Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-]=C=O.[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12>>[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12
Reactant: CC(C)(C)N=C=O
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Agent: [N-]=C=O
Product: CC(C)(C)NC(=O)Nc1cccc(N2CN=c3occc3=C2N)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using t-butyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 326 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]#[C:13][C:14]([CH3:26])([CH3:25])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(#N)C.Cl[Pd]Cl>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:12]=[C:13]([C:14]([CH3:26])([CH3:25])[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[NH:1]2)=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C#Cc1cc([N+](=O)[O-])c(F)cc1N)C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: CC(C)(C(=O)OCc1ccccc1)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of benzyl 4-(2-amino-4-fluoro-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (20.0 g, 56 mmol) in acetonitrile (100 mL) was added PdCl2 (5.0 g, 28 mmol) at room temperature. The mixture was stirred at 80° C. overnight. The mixture was filtered off and the solvent was evaporated in vacuo, the residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate (18.0 g, 90%). 1H NMR (300 MHz, CDCl3) 8.96 (br s, 1H), 8.33 (d, J=7.2 Hz, 1H) 7.35-7.28 (m, 5H) 7.08 (d, J=11.7 Hz, 1H), 6.47 (s, 1H), 5.18 (s, 2H) 1.69 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=1.C(O)(=O)C>C(O)C>[CH:15]1([C@@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: N#C[C@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CC(C)(CO)n1cc(N)cn1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CO)n1cc(Nc2nccc(N3CC[C@](C#N)(C4CC4)C3=O)n2)cn1
Yield: 37.9 %

Procedure:
A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Step A of Example 105, 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol (120 mg) obtained in Step H of Example 103 and acetic acid (48 μL) in ethanol (20 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:16][O:15][N:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:35](=[O:36])[O:12][N:11]=[C:10]2[C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])=[N:16][O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[Si](OCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
N-(3-chloro-4-fluorophenyl)-N′-hydroxy-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carboximidamide (2.2 g, 5.0 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (31 mL) followed by addition of N,N-carbonyldiimidazole (980 mg, 6 mmol). The reaction was heated to 70° C. and monitored by LCMS. Another 0.5 eq of N,N-carbonyldiimidazole was added and the reaction was stirred overnight at 70° C. The reaction was cooled and concentrated in vacuo. The crude oil was dissolved in chloroform and loaded onto a 120 g ISCO cartridge, eluted with 25% EtOAc/Hexane. The combined fractions were stripped to dryness to give the desired product as a white solid (1.74 g, 73%). 1H NMR (400 MHz, DMSO-d6) δ: 7.95 (m, 1H), 7.65 (m, 1H), 7.64 (m, 1H), 5.12 (s, 2H), 1.14 (m, 3H), 1.04 (d, J=7.0 Hz, 18H); MF═C20H26ClFN4O4Si; LCMS calculated for C20H27ClFN4O4Si(M+H)+: m/z=469.147.
Reaction SMILES: [CH3:1][C@H:2]([NH2:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C[C@@H:12](N)[C@@H:13]([OH:20])C1C=CC=CC=1>>[C:13]([NH:10][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1])(=[O:20])[CH3:12]
Reactant: C[C@@H](N)[C@@H](O)c1ccccc1
Reactant: C[C@H](N)Cc1ccccc1
Product: CC(=O)NC(C)Cc1ccccc1

