Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][S:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[CH:51]=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40](O)=[O:41].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.ClCCl.CO.C(OCC)(=O)C>[CH3:36][S:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[CH:51]=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:41]
Reactant: CSc1ccc(-n2cnnn2)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4SC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.53 g, 1.0 mmol) and dichloromethane (10 mL). Add 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.24 g, 1.0 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), N,N-diisopropylethylamine (0.34 mL, 2.0 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2 mmol). After 18 hours, dilute the reaction mixture with ethyl acetate and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate, 2% methanol/ethyl acetate, and the 8% methanol/ethyl acetate to give a residue. Combine the residue and dichloromethane, extract with brine, twice with a saturated aqueous solution of ammonium chloride, and then a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.34 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: C1(=O)OCCO1.[F-:7].[K+].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].ClC([O-])=O>>[F:7][C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: [F-]
Agent: O=C([O-])Cl
Agent: [K+]
Solvent: O=C1OCCO1
Product: O=C(F)Oc1ccccc1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
The preparation was carried out as in Example 2 but using 250 g of ethylene carbonate, 89 g (1.53 mol) of potassium fluoride and 156.6 g (1.0 mol) of phenyl chloroformate. After addition of the chloroformate, stirring of the reaction mixture was continued at 45°-50° C. for 2 hours. Evaporation under vacuum was carried out as above. By distillation under reduced pressure, 131 g (93.5% yield) of phenyl fluoroformate with a boiling point of 62°-64° at 40 mm Hg were recovered.
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][C:17]=2[N+:18]([O-])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[NH2:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1cccc2ccccc12
Solvent: CCO
Product: Nc1ccncc1Oc1cccc2ccccc12
Reaction time: 5 h
Yield: 63.7 %

Procedure:
A suspension of 3-(1-naphthyloxy)-4-nitropyridine-N-oxide (7.5 g) in 250 ml ethanol containing 0.5 g PtO2 was hydrogenated at 50 psi for five hours and filtered through Celite. The filtrate was concentrated to 6 g oil. This oil was purified by HPLC (silica, 50% ethyl acetate in dichloromethane) to give 4 g oil. Final purification was achieved by converting the oil to the hydrochloride salt in methanol/ether and immediately thereafter reconverting the salt to the free base with sodium carbonate to afford 3.5 g solid product. This solid was recrystallized from diethyl ether to give a solid, 2.3 g, m.p. 107°-109°.
Reaction SMILES: N1C2=CN=NC2=[CH:4]N=N1.[C:10]([NH:13][C:14]1[N:19]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25]N=3)=[C:18]2[N:17]=[CH:16][N:15]=1)(=[O:12])[CH3:11].C(NC1N2N=CC(C3C=NC=CN=3)=C2N=CN=1)(=O)C>>[C:10]([NH:13][C:14]1[N:19]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:4]=3)=[C:18]2[N:17]=[CH:16][N:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ncnc2c(-c3ccncn3)cnn12
Reactant: c1nn[nH]c2cnnc1-2
Agent: CC(=O)Nc1ncnc2c(-c3cnccn3)cnn12
Product: CC(=O)Nc1ncnc2c(-c3ccncc3)cnn12

Procedure:
By replacing the pyrazolotriazine employed in Example 4 by an equivalent quantity of the end product of Example 2 or Example 3 there is obtained, respectively, 4-acetamido-8-(4-pyrimidinyl)-pyrazolo-[1,5-a][1,3,5]triazine and 4-acetamido-8-(2-pyrazinyl)-pyrazolo[1,5-a][1,3,5]triazine.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH2:26][O:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:27][NH:26][C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:24]
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: NOCCO
Product: CC1(C)c2cc(C(=O)NOCCO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-aminooxy-ethanol.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH2:46])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(Cl)Cl.O.C(Cl)CCl>[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH:46][C:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NCCc1cccc2c(OCc3ccccc3)cccc12
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: O=C(NCCc1cccc2c(OCc3ccccc3)cccc12)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of diphenylacetic acid (0.171 g) in methylene chloride (10 ml), dimethylaminopyridine (0.01 g) and 1-benzyloxy-5-(2-aminoethyl)naphthalene (0.196 g) were added at room temperature. After 10 minutes, EDC. HCl (0.154 g) was added to the mixture solution. The mixture was stirred overnight at room temperature for 1 night. After termination of reaction, water and methylene chloride were added to the reaction mixture. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, dried over and concentrated under reduced pressure. The residue was purified on silica gel chromatography to give the title compound (0.172 g) having the following physical data.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH:22]1([CH2:28][N:29]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: CC(=O)CCC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Yield: 92.4 %

Procedure:
To a solution of 5a (6.4 g, 22.2 mmol) in toluene (100 mL) was added cyclohexylmethanamine (2.8 g, 24.4 mmol) and TsOH (0.3 g). This mixture was refluxed for 20 h, cooled, concentrated and purified by CC to afford compound 5b (7.5 g, 93%) as yellow oil.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:18]([C:22]1[C:26]([CH2:27][OH:28])=[C:25]([CH3:29])[O:24][N:23]=1)[CH2:19][CH2:20][CH3:21]>C(Cl)Cl.CCOCC>[CH2:18]([C:22]1[C:26]([CH:27]=[O:28])=[C:25]([CH3:29])[O:24][N:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCc1noc(C)c1C=O
Yield: 85.7 %

