Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.C(O)(=O)C.C[CH:12]([CH3:22])[C:13](=O)[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH:23]([C:26](C)=[O:27])([CH3:25])[CH3:24].[F:29][C:30]1C=CC(C=O)=[CH:32][C:31]=1[O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)(C)C>[F:29][C:30]1[CH:22]=[CH:12][C:13]([CH:14]=[C:15]([C:26](=[O:27])[CH:23]([CH3:25])[CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:32][C:31]=1[O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOC(=O)CCC(=O)C(C)C
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CCOC(=O)C(=Cc1ccc(F)c(Oc2ccccc2)c1)C(=O)C(C)C

Procedure:
2.8 ml (29 mmol) of piperidine and 1.7 ml (29 mmol) of acetic acid are added to a solution of 79 g (0.5 mol) of ethyl 4-methyl-3-oxo-pentanecarboxylate (prepared from methyl isopropyl ketone analogously to the process of S. B. Soloway and F. B. La Forge, J. Am. Chem. Soc. 69, 2677 (1947)) and 108 g (0.5 mol) of 4-fluoro-3-phenoxy-benzaldehyde in 300 ml of isopropanol and stirred overnight at RT. The mixture is then concentrated, the residue is taken up in 500 ml of ether, washed twice with water and once with saturated sodium chloride solution, dried over sodium sulphate and the solvent removed. The residue is distilled under high vacuum until the last fraction passes over at 185° C. and 0.3 mbar. All distillates (44 g) are discarded. The distillation residue contains the product: brownish oil (144.7 g, 81%), which is reacted further without purification. Rf =0.25 (petroleum ether/ethyl acetate 10:1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[N:12]([O-])=O.[Na+].O.O.[Cl:18][Sn]Cl>Cl.O>[ClH:18].[NH:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH3:11])[NH2:12]
Reactant: Cl[Sn]Cl
Reactant: Cc1cc(C(N)=O)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(N)=O)ccc1NN
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
0.5 g of the compound of step A is dissolved in 10 ml of 1N HCl and 5 ml of concentrated HCl. The mixture is cooled to 0° C. and a solution of 230 mg of NaNO2 in 3 ml of water is added. After 15 minutes at -10° C., a solution of 1.5 g of SnCl2.2H2O in 5 ml of concentrated HCl is added. After 1 hour the precipitate is filtered off and dried under vacuum over P2O5 to obtain 390 mg of the expected product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 86.4 %

Procedure:
Combine [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 4.2 mmol), 4-fluoronitrobenzene (0.6 g, 4.2 mmol), cesium carbonate (2.7 g, 8.4 mmol), and N,N-dimethylformamide (35 mL), stir and heat at 100° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (9.5 g). The crude product is purified by flash column chromatography on silica gel eluting with (10% conc. ammonium hydroxide in ethanol) and chloroform to yield {2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.3 g): 1H NMR (CDCl3, 300.00 MHz): 8.23 (d, 2H, J=9.2 Hz), 7.32-7.25 (m, 2H), 7.10-7.00 (m, 4H), 4.63 (s, 1H), 3.43 (m, 2H), 2.86 (t, 2H, J=7.0 Hz), 1.48 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a light yellow solid (331 mg).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[F:32]C1C=CC(CCBr)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:32][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc(F)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(4-fluorophenyl)ethylbromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([NH:13][C:14](=[O:16])C)=[N:9]2)[CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([NH:13][CH:14]=[O:16])=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC1=NN(c2cccc(Cl)n2)CC1
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: O=CNC1=NN(c2cccc(Cl)n2)CC1

Procedure:
A mixture of 5.0 g. of 2-(3-amino-2-pyrazolin-1-yl)-6-chloropyridine (prepared as described in Example 3) and 25 ml. of a mixture of formic acid and acetic anhydride (Feiser and Feiser, Reagents for Organic Synthesis, Vol. 1, page 4) at room temperature gives an immediate yellow precipitate. The precipitate is collected by filtration then is recrystallized from acetone-hexane to give 3.05 g. of the product of the Example as off-white crystals, m.p. 190°-192° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][C:40]2([CH3:44])[CH2:43][O:42][CH2:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][C:40]2([CH3:44])[CH2:41][O:42][CH2:43]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CC2(C)COC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2(C)COC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 5.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.47 g), sodium hydrogen carbonate (2.23 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-1-[(3-methyloxetan-3-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.78 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless powder (0.048 g, 5%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[C:14](=O)([O:20]C(C)(C)C)[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].O.Cl>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[N:3]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(Br)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 24.0 g of 3-bromo-5-nitro-1H-indazole and 12.2 g of 4-(dimethylamino)pyridine in 50 ml tetrahydrofuran was added dropwise 23 ml of di-tert-butyl carbonate at room temperature. After stirring at room temperature for 30 minutes, the mixture was added with water, acidified by adding diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 20.5 g of the title compound as colorless needles.
Reaction SMILES: CC(CCCCC)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[CH2:21](OC1C=CC(O)=CC=1)CCCCCCC.C(C1C=CC(C(O)=O)=CC=1)CCC.C[CH:51]([CH2:65][CH2:66][CH2:67][CH3:68])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][O:57][C:58]1[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=1.CC(CCCC)CCCCCBr.C1(C=CC(O)=CC=1)O>>[CH3:21][CH:53]([CH2:52][CH2:51][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:54][CH2:55][CH2:56][O:57][C:58]1[CH:59]=[CH:60][C:61]([O:13][C:11](=[O:12])[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH3:3])=[CH:15][CH:14]=2)=[CH:62][CH:63]=1
Reactant: CCCCC(C)CCCCCOc1ccc(O)cc1
Reactant: CCCCCC(C)CCCCc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCOc1ccc(O)cc1
Agent: CCCCC(C)CCCCCBr
Agent: CCCCc1ccc(C(=O)O)cc1
Agent: Oc1ccc(O)cc1
Product: CCCCCCC(C)CCCOc1ccc(OC(=O)c2ccc(CCCC)cc2)cc1

