil was dissolved in CH3CN (0.5 mL) and purified on a Gilson automated system affixed with a YMC J'sphere H80 20×50 mm column (eluting with 5-95% CH3CN +0.1% TFA in water +0.1% TFA over 10 min) to afford pure 2A-1a.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(OC)c(F)c1
Temperature: 120 °C
Yield: 87.8 %

Procedure:
The mixture of 3-fluoro-4-methoxybenzaldehyde (5.1 g, 33.0 mmol) and (carbethoxymethylene)triphenylphosphorane (17.2 g, 49.5 mmol) in anhydrous toluene (165 mL) was refluxed at 120° C. under nitrogen for 4 hours. The solvent was removed in vacuo and purified by silica gel chromatography (10-20% EtOAc in hexanes) to provide (E)-ethyl 3-(3-fluoro-4-methoxyphenyl)acrylate (537) (6.5 g, 87.6%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:38][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)C(N)=O
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)C(C)(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and 2,2-dimethylpropanamide, the title compound was obtained as crystals, melting at 170°-172° C. (from ethyl acetate).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](N(CC)C)=[O:33])[CH2:26]5)[N:24]=4)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:51][C:52]1[CH:61]=[CH:60][CH:59]=[CH:58][C:53]=1C(OC)=O>CN(C=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@@H:27]([N:31]6[CH2:51][C:52]7[C:53](=[CH:58][CH:59]=[CH:60][CH:61]=7)[C:32]6=[O:33])[CH2:26]5)[N:24]=4)=[CH:14][CH:13]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4CCN(C5CCCC5)CC4)cc3)n2)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ncc(N2CCC[C@@H](N3Cc4ccccc4C3=O)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added DIEA (180 μL, 1.0 mmol) and then methyl 2-bromomethylbenzoate (46 mg, 0.2 mmol) at RT. The reaction temperature was raised to 60° C. and the mixture was stirred for overnight. It was cooled to RT, quenched with 0.5 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(1-oxoisoindolin-2-yl)piperidin-1-yl)pyrazine-2-carboxamide (450), as HCl salt (19 mg). LC-MS (ESI): m/z (M+1) 580.8. UV: λ=269, 275, 304, 335, 372 nm. Proton NMR (CD3OD): δ 7.84 (1H, d, J=7.5 Hz), 7.69 (1H, s), 7.66-7.58 (2H, m), 7.56-7.52 (3H, m), 7.12 (2H, d, J=8.5 Hz), 4.67-4.57 (3H, m), 4.40-4.30 (2H, m), 3.64 (2H, m), 3.55 (1H, m), 3.27-3.06 (4H, m), 2.76 (1H, m), 2.24-1.72 (18H, m) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH:17]1[C:13]2=[N:14][CH:15]=[CH:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[C:12]2[CH:19]=[CH:18]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]ccc23)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Nc2ccnc3[nH]ccc23)cc1

Procedure:
36 mg of 10% palladium-on-carbon are added to a solution of 170 mg (0.67 mmol) of N-(4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-4-amine in 6 ml of ethanol, and the suspension is stirred in a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through Celite and the Celite is washed with ethanol. Concentration under reduced pressure gives the target product.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
Orcinol monohydrate (7.10 g, 50 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to a mixture of NaH (95%, 24 g, 100 mmol) in N,N-dimethylformamide (60 mL) and the mixture was stirred at room temperature for 20 min. Benzyl bromide (8.55 g, 50 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to the mixture and stirred at room temperature for 2 hours. Water (100 mL) was added slowly to the reaction mixture. The reaction mixture was extracted with ethyl acetate (3×100 mL) and then the organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After the solvent was evaporated, the residue was purified by flash column chromatography (silica gel, 3:1 hexane:ethyl acetate) to give the title compound as a yellow oil (5.20 g, 48%). 1H-NMR (300 MHz, CDCl3) δ7.39 (m, 5H), 6.40 (s, 1H), 6.29 (t, J=5.3 Hz, 1H), ), 6.26 (s, 1H), 5.25 (s, 1H), 4.99 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:21][O:22][C:23](=[O:50])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([O:43][CH:44]([CH3:46])[CH3:45])=[C:35]([CH:47]=O)[C:34]=2[CH3:49])=[CH:27][CH:26]=1>O1CCCC1>[CH3:21][O:22][C:23](=[O:50])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([O:43][CH:44]([CH3:45])[CH3:46])=[C:35]([CH:47]=[CH2:1])[C:34]=2[CH3:49])=[CH:27][CH:26]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Yield: 38 %

