Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16]C2C=CC=CC=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])CO)C1C=CC=CC=1.F[C:57](F)(F)[C:58](O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:58]2[CH:57]=[CH:54][CH:10]=[CH:9][CH:14]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@:12]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])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:11][C@@:10]1([CH2:54][OH:55])[CH2:32][O:31]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Reaction time: 4 h
Yield: 104.3 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 3m (1.0 g, 1.29 mmol) was dissolved in 10 mL dichloromethane, followed by addition of trifluoroacetic acid (0.19 mL, 2.58 mmol). The reaction mixture was stirred for 4 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 3n (500 mg, yellow grease), yield: 52.1%. MS m/z (ESI): 760.3 [M+18]. 1H NMR (400 MHz, CD3OD): δ 7.37-7.30 (m, 13H), 7.23-7.18 (m, 3H), 6.91-6.89 (m, 2H), 6.68 (dd, 1H), 6.55 (dd, 1H), 4.93-4.90 (m, 2H), 4.79-4.56 (m, 4H), 4.30-4.28 (m, 2H), 4.18-4.05 (m, 4H), 3.83-3.49 (m, 5H), 1.33 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[O:28]1[CH2:29][CH2:30][CH2:31][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(N3CCCOCC3)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCOCC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
To a solution of Intermediate A (145 mg, 0.614 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 74 mg, 1.84 mmol). The mixture was stirred at RT for 15 min, then a solution of Intermediate 49a (100 mg, 0.614 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 2.25 h. The cooled mixture was diluted with water and extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the title compound as a pale brown gum (93 mg, 40%). LCMS (Method 3): Rt 0.43 min, m/z 380 [MH+].
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(OCC)(=O)C>[C:1]1([S:11]([NH:15][C:16]2[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc2ccccc12
Yield: 61.7 %

Procedure:
Prepared according to the procedure described for Example 127 using 1-naphthalenesulfonyl chloride (0.68 g, 3.0 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol), and ethyl acetate instead of dichloromethane to afford the product (0.8 g); m.p. 212-213° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:53]>C(OCC)(=O)C>[ClH:53].[ClH:53].[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC(OC)CC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCC(OC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-[(4-methoxypiperidin-1-yl)carbonyl]piperidine-1-carboxylate (65 mg) was dissolved in ethyl acetate (5 ml), 4 N hydrogen chloride-ethyl acetate solution (7 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object compound (57 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:28])[NH:14][C:15](=[O:27])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>>[CH3:26][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:16]2[C:15](=[O:27])[NH:14][C:13](=[O:28])[C:12]=2[C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:31]4[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=4)=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[CH:18]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(Br)ccc34)C(=O)NC2=O)c2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Product: Cn1ccnc1-c1ccc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)cn(C)c2c1
Yield: 38 %

Procedure:
3-(1-Methyl-1H-indol-3-yl)-4-[1-methyl-6-(1-methyl-1H-imidazol-2-yl)-1H-indol-3-yl]-pyrrole-2