Procedure:
The procedure of Example 1 was followed except that the 4-(5'-methyldecyl)benzoic acid and 4-n-octoxyphenol were replaced by 4-n-butylbenzoic acid and 4-(6'-methyldecyloxy)-phenol prepared by reacting 6-methyldecylbromide with hydroquinone to thereby give the title compound.
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]2[C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)=[N:17]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][C:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]2[C:24]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)=[N:17]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 3-[2-(2-t-butoxycarbonylmethyl-1-cycloheptenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.15 g) in dry dichloromethane (0.5 ml) at room temperature was added trifluoroacetic acid (0.46 ml). After stirring for one day at room temperature, the solution was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate. The separated aqueous layer was acidified with 1N-hydrochloric acid to pH 3 and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethanol—water to give 3-[2-(2-carboxymethyl-1-cycloheptenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (0.083 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C(Cl)Cl.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>[F:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(I)ccn1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1ccnc(F)c1
Temperature: 80 °C
Yield: 54.9 %

Procedure:
To a solution of 2-fluoro-4-iodo-pyridine (0.5 g, 2.24 mmol) and (2-methoxyphenyl)boronic acid (0.34 g, 2.24 mmol) in DME/water 2:1 (15 mL) was added Pd(PPh3)2Cl2 (20 mg, 0.028 mmol) and K2CO3 (20 mg, 0.15 mmol). The mixture was heated at 80° C. for 6 hours. It was diluted with DCM, washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, DCM/MeOH 100:0 to 90:10) to give the title compound A3 (0.25 g, 55%). MS (ES) C12H10FNO requires: 203. found: 204 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN([CH:17]=[O:18])C.C(Cl)(=O)C(Cl)=O.[CH2:25]([N:27](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]([O:18][CH3:17])[CH3:25])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Fluoro-3-nitrobenzoic acid (100 gm, 0.54 mol) was taken up in dry methylene chloride (1 L) and 1.5 mL of DMF was added. To this solution was added oxalyl chloride (61 mL, 0.702 mol). After 1.5 hours, the solvent was removed in vacuo and the crude acid chloride (yellow oil) was taken up in methylene chloride (50 mL) and slowly added to a stirring mixture of triethylamine (150.5 mL, 1.08 mol) and Weinreb amine hydrochloride (68.5 gm, 0.702 mol) in methylene chloride (950 mL) at 0 deg C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with saturated sodium dihydrogen phosphate, followed by water. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to an orange-yellow oil. The crude oil was triturated with pentane to give 110.28 gm (90%) of a yellow to off white powder.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)CC(F)=C(F)F
Solvent: ClCCl
Product: O=C(CC(F)=C(F)F)OCc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 3,4,4-trifluoro-3-butenoyl chloride (2.8 g, 0.0176 mole) and benzyl alcohol (0.9 g, 0.0083 mole) in 20 mL dichloromethane is heated at reflux for 40 h. The solution is cooled to room temperature, diluted with dichloromethane (15 mL), washed successively with 5% sodium bicarbonate, water and brine, and dried. Evaporation of the solvent gave 1.75 g of analytically pure product as a pale yellow oil, a 92% yield.
Reaction SMILES: C(O[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=O)C1C=CC=CC=1.Cl.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][NH:9]1)=[O:17]
Reactant: O=C(O)C1CCCCN1OCc1ccccc1
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)C1CCCCN1

Procedure:
The general procedure of Referential Example 131 was repeated through use of N-benzyloxypiperidine-2-carboxylic acid (6.4 g) and dimethylamine hydrochloride (2 g), to thereby give the title compound as an oily product (3.8 g, quantitative amount).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[N:17][CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:38]([C:36]1[CH:37]=[C:33]([NH:32][C:31]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:18]=[N:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][CH:14]=3)[CH2:4][CH2:3]2)=[O:30])[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: N[C@H]1CC[C@@H](Oc2ccc(C(=O)N3CCOCC3)nc2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc(C(=O)N4CCOCC4)nc3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 30 %

