Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][NH:7][C:6]1=[S:13].[OH-].[Na+].[CH3:21]I>C(O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[S:13][CH3:21]
Reactant: CI
Reactant: Cc1n[nH]c(=S)n(Cc2cc(F)ccc2Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (16, 914 mg, 2.77 mmol) in ethanol (15 mL) was added NaOH (111 mg, 2.77 mmol) followed by MeI (787 mg, 5.54 mmol). The mixture was stirred at RT for 10 min to produce a clear yellow solution. The reaction was diluted with water (100 mL), and extracted with EtOAc (30 mL×2). The extracts were washed with brine, dried over MgSO4 and concentrated to give the crude product. This was purified by silica gel column, and eluted with 20-25% ethyl acetate in petroleum ether to give 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (17). 1H NMR (400 MHz, DMSO, ppm): δ 7.73 (m, 1H), 7.16 (br, 1H), 7.05 (d, 1H), 5.09 (s, 2H), 2.56 (s, 3H), 2.32 (s, 3H). MS: m/z, 344 (100%, M+1), 346 (100%).
Reaction SMILES: Br[CH:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[CH3:11][C:7]1[N:6]=[C:5]([C:3]2[N:22]=[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]3[C:2]=2[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)C(Br)c2ccc3ncccc3c2)n1
Reactant: Nc1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc3ccccn3c2-c2ccc3ncccc3c2)n1
Temperature: 80 °C
Yield: 24.8 %

Procedure:
A solution of 2-bromo-1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone of Step D (60 mg, 0.176 mmol)in dimethylformamide (1 mL) was treated with 2-aminopyridine (50 mg, 0.53 mmol, 3 equiv), and heated to 80° C. over 4.5 hours. After cooling down, the mixture was treated with water and extracted with ethyl acetate. The organics were concentrated in vacuo and reverse phase column chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provided the title compound (14.7 mg, 25%). HPLC tR=1.71 min, LCMS 337.3 (M+1).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:33])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=C(c1ccccc1-c1cccc(Cl)c1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 3′-chloro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C27H23ClN4O, 454.95; m/z found, 455.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[C:8]([NH:10][C:11](=[O:12])[C:5]=1[CH:6]=2)=[O:9])([O-:3])=[O:2].[CH:15](Br)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:15]([N:10]1[C:11](=[O:12])[C:13]2=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]2[C:8]1=[O:9])([CH3:17])[CH3:16]
Reactant: CC(C)Br
Reactant: O=C1NC(=O)c2cc1ccc2[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 60 °C
Yield: 70 %

Procedure:
4-Nitroisophthalimide (25.0 g, 130.0 mmol) was dissolved in DMF (250 mL). Isopropyl bromide (61.0 mL, 650 mmol) and potassium carbonate (36.0 g, 260 mmol) were added and the mixture was heated to 60° C. overnight. Water (1.0 L) was added, and the precipitate formed was collected by filtration, washed twice with water and dried overnight in a vacuum oven to afford 21.3 g (70%) of pure N-isopropyl-4-nitrophthalimide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24]([O:30]C)=[N:25][CH:26]=[CH:27][C:28]=4I)[NH:20]3)=[C:16]([CH3:32])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:33].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4[Cl:33])[NH:20]3)=[C:16]([CH3:32])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nccc(I)c1-c1nc2c(C)nc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2[nH]1
Reactant: Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[8-(4-iodo-2-methoxy-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 2.54 mmol) in glacial acetic acid (30 mL) was added 11.6 M HCl (30 mL). The reaction mixture was stirred at 75° C. for 6 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (250 mL) followed by the addition of triethylamine (2.78 mL, 20 mmol). The solution was cooled to 0° C. and di t-butyl dicarbonate (573 mg, 2.63 mmol) was added. The reaction mixture was stirred at 23° C. for 2 hours, poured on saturated NaHCO3 solution and extracted with CH2Cl2 (3×200 mL). The combined organic layers, were dried over MgSO4 and concentrated to give the title compound as a yellow solid. (0.691 g, 62%). HPLC 93%; LCMS (+ESI, M+H+) m/z 446; IR (KBr, cm−1) 3431, 2974, 1700, 1506, 1229; 1H NMR (400 MHz, DMSO+D2O) δ 7.64 (d, J=7.0 Hz, 0.7H), 7.32 (d, J=7.0 Hz, 0.3H), 6.89 (d, J=7.0 Hz, 0.3H), 6.59 (d, J=7.0 Hz, 0.7H), 3.75 (br s, 4H), 3.45 (br s, 4H), 2.60 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:37])[C:15]([N:17]1[CH2:20][CH:19]([O:21][C:22]2[C:27]3[CH:28]=[C:29]([CH3:31])[O:30][C:26]=3[CH:25]=[C:24]([C:32](OCC)=[O:33])[CH:23]=2)[CH2:18]1)=[O:16]>ClCCl>[CH3:37][N:14]([CH3:13])[C:15]([N:17]1[CH2:20][CH:19]([O:21][C:22]2[C:27]3[CH:28]=[C:29]([CH3:31])[O:30][C:26]=3[CH:25]=[C:24]([C:32]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:33])[CH:23]=2)[CH2:18]1)=[O:16]