Procedure:
A solution of methylidene triphenyl phosphorane [5 mL of 0.1M solution, 0.5 mmol, generated from methyl triphenylphosphonium bromide (2.5 g, 7 mmol) and 1.6M n-butyllithium solution in hexanes (2.9 mL, 4.7 mmol) in 50 mL of tetrahydrofuran] was added to a solution of [4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 144, 0.052 g, 0.13 mmol) in tetrahydrofuran (1 mL). After 1 h the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil that after flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent afforded the title compound (0.02 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=1)=[O:4].[CH2:18](I)[CH3:19].[H-].[Na+].Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH3:19])[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2c(c3cc(C(=O)OC)ccc31)CCCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1,2,3,4-Tetrahydrocarbazole-6-carboxylic acid methyl ester (460 mg) prepared by the method described in Journal of Chemical Society, p.809 (1926) was dissolved in 2.5 mL of DMF, and the solution was added with 0.3 mL of ethyl iodide and 120 mg of sodium hydride and stirred at room temperature at 50° C. for 2 hours under a nitrogen flow. Then, the reaction mixture was added with water, neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane) to obtain 490 mg of N-ethyl-1,2,3,4-tetrahydrocarbazole-6-carboxylic acid methyl ester.
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-:13])(=O)=O)=CC=1.[C:14]([O:22][CH3:23])(=[O:21])/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18].[H-].[Na+]>CN(C=O)C>[NH:12]1[CH:13]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]([C:14]([O:22][CH3:23])=[O:21])=[CH:11]1
Reactant: COC(=O)/C=C/C(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]cc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
TOSMIC (1.5 g, 7.7 mmol) was added to a solution of dimethyl fumarate (1 g, 6.9 mmol) and sodium hydride (60%, 0.59, 12.5 mmol) in dry DMF (25 ml) at 0° C., and the solution stirred at 0° C. for 15 minutes. The reaction was poured onto ice-water and the product filtered and recrystallised from aqueous ethanol. 0.61 g, 48%. 1H-n.m.r. (DMSO-d6) δ (ppm) 3.68 (6H, s, 2×CH3), 7.39 (2H, s, 2×CH), 11.81 (1H, s, NH).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:18])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[CH:11]2)[CH2:2][CH2:3][CH3:4].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32]>CN(C)C=O>[CH2:1]([NH:5][C:6]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[C:11]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CCCCNC(=O)Cc1ccc2c(ccn2C)c1
Solvent: CN(C)C=O
Product: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
A solution of N-butyl-1-methylindole-5-acetamide (0.46 g) and methyl 4-bromomethyl-3-methoxybenzoate (0.49 g) in dimethylformamide (10 ml) was heated at 80° under a nitrogen atmosphere for 18 hr. Additional methyl 4-bromomethyl-3-methoxybenzoate (0.49 g) was added to the reaction and stirring was continued for 18 hr at 80°. The dimethylformamide was evaporated: and the oily residue was purified by flash chromatography, eluting with 1:1 ethyl acetate:hexane to give methyl 4-(5-butylcarbamoylmethyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (0.23 g, 30%) as a white solid; NMR (250 MHz, CDCl3): 0.84(t, 3H, N(CH2)CH3), 1.35-1.16(m, 4H, NCH2 (CH2)2), 3.13(q, 2H, NCH2), 3.65(s, 2H, ArCH2CO), 3.75(s, 3H, NCH3), 3.90(s, 3H, OCH3), 3.94(s, 3H, OCH3), 4.09(s, 2H, ArCH2Ar'), 5.34(br, 1H, NH).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=1.[H-].[Na+].O>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:11]=1
Reactant: OCC1CCOCC1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(OCC2CCOCC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-yl methanol (1.00 g) and 2,6-difluoropyridine (1.19 g) in DMF (10 mL) was added 60% sodium hydride (410 mg), and the mixture was stirred at 80° C. for 8 hours. Water (50 mL) was added dropwise to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20) to obtain 2-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (1.36 g).
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[NH2:11][N:12]1[C:16]([NH2:17])=[N:15][N:14]=[C:13]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[C:5]1([C:2]2[CH:3]=[N:11][N:12]3[C:13]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)=[N:14][N:15]=[C:16]3[N:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Product: Oc1ccc(Cc2nnc3nc(-c4ccccc4)cnn23)cc1

