Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:9])[CH2:10][Br:11])#[N:2]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: N#Cc1cc(CBr)ccc1F
Yield: 63.1 %

Procedure:
A solution of 3-Cyano-4-fluorotoluene (1.0 g, 7.4 mmol), N-bromosuccinimide (1.3 g, 7.4 mmol) and catalytic 2,2i-azobisisobutyronitrile (AIBN) in benzene was heated to reflux for 16 hours, evaporated to dryness and flash chromatographed over silica gel eluting with 10% ethyl acetate/hexane to provide 1.0 g of 3-cyano-4-fluorobenzyl bromide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:25][C:23]1[CH:24]=[C:19]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[CH:32]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:20]=[C:21]([CH3:26])[N:22]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc(C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc(C)n1
Yield: 50 %

Procedure:
The title compound was synthesized as described for Example 12 in 50% yield starting from 1-(3-bromophenyl)-1-(2,6-dimethylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (70.2 mg, 0.17 mmol), pyrimidin-5-ylboronic acid (23.3 mg, 0.19 mmol), PdCl2(dppf)-CH2Cl2 adduct (14.0 mg, 0.02 mmol), and K2CO3 (aq) (0.26 mL, 0.51 mmol).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C:12]([CH3:26])([CH3:25])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[Cl:45])[CH2:40][NH2:41]>>[Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C:12]([CH3:25])([CH3:26])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:44]([Cl:45])=[C:37]([Cl:36])[CH:38]=2)=[O:23])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(Cc1cccc(CCC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CC(C)(Cc1cccc(CCC(=O)NCc2ccc(Cl)c(Cl)c2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Yield: 64 %

Procedure:
The title compound was prepared from 3-{3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl )phenyl]ethyl}amino)-2-methylpropyl]phenyl}propanoic acid (preparation 144) and 3,4-dichlorobenzylamine, using a method similar to that of preparation 38, as a clear oil in 64% yield. 1H NMR (400 MHz, CD3OD) δ: 7.40 (3H, m), 7.18 (1H, m), 7.08 (5H, m), 6.78 (1H, d), 4.61 (3H, m), 4.23 (2H, s), 2.90 (3H, m), 2.60 (5H, m), 1.08 (3H, s), 1.04 (3H, s), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m/z 659 [M+H]+
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[BH4-].[Na+].Cl>CO>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloroacetophenone (15.5 g, 100 mmoles) was dissolved in 100 ml of methanol, and a solution of 5.67 g (150 mmoles) of sodium borohydride in 250 ml of methanol was slowly added to the solution. The resulting solution was stirred overnight at room temperature. To the reaction mixture was added 1 N hydrochloric acid, and the organic layer was extracted with diethyl ether. The organic layer was collected and dried over anhydrous sodium sulfate, followed by concentration to obtain 1-(4-chlorophenyl)ethanol [1H-NMR (300 MHz, CDCl3) 1.48 (d, J=6.3 Hz, 3H), 4.88 (q, J=6.6 Hz, 1H), 7.31 (s, 4H)] in a nearly pure form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][N:6]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:7]1[NH:12][C:11](=[S:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[C:9](=[O:26])[CH:8]=1.C(=O)([O-])O.[Na+].I[CH2:50][CH3:51]>C(#N)C>[CH3:37][O:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[CH2:27][N:6]([CH2:5][C:4]1[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=1[O:2][CH3:1])[C:7]1[N:12]=[C:11]([S:13][CH2:50][CH3:51])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:16][CH:15]=2)[C:9](=[O:26])[CH:8]=1
Reactant: CCI
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2OC)c2cc(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCSc1nc(N(Cc2ccc(OC)cc2OC)Cc2ccc(OC)cc2OC)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[bis(2,4-dimethoxybenzyl)amino]-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrimidin-4(1H)-one (0.65 g) in acetonitrile (7 mL) were added 1M aqueous sodium hydrogen carbonate solution (1.05 mL) and iodoethane (0.425 mL), and the mixture was stirred at 70° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.68 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:17][CH:16]=3)=[O:15])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: C[C@@H]1COC(=O)N1Cc1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4C(=O)OC[C@H]4C)cc3)CC2)c(C)c1
Yield: 86.6 %