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1cc(OC2CN(C(=O)N(C)C)C2)c2cc(C)oc2c1
Agent: C[Al](C)Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(OC3CN(C(=O)N(C)C)C3)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of 2-amino-5-methylpyridine (203 mg, 1.88 mmol) in dichloromethane (5 mL) at 0° C. was added Al(CH3)2Cl (1.88 mL, 1M in hexanes) drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 4-({1-[(dimethylamino)carbonyl]azetidin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (65 mg, 0.19 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over Na2SO4. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (95/5 to 85/15) to give the title compound (70 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 3 H) 2.37 (s, 3 H) 2.78 (s, 6 H) 3.30-3.44 (m, 2 H) 3.44-3.60 (m, 1 H) 3.88 (dd, J=12.13, 6.06 Hz, 1 H) 4.05 (dd, J=11.75, 2.40 Hz, 1 H) 6.70 (s, 1 H) 6.98 (d, J=9.60 Hz, 1 H) 7.71-7.85 (m, 1 H) 7.92 (s, 1 H) 8.17 (d, J=8.34 Hz, 1 H) 8.28-8.44 (m, 2 H); MS (ESI, pos): 409.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1.C1(N=C=N)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:35][CH2:36][C:37]([C:40]1[O:44][C:43]([C:45]2[CH:46]=[CH:47][C:48]([Cl:52])=[C:49]([OH:51])[CH:50]=2)=[C:42]([C:53]2[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=2)[CH:41]=1)([CH3:39])[CH3:38]>CN(C=O)C>[Cl:52][C:48]1[CH:47]=[CH:46][C:45]([C:43]2[O:44][C:40]([C:37]([CH3:39])([CH3:38])[CH2:36][NH:35][C:12]([CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][O:3][CH3:2])[CH2:11][CH2:10]3)=[O:14])=[CH:41][C:42]=2[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][CH:58]=2)=[CH:50][C:49]=1[OH:51]
Reactant: COCCN1CCC(C(=O)O)CC1
Reactant: CC(C)(CN)c1cc(-c2ccncc2)c(-c2ccc(Cl)c(O)c2)o1
Agent: Cl
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCC(C(=O)NCC(C)(C)c2cc(-c3ccncc3)c(-c3ccc(Cl)c(O)c3)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
A solution of the product of Example 4 Step 2 (265 mg, 1.18 mmol) in DMF (5 ml) was treated with N-cyclohexylcarbodiimide, N′-methyl polystyrene (1.8 g) and 1-hydroxybenzotriazole hydrate (162 mg, 1.19 mmol). The mixture was stirred at room temperature for 30 minutes and then treated with a solution of the product of Example 3 Step 2 (407 mg, 1.19 mmol) in DMF (2 ml). After stirring for a further 16 hours, the reaction mixture was applied to a Bond Elut SCX cartridge. The cartridge was eluted with methanol and then 0.880 ammonia solution/methanol (1:9) to elute the product. After concentrating in vacuo, the product was purified further by chromatography on silica gel eluting with chloroform/ethanol/0.880 ammonia solution (90:9:1) to yield the title compound (340 mg, 56%); MS (ES+) m/e 512, 514 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:30])[C:15]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:16]N(C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:32]1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:30])[C:15]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:16][OH:32])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1CCOC1
Reactant: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc3c(c2)CCCC3)cc1OC
Agent: Cl
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Three grams (3.00 g) of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (7.35 mmol), 30 ml of 5% hydrochloric acid and 30 ml of tetrahydrofuran were mixed and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 2.20 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[N+:30]([C:33]1[NH:34][CH:35]=[CH:36][N:37]=1)([O-:32])=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:12]([CH2:11][C:3]1([CH2:2][N:34]2[CH:35]=[CH:36][N:37]=[C:33]2[N+:30]([O-:32])=[O:31])[CH2:4][O:5][C:6]([CH3:10])([CH3:9])[O:7][CH2:8]1)[Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OCC(CBr)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2ccnc2[N+](=O)[O-])CO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
