Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:28])[N:10]2[CH:29]=[C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:31][C@H:9]2[C@@H:8]1O)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCC1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:16]1[CH:17]=[C:12]2[C:11]([N:10]3[C@H:9]([CH:8]=[N:7][C:13]2=[CH:14][C:15]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:31][C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29]3)=[O:28]
Reactant: C=CCOC(=O)N1c2cc(OCc3ccccc3)c(OC)cc2C(=O)N2C=C(CC(=O)OC)C[C@H]2[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: COC(=O)CC1=CN2C(=O)c3cc(OC)c(OCc4ccccc4)cc3N=C[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A catalytic amount of tetrakis(triphenylphosphine)palladium (5.0 mg, 4.33 μmol) was added to a stirred solution of the Alloc-protected carbinolamine 23 (88 mg, 0.17 mmol), triphenylphosphine (2.27 mg, 8.65 μmol) and pyrrolidine (13 mg, 0.18 mmol) in CH2Cl2 (15 mL). After 2 hours stirring at room temperature under a nitrogen atmosphere, TLC (80% EtOAc/Petroleum Ether) revealed the complete consumption of starting material. The solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (60% EtOAc/Petroleum Ether) to afford the novel PBD (SJG-245) as a colourless glass (54 mg, 77%) which was repeatedly evaporated in vacuo with CHCl3 in order to provide the N10-C11 imine form 24: 1H NMR (270 MHz, CDCl3) (imine) δ7.80 (d, 1H, J=4.03 Hz, HC═N), 7.50 (s, 1Harom), 7.45-7.26 (m, 5Harom), 6.91 (br s, 1H, NCH═CCH2OC2CH3), 6.83 (s, 1Harom), 5.21-5.12 (m, 2H, PhCH2O), 3.94 (s, 3H, OCH3), 3.73 (s, 3H, CO2CH3), 3.23 (s, 2H, NCH═CCH2CO2CH3), 3.15 (m, 2H, NCH═CCH2CO2CH3CH2); 13C NMR (67.8 MHz, CDCl3) (imine) δ170.7 (CO2CH3), 162.7 (HC═N), 161.4 (NC═O), 150.9 (Carom), 148.1 (Carom), 140.1 (Carom), 136.0 (Carom), 128.7, 128.2 and 127.3 (BnC—Harom), 127.3 (NCH═CCH2CO2CH3), 119.2 (Carom), 117.5 (NCH═CCH2CO2CH3), 111.8 (C—Harom), 111.5 (C—Harom), 70.8 (PhCH2O), 56.2 (OCH3), 53.8 (NCHHC═N), 52.0 (CO2CH3), 37.4 (NCH═CCH2CO2CH3), 33.6 (NCH═CCH2CO2CH3CH2)
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][C:10]2[CH2:11][S:12][C@@H:13]3[C@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:32](=[O:44])[N:14]3[C:15]=2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:3]=1.CC1[O:51]C(=O)C=C(SC2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=O)N3C(=O)[C@@H](NC(=O)CC4C=CC=CC=4)[C@H]3SC=2)C=1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][C:10]2[CH2:11][S:12](=[O:51])[C@@H:13]3[C@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:32](=[O:44])[N:14]3[C:15]=2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:3]=1
Reactant: Cc1cc(SC2=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)cc(=O)o1
Reactant: Cc1cc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)cc(=O)o1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3S(=O)C2)cc(=O)o1
Reaction time: 0.67 h

