Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2.[OH-:27].[K+]>C(O)(C)(C)C>[NH2:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH2:26])=[O:27])=[N:23][CH:24]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(N)c2ccc(C#N)nc2)CCN(C)C1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
To a solution of 5-[1-amino-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carbonitrile (400 mg, 1.15 mmol) in tert-butanol (20 mL) was added crushed KOH (194 mg, 3.47 mmol) and the reaction mixture was stirred at 80° C. for 1 h. The progress of reaction was monitored by LCMS. The reaction mixture was concentrated to dryness. The residue was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 5-[1-amino-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carboxylic acid amide (70 mg). The racemate can be further separated into the optically active forms by chiral preparative HPLC. 1H NMR (CDCl3, free base) δ (ppm): 8.5 (s, 1H), 8.2 (d, 1H), 7.9 (d, 1H), 7.2 (m, 2H), 7.0 (d, 1H), 5.6 (bs, 1H), 4.6 (t, 1H), 4.1 (d, 2H), 3.7 (q, 2H), 2.9 (t, 2H), 2.8 (m, 1H), 2.6 (m, 1H), 2.58 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:13]([O-:15])=[O:14])[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2
Reactant: CC1Cc2cc(Cl)ccc2C1=O
Reactant: O=[N+]([O-])O
Product: CC1Cc2cc(Cl)c([N+](=O)[O-])cc2C1=O

Procedure:
According to Example 1 (a), 28.0 g (0.155 mole) of 5-chloro-2-methyl-1-indanone and 180 ml of fuming nitric acid yield the nitro compound having a melting point of from 75° to 78° C., which after recrystallization from ethanol rises to 87° to 89° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:32])[CH2:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1>C(Cl)(Cl)Cl>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:32])[CH2:29][CH2:30][CH2:31]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:19]([O-:6])=[CH:18][C:17]=2[N:26]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC1(Cn2c(CCl)nc3cnc4ccccc4c32)CCC1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2nc(CCl)n(CC3(O)CCC3)c2c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperoxybenzoic acid (9.15 g of 70% pure material, 37.1 mmol) was added to a suspension of 1-{[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (8.00 g, 26.5 mmol) in chloroform (100 mL) under a nitrogen atmosphere, and the reaction was stirred at room temperature overnight. Additional chloroform (200 mL) was added, and the solution was washed sequentially with saturated aqueous sodium bicarbonate (2×80 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1-{[2-(chloromethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol as a yellow solid.
Reaction SMILES: [S:1]1C=C[CH:3]=[C:2]1[CH:6]=[O:7].[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][O:12][C:13]([CH3:18])([CH2:16]O)CO>C1C=CC=CC=1>[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][O:12][C:13]1([CH3:18])[S:1][CH:2]([CH:6]2[O:7][CH2:3][CH2:2][CH2:6][O:7]2)[CH:3]=[CH:16]1
Reactant: O=Cc1cccs1
Reactant: CC(CO)(CO)OCc1ccccc1F
Solvent: c1ccccc1
Product: CC1(OCc2ccccc2F)C=CC(C2OCCCO2)S1