Procedure:
Using (R)-4-(4-methyl-2-oxooxazolidin-3-ylmethyl)benzoic acid (141 mg) described in Preparation Example 64 and 1-(3,5-dimethylpyridin-2-yl)piperazine (126 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (212 mg) was obtained.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.00 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 352 mg (72%) colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:29])[CH:3]=1.[CH2:30]([O:37][CH2:38][CH2:39]O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C.CO.C(OCC)C>[CH2:30]([O:37][CH2:38][CH2:39][O:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1
Reactant: OCCOCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCCOCc2ccccc2)cc(C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Yield: 39.8 %

Procedure:
To a solution of methyl 3-{4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (0.50 g, 1.28 mmol), 2-(benzyloxy)ethanol (0.20 mL, 1.41 mmol) and tributylphosphine (0.48 mL, 1.92 mmol) in tetrahydrofuran (10 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.48 g, 1.92 mmol) at 0° C. with stirring. The reaction mixture was stirred at room temperature for 18 hrs., and an equivalent amount of the aforementioned reagents (2-(benzyloxy)ethanol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) were added at the same temperature and the mixture was further stirred for 18 hrs. Diethyl ether was added to the reaction mixture and insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give a colorless oil. Then, to a mixture of the oil, methanol (4 mL) and tetrahydrofuran (8 mL) was added 1 N aqueous sodium hydroxide solution (2.6 mL) at room temperature with stirring, and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was neutralized with 1 N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) to give the title compound (0.26 g, yield 39%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1([F:40])[CH2:7][CH2:6][CH:5]([C:8]([NH:10][CH2:11][C:12]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:14][N:15]2[C@H:20]3[CH2:21][CH2:22][C@@H:16]2[CH2:17][CH:18]([N:23]2[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]2[CH3:32])[CH2:19]3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:44].O>CN(C=O)C>[F:40][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]([N:10]([CH3:44])[CH2:11][C:12]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:14][N:15]2[C@H:20]3[CH2:21][CH2:22][C@@H:16]2[CH2:17][CH:18]([N:23]2[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]2[CH3:32])[CH2:19]3)=[O:9])[CH2:4][CH2:3]1
Reactant: CI
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN(C)C(=O)C1CCC(F)(F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a solution of the title compound from example 21 (100 mg, 0.18 mmol) in dry DMF (1.5 mL) was added sodium hydride (9 mg, 0.22 mmol) as a 60% suspension in mineral oil and the solution stirred under a nitrogen atmosphere at room temperature for 30 min. Iodomethane (0.06 mL, 0.9 mmol) was added and the reaction stirred at room temperature for 2 h. Water was added and the reaction partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-5% methanol/CH2Cl2 followed by purification by HPLC eluting with 5-70% water/acetonitrile/0.1% TFA to afford the title compound (9 mg, 7%) which was isolated as the trifluoroacetate salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]2[CH2:7][N:8]([C:14]3[CH:23]=[C:22]([NH:24]C(=O)OC(C)(C)C)[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH3:32])[CH:20]=4)[N:15]=3)[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]2[CH2:7][N:8]([C:14]3[CH:23]=[C:22]([NH2:24])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH3:32])[CH:20]=4)[N:15]=3)[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NC(=O)OC(C)(C)C)c3cc(C)ccc3n1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(N)c3cc(C)ccc3n1)C2
Yield: 22.2 %

Procedure:
A mixture solution of tert-butyl [2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamate (59.0 mg, 0.12 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (2.0 mL) was stirred at room temperature for 6 hours. Then the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 10.2 mg of the product as a white solid (yield was 21.5%). MS obsd. (ESI+) [(M+H)+] 384, 1H NMR (400 MHz, CD3OD) δ ppm 7.72 (d, J=8.34 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J=2.78 Hz, 1 H), 7.43 (d, J=8.34 Hz, 1 H), 7.29 (dd, J=8.46, 1.89 Hz, 1 H), 7.12 (dd, J=8.34, 2.78 Hz, 1 H), 6.27 (s, 1 H), 5.02 (s, 2 H), 4.47 (brs, 2 H), 3.82 (s, 3 H), 3.56 (t, J=4.80 Hz, 2 H), 2.42 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].Cl.[N:11]([O-])=[O:12].[Na+].[Cl-].[Na+]>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[N:11]=[O:12]
Reactant: COCCNCCOC
Reactant: O=N[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COCCN(CCOC)N=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To the mixture of 133 g of bis(2-methoxyethyl)amine, 145 ml of concentrated HCl (36%) and 400 g of ice, 70 g of sodium nitrite dissolved in 250 ml of water was added dropwise slowly while keeping the reaction temperature at 10° C. or below, and then stirred for 2 hours at 10° C. or less and for further 2 hours at room temperature. 250 g of sodium chloride was added thereto, and the mixture was thrice extracted with 500 ml of ethyl acetate and dried with magnesium sulfate. After removing the solvent, the mixture was purified by a silica gel column by using the mixed solvent (hexane/ethyl acetate: 3/1) to obtain 85 g of bis(2-methoxyethyl)nitrosoamine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH3:19]>>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]([NH:20][CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])=[O:14])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C=CC(=O)O)cc1
Reactant: CCC(N)CC
Product: CCOc1ccc(C=CC(=O)NC(CC)CC)cc1