Procedure:
A stirred solution of diphenylmethyl 3-(6-methyl-2-oxo-2H-pyran-4-ylthio) -7β-phenylacetamidoceph-3-em-4-carboxylate and diphenylmethyl 3-(6-methyl-2-oxo-2H-pyran-4-ylthio) -7β-phenylacetamidoceph-2-em-4-carboxylate (763 mg) in dichloromethane (10 ml) was cooled in an ice bath, and a solution of m-chloroperbenzoic acid (211 mg of 85%) in dichloromethane (5 ml) was added. The mixture was stirred at 0° for 40 mins. and then washed with sodium bicarbonate solution, sodium metabisulphite solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The title compound (581 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 1:1 hexane:ethyl acetate going to neat ethyl acetate). υmax (CHCl3) 3390, 1805, 1720 cm-1, δH (CDCl3) 2.14 (3H, s) 3.36 (1H, d, J 18.1Hz), 3.60 (2H, s), 3.75 (1H, d, J 18.2Hz), 4.51 (1H, d, J 4.8Hz), 5.72 (1H, s), 5.95 (1H, s) 6.13 (1H, dd, J 4.8 and 9.7Hz), 6.94 (1H, d, J 9.7Hz), 6.97 (1H, s), 7.2-7.4 (15H, m).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15](C)[CH2:16][OH:17].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:17][CH2:16][CH2:15][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[CH:1]=1)(=[O:21])[CH3:20]
Reactant: CC(CO)c1ccc2c(c1)Cc1ccccc1O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc2c(c1)Cc1ccccc1O2
Reaction time: 24 h

Procedure:
One gram of 2-(2-xanthenyl)-propanol is allowed to stand for 24 hours in 5 ml. of pyridine and 5 ml. of acetic anhydride. The mixture is concentrated, worked up as usual, and the product is 2-(2-xanthenyl)-propyl acetate, m.p. 62°-64°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[CH3:22][N:23]([CH3:38])[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[S:34](Cl)(=[O:36])=[O:35].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:34]([C:29]1[C:30]2[C:25](=[C:24]([N:23]([CH3:38])[CH3:22])[CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH:28]=1)(=[O:36])=[O:35])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc2c(S(=O)(=O)NCCN=[N+]=[N-])cccc12
Yield: 86 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 5-(dimethylamino)naphthalene-1-sulfonyl chloride (0.321 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.241 g, 2.38 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide (0.328 g, 86%). 1H NMR (300 MHz, CDCl3) δ 8.52 (d, 1H), δ 8.28 (d, 1H), δ 8.22 (d, 1H), δ 7.53 (t, 1H), δ 7.50 (t, 1H), δ 7.17 (d, 1H), δ 5.58 (t, 1H), δ 3.28 (t, 2H), δ 3.03 (q, 2H), δ 2.85 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 152.3, 134.8, 130.9, 130.1, 129.7, 128.9, 123.4, 118.9, 115.6, 51.0, 45.6, 42.6 ppm; HRMS (ESI) calcd for C14H17N5O2S (M+) 319.1103. found 319.1104.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=3)[C:23]3[N:24]=[N:25][N:26]([CH3:28])[N:27]=3)[C:17]3[CH:44]=[C:45]([CH3:52])[C:46]([C:48]([F:51])([F:50])[F:49])=[CH:47][C:16]2=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:33]=1)[CH2:29][N:22]([C@H:18]1[CH2:19][CH2:20][CH2:21][N:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:16]2[CH:47]=[C:46]([C:48]([F:49])([F:50])[F:51])[C:45]([CH3:52])=[CH:44][C:17]1=2)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCN(C(=O)OC(C)(C)C)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-piperidine-1-carboxylic acid tert-butyl ester (0.09) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL). After stirring for 1 h at room temperature, quench the reaction with concentrated sodium carbonate (10 mL) and dilute with dichloromethane (20 mL) and water (20 mL). Separate the organics and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the reaction over silica gel eluting with methanol/dichloromethane (0-5%) to afford the title compound as a colorless foam. MS (ES+): 650 (M+H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]CC)=[CH:24][CH:23]=1)[CH3:20]>COC(C)C(O)C>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:30])=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOC(=O)Nc1ccc(OCC)cc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: COC(C)C(C)O
Product: CCOc1ccc(NC(=O)NCCCOc2cccc(CN3CCCCC3)c2)cc1
Yield: 6.4 %