1.70 g (3.56 mmol equivalents) of 5-bromomethyl-5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-1,3-dioxane was dissolved in 36 mL of dimethylformamide, 402 mg (3.56 mmol equivalents) of 2-nitroimidazole and 1.48 g (10.7 mmol equivalents) of potassium carbonate were added thereto, and the mixture was heated in an oil bath to 80° C. and then stirred for 18 hours. After completion of the reaction, water was added dropwise, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=3/1) to give 362 mg (0.71 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C[N+]([O-])=O>[F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: O=[N+]([O-])O
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1c(F)ccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 17.1 %

Procedure:
6-Fluoro-3-hydroxybenzoic acid (100 mg, 0.64 mmol) was dissolved in CH3NO2 (10 mL) and cooled to 0° C. HNO3 (90%, 31 μL, 0.64 mmol) was added and the reaction was left at 0° C. for 4 h and then at room temperature over night. Evaporation and purification by flash chromatography on SiO2 (Toluene-EtOAc-HOAc) gave the product (22 mg). 1H NMR (CD3OD): δ 7.32 (t, J=9.0 Hz, 1 H), 7.15 (dd, J1 =9.3 Hz, J2 =4.4 Hz, 1 H); 13C NMR: δ 164.97, 153.68 (d, J=247 Hz), 148.78, 122.67, 122.56, 122.45, 122.13.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:23][CH3:24])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[CH:18]1([C:17]2[N:10]3[C:11]([C:12](=[O:14])[NH:13][C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])[CH:7]=[CH:6][CH:5]=4)=[N:9]3)=[C:15]([CH2:23][CH3:24])[N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCc1nc(C2CCCC2)n2nc(-c3cccc(N)c3)[nH]c(=O)c12
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc(NC(=O)C(C)(C)C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 mg (0.16 mmol) 2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one (Example 29) and 78 mg (0.77 mmol) triethylamine are dissolved in 4 ml dichloromethane. 37 mg (0.31 mmol) 2,2-dimethylpropanoyl chloride are added dropwise. The mixture is stirred for 2 hours at room temperature and then washed with 1 N potassium hydrogensulfate solution and with saturated sodium hydrogencarbonate solution. The organic layers are dried and evaporated to dryness in vacuo. The product is purified by chromatography (flash or column chromatography).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[Br:16]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:16][C:13]1[CH:14]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[N:3][C:2]=2[CH3:1])[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: Cc1nnccc1Oc1cccnc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnccc1Oc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
3-(3-Methylpyridazin-4-yloxy)pyridin-2-amine (0.50 g, 2.5 mmol) was dissolved in DMF (7 mL). N-Bromosuccinimide (0.46 g, 2.6 mmol) was added and the solution stirred at ambient temperature for 5 minutes. The solution was diluted with water and filtered through celite (rinsing with chloroform). The solution was extracted with chloroform, dried (Na2SO4), filtered and concentrated. Flash chromatography gave 5-bromo-3-(3-methylpyridazin-4-yloxy)pyridin-2-amine (0.66 g, 95%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:13])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12].CCN(CC)CC.[CH3:21][O:22][C:23](=[O:26])[C:24]#[CH:25]>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:26])[CH:24]=[CH:25][O:1][NH:2][C:3](=[NH:13])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: C#CC(=O)OC
Reactant: COCCOCCOCC(=N)NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOCC(=N)NOC=CC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of crude N-hydroxy-2-[2-(2-methoxy-ethoxy)-ethoxy]-acetamidine (3.02 g) and NEt3 (2.30 mL) in DCM (40 mL) was added propynoic acid methyl ester (1.43 mL) dropwise. The mixture was stirred for 30 min at RT, washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue, crude 3-({2-[2-(2-Methoxy-ethoxy)-ethoxy]-acetimidoyl}-aminooxy)-acrylic acid methyl ester (4.50 g) was directly used in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.I.O.[I-].