Procedure:
To a stirred solution of PCC (4.96 g, 23 mmol) and anhydrous magnesium sulfate (7.40 g, 61 mmol) in DCM (60 mL) was added a solution of (3-butyl-5-methyl-isoxazol-4-yl)-methanol (2.6 g, 15 mmol) in DCM (60 mL) at room temperature and under argon. After 3 h the reaction mixture was diluted with ether (100 mL) and filtered through a bed of silica and the filtrate was concentrated. Purification by chromatography (silica heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (2.15 g, 84%) as a colourless liquid. MS: m/e=170.3 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:25])=O.N1C=CC=CC=1.[Cl-].[Li+]>CN(C)C=O>[Cl:25][CH2:2][C:3]1[C:8]2[N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: C[Si](C)(C)CCOCN1C(=O)CCCc2cccc(CO)c21
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCN1C(=O)CCCc2cccc(CCl)c21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Analogously to Method E, 0.320 g of 9-hydroxymethyl-1-(2-trimethylsilanylethoxymethyl)-1,3,4,5-tetrahydrobenz[b]azepin-2-one is reacted with 0.100 ml of thionyl chloride and 0.080 ml of pyridine. The resulting intermediate is subsequently dissolved in 30 ml of N,N-dimethylformamide and the solution is admixed with 0.190 g of lithium chloride. The reaction mixture is subsequently stirred at 45° C. over 2 hours and subsequently concentrated by evaporation. The residue is taken up in 100 ml of tert-butyl methyl ether and the solution is washed with 80 ml of water. The aqueous phase is extracted with 60 ml of tert-butyl methyl ether and the combined organic phases are subsequently dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane); Rt=5.38.
Reaction SMILES: [Ni:1].CO.[C:4]([CH:8]1[C:15](C(C)(C)C)(O)[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9]1)(C)(C)[CH3:5].CC(O)C>C1C=CC=CC=1>[Ni:1].[CH3:11][OH:12].[CH3:5][CH2:4][CH2:8][CH2:9][CH2:10][CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(C)C1C=C(CO)C=CC1(O)C(C)(C)C
Agent: [Ni]
Solvent: CC(C)O
Solvent: CO
Solvent: c1ccccc1
Product: CCCCCCCC

Procedure:
[2,2'-thiobis-(4-t-octylphenolato)]-2-propanol nickel II (83.9 g) prepared as described in Example 4 was dissolved in benzene (250 ml) and 3,4-di-t-butyl-4-hydroxybenzyl alcohol (35.5 g) was added. The temperature of the mixture was raised to reflux and the resulting solution was refluxed for 2.25 hr. Displaced 2-propanol and benzene (150 ml) were then distilled from the reaction mixture. Remaining solvent was removed by rotary evaporation. From the residue the complex [2,2'-thiobis-(4-t-octylphenolato)]-3,4-di-t-butyl-4-hydroxybenzyl alcohol nickel II was obtained by recrystallization from n-octane as a green solid m.p. 253°-255° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([F:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)[C:7]=2[CH:14]=1
Reactant: COc1ccc2occ(CCI)c2c1
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Product: COc1ccc2occ(CCN3CCN(c4cc(F)cc5cccnc45)CC3)c2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline was prepared by following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-fluoro-8-piperazino quinoline (231 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown low melting solid. Yield: 130 mg (32%); (M+H): 406; 1HNMR (400 MHz, CDCl3); δ 8.83˜8.82 (dd, J1=1.6 Hz, J2=1.6 Hz, 1H); 8.06˜8.05 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H); 7.60˜6.88 (m, 7H); 3.86 (s, 3H); 3.66˜3.56 (broad s, 4H); 2.93˜2.82 (m, 8H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].C(Cl)Cl.CS(C)=O.N1C=CC=CC=1.S(=O)(=O)=O>O>[CH2:1]([C:3]1([CH2:18][CH:19]=[O:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Agent: O=S(=O)=O
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC=O)OCC3
Reaction time: 48 h
Yield: 51.6 %

Procedure:
To a stirred solution of compound 1 (136 mg, 0.5 mmol), CH2Cl2 (2 mL), dry DMSO (142 μL, 2.0 mmol, 4.0 eq), and dry TEA (697 μL, 5.0 mmol, 10.0 eq) at room temperature under argon, sulfur trioxide-pyridine complex (Pyr-SO3, 318 mg, 2.0 mmol, 4.0 eq) was added in a portion-wise manner and stirred for two days. The resulting mixture was then diluted with water and extracted three times with Et2O. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 20:80:EtOAc:Hexane to give a yellow-white solid (70 mg, 52%). Spectral data were identical to those reported above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-4-{[(2R)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[O:12][C:4]1[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc3ccn(C)c23)c(C)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(C)c23)c(C)c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
In a sealed tube was added 2-chloro-4-(mesityloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (52.7 mg, 0.18 mmol), 4-aminobenzonitrile (83 mg, 0.70 mmol), TFE (1.0 mL) and TFA (0.11 mL, 1.44 mmol). The reaction mixture was stirred at 90° C. for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (5:1-2:1), to give the product as a light yellow solid
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O>C1(C)C(C)=CC=CC=1>[Cl:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH:3]([OH:11])[CH2:2][NH:1][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1cccc(Cl)c1

