Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@H:21]([CH2:36][C:37]3[CH:45]=[C:44]([CH3:46])[C:43]4[C:39](=[CH:40][N:41](COCC[Si](C)(C)C)[N:42]=4)[CH:38]=3)[C:22](=[O:35])[N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@H:21]([CH2:36][C:37]3[CH:38]=[C:39]4[C:43](=[C:44]([CH3:46])[CH:45]=3)[NH:42][N:41]=[CH:40]4)[C:22](=[O:35])[N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[CH2:27][CH2:28]3)=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-3-(7-Methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (102 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL), and stirred at room temperature for 2 h. The reaction was concentrated and purified by column chromatography (5:95:1 methanol/dichloromethane/triethylamine). The residue was dissolved in 10% methanol/dichloromethane and passed through a plug of basic alumina to give 56.4 mg (67%) as a white solid. 1H-NMR (CD3OD, 500 MHz) δ −0.50-0.01 (m, 0.7H), 0.50-0.85 (m, 0.8H), 1.00-2.05 (m, 16H), 2.05-2.55 (m, 7H), 2.55-3.00 (m, 4H), 3.00-3.15 (m, 2H), 3.70-4.50 (m, 4H), 5.41 (m, 0.3H), 5.48 (dd, J=9.5, 6.1, 0.6H), 7.01 (m, 1H), 7.11 (m, 1H), 7.21 (m, 1H), 7.36 (m, 2H), 7.44-7.65 (m, 2H), 7.90 (m, 1H). Mass spec.: 625.33 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][C@@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:12][C@@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H]1CC[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC[C@H](OS(C)(=O)=O)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
After ethyl (1R*,3S*,4S*)-3-tert-butoxycarbonylamino-4-hydroxycyclohexane-1-carboxylate (16 g) and triethylamine (38 ml) were dissolved in dichloromethane (150 ml), and the solution was cooled to −78° C., methanesulfonyl chloride (13 ml) was added dropwise at the same temperature. After stirring for 15 minutes at the same temperature, the mixture was heated to 0° C. and stirred for 30 minutes and then 2 hours at room temperature. After 0.1N hydrochloric acid was added, and the mixture was diluted with dichloromethane, the resultant organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude ethyl (1R*,3S*,4S*)-3-tert-butoxycarbonylamino-4-methanesulfonyloxycyclohexane-1-carboxylate.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:15]N1C(=O)CCC1=O>CCO.O1CCOCC1>[Cl:15][C:11]1[N:12]=[C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH:9][C:10]=1[CH2:13][OH:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCc1ncc(CO)[nH]1
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCCCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of 2-heptyl-5-(hydroxymethyl)-imidazole (10.0 g, 51 mmol) in EtOH/1,4-dioxane (1:1; 600 mL) was added N-chlorosuccinimide (7.9 g, 59 mmol). After being stirred for 1 hour at room temperature the solvents were removed on a rotary evaporator and the solid residue was partitioned between ethyl acetate and water (300 mL each). The organic phase was washed with water (150 mL), dried (MgSO4), filtered and concentrated to afford 12.4 g crude product. Recrystallization (1:1 EtOAc/hexane, 60 mL) gave 5.7 g (45%) of white crystals; m.p. 134°-140°. NMR (200 MHz, CDCl3 /CD3OD) δ4.50 (s, 2H); 4.00-3.80 (br s, 2H); 2.65 (t, 2H, 5 Hz); 1.80-1.60 (m, 2H); 1.40-1.20 (m, 8H); 0.90-0.80 (m, 3H). Mass Spec. 230.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([N:15]2[CH2:24][C@@H:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])=[CH:4][CH:3]=1.[O:40]([C:42]#[N:43])[K].C(O)(=O)C>CN(C=O)C>[NH2:43][C:42]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:9]([C:13]([N:15]2[CH2:24][C@@H:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])[CH2:10]1)=[O:40]
Reactant: N#CO[K]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CN(C(N)=O)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolineamide (84 mg, 0.15 mmol) prepared in Example E1-1 in DMF was added dropwise KOCN (24 mg, 0.3 mmol) and a catalytic amount of acetic acid. The reaction mixture was stirred at rt for 1 h, extracted with EtOAc, washed with excessive amount of water and brine, and the organic solution was dried over MgSO4. The residue was purified by HPLC to give the title compound.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].Cl[C:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:16][N:15]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[CH2:14]2)[O:10][N:9]=1>O1CCOCC1>[N:31]1([C:29]([N:15]2[CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=3)[CH2:18][CH:13]([C:11]3[O:10][N:9]=[C:8]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:12]=3)[CH2:14]2)=[O:30])[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: OCC(F)(F)F
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(OCC(F)(F)F)no2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 112 mg (1.12 mmol) of 2,2,2-trifluoroethanol in 4.00 ml of 1,4-dioxane were added, at RT, 4 Å molecular sieve and 0.23 ml (0.45 mmol; 2 M solution in THF) of phosphazene P4 base. Subsequently, 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 2.0 ml of 1,4-dioxane were added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered, diluted with dichloromethane and washed with 1 N aqueous hydrogen chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 12.4 mg (11% of theory)
Reaction SMILES: [C:1]1([C:6](Cl)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][C:25]1=[O:33])[CH3:23]>O>[CH2:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:6](=[O:7])[C:1]3[S:5][CH:4]=[CH:3][CH:2]=3)=[CH:30][CH:31]=2)[CH2:26][C:25]1=[O:33])[CH3:23]
Reactant: CCN1C(=O)Cc2ccccc21
Reactant: O=C(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN1C(=O)Cc2cc(C(=O)c3cccs3)ccc21
Temperature: 100 °C
Yield: 47.7 %

