Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:12][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:10]
Reactant: BrP(Br)Br
Reactant: OCc1cccc(Cl)c1F
Solvent: ClCCl
Product: Fc1c(Cl)cccc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-chloro-2-fluoro-phenyl)-methanol (3.2 g, 20 mmol) in DCM (20 mL) was added dropwise PBr3 (1 mL) at 0° C. The reaction mixture was stirred at room temperature for another 1 hour before quenching with satd. aq. NaHCO3 solution. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the desired product without further purification (4.1 g, 92%). MS: 223.2 (M+H)+.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)[CH3:5])=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH:4]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1cnccn1
Agent: [Pd]
Solvent: CCO
Product: CC(N)c1cnccn1
Yield: 88.1 %

Procedure:
2-(1-Azidoethyl)pyrazine (0.77 g) and 10% palladium on carbon (0.075 g) were stirred in ethanol (40 mL) under an atmosphere of hydrogen at room temperature for 2 h. The mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure to yield 2-(1-aminoethyl)pyrazine (0.56 g) as a pale oil
Reaction SMILES: Cl[Si:2]1([CH3:6])[CH2:5][CH2:4][CH2:3]1.[CH3:7][N:8]([Si](C)(C)C)[C:9](=[O:11])[CH3:10]>>[CH3:6][Si:2]1([N:8]([CH3:7])[C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3]1
Reactant: C[Si]1(Cl)CCC1
Reactant: CC(=O)N(C)[Si](C)(C)C
Product: CC(=O)N(C)[Si]1(C)CCC1

Procedure:
To 30.02 g 1-chloro-1-methylsilacyclobutane was added 36.10 g N-methyl-N-(trimethylsilyl)acetamide. The reaction products were fractionally distilled. The title compound was isolated as a clear, colorless fluid with a boiling point of 68°-76° C. at 3.6 mm Hg. The yield was 31.56 g (86%). The product was identified by NMR and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9]N(C)C)[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(O)(=O)C(O)=[O:19]>C(Cl)Cl.O>[Cl:13][C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([Cl:1])=[CH:7][C:6]=1[CH2:8][CH:9]=[O:19]
Reactant: CN(C)C=Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: ClCCl
Product: O=CCc1cc(Cl)c([N+](=O)[O-])cc1Cl