Procedure:
Using the procedure of Example 51, thiophene-2-carboxaldehyde and 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol were reacted, using benzene as solvent, to give, after separation by column chromatograph, c-5-(2-fluorobenzyloxy)-5-methyl-r-2-thienyl-1,3-dioxane, m.p. 111°-112°, and t-5-(2-fluorobenzyloxy)-5-methyl-r-2-thienyl-1,3-dioxane, m.p. 84°-85°.
Reaction SMILES: [O:1]([C:8]1[CH:39]=[CH:38][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[C:15]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[N:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]([C:8]1[CH:39]=[CH:38][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:27][CH:26]=3)=[N:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
After a mixture of ethyl 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyloxy)-1H-pyrazole-4-carboxylate (500 mg), 1N sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyloxy)-1H-pyrazole-4-carboxylic acid (450 mg, yield: 95%). This was recrystallized from acetone-hexane. Melting point: 141–142° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:31])([CH2:29][CH3:30])[C:27]#[CH:28]>CCOCC.CO.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:28]#[C:27][C:26]([OH:31])([CH3:25])[CH2:29][CH3:30])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C#CC(C)(O)CC
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Cu]I
Solvent: CCOCC
Solvent: CO
Product: CCC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 3-methyl-1-pentyn-3-ol were reacted in the presence of CuI and (PhP3)2PdCl2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/MeOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-pentynyl)anilino]-N-(2-hydroxyethoxy)benzamide (77%) as a white solid; m.p. (CH2Cl2/Hexane) 127-131° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.79 (br s, 1 H), 8.79 (br s, 1 H), 7.45-7.39 (m, 1 H), 7.28-7.18 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.6 Hz, 1 H), 5.31 (br s, 1 H), 4.71 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.68-1.57 (m, 2 H), 1.40 (s, 3 H), 0.98 (t, J=7.4 Hz, 3 H). Anal. Calcd for C21H21F3N2O4: C, 59.7; H, 5.0; N, 6.6. Found C, 59.9; H, 5.1; N, 6.9.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>C(OCC)C>[C:1]([NH:5][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 1 L three-necked round-bottomed flask was charged with diethylether (500 mL), tert-butylamine (11.3 mL, 105 mmol), and triethylamine (14.9 mL, 105 mmol). To this vigorously stirred solution at 0° C. was slowly added pivaloyl chloride (8.9 mL, 100 mmol) and the resultant white slurry was stirred for 18 h at ambient temperature. This slurry was then filtered with a water aspirator pump and the volatile components of the filtrate were removed under reduced pressure. The resultant crystalline solid was sublimed at 55° C./0.05 Torr to afford LtBu,tBuH as white crystals (15.41 g, 98%): mp 116-118° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: OCCCBr
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(CCCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
N-piperazine carboxylic acid ethyl ester (25.50 g, 161.39 mmol), 3-bromo-1-propanol (22.43 g, 161.39 mmol), potassium carbonate (55.68 g, 403.48) and anhydrous acetonitrile (200 mL) were placed in a 500 mL round bottom flask, heated for refluxing and stirred overnight. The reaction was cooled down to room temperature, filtered, concentrated and subjected to a column chromatography (eluting agent: dichloromethane/methanol/triethylamine system, v/v/v 100:1:0.5) to obtain a light yellow oily substance, 26.60 g, yield 76.3%, which was directly used in the next step of reaction.
Reaction SMILES: [CH2:1]([O:15][C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:35](I)[CH3:36]>O>[CH2:35]([O:22][C:21]([C:19]1[S:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23])[CH3:36]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 10.6 g (0.031 mole) of 5-tetradecyloxy-2-thiophene carboxylic acid, 4.3 g (0.034 mole) of potassium carbonate, and dimethylformamide is stirred at room temperature after which 15.6 g (0.10 mole) of ethyl iodide is added. The mixture is heated at 50° C with stirring overnight and poured into water and extracted with the ether. The ether layer is washed with water and salt water and then dried over sodium sulfate, filtered, and the ether is distilled off to give 5-tetradecyloxy-2-thiophenecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[S:21]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])(=[O:24])(=[O:23])[NH2:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: NS(=O)(=O)c1cccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 84.7 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and m-sulfamoylaniline (100 mg, 0.58 mmol) to give 209 mg of the title compound (85%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.33 (s, 1H), 8.13 (s, 1H), 7.70~7.78 (m, 1H), 7.45~7.55 (m,2H), 7.24 (bs, 1H), 7.15 (bs, 1H), 5.15~5.28 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.65 (dd, 1H, J=18, 13.5 Hz), 2.58 (dd, 1H, J=18, 5.4 Hz), 2.12 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[O:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:28][CH:25]3[CH2:24][CH2:23][N:22]([CH:19]4[CH2:20][CH2:21][O:16][CH2:17][CH2:18]4)[CH2:27][CH2:26]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: O=[N+]([O-])c1ccc(C2CC2)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2CC2)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 90 °C
Yield: 58.5 %