Procedure:
To a mixture of 27.3 g. (19.9 mmoles) of 2-thenoyl chloride, 30 ml. of nitrobenzene and 32.95 g. of aluminum chloride was gradually added 10 g. (62 mmoles) of 1-ethyloxindole, and the resulting reaction mixture heated at 100° C. for 75 minutes. The reaction was cooled to room temperature and poured into 2 l. of ice and water. The product was extracted with methylene chloride and the dried extract concentrated to dryness, 11.05 g. The product was recrystallized from methylene chloride-hexane, 8.03 g. (47.7% yield)m, m.p. 158°-160° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)COc1ccccc1
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Phenoxy-acetic acid ethyl ester (9.1 mL) is added to chlorosulfonic acid (15 mL) at 0° C. dropwise. The reaction is stirred at 0° C. for 30 min, it is allowed to warm to room temperature. After 2 hrs, the reaction mixture is poured into ice, solid product is collected by filtration and dried under vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[C:5](=[O:10])[CH:6]([Br:12])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(O)C(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(Br)C(=O)C(=O)OCC

Procedure:
In a modification of the method described in JCS Perkin Trans. I 1972, 2584, a mixture of 2-hydroxy-hexanoic acid ethyl ester (5 g, 31 mmol), N-bromosuccinimide (12 g, 67 mmol) and catalytic AIBN in anhydrous CCl4 (60 mL) is refluxed. After heating for about 20 minutes, the reaction initiates with evolution of a red-brown gas. After refluxing 4 hours, the resulting mixture is filtered and the filtrate evaporated at reduced pressure to obtain 3-bromo-2-oxo-hexanoic acid ethyl ester as a dark liquid. Step 2. Preparation of 3-(1-propyl)-imidazolo[1,2-a]pyridine-2-carboxylate
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](N(OC)C)=[O:27])=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1.[CH2:43]([Mg]Br)[CH2:44][CH3:45].Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[O:27])[CH2:43][CH2:44][CH3:45])=[CH:22][N:21]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1
Reactant: CCC[Mg]Br
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N(C)OC)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: C1CCOC1
Product: CCCC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-N-methoxy-N-methyl-2-propenamide (0.80 g) and tetrahydrofuran (30 mL) was added dropwise propylmagnesium bromide (2M tetrahydrofuran solution, 4.2 mL) at 0° C. and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (1E)-1-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-1-hexen-3-one as colorless crystals (0.32 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([NH2:24])[CH3:23])=[N:20][CH:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([NH:24][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)[CH3:23])=[N:20][CH:21]=1
Reactant: C[C@@H](N)c1ccc(Br)cn1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-isopropylphenylacetic acid (0.356 g, 2.000 mmol), (1R)-1-(5-bromopyridin-2-yl)ethanamine hydrochloride (0.475 g, 2.000 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.383 g, 2.000 mmol), and 1-hydroxy-7-azabenzotriazole (0.272 g, 2.000 mmol) in 15.0 ml of CH2Cl2 was added slowly triethylamine (0.836 ml, 6.000 mmol). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Organics were extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (0-80% EtOAc/Hex) gave N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-(4-isopropylphenyl)acetamide as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.503 (d, J=2.20 Hz, 1H); 7.740 (dd, J=2.20 Hz, J=8.30 Hz, 1H); 7.207 (d, J=8.30 Hz, 2H); 7.182 (d, J=8.30 Hz, 2H); 7.102 (d, J=8.30 Hz, 1H); 6.591 (br d, J=7.08 Hz, 1H); 5.094 (dq, J=7.08 Hz, 1H); 3.571 (d, J=15.87 Hz, 1H); 3.536 (d, J=16.11 Hz, 1H); 2.907 (sept, J=6.83 Hz, 1H); 1.391 (d, J=6.59 Hz, 3H); 1.254 (d, J=6.83 Hz, 6H); MS (Electrospray): m/z 361.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][CH2:12]O>S(=O)(=O)(O)O>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:12]
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(N)nc1
Yield: 92 %