[Na+]>C(#N)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (12.0 g, 46.3 mmol) was dissolved in 20 mL of anhydrous acetonitrile and 4-(trifluoromethyl)aniline was added (7.0 mL, 55.6 mmol), followed by 47% HI/H2O (2.0 L) and sodium iodide (10.3 g, 69.5 mmol). The mixture was heated at refluxed overnight and solvents were removed under vacuum. The residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to a yellow solid which was purified by silica gel flash chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as a brown oil (15 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(N(CC)CC)C.O1CCCC1.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[CH:21]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(I)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(3-iodophenylacetamido)-4-chlorobenzoate (m.p. 100°-101° C.; prepared by the general procedure described above; 860 mg, 2 mmol) in triethylamine (20 ml) and tetrahydrofuran (5 ml), was added copper (I) iodide (5 mg), bis(triphenylphosphine)palladium (II) dichloride (20 mg) and phenylacetylene (0.33 ml, 306 mg, 3 mmol), and the mixture stirred overnight at room temperature and then for 5 h at reflux. The solvents were removed, the residue partitioned between ethyl acetate (30 ml) and aqueous citric acid (10%, 25 ml), and the organic layer washed with water (25 ml) and brine (25 ml). After drying (MgSO4), the solution was evaporated and the residue subjected to chromatography on silica gel (4:1 petrol-ethyl acetate as eluant) to afford methyl 4-chloro-2-(3-phenylethynylphenyl)acetamidobenzoate as a colourless gum (824mg); δH (CDCl3) 3.75 (2H, s, --CH2 --), 3.87 (3H, s, CO2Me), 7.03 (1H, dd, J 9.4 and 2.1 Hz, 5-H), 7.33-7.38 (5H, m, ArH), 7.48-7.55 (4H, m, ArH), 7.91 (1H, d, J 9.4 Hz, 6-H), 8.82 (1H, d, J 2.1 Hz, 3-H), and 11.14 (1H, br s, --NHCO--).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccncc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnccc1C
Yield: 53.3 %

Procedure:
To solution of 3-amino-4-methylpyridine (540.2 mg, 5.0 mmol, 1 equiv) in dichloromethane (20 mL) was added pyridine (0.8 mL, 10.0 mmol, 2 equiv) and acetic anhydride (0.57 mL, 6.0 mmol, 1.2 equiv). The resultant solution was stirred at room temperature for 16 h and concentrated in vacuo to provide a crude residue. The residue was diluted with dichloromethane (200 mL), and washed with saturated sodium bicarbonate aqueous solution (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield 3-acetylamino-4-methylpyridine (400.2 mg) as yellow solid which was used without further purification.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+].C(O)C>O.Cl>[C:20]1([NH:26][N:27]=[C:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13]([NH2:15])=[O:14])[C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1ccccc1
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)N1c2ccccc2CC(=NNc2ccccc2)c2ccccc21
Temperature: 60 °C

Procedure:
A mixture of 0.2 g (0.8 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, 0.5 g (4.6 mmol) of phenylhydrazine and 0.5 g (6 mmol) of sodium acetate in a mixture of 5 mL of water, 5 mL of ethanol and 3 drops of concentrated hydrochloric acid was heated at 60° C. for thirty minutes and then allowed to cool to room temperature. The precipitate was then filtered and washed with cold water and dilute ethanol to give the desired product as yellow crystals of m.p. 220° to 220.8° C.
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]23[O:21][CH2:20][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][O:19]2)[CH2:16][O:15]3)=[CH:10][CH:9]=1)#[CH:7].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O1CCCC1>[Si:25]([C:7]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]23[O:15][CH2:16][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][O:19]2)[CH2:20][O:21]3)=[CH:12][CH:13]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC12COC(c3ccc(C#C[Si](C)(C)C(C)(C)C)cc3)(OC1)OC2
Reaction time: 0.17 h

Procedure:
n-Butyllithium (0.79 ml of 1.6M solution, in hexane) was added to a stirred solution of 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane (0.25 g.) in dry tetrahydrofuran (15 ml) at 0°, under nitrogen. The reaction mixture was stirred at 0° for 10 minutes. t-Butyldimethylsilyl chloride (0.23 g.) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated in vacuo. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on alumina (Alumina Woelm TSC), eluting with 2:3 dichloromethane:hexane saturated with ammonia. 1-[4-(2-t-Butyldimethylsilylethynyl)phenyl]-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane was obtained as pale yellow crystals (0.32 g.).