Procedure:
The mixture of 3-(3-piperidinomethylphenoxy)propylamine (4.7 g) and ethyl N-(4-ethoxyphenyl)carbamate (4.0 g) in 3-methoxy-2-butanol (20 ml) was refluxed for 6 hours and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane, washed with water, diluted hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the resulting residue was purified by silica gel flash column chromatography to give the precipitate (0.9 g; yield 11.4%). This precipitate was recrystallized from ethanol to give the title compound (0.5 g), mp 109-111° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Li])CCC.[CH2:21]([N:28]1[CH2:36][CH:35]2[CH:30]([CH2:31][CH2:32][CH2:33][C:34]2=[O:37])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.CCCCCC>[CH2:21]([N:28]1[CH2:36][CH:35]2[CH:30]([CH2:31][CH2:32][CH2:33][C:34]2([C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[OH:37])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C1CCCC2CN(Cc3ccccc3)CC12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC2CN(Cc3ccccc3)CC21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.06 cm3 of 3,5bis(trifluoromethyl)bromobenzene in 15 cm3 of dry tetrahydrofuran is added, at -78° C., a solution of 10.9 cm3 of 1.6M butyllithium in hexane. This solution is stirred for 30 minutes at -78° C., and a solution of 1 g of (3aRS,7aSR)-2-benzyl-4-perhydroisoindolone in 5 cm3 of tetrahydrofuran is then run in dropwise. The reaction mixture is subsequently stirred at room temperature for 18 hours, treated with 20 cm3 of water and then extracted with 20 cm3 of ethyl acetate. The organic phase is separated out after settling has taken place, washed with twice 20 cm3 of water, then with 20 cm3 of saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 20 cm3 fractions. Fractions 26 to 37 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.82 g of (3aRS,4RS,7aSR)-2-benzyl-4-[3,5-bis(trifluoromethyl)phenyl]-4-perhydroisoindolol is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1C[CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30]OCC4C=CC=CC=4)[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49]C=C[CH:46]=3)[N:15]=2)[CH2:10]1.[CH2:57](N1CC[C@H](NC)C1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.F[C:72](F)(F)[C:73](O)=O.Cl[C:79]1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC(F)=CC=2)C2C=CC=CC=2)N=1.C(OC(=O)N([C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)[C@H](O)[C@@H]1O)C(=O)CC)(C)(C)C.C(N)(=O)CC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:57]([N:8]1[CH2:73][CH2:72][C@H:10]([N:11]([CH3:12])[C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30][CH3:79])[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:45]3[CH:50]=[CH:49][C:2]([F:7])=[CH:3][CH:46]=3)[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:15]=2)[CH2:9]1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccc(F)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CN[C@H]1CCN(Cc2ccccc2)C1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: CCC(N)=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccc(F)cc4)nc(N(C)[C@H]4CCN(Cc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate (Example 1 step 2) by replacing (3R)-3-(Boc-amino)pyrrolidine with ((S)-1-benzyl-pyrrolidin-3-yl)-methyl-amine and by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-((1S,2R,3S,4R)-4-{2-chloro-6-[2-(4-fluoro-phenyl)-2-phenyl-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate [prepared from [(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionyl-carbamic acid tert-butyl ester (Intermediate G) and the appropriate amine using a procedure analogous to 2R,3S,4R)-4-{6-[2,2-Bis-(4-hydroxy-phenyl)-ethylamino]-2-chloro-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 22 steps 1 and 2)]. (MH+ 693.5)
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH2:44][CH3:45])[C:3]([O:5][CH:6]1[CH:15]2[C:10]([CH:11]=[CH:12][CH:13]([CH3:42])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([O:24][C:25](=[O:40])[CH2:26][CH2:27][C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37](=O)[NH2:38])=[CH:33][CH:32]=3)=[O:29])[CH2:21][C:20](=[O:41])[O:19]2)=[CH:9][CH:8]([CH3:43])[CH2:7]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:56])=CC=1>C1C=CC=CC=1>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][C:25]([O:24][CH:22]2[CH2:21][C:20](=[O:41])[O:19][CH:18]([CH2:17][CH2:16][CH:14]3[CH:15]4[C:10](=[CH:9][CH:8]([CH3:43])[CH2:7][CH:6]4[O:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:46])[CH2:44][CH3:45])[CH:11]=[CH:12][CH:13]3[CH3:42])[CH2:23]2)=[O:40])=[CH:32][CH:33]=1)(=[S:56])[NH2:38]
Reactant: CCC(C)(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(OC(=O)CCC(=O)Oc4ccc(C(N)=O)cc4)CC(=O)O3)C21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CCC(C)(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(OC(=O)CCC(=O)Oc4ccc(C(N)=S)cc4)CC(=O)O3)C21
Temperature: 50 °C
Reaction time: 6 h
Yield: 9.8 %