Procedure:
Prepared in a similar manner to example 4 using 3-(4-ethoxy-phenyl)-acrylic acid and 3-pentylamine. MS (M+H, 262.2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32]CC2C=CC=CC=2)=[C:28]([O:40]CC2C=CC=CC=2)[CH:27]=1)[C:10]([O:12][C@H:13]([CH3:24])[CH2:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[OH:40][C:28]1[CH:27]=[C:26]([CH2:25][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([O:12][C@H:13]([CH3:24])[CH2:14][O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[O:11])[CH:31]=[CH:30][C:29]=1[OH:32]
Reactant: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of (1R)-1-methyl-2-phenylcarbonyloxyethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (5) (2.6 g, 4.85 mmol) in 40 mL of tetrahydrafuran, 10% Pd—C (200 mg) pre-mixed with 10 mL of methanol was added under a nitrogen atmosphere. The nitrogen atmosphere was exchanged with hydrogen using the evacuation refill cycle method. The mixture was stirred under hydrogen at room temperature for 2 hours. After filtration and washing with methanol, the filtrate was concentrated and chromatographed (silica gel, 30% ethyl acetate in hexane) to afford 1.87 g (100% yield) of the title compound (1). MS (ESI) m/z 460.20 (M+H)+ and 458.17 (M−H)−.
Reaction SMILES: [Li][N:2]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[S:3]([C:6]([F:9])([F:8])[F:7])(=[O:5])=[O:4]>S(=O)(=O)(O)O>[NH:2]([S:3]([C:6]([F:9])([F:7])[F:8])(=[O:5])=[O:4])[S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11]
Reactant: [Li]N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Yield: 75.2 %

Procedure:
The imide HN(SO2CF3), was obtained from the lithium salt. LiN(SO2CF3)2 (10 g, 35 mmole) was added to 50 mL concentrated sulfuric acid. The free imide was distilled at about 90° C., 10 mm Hg and purified by sublimation at about 70° C., 1-2 mm Hg giving 7.4 g (74%) HN(SO2CF3)2. The silver salt was then obtained from the imide. Ag2CO3 (2.0 g, 0.2 mmol) was added slowly to a stirring, solution of HN(SO2CF3)2 (3.5 g, 12.0 mmole) in 25 mL water. The mixture was then digested, wrapped in foil, at 60° C. for 1 h and the excess Ag2CO3 filtered off. The water was removed under vacuum giving white powder of AgNTf2. Dissolution of the powder in diethyl ether (25 mL) followed by filtration and removal of all volatiles under vacuum gave 4.6 g (95%) of white AgNTf2.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[C:4]([NH:6][CH:7]([C:27]#[N:28])[CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[CH:13]=[CH:12]2)=[O:5].C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[C:4]([NH:6][CH:7]([C:27]1[NH:40][N:39]=[N:38][N:28]=1)[CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[CH:13]=[CH:12]2)=[O:5]
Reactant: N#CC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)c1nnn[nH]1)c1c(Cl)cccc1Cl
Yield: 36 %

Procedure:
To 2,6-dichloro-N-{1-cyano-2-[2-(2,6-dichlorophenyl)-6-quinolinyl]ethyl}benzamide 58 (0.358 g) in toluene (5 ml) are added trimethylsilyl azide (184 μl) and dibutyltin oxide (17 mg). The solution is heated at reflux overnight, then evaporated under vacuum. The resulting residue is purified twice over silica gel using one time CH2Cl2/CH3OH 85/15 as eluent and the second time CH2Cl2/(CH3OH-10% NH4OH) 85/15 to give 2,6-dichloro-N-[2-[2-(2,6-dichlorophenyl)-6-quinolinyl]-1-(1H-tetraazol-5-yl)ethyl]benzamide 126.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]#[C:13][CH2:12][CH2:11][OH:15])([O-:10])=[O:9]
Reactant: C#CCCO
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1C#CCCO
Reaction time: 16 h
Yield: 78.5 %