Procedure:
2,5-Dichloro-4-(2-dimethylaminoethenyl)-nitrobenzene (10 g, 38.3 mmol) was dissolved in methylene chloride (200 ml) and stirred with a solution of oxalic acid (14.5 g, 115 mmol) in water (80 ml) at room temperature for 18 hours. The layers were separated and the aqueous layer extracted with methylene chloride (50 ml). The combined organic layers were washed with water and brine, dried over magnesium sulfate and filtered. The solution was evaporated to yield the title compound. NMR (CDCl3) δ 9.70 (s, 1), 8.01 (s, 1), 7.49 (s, 1), 3.98 (s, 2).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
6-Amino-9-benzyl-2-pentylaminopurine (70 mg, 0.23 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (80 mg, yield 91%).
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:12][C:13]([C@H:15]1[C@H:20]([NH:21][C:22](=[O:24])[CH3:23])[C@@H:19]([NH:25][C:26]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:18]=[C:17]([C:43]([O:45][CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[O:16]1)=O.[CH2:59]([NH:62][CH2:63][CH2:64][CH3:65])[CH2:60][CH3:61]>O1CCCC1>[CH:46]([O:45][C:43]([C:17]1[O:16][C@@H:15]([C:13](=[O:12])[N:62]([CH2:63][CH2:64][CH3:65])[CH2:59][CH2:60][CH3:61])[C@H:20]([NH:21][C:22](=[O:24])[CH3:23])[C@@H:19]([NH:25][C:26]([NH:35][C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])=[N:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:18]=1)=[O:44])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(=O)N[C@@H]1[C@@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C=C(C(=O)OC(c2ccccc2)c2ccccc2)O[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,3R,4S)-3-Acetylamino-4-[2,3-bis(tert-butoxycarbonyl)-guanidino]-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid 6-benzhydryl ester 2-(2,3,4,5,6-pentafluoro-phenyl) ester (0.70 g) in dry tetrahydrofuran (5 ml) was added dipropylamine (0.141 g) and the reaction was stirred at 23° C. for 4 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel (Merck 9385, 50 g) using medium pressure (~4psi) and cyclohexane/ethyl acetate (1:1 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a pale yellow foam. (0.341 g). 1H NMR (250MHz, D6 -DMSO) 11.46 (1H, s), 8.27 (1H, d, J=6.25 Hz), 8.16 (1H, d, J=7.5Hz), 7.48--7.27 (10H, m), 6.97 (1H, s), 6.14 (1H, d, J=5Hz), 5.18 (1H, m), 4.67 (1H, m), 4.10 (1H, m), 3.61--3.24 (3H, m), 3.14 (1H, m), 1.84 (3H, s), 1.60--1.34 (4H, m), 1.46 (9H, s), 1.40 (9H, s), 0.85 (3H, t, J=7Hz), 0.74 (3H, t, J=7Hz); Mass Analysis; C39H53N5O9. 1.0C6HF5O. Required: C, 58.75; H, 5.92; N, 7.61. Found C, 58.64; H, 5.75; N, 7.61.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[O:10])=[C:4]([C:19](=[O:28])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)[CH:3]=1.S.IC.[CH3:32][NH:33][CH2:34][CH2:35]N>N1C=CC=CC=1.C(N(CC)CC)C.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:33]([CH3:32])[CH2:34][CH2:35][N:18]=3)=[CH:15][CH:16]=2)=[O:10])=[C:4]([C:19](=[O:28])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)[CH:3]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CNCCN
Agent: S
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CI
Product: CN1CCN=C1c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of N-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamide (683 mg, 1.66 mmol) in anhydrous pyridine (10 ml) and triethyl amine (1 ml) was saturated with hydrogen sulfide gas at 0° C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the residue was dissolved in anhydrous acetone (5 ml) and iodomethane (1 ml, 16.6 mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the residue was dissolved in anhydrous methanol (5 ml) and added a solution of N-methylethylenediamine (0.732 ml, 8.3 mmol) and acetic acid (1.5 ml) in anhydrous methanol (5 ml). The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP—HPLC to give N-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder. MS found for C23H19Cl2N5O2 M+=468 (M+2)+=470.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74]>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:67][CH2:68][CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (Example 13) (300 mg, 0.67 mmol), HATU (281 mg, 0.74 mmol) and N,N-diisopropylethylamine (190 mg, 1.47 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (160 mg, 1.0 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}carbamate as white solid. Yield: 395 mg, 100%.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][C@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27](OC)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:20][CH2:21][C@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=1)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)[C@H](CO[C@H](C)CO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(F)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
Trimethylaluminium (2M in hexane)(0.474 mL, 0.95 mmol) was added to 5-fluoropyridin-2-amine (102 mg, 0.91 mmol) in toluene (7 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AN2) (430 mg, 0.82 mmol) in toluene (7 mL) was added and the reaction was allowed to warm to room temperature and then heated to 100° C. for 5 hours in the microwave reactor. The reaction was allowed to cool to room temperature before adding EtOAc (30 mL) and 20% sodium potassium tartrate solution (30 mL), which was stirred vigorously for 16 hours. The phases were separated and the organic layer was washed with sat. brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to give (2S)-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (303 mg, 61.1%). 1H NMR (400 MHz, DMSO) δ-0.01 (d, 6H), 0.80 (s, 9H), 1.09 (d, 3H), 3.46-3.63 (m, 2H), 3.67-3.77 (m, 1H), 4.07-4.20 (m, 2H), 5.90-5.95 (m, 1H), 7.71-7.80 (m, 2H), 8.02-8.08 (m, 1H), 8.33-8.39 (m, 2H), 8.58 (s, 1H), 8.63 (s, 1H), 8.67-8.71 (m, 1H), 11.09 (s, 1H); m/z (ES+), (M+H)+=602.48; HPLC tR=3.33 min
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:16]12[N:23]([C:24](=[O:35])[CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27]Cl)[CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl>CN(C)C=O>[CH:20]12[N:23]([C:24](=[O:35])[CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27][N:13]3[CH2:14][CH2:15][N:10]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[CH:2][NH:1]5)[CH2:11][CH2:12]3)[CH:16]([CH2:22][CH2:21]1)[CH2:17][CH2:18][CH2:19]2
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C(C(CCCl)c1ccccc1)N1C2CCCC1CC2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C(CCN1CCN(c2cccc3[nH]ccc23)CC1)c1ccccc1)N1C2CCCC1CC2