Procedure:
Succinic acid 4-carbamoyl-phenyl ester 2-{2-[8-(2,2-dimethyl-butyryloxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-naphthalen-1-yl]-ethyl}-6-oxo-tetrahydro-pyran-4-yl ester (2) (0.35 g, 0.000548 mol) and Lawesson reagent (0.221 g, 0.000548 mol) were dissolved in 30 ml of anhydrous benzene. The reaction was warmed to 50° C. and stirred for 6 h. The solvent was removed under reduced pressure; the crude residue was purificated by silica gel column (dichloromethane/methyl alcohol 9.5:0.5) to furnish 35 mg of the pure compound 3 (10% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[C:8]([CH3:25])[CH:7]=1)=[O:5])[CH3:2].[ClH:26]>O1CCOCC1.C(OCC)C>[ClH:26].[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[C:8]([CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Tert-butyl 4-(4-(ethylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (0.9323 g, 2.68 mmol) was diluted with 4.0M HCl in dioxane (8 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen, washed with ether (5 mL) and dried in vacuum to afford N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (0.7528 g, 2.65 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.29 (s, 3 H) 3.00-3.14 (m, 4 H) 3.16-3.32 (m, 6 H) 7.07 (d, J=8.34 Hz, 1 H) 7.62-7.71 (m, 2 H) 8.34 (t, J=5.43 Hz, 1 H) 9.17 (br. s., 2 H). ESI-MS: m/z 248.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>>[ClH:19].[C:31]([NH:35][C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][S:20][C:15]2[C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[N:23][CH:24]=1)=[O:30])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)cn3)c2CC1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)nc1
Product: Cl

Procedure:
Use a method similar to the Example 375, using 3-tert-butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and tert-butylamine to give, after deprotection by the General Procedure 14, the title compound as an off-white solid. MS (APCI+) m/z: 404 (M+H)+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]([OH:53])[CH2:51][CH3:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@:10]([CH:50]([OH:53])[CH2:51][CH3:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)CC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)CC)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 274.2 %

Procedure:
To a solution of 1-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]propan-1-ol 3a (42 mg, 0.06 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 5 mL) were added o-dichlorobenzene (41.16 mg, 0.28 mmol) and 10% Pd/C (5.72 mg, 0.006 mmol) in turn. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtered cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The combined filtrates were concentrated in vacuo. The residue was purified to give the title compound 3 as a pale yellow solid (76.5 mg, 51.0%, HPLC: 94.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 465.1[M+H]+; and 1H NMR (400 MHz, CDCl3) δ(ppm): 7.35 (m, 2H), 7.32 (m, 1H), 7.06 (d, 2H), 6.77 (d, 2H), 4.19 (d, 1H), 4.10 (d, 1H), 3.96 (m, 4H), 3.76 (m, 3H), 3.68 (m, 1H), 1.54 (m, 2H), 1.36 (t, 3H), 0.95 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:27]=[CH:26][C:11]2[NH:12][C:13]([CH:15]3[CH2:18][N:17]([C:19]4[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=4)[CH2:16]3)=[N:14][C:10]=2[CH:9]=1.C(OC(N1CC(C(O)=O)C1)=O)(C)(C)C.C(OCC)(=O)C>CC(N(C)C)=O.O>[Cl:7][C:8]1[CH:27]=[CH:26][C:11]2[NH:12][C:13]([CH:15]3[CH2:16][N:17]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[N:20]=4)[CH2:18]3)=[N:14][C:10]=2[CH:9]=1
Reactant: C1COCCN1
Reactant: Clc1ccc2[nH]c(C3CN(c4ccnc(Cl)n4)C3)nc2c1
Agent: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc2[nH]c(C3CN(c4ccnc(N5CCOCC5)n4)C3)nc2c1
Temperature: 75 °C
Yield: 84 %