Procedure:
General procedure A was followed with the reaction of oxo-phenyl-acetaldehyde and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol to provide 4-(7-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol and the desired product 4-(6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (example 3).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[NH2:18][OH:19].[OH-].[K+].CO>C1COCC1>[OH:19][NH:18][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: NO
Reactant: COC(=O)CCCCCSc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCCCCSc1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 6-(4-chlorophenylsulfanyl)-hexanoic acid methyl ester (0.59 g, 2.2 mmol) in distilled THF (13 mL) containing 50% aqueous hydroxylamine (1.3 mL, 19.6 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 3.5 mL, 3.5 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (13 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×25 mL) and the combined extracts were washed with brine (20 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.54 g, 90%) as a white powder, mp 83-85° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20]>CCN(CC)CC>[Cl:14][C:9]1[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:20][C:19]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:17]([O:16][CH3:15])[CH:18]=3)[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1ncnc(-c2cccnc2Cl)n1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncnc(-c3cccnc3Cl)n2)cc(OC)c1OC
Yield: 89.2 %

Procedure:
2-Chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (1.7 g, 7.5 mmol) was stirred overnight at RT with 3,4,5-trimethoxyaniline (1.5 g, 8.3 mmol) in IpOH (200 mL). After addition of Et3N (2 ml), stirring was continued for an additional day. The mixture was concentrated, triturated with t-BuOMe and filtered, rinsing with a small amount of IpOH. The [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine (2.5 g) was isolated as the Et3HN+Cl− salt. Part of this material was filtered through a plug of silica and analyzed. MS m/z=374 [M+H]+; 3H). Calc'd for C17H16ClN5O3: 373.09. Remaining material was used without filtering in the next step.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[CH2:15][CH2:14][C:6]2=[C:7]([C:11]([OH:13])=O)[S:8][C:9]([CH3:10])=[C:5]2[CH2:4]1)[CH3:2].Cl.[CH2:19]([C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([CH3:31])[N:30]=1)[C:24]([NH:26][NH2:27])=O)[CH3:20]>>[CH2:16]([C:3]1([CH2:1][CH3:2])[CH2:15][CH2:14][C:6]2=[C:7]([C:11]3[O:13][C:24]([C:23]4[CH:28]=[C:29]([CH3:31])[N:30]=[C:21]([CH2:19][CH3:20])[CH:22]=4)=[N:26][N:27]=3)[S:8][C:9]([CH3:10])=[C:5]2[CH2:4]1)[CH3:17]
Reactant: CCc1cc(C(=O)NN)cc(C)n1
Reactant: CCC1(CC)CCc2c(C(=O)O)sc(C)c2C1
Agent: Cl
Product: CCc1cc(-c2nnc(-c3sc(C)c4c3CCC(CC)(CC)C4)o2)cc(C)n1

Procedure:
4-[5-(5,5-Diethyl-3-methyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-pyridine is synthesized from 5,5-diethyl-3-methyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid and 2-ethyl-6-methyl-isonicotinic acid hydrazide hydrochloride in analogy to Example 9; LC-MS: tR=0.98 min, [M+1]=396.39.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[O:20]1[CH:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21]1.[OH:31][P:32]([OH:35])([OH:34])=[O:33]>CO.C(O)C>[P:32](=[O:31])([OH:35])([OH:34])[OH:33].[OH:20][CH:22]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21][N:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:19][CH:18]=2)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(CC(O)COc3ccccc3)CC2)cc1

Procedure:
To a solution of 13.31 g (47 mmol) 1-[4-[(methylsulfonyl)amino]benzoyl]piperazine in 50 mL methanol add 6.4 mL (47 mmol) 1,2-epoxy-3-phenoxypropane. Stir the reaction mixture at roomtemperature under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride: MeOH, 9:1). When the reaction is complete, remove the solvents in vacuo toobtain an oil. Dissolve the oil in ethanol with one equivalent of H3PO4 and remove the solvents to obtain the title compound.