Procedure:
The commercially available precursor to dextroamphetamine is 1R,2S-(−)-norephedrine. Attempts were made to O-acetylate the norephedrine free base, but produced mostly N-acetylamphetamine according to an analysis of the carbonyl region of the infrared spectra. In one experiment, norephedrine free base in acetic acid was treated with 0.5 equivalents of sulfuric acid and then treated with 1.1 equivalents of acetic anhydride with heating to 63° C. to obtain a clear solution. Catalytic reduction followed by basification gave an oil that was composed of 13.96% amphetamine and 68% norephedrine, an indication that the acetylation procedure on a sulfate salt was only partially successful. In another experiment, a 10 mol portion of norephedrine hydrochloride was acetylated with a 20% excess of acetic anhydride in 2 mL acetic acid/g of salt and progress of the reaction followed fours (Table 2). The reaction mixture was diluted with 130 mL water and subjected to catalytic hydrogenation for 22 hours to obtain 10.4 g of oil. The long reaction time is attributed to the presence of acetic acid in the reduction mixture. Yield of amphetamine from norephedrine hydrochloride based on the weight of product and HPLC analysis is 66% (Experiments A and B). For these experiments, it can be seen that the best results were obtained with the salts of phenylpropylamine or norephedrine, particularly the hydrochloride salt.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1S([O-])(=O)=O.[Na+].[NH2-:16].[Na+].N>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:16]
Reactant: [NH2-]
Reactant: O=S(=O)([O-])c1ccc2ccccc2c1
Agent: N
Agent: [Na+]
Product: Nc1ccc2ccccc2c1
Yield: 85.7 %

Procedure:
In a 200-ml autoclave were placed 27.4 grams (0.119 mole) of anhydrous sodium 2-naphthalene sulfonate, 10 grams (0.25 mole) of sodium amide and 80 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 120° C for 10 hours. The reaction pressure in the autoclave was 90 atm. during the reaction. After the ammonia was removed, 15 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 2-naphthylamine. Recrystallization from methanol gave 14.6 grams of 2-naphthylamine having a melting point of 111° to 112° C. Yield was 85.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH:12]2OCCO2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([NH:21][CH2:22][CH2:23][NH2:24])(=[O:20])[CH3:19]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:24]([CH2:23][CH2:22][NH:21][C:18](=[O:20])[CH3:19])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CCC1OCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1-c1ccc(Cl)c(Cl)c1
Yield: 84.2 %

Procedure:
3',4'-Dichloro-3-(1,3-dioxolan-2-yl)propiophenone (10.0 g) was dissolved in 20 ml of acetic acid and added under argon and while stirring to a solution of 7.4 g of N-acetylethylenediamine in 80 ml of acetic acid. The reaction mixture was heated to reflux overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 200 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 12.5 g of dark brown oil were chromatographed on 500 g of silica gel with ethyl acetate as the eluent. 9.1 g (84%) of N-[2-[2-(3,4-dichlorophenyl)-pyrrol-1-yl]ethyl]acetamide were isolated as a yellow-brown oil. MS: m/e=296, 298, 300 (9:6:1, M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCCCCC>[CH2:18]([N:25]1[CH2:30][CH2:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)([OH:31])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2ccc(OC(F)(F)F)cc2)CCN(Cc2ccccc2)CC1

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 8.5, starting with 20 g of 1-bromo-4-(trifluoromethoxy)benzene in 300 ml of THF, 89.3 ml of a 1.6M solution of n-butyllithium in hexane and 24.1 ml of 1-benzyl-4-piperidinone in 50 ml of THF. 18.5 g of the expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=[O:29])C>>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:29])=[O:20])=[CH:15][CH:14]=2)[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(C=O)cc1
Reactant: CC(=O)O
Product: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(C(=O)O)cc1
Temperature: 45 °C

Procedure:
To a solution of 2.1 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-formylphenyl)-5-oxazolidinecarboxylate in 25 cm3 of acetic acid are added 1.06 g of sodium perborate hydrate. The reaction medium is heated with stirring to a temperature in the region of 45° C., maintained for 10 hours at this temperature and then cooled to a temperature in the region of 20° C. and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual oil is dissolved in 75 cm3 of ethyl acetate and the solution obtained is washed with 5 times 5 cm3 of distilled water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 2.2 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-carboxyphenyl)-5-oxazolidinecarboxylate are thus obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[C@@H:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:10][C@H:9]1[C:38]([O:40]C)=[O:39].[OH-].[K+]>O.CO>[C:26]([CH2:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[NH:15][CH2:14][C:13]([N:12]2[C@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C@@H:9]([C:38]([OH:40])=[O:39])[CH2:10][C@@H:11]2[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[O:30])[CH:24]=[CH:23][CH:22]=1)([OH:28])=[O:27]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](C(=O)OC(C)(C)C)C[C@@H](C(=O)OC)[C@H]2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)[C@H]1C[C@H](C(=O)O)[C@@H](c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 64.8 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 0.6 g of 2-tert-butyl 4-methyl (2R*,4R*,5S*)-(-)-5-(2-fluorophenyl)-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}pyrrolidine-2,4-dicarboxylate and 0.12 g of potassium hydroxide in a mixture of 10 cm3 of distilled water and 25 cm3 of methanol. After treatment, there is obtained 0.37 g of 2-tert-butyl hydrogen (2R*,4S*,5S*)-(+)-1-{2-[3-(3-(carboxymethyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)pyrrolidine-2,4-dicarboxylate, the spectroscopic analyses of which are in accordance with those of the first product of Example 52.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Li+].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].O>CN1CCCC1=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: Nc1ccccc1O
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CC(=O)Nc1ccccc1O
Yield: 34.1 %