Procedure:
A solution of 6-aminonicotinic acid (2.0 g, 14.4 mmol) in anhydrous EtOH (70 mL) and concentrated sulfuric acid (14 mL) was heated to reflux for 16 h. The solution was concentrated under reduced pressure, neutralized with saturated aqueous Na2CO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to give 6-aminonicotinic acid ethyl ester (2.18 g, 92%) as a white powder. 1H NMR (CDCl3) δ 1.37 (t, 3H, J=6.0 Hz), 4.34 (q, 2H, J=7.0 Hz), 4.89 (br s, 2H (NH2)), 6.46 (d, 1H, J=7.5 Hz), 8.02 (d, 1H, J=7.5 Hz), 8.73 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[C:3]([NH:17][C:14]2[CH:13]=[C:12]([O:11][CH3:10])[NH:16][N:15]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1cc(N)n[nH]1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (1.20 g, 5.26 mmol) in THF (10 ml) at room temperature was added 5-methoxy-1H-pyrazol-3-amine (594 mg, 5.26 mmol) and triethylamine (685 mg, 6.3 mmol) and the reaction mixture was stirred at 40° C. overnight. The suspension was filtered and washed with water and dried to give the desired product as a white solid. MS: 305 (M+1).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH3:6][O:7][N:8]=[C:9]1[CH2:13][C@@H:12]([CH2:14][OH:15])[N:11]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:17])[CH2:10]1>C(Cl)Cl>[CH3:4][S:1]([O:15][CH2:14][C@@H:12]1[CH2:13][C:9](=[N:8][O:7][CH3:6])[CH2:10][N:11]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17])(=[O:3])=[O:2]
Reactant: CON=C1C[C@@H](CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CON=C1C[C@@H](COS(C)(=O)=O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 0 °C

Procedure:
Mesyl chlorid (48 μl, 0.62 mmol) was added to a solution of alcohol (2) (EZ mixture, 80 mg, 0.25 mmol) in DCM (8 ml) cooled at 0° C. and maintained under nitrogen atmosphere. The reaction mixture was then allowed to warm to r.t. and monitored by tlc. Completion was achieved after 1 h30. Organic phase was washed with saturated ammonium chlorid solution and brine, dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH2:33]Br)=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:33][C:31](=[O:32])[C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)CN2C(=O)N(C(=O)c3cccc4ccccc34)C(=O)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 2-bromo-4-methylacetophenone (27 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 12 mg of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:9]2)[CH:3]=1.C(N(CC)C(C)C)(C)C>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:8]=[C:4]2[CH:3]=1
Reactant: COc1ccc(C2=NC2c2cc(Br)ccn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Temperature: 175 °C
Yield: 69.8 %

Procedure:
In a 20 mL microwave reactor was placed a solution of 4-bromo-2-(3-(4-methoxyphenyl)-2H-azirin-2-yl)pyridine (1.3 g, 4.3 mmol) and N,N-diisopropylethylamine (375 μL, 2.2 mmol) in 1,2-dichloroethane (10 mL). The mixture was heated to 175° C. for 1 hour. The cooled mixture afforded a precipitate which was filtered and dried under reduced pressure to afford the title compound as a white solid (910 mg, 70%). LCMS m/z 303.0, 305.0 (M+H)+, ret. time=2.88 min.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:38][CH2:39][CH2:40][CH3:41])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1>>[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:38][CH2:39][CH2:40][CH3:41])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:2](=[O:3])[O:4][CH2:5][CH:6]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 70.8 %