Procedure:
A stirred mixture of 4-cyclopropyl-2-fluoro-1-nitrobenzene (D37, 180 mg, 0.99 mmol), 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (diHCl salt of D9, 280 mg, 1.1 mmol) and N,N-diisopropylethylamine (0.56 ml, 3.3 mmol), in dimethylformamide (5 ml) was stirred at room temperature for 3 hrs, then heated at 90° C. for 18 hrs. The cooled mixture was concentrated under vacuum and the residue treated with dilute K2CO3 solution (20 ml) and extracted with ethyl acetate (3×30 ml). The combined extract was washed with water, dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (40 g) eluting with 1-10% methanol/dichloromethane to afford the title compound as an orange solid (200 mg, 59%). M++H=346.0.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:18]=[C:17](F)[C:14]([C:15]#[N:16])=[C:13]([F:20])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:21]1([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.O>[C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([F:20])[C:14]([C:15]#[N:16])=[C:17]([O:27][CH2:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:18]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCc1cc(F)c(C#N)c(F)c1
Reactant: OCC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1cc(F)c(C#N)c(OCC2CCCC2)c1
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a stirred solution of the above benzonitrile intermediate (8.66 mmol) and cyclopentanemethanol (781 mg, 7.8 mmol) in THF (45 mL) at 0° C. was added N-sodium hexamethyldisilazane (1 M in THF, 7.8 mL, 7.8 mmol) and the reaction was stirred overnight. It was diluted with water, extracted with dichloromethane, washed with brine, dried with sodium sulfate, concentrated and dried in vacuo to give 4-(N-boc-2-aminoethyl)-2-cyclopentylmethoxy-6-fluorobenzonitrile (1.27 g, 3.5 mmol, 45%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].O>C(Cl)Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11])[CH2:2]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 7.0 g (55.0 mmol) of (R)-3-quinuclidinol were suspended in 100 ml of CH2Cl2. After cooling the suspension to 0° C., a solution of 1,1′-carbonyldiimidazole (10.7 g, 66.0 mmol) in 150 mL of CH2Cl2 was added. The reaction mixture was stirred at 0° C. for 4 hours, then water was added (100 ml). The organic layer was separated, washed with water, dried over sodium sulphate and the solvent was evaporated under reduced pressure. The residue oil (13.1 g) was used without further purification.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34]>CN(C=O)C.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.[Cu](I)I>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[C:34]#[C:33][CH2:32][OH:35])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(C#CCO)n2Cc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (300 mg, 0.588 mmol, intermediate 14) in anhydrous DMF (12 mL) was added prop-2-yn-1-ol (0.15 ml, 2.545 mmol), bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.043 mmol), copper iodide (10 mg, 0.053 mmol) (45 mg, 0.402 mmol) and TEA (3 mL, 21.6 mmol). Then the mixture was degassed and refilled with nitrogen 3 times. The reaction was stirred at 85° C. overnight under nitrogen. The mixture was cooled, filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/ethyl acetate (3:1 to 1:1) to give 7-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (170 mg, 59.5% yield) as a light yellow solid. LCMS retention time 1.523 min; LCMS MH+ 487.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:36]=[CH:35]C(N)=[CH:32][CH:31]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].CI.[CH3:45][N:46]([CH:48]=O)[CH3:47]>>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:48]([N:46]([CH3:45])[CH3:47])=[CH:35][CH:36]=2)[N:22]=[CH:21]1
Reactant: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1ccc(CCOc2ccccc2-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
To a solution of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethyl)aniline (100 mg, 0.192 mmol) in DMF (4 mL) was added NaH (15 mg, 0.575 mmol) followed by methyl iodide (24 μL, 0.383 mmol). The reaction was stirred at room temperature for 20 h and quenched with water. Methanol (3 mL) and acetic acid (1 mL) were added to the reaction mixture and heated at 80° C. for 2 h. The mixture was poured into water (10 mL) and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried and concentrated. The crude product was purified by flash column chromatography (silica gel, 3%-7% MeOH/DCM as eluent) to afford the desired product as a gel (32 mg, 0.104 mmol, 54%). 1H NMR: 3.02 (s, 6H), 3.16 (t, 2H, J=6.4 Hz), 4.39 (t, 2H, J=6.4 Hz), 6.99 (t, 4H, J=7.8 Hz), 7.18-7.24 (m, 2H), 7.35 (d, 2H, J=10.8 Hz), 7.69 (s, 1H), 7.70 (d, 1H, J=7.2 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1>C1C=CC=CC=1>[Cl:11][C:12]1[C:17]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: OCc1ccccc1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1nccnc1OCc1ccccc1

Procedure:
Sodium hydride (0.10 mole) is added to 0.10 mole of benzyl alcohol in 100 ml. dry benzene and the mixture is refluxed 1-2 hours. The cooled solution is treated with 0.10 mole of 2,3-dichloropyrazine in 100 ml. of benzene. The mixture is refluxed for 20-60 hours, cooled, washed with water, dried, and evaporated and the product distilled in vacuo to give 2-chloro-3-benzyloxypyrazine.
Reaction SMILES: Br.Br.[CH3:3][C:4]([NH2:9])([CH3:8])[CH2:5][CH2:6][NH2:7].C[O-].[Na+].[Br:13][C:14]#[N:15]>CO.O>[BrH:13].[CH3:3][C:4]1([CH3:8])[CH2:5][CH2:6][NH:7][C:14]([NH2:15])=[N:9]1
Reactant: N#CBr
Reactant: CC(C)(N)CCN
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CCNC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 195.8 %

Procedure:
1.95 g of 3-methylbutane-1,3-diamine dihydrobromide are suspended in 20 mL of MeOH, 1.2 g of sodium methanolate are added. The mixture is stirred at RT for 2 h. The mixture is filtered and then dry evaporated. The reaction crude is solubilized in 20 mL of water, cooled with an ice bath. 0.78 g of BrCN are added and stirred at RT for 12 h. The mixture is dry evaporated, 3 g (quantitative yield) of 4,4-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrobromide are obtained as a translucent oil which will be used as such for the following:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23])=O.N1CCCC1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 5-fluoro-1,3-dihydroindol-2-one (A2) (20 g, 132 mmol), 5-formyl-2,4-dimethylpyrrole-3-carboxylic acid (A1) (21.1 g, 126 mmol), pyrrolidine (5 ml) and absolute ethanol (400 mL) were heated to reflux for 3 hours. Then the mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 mL). The solid was stirred in ethanol (350 ml) at reflux for 0.5 h again. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 mL) and dried under vacuum overnight to give (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (A3) (35.3 g, 93%) as orange solid. LC-MS observed [M−H]+: 299.2.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:16]C.O>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][CH3:16])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: OCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 3-(4-bromophenoxy)-1-propanol (10.0 g). To the mixture was added under ice-cooling 65% sodium hydride (2.4 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise iodoethane (3.8 ml), and the mixture was stirred for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-bromo-4-(3-methoxypropoxy)benzene (8.6 g).