Procedure:
20 g of o-amino phenol was dissolved in 200 mL of N-methyl-2-pyrrolidone (NMP), and then the solution was ice-cooled. To the solution was added 8.546 g (1.1 times in mol) of lithium chloride. After lithium chloride was entirely dissolved, 17.42 g (1.05 times in mol) of acryloyl chloride was dropped into the solution, and the solution was stirred under ice-cooling for 5 hours. The reaction mixture was poured into 1.8 L of water, and an organic layer was extracted with 700 mL of diethyl ether. The diethyl ether layer was sequentially washed with 0.2 N hydrochloric acid, brine and water, and dried over magnesium sulfate. Diethyl ether was evaporated off under a reduced pressure. 80 mL of diisopropyl ether was added to the solidified residue, and the solution was heated and stirred to wash and filter the residue. The same washing process was carried out once again to obtain 10.2 g of N-(2-hydroxyphenyl)acrylamide as white powder (yield: 34%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:11][C:10]=1[C:19]([OH:21])=O)=O)(C)(C)C.[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][CH2:32][C@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]1>>[NH2:8][C:9]1[S:13][C:12]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:11][C:10]=1[C:19]([NH:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][CH2:32][C@H:31]([NH2:35])[CH2:30]1)=[O:21]
Reactant: CC(C)(C)OC(=O)Nc1sc(C2CCCC2)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Product: Nc1sc(C2CCCC2)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Yield: 48 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-cyclopentylthiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (22 mg, 48%). 1H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.24 (s, 1H), 7.10 (d, J=5.3 Hz, 1H), 3.23 (m, 3H), 3.07 (d, J=10.5 Hz, 1H), 2.96 (d, J=9.7 Hz, 2H), 2.67-2.53 (m, 2H), 2.43-2.34 (m, 1H), 2.03 (d, J=8.1 Hz, 2H), 1.87 (d, J=12.5 Hz, 1H), 1.84-1.58 (m, 5H), 1.17 (d, J=13.3 Hz, 1H). ESIMS m/z=387.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][NH2:22])=[CH:12]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[C:12]3[NH:11][C:19]4[C:14]([C:13]=3[CH2:20][CH2:21][NH:22]2)=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0.5 M solution of 4-methoxybenzaldehyde in dichloromethane (800 μl) was added a 0.25 M solution of 2-(1H-indol-3-yl)ethanamine in dichloromethane (800 μl) followed by trifluoracetic acid (20 μl). The mixture was sealed and shaken at room temperature for 24 hours. The mixture was evaporated to dryness resuspended in toluene (1 ml) vortexed and re-evaporated to dryness. To the residue was added methanol (1.5 ml) and dichloromethane (1 ml). After vortexing the solution was filtered through a pre-washed (methanol, 5 ml) SCX cartridge (Bakerbond JT7090-07, aromatic sulfonic acid). 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, was eluted from the cartridge with 0.5 M aqueous ammonia in methanol (5 ml). Evaporation to dryness gave 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole that was used directly for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[CH:26]1([C:30]([NH:1][C:2]2[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([CH3:19])[CH:18]=3)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Reactant: O=C(Cl)C1CCC1
Product: Cc1cc(C(C)NC(=O)c2ccnc(NC(=O)C3CCC3)n2)cnc1OCC(F)(F)F