Procedure:
Using the general method of Example 55, 9-fluorenylmethyl chloroformate (0.085 g, 0.33 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.105 g, 0.33 mmol) to provide 0.125 g of 9H-9-fluorenylmethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder. Analysis: Calculated for C32H34N6O2+¼H2O: % C, 71.29; % H, 6.45; % N, 15.59; Found: % C, 70.99; % H, 6.35; % N, 15.55.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Ga+3:4].[CH2:5]([Mg]Cl)[C:6]([CH3:9])([CH3:8])[CH3:7]>C(OCC)C>[CH2:5]([Ga:4]([CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: [Ga+3]
Reactant: CC(C)(C)C[Mg]Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)(C)C[Ga](CC(C)(C)C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A flask charged with 9.578 g. (54.41 mmol) of freshly sublimed gallium trichloride dissolved in 250 ml. of dry diethyl ether (from sodium/benzophenone), was fitted with a condenser, mechanical stirrer and a pressure equalizing addition funnel. Under a cover of argon, 100 ml., 2.27M neopentyl magnesium chloride in diethyl ether solution (previously prepared from purified neopentyl chloride and magnesium turnings) was transferred to the addition funnel. The Grignard reagent was then added to the gallium trichloride solution over a period of 20 min. After the addtion was complete, the reaction mixture was stirred at room temperature for 18 hours. The stirrer, condenser and addition funnel were replaced by stoppers and Teflon vavle adapter. The diethyl ether was then removed by vacuum distillation at room temperature. The crude product, a trisneopentylgallium etherate mixture, was isolated by vacuum distillation at 125° C. into a side-arm flask (cooled to -196° C.) attached to the reaction flask by means of an 85° elbow. This distillation must be continued for approximately 5 hours. The diethyl ether was then removed from stirred, crude trisneopentyl gallium by simple vacuum distillation at room temperature for 1 hour. The product is finally purified by vacuum distillation in a short path still at 59.5° C. (0.01 mm, static vacuum). The yield of purified trisneopentyl gallium was 14.04 g (49.58 mmol, 91.1% based on gallium trichloride).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.C([O:10][C:11](=[O:36])[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[C:29](=N)[N:28]([CH2:31][CH3:32])[C:27]3[C:22](=[CH:23][N:24]=[C:25]4[NH:35][CH:34]=[CH:33][C:26]4=3)[CH:21]=2)[CH:13]=1)C>>[CH2:31]([N:28]1[C:27]2[C:22](=[CH:23][N:24]=[C:25]3[NH:35][CH:34]=[CH:33][C:26]3=2)[CH:21]=[C:20]([C:14]2[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=2)[C:11]([OH:10])=[O:36])[C:29]1=[O:3])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(OC)cc(-c2cc3cnc4[nH]ccc4c3n(CC)c2=N)c1
Product: CCn1c(=O)c(-c2cc(OC)cc(C(=O)O)c2)cc2cnc3[nH]ccc3c21
Temperature: 120 °C

Procedure:
Acetic anhydride (0.123 mL, 1.3 mmol) is added to (3-(9-ethyl-8-imino-8,9-dihydro-3H-3,4,9-triaza-cyclopenta[a]naphthalen-7-yl)-5-methoxy-benzoic acid ethyl ester (100 mg, 0.26 mmol) in sealed tube and heated at 120° C. for 2.5 hr. The acetic anhydride is evaporated and 6N HCl (3 mL) is added and the mixture is again heated at 105° C. for 1 hr. The reaction mixture is brought to room temperature and poured in ice cold water. The acid is crystallized out and filtered. It is washed with water and dried to give the desired product. MS m/z 364.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:25])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([Cl:25])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(S(=O)(=O)Oc2ccccc2)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Oc2ccccc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a suspension of 2-methoxy-5-phenoxysulfonylbenzoic acid (4.0 g, 13 mmol) in dry toluene (100 mL) was added oxalyl chloride (2.3 mL, 26 mmol) at room temperature. A drop of DMF was added and the mixture stirred at room temperature for 2 h. The mixture was evaporated in vacuo and the residue triturated with 1:1 toluene/hexane to give the title compound as a solid (4.04 g).