Procedure:
A mixture of morpholine (0.19 mL, 2.19 mmol) and 5-chloro-2-(1-(2-chloropyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole, as prepared according to Example 1a, but using 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid in place of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester, (0.069 g, 0.22 mmol) in DMA (1 mL) under argon was heated to 75° C. for 5 h, then cooled to RT. Ethyl acetate and water were added, the resulting layers were separated, and the organic layer was washed with water (2×), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography to give 4-(4-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-2-yl)morpholine (0.068 g, 0.18 mmol, 84% yield) as a white solid. [M+1] 371. IC50 (uM) 0.645.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Yield: 75 %

Procedure:
A mixture of potassium phthalimide (1.16 g, 6.29 mmoles) and 40 ml of dried N,N-dimethylformamide was heated up to 110° C. To this mixture was added dropwise a solution of methyl 22-tosyloxydocosanoate (2.20 g, 4.19 mmoles) in 70 ml of N,N-dimethylformamide, and the reaction mixture was reacted for 2 hours at 110° C. After the completion of reaction, the reaction mixture was subjected to the same after-treatment steps as in Reference Example 2, to give methyl 22-phthalimidodocosanoate (1.57 g, 95%) having the following properties.
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[O:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH3:20]COC(C)=O>>[CH3:20][C@H:2]1[C@@H:14]2[C:16](=[O:15])[C@H:17]([CH:18]=[CH:19]2)[N:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:4]
Reactant: CC(Br)C(=O)NOCc1ccccc1
Reactant: c1ccoc1
Reactant: CCOC(C)=O
Product: C[C@@H]1C(=O)N(OCc2ccccc2)[C@H]2C=C[C@H]1C2=O
Yield: 67 %

Procedure:
Prepared in 67% yield (63.3 mg, 0.26 mmol) from the reaction of 2-bromo-N-(phenylmethoxy)propanamide (100.7 mg, 0.39 mmol) with furan via general procedure B. Rf=0.3 (3:1, hexanes:EtOAc); 1H-NMR (500 MHz, CDCl3): δ 7.47-7.32 (m, 5H), 6.57 (dd, J=6.2, 1.0 Hz, 1H), 6.41 (dd, J=6.0, 1.7 Hz, 1H), 5.25 (d, J=1.5 Hz, 1H), 5.00 (d, J=11.0 Hz, 1H), 4.87 (d, J=11.0 Hz, 1H), 4.85 (dd, J=5.0, 1.9 Hz, 1H), 3.17 (qd, J=7.4, 5.0 Hz, 1H), and 1.09 (d, J=7.4 Hz, 3H); 13C-NMR (126 MHz, CDCl3): δ 172.7, 136.1, 135.8, 133.8, 129.7, 128.9, 128.7, 91.6, 82.9, 78.1, 45.1, and 10.6; IR (film) 3089, 2970, 2970, 2934, 2876, 1697, 1497, 1455, 1377, 1209, 1053 cm-1; HRMS calculated for C14H16NO3 (M+H)+ 246.1125, observed 246.1118.