Procedure:
The title compound was prepared from 4-(1H-indol-4-yl)-piperazine (1.0 g, 4.97 mmole), 1-(8-aza-bicyclo[3.2.1]oct-8-yl)-4-chloro-2-phenyl-butan-1-one (1.6 g, 4.97 mmole), diisopropylethylamine (0.65 g, 4.97 mmole) and potassium iodide (0.83 g, 4.97 mmole) in dimethylformamide (8 mL) in the manner described in example 2 to yield 0.6 g of product as the hydrochloride 0.75 hydrate, m.p. 150°-170° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[C:26]1([S:23]([N:18]2[C:19]3[C:15](=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:25])=[O:24])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21

Procedure:
A solution of 125 mg (0.28 mmole) 4-(1-benzenesulfonyl-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 2 mL trifluoroacetic acid was stored at room temperature for 10 minutes. The solution was concentrated under reduced pressure and the residue was partitioned between 3 mL 10% sodium carbonate and 20 mL ethyl acetate. The organic phase was washed with 5 mL water, dried (magnesium sulfate) and concentrated. 1-Benzenesulfonyl-4-piperazin-1-yl-1H-indole (5) was isolated as the hydrochloride salt from ethyl acetate-ethyl ether, 73 mg, M+H=342; m.p.294-295° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(C(F)(F)F)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc(C(F)(F)F)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 12-3 (810 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (600 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:15]([CH3:14])[C@H:16]3[CH2:35][N:20]4[C:21]5[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]4[CH2:18][CH2:17]3)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C1(c2ccc(F)cc2)CC1
Product: CN(C(=O)C1(c2ccc(F)cc2)CC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-(4-fluorophenyl)cyclopropanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 321.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C@H:38]1[O:42][C@@H:41]([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[CH2:40][CH2:39]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C@@H:41]1([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[O:42][C@H:38]([CH2:37][OH:36])[CH2:39][CH2:40]1
Reactant: Cc1cn([C@H]2CC[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 1M solution of tetra-butylammonium fluoride in THF (0.35 mL, 0.35 mmol), was added to a solution of 5'-O-(t-butyldiphenylsilyl)-3'-deoxythymidine (0.162 g, 0.35 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours, at which time thin layer chromatography indicated complete disappearance of the starting material. The solvent was removed under reduced pressure. The residue was dissolved in a minimum volume of chloroform and then purified by passing it through a vacuum column packed with silica gel. The column was eluted with methanol, followed by 6% methanol in chloroform. Compound 11 was obtained from the final eluent as a white crystalline solid. The product obtained was twice crystallized from ethyl acetate. Yield 0.063 g, 80%. 1H NMR (DMSO- d6, 90 MHz): δ 1.77 (s, 3 H, 5-CH3); 1.7-2.3 (m, 4 H, 2' and 3' H); 3.60 (m, 2 H, 5'-H); 4.00 (m, 1 H, 4'-H); 5.01 (t, 1 H, 5'-OH, J=5.4 Hz, D2O exchangeable); 5.95 (dd, 1 H, 1'-H, J=5.5 and 6.5 Hz); 7.79 (s, 1 H, 6-H); 11.20 (br s, 1 H, NH, D2O exchangeable); mp 151°-152° C.; [α]D +18.3(c=0.999, MeOH).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([CH2:28][O:29][CH:30]2[CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=3)[CH2:34][CH2:33][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:31]2)[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([CH2:28][O:29][CH:30]2[CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][F:7])[CH:37]=3)[CH2:34][CH2:33][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:31]2)[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(CO)c2)C(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(CF)c2)C(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 101.6 %