Procedure:
Intermediate 17b (234 mg, 0.66 mmol) was dissolved in 1,4-dioxane (7.0 mL) and [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 268 mg, 0.66 mmol) and diisopropylethylamine (229 μL, 1.32 mmol) were added. The reaction mixture was heated to 60° C. for 20 h, then cooled, partitioned between EtOAc (50 mL) and water (50 mL), and extracted into EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (120 mg, 0.20 mmol, 30%). LCMS (Method 5): Rt 4.76 min, m/z=609 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.85-2.05 (2H, m), 2.05-2.18 (2H, m), 2.38 (3H, s), 3.57-3.76 (8H, br m), 4.86-4.92 (1H, dd, J 8.6, 5.5 Hz), 5.54-5.57 (1H, t, J 4.3 Hz), 6.33 (1H, s), 7.20-7.34 (9H, m), 7.58-7.65 (2H, m), 8.24-8.26 (1H, dd, J 2.4, 0.8 Hz).
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[NH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])=[N:21][CH:20]=[C:19]([Br:30])[CH:18]=2>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[Br:30][C:19]1[CH:20]=[N:21][C:22]2[C:23]3[N:24]([CH2:25][C:26]([CH3:27])([OH:28])[CH3:29])[C:1]([CH2:2][CH3:3])=[N:13][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)cnc12
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)O
Yield: 75 %

Procedure:
Pyridine hydrochloride (0.095 g, 0.82 mmol) and triethyl orthopropionate (6.36 g, 36.1 mmol) were sequentially added to a solution of 1-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (10.2 g, 32.8 mmol) in toluene (200 mL), and the resulting mixture was heated at reflux for three hours. Most of the solvent was removed under reduced pressure, and a solid was present. The solid was isolated by filtration and dried to provide 8.59 g of 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol as a light yellow solid. A small portion of the solid was recrystallized from acetonitrile to provide an off-white solid, mp 207-208° C.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7](Cl)([Cl:9])[Cl:8].[OH-].[Na+].CCCCCCCC>ClCCl>[Cl:8][C:7]1([Cl:9])[CH:6]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]2
Reactant: C1=CCCCC1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCCC
Solvent: ClCCl
Product: ClC1(Cl)C2CCCCC21
Temperature: 40 °C

Procedure:
In a flask provided with a one-blade paddle mixer, a mixture of 1.64 grams of cyclohexene, 23.7 grams of chloroform, 20 milliliters of 50%w aqueous sodium hydroxide, 5 milliliters of dichloromethane, 1 milliliter of n-octane (to serve as a GLC marker) and 0.010 gram of the catalyst indicated in Table I was stirred vigorously at 40° C. Samples were taken after stirring had been started at the times indicated in Table I. Table I presents the yields of 7,7-dichloronorcarane. The selectivity to the latter compound was 100% in all cases. A dash indicates that no analysis was effected.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]1([N:12]2[CH2:2][CH2:3][C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCc1ccccc1CCl
Reactant: Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc(N2CCc3ccccc3C2)cc1
Yield: 29.7 %

Procedure:
A mixture of 2-(2-chloroethyl)benzyl chloride (19 g), aniline (9.3 g), and triethylamine (22.22 g,) in chloroform (80 ml) was heated at reflux for 6 hrs. The reaction mixture was cooled and washed with 2M sodium hydroxide solution (3×100 ml). The chloroform layer was dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled in vacuo to afford 2-phenyl-1,2,3,4-tetrahydroisoquinoline (6.2 g. b.pt. 112°-113°/0.08-0.1 mmHg) characterised by its nmr spectrum.
Reaction SMILES: [C:1]([N:11]1[CH2:32][CH2:31][N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12]1)=[CH:19][C:18]([NH:24]C(=O)C(F)(F)F)=[CH:17][CH:16]=3)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+]>O>[NH2:24][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:31][CH2:32][N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH2:12][CH:13]1[C:22](=[O:23])[NH:21]2
Reactant: O=C1Nc2cc(NC(=O)C(F)(F)F)ccc2N2CCN(C(=O)OCc3ccccc3)CC12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc2c(c1)NC(=O)C1CN(C(=O)OCc3ccccc3)CCN21

Procedure:
A mixture of 2.8 g. of 3-carbobenzoxy-2,3,4,4a-Tetrahydro-8-(2,2,2-trifluoroacetamido)-1H-pyrazino[1,2-a] quinoxalin-5(6H)-one, 0.5 g. sodium hydroxide and 200 ml. of water is boiled for 15 minutes, then cooled. The mixture is then extracted with methylene chloride. The organic portion is then extracted with dilute hydrochloric acid. The aqueous acid phase is then basified with dilute sodium hydroxide and extracted with methylene chloride. The organic phase is dried and concentrated to give 1.6 g. of pale yellow solid product, m.p. 130°-135°.