Procedure:
A solution of o-bromonitrobenzene (8.1 g, 0.04 mol) in 160 ml of triethylamine, under nitrogen, is treated sequentially with bis(triphenylphosphine)palladium(II)chloride (0.28 g, 0.4 mmol), 3-butyne-1-ol (2.81 g, 0.04 mol) and copper(I)iodide (0.15 g, 0.8 mmol), stirred for about 16 hours and filtered. The filtercake is washed with toluene. The filtrates are combined and concentrated in vacuo to give the title product as a dark oil, 6.0 g, 78.5% yield, identified by NMR and mass spectral analyses.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH:9]1([C:12](=O)[CH2:13][C:14](=O)[CH3:15])[CH2:11][CH2:10]1>O>[NH2:7][C:6]1[N:8]=[C:12]([CH:9]2[CH2:11][CH2:10]2)[CH:13]=[C:14]([CH3:15])[N:5]=1
Reactant: N=C(N)N
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=C(O)O
Solvent: O
Product: Cc1cc(C2CC2)nc(N)n1
Temperature: 95 °C

Procedure:
15 g of guanidine carbonate are added to a mixture of 10 g of 1-cyclopropyl-butane-1,3-dione and 150 g of water, and stirring is maintained at 95° C. for 5 hours. The mixture is then concentrated by evaporation to a volume of 50 ml, and the cooled aqueous concentrate is extracted three times with 100 ml of ethylene chloride each time. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The residue crystallises to thus yield 5 g of the title compound, m.p. 113°-115° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[O:27])=O)C1C=CC=CC=1.Cl.[H][H]>[Pd].CO>[CH3:20][S:17]([O:16][C@H:14]1[CH2:15][NH:11][C@H:12]([CH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[O:27])[CH2:13]1)(=[O:18])=[O:19]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(N)=O)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)O[C@H]1CN[C@H](COCCNC(N)=O)C1

Procedure:
A mixture of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (13.25 g), concentrated hydrochloric acid (3 ml), methanol (150 ml) and 10% palladium on carbon (0.5 g) was stirred under atmospheric pressure of hydrogen at ambient temperature for 4 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-methanesulfonyloxy-2-[(2-ureidoethyl)oxymethyl]pyrrolidine. To a solution of the compound obtained above in a mixture of tetrahydrofuran (100 ml) and water (100 ml) was dropwise added a solution of allyl chloroformate (3.75 ml) in tetrahydrofuran (30 ml) under ice-cooling with stirring, keeping the pH between 8.5-9.5 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 1 hour and extracted with ethyl acetate (100 ml×2). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (150 g) and eluted with a mixture of methanol and chloroform (2:98 and then 4:96 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (11.02 g).
Reaction SMILES: [CH2:1]([O:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:11])[CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[S:25](Cl)([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[S:25]([O:27][CH2:28][CH3:29])([O:10][CH2:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:11])=[O:26]
Reactant: CCCCCCOC(C)(CO)OCCCCCC
Reactant: CCOS(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCOC(C)(COS(=O)OCC)OCCCCCC
Temperature: 23 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
To a solution of alcohol 4 (20.6 g, 79.1 mmol) in CH2Cl2 (200 mL) is added pyridine (8.12 g, 102.8 mmol) and ethyl chlorosulfite (12.2 g, 94.9 mmol). The reaction mixture is stirred at 23° C. for 10 hours. The reaction is quenched with water (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic layers are washed with HCl (1N, 100 mL), saturated NaHCO3 (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propanyl ethyl sulfite 6 (24.5 g, 88%) as a colorless oil: Rf (15% EtOAc/hexane)=0.44; IR (thin film, cm−1) 2932, 2872, 1467, 1379, 1213, 1194, 1176, 1001, 888; 1H NMR (600 MHz, CDCl3) δ 4.11-4.00 (m, 2H), 3.93 (d, J=10.8 Hz, 1H), 3.77 (d, J=10.8 Hz, 1H), 3.42-3.37 (m, 4H), 1.51-1.48 (m, 4H), 1.33 (s, 3H), 1.31-1.24 (m, 15H), 0.85 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 99.0, 62.9, 60.8, 58.5, 58.3, 31.6, 29.8, 25.9, 22.6, 20.9, 15.3, 14.0.