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.06 mmol, Step-1 of Example 223, single enantiomer) and cyclobutanecarbonyl chloride (33 mg, 0.28 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.C(=O)([O-])[O-].[K+].[K+].[K].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.O>C(#N)C>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:22]1[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]2[C:18]1=[O:28]
Reactant: Cc1c(Cl)cccc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CC#N
Solvent: O
Product: Cc1c(Cl)cccc1CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
700 mg of 3-chloro-2-methylbenzyl chloride was dissolved in 10 mL of acetonitrile, and 829 mg of potassium carbonate and 889 mg of phthalimide potassium were added thereto at room temperature, followed by warming to 80° C., and then continuously reacting overnight. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.15 g (yield 100%) of a title compound as a white crystal.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH:9]([F:11])[F:10])[C:4]([F:7])([F:6])[F:5].[F:14]C(F)=C>>[F:1][C:2]([F:12])([F:13])[C:3]([F:14])([CH2:8][CH:9]([F:10])[F:11])[C:4]([F:6])([F:5])[F:7]
Reactant: FC(F)CC(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)F
Product: FC(F)CC(F)(C(F)(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1,4,4-pentafluorobutane may be prepared by reacting commercially available 1,1-difluoroethylene according to the procedure of George L. Fleming et al., supra, to form a product which may then be hydrogenated to form 2-trifluoromethyl-1,1,1,2,4,4-hexafluorobutane which may then be dehydrohalogenated and then hydrogenated to form 2-trifluoromethyl-1,1,1,4,4-pentafluorobutane
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH3:19])[CH:7]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:8]2[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:6]([CH3:19])[CH:7]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: C1CCNCC1
Reactant: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)CCl
Product: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)CN1CCCCC1
Yield: 81.4 %

Procedure:
A solution of 4 g (0.013 mole) of 2-chloro-1-[4-(4-chlorobenzoyl)-1-methyl-1H -pyrrol-2-yl]-ethanone (11) and 4.08 mL (0.039 mole) of piperidine in 60 mL 2-PrOH was heated under reflux for 1 h. The solvent was evaporated in vacuo and the residue was taken up in diethyl ether/THF, washed with water, brine, and dried (MgSO4). Evaporation of the solvent gave a tan solid which was recrystallized from 2-PrOH to give 3.65 g of product: mp 129-130° C.; mass spectrum (Cl—CH4) m/z=345 (M+1); NMR 300 MHz (CDCl3) d 7.8 (m, 2H); 7.6 (s, 1H); 7.45 (d, 2H); 7.35 (s, 1H); 4.0 (s, 3H); 3.6 (s, 2H); 2.5 (br s, 4H); 1.6 (m, 4H); 1.4 (m, 2H). Anal Calcd for C19H21Cl2N2O2: C, 66.18; H, 6.14; N, 8.12. Found: C, 66.25; H, 6.16; N, 8.08.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].C(OCC)(=O)C>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[F:2])[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2ccncc2F)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccncc2F)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
5-(3-Fluoro-pyridin-4-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep 67, 243 mg, 1.1 mmol) was dissolved in DMF (2 ml). K2CO3 (153 mg, 1.1 mmol) was added and the mixture was stirred at room temperature for 1 hour. 3-Bromo-1,1dimethoxy-propane (225 mg, 1.11 mmol) was then added and after stirring the reaction at room temperature for 48 hours, the reaction was left at 4° C. for 17 days. Ethyl acetate was then added and the mixture washed with water and brine. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography with DCM-MeOH—NH4OH 98-2-0.2 to afford 75 mg of the title compound (22% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(Cl)Cl>CN(C=O)C>[Si:20]([O:10][CH2:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccnc(Cl)c1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
A mixture of (2-chloro-3-fluoropyridin-4-yl)-methanol (200 mg, 1.24 mmol), imidazole (253 mg, 3.72 mmol) and tert-butyldimethylchlorosilane (373 mg, 2.48 mmol) in DMF was stirred at room temperature for 2 hours. Methylene chloride was then added to the reaction solution, and the solution was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound (319 mg, 93%).