Procedure:
A solution of 18 mg (0.106 mmol) of diethylamino-sulphur trifluoride (DAST) in 1 ml of methylene chloride was cooled to -65° C. and a solution of 56 mg (0.101 mmol) of tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-hydroxymethyl-phenyl)-piperidine-1-carboxylate in 1 ml of methylene chloride was added dropwise thereto at -60° C. to -65° C. within 3 minutes. The resulting yellow solution was warmed to room temperature and stirred for one hour. Subsequently, the mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. There were obtained 57 mg of crude tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-fluoromethyl-phenyl)-piperidine-1-carboxylate, which was used in the next step without further purification and characterization.
Reaction SMILES: [C]=O.[F:3][CH2:4][C:5]1([CH2:27][F:28])[CH:10]=[C:9](OS(C(F)(F)F)(=O)=O)[C:8]2[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:7]=2[O:6]1.[C:29]([O-:32])(=[O:31])C.[K+].[Cl-].[Li+].[OH-].[Na+].Cl>CN(C)C=O>[F:3][CH2:4][C:5]1([CH2:27][F:28])[CH:10]=[C:9]([C:29]([OH:32])=[O:31])[C:8]2[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:7]=2[O:6]1
Reactant: CC(=O)[O-]
Reactant: O=S(=O)(OC1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21)C(F)(F)F
Agent: Cl
Agent: [C]=O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 87 %

Procedure:
A three-necked 50-ml flask (equipped with a reflux condenser, a thermometer, and a CO introducing pipe connected with a balloon charged with carbon monoxide gas) was charged with 2.00 g (4.85 mmol) of trifluoromethanesulfonic acid 2,2-bis(fluoromethyl)-6- (trifluoromethyl)-2 H-1-benzopyran-4-yl ester, 1.90 g (19.4 mmol) of potassium acetate, 206 mg (4.85 mmol) of lithium chloride, and 25 ml of N,N-dimethylformamide. Under stirring of the mixture, 50 mg (0.0485 mmol) of tris(dibenzylidene)(chloroform)dipalladium (Pd2(dba)3(CHCl3)) were added. Under normal pressure, the reaction was conducted at 25° C. for 2 hr, while maintaining carbon monoxide atmosphere. After the reaction, the reaction liquid was poured into 50 ml of 2 mol/L sodium hydroxide aqueous solution, followed by shaking for 20 min, then adding concentrated hydrochloric acid to make it acid, and then extraction two times with 50 ml of MTBE. The resulting two MTBE extracts were combined together, followed by washing with water, then by drying with 5 g of magnesium sulfate anhydride, and then by filtration. Then, the MTBE was distilled off by an evaporator. The resulting residue was dissolved in 50 ml of a saturated sodium hydrogencarbonate aqueous solution, followed by washing with 5 ml of methylene chloride. The resulting aqueous layer was made acid by concentrated hydrochloric acid, followed by extraction two times with 50 ml of MTBE. The resulting two MTBE extracts were combined together, followed by washing with water, then by drying with 5 g of magnesium sulfate anhydride, and then by filtration. Then, the MTBE was distilled off by an evaporator, thereby obtaining 1.30 g (4.22 mmol) of 2,2-bis(fluoromethyl)-6-(trifluoromethyl)-2 H-1- benzopyran- 4-carboxylic acid (yield: 87.0%).
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[C-:16]#[N:17].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=1)[C:16]#[N:17]
Reactant: [C-]#N
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (222 mg, 1.0 mmol) in ethyl acetate (5 mL) was added a solution of KCN (195 mg, 3.0 mmol) and NaHSO3 (312 mg, 3.0 mmol) dissolved in H2O (10 mL). The reaction was stirred at rt for 8 h. Another portion of KCN (195 mg, 3.0 mmol) and NaHSO3 (312 mg, 3.0 mmol) dissolved in H2O (10 mL) was added. It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated to give 130A as an oil. It was used for next step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 5.57 (s, 1H) 5.78-6.04 (m, 1H) 7.28 (d, J=6.15 Hz, 1H) 7.39 (s, 1H) 7.43-7.52 (m, 2H). 19F NMR (376 MHz, CDCl3) δ ppm −136.72, −88.04.