Procedure:
A mixture of 9.5 parts of α-(aminomethyl)-m-chlorobenzyl alcohol, 7.15 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred in an oil-bath at 150°-160°C. while a great part of the xylene is distilled off. The resulting residue is diluted with a few parts of acetone and the product is allowed to crystallize. It is filtered off and crystallized from 4-methyl-2-pentanone, yielding m-chloro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol; m.p. 108.5°C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15](NC)=[O:16])(=[O:13])=[O:12]>ClC1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:12])=[O:13]
Reactant: CNC(=O)NS(=O)(=O)c1ccccc1OCCCl
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1OCCCl
Yield: 98.4 %

Procedure:
12.5 g of N-[2-(2-chloroethoxy)-phenylsulfonyl]-N'-methylurea are suspended in 210 ml of chlorobenzene. This suspension is dried by azeotropic destilling off 20 ml of the solvent. 7.0 g of phosgene are introduced into the reaction mixture within 45 minutes at a temperature of 120°-130° C. Evaporation to dryness of the resulting clear solution yields 11.0 g of 2-(2-chloroethoxy)-phenylsulfonyl isocyanate in form of a yellowish oil.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH2:25]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:16]=[N:17][C:18]=1[Cl:22])[CH:24]=[CH2:23]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 72.8 %

Procedure:
3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (1.0 g, 2.57 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (15 mg) and allyltributyltin (1.6 mL, 5.1 mmol). The mixture was stirred and refluxed for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (660 mg, 73%): 1H NMR (CDCl3, 300 MHz) δ 1.24-1.40 (m, 2H), 1.46 (s, 9H), 1.62 (m, 1H), 1.88 (m, 1H), 2.02 (m, 1H), 3.38 (m, 1H), 3.45 (d, 2H, J=7.0 Hz), 3.90 (m, 1H), 4.16 (m, 2H), 5.10-5.20 (m, 2H), 5.94 (m, 1H), 7.14 (m, 1H), 7.96 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([O:22][CH3:23])[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].CO>O.C(OCC)(=O)C.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([O:22][CH3:23])[CH:15]=1)[N:12]=[CH:11][C:10]([C:24]#[N:25])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12

Procedure:
A mixture of 2.15 g (5 mmol) of 4-[(3-bromophenyl)amino]-8-methoxy-6-nitro-quinoline-3-carbonitrile, 1.95 g (37.5 mmol) of ammonium chloride, and 1.26 g (22.5 mmol) iron was stirred at reflux in 40 ml of water and 40 ml of methanol for 3 hours. The mixture was diluted with 500 ml of hot ethyl acetate and the hot mixture was filtered. The filtration was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solution was concentrated and 0.43 of dark yellow solid was collected: mass spectrum (electrospray, m/e): M+H 368.9 and 370.9.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>>[C:1]([NH:4][C@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@H]1CCNC1

Procedure:
An alternate preparation of (3S)-3-acetamidopyrrolidine (12) began by repeating steps (a) and (b) as described above. However, instead of reducing the product (10) with thiolacetic acid, the reduction was accomplished with hydrogen in the presence of a platinum catalyst to obtain the amine (11). The amine was thereafter acylated with acetic anhydride and the R1 group was cleaved as described above to obtain (12), where R4 is acetyl.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22]>>[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)(=[O:24])=[O:25])[CH3:22]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1

Procedure:
The title compound is prepared starting with (4-Bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone and 4-ethanesulfonylphenyl boronic acid perform a procedure analogous to Procedure FF. MS (m/e): 427.2 (M+1)
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26].[H-].[Na+].[Br-].[Na+]>COCCOC>[CH2:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CCOCCCCOCCCCBr
Reactant: OCc1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)CCOCCCCOCCCCOCc1ccc2c(c1)OCO2
Reaction time: 20 h

Procedure:
To a solution of 1.23 g (0.0081 mol) of piperonyl alcohol and 2.50 g (0.0085 mol) of 1-bromo-4-(4-isopentyloxy-butyloxy)-butane in 30 cc of absolute 1,2-dimethoxy-ethane, there is carefully added under nitrogen and while stirring, over the course of 20 minutes, 0.34 g (0.0077 mol) of 55% sodium hydride dispersion in oil. The mixture is stirred at 60° for 20 hours and the resulting sodium bromide is subsequently suction filtered, washed with ether and the filtrate is evaporated. After chromatography of the residue on silica gel with hexane/ethyl acetate (97:3) to (9:1), the [4-(4-Isopentyloxy-butyloxy)-butyl]-piperonyl ether is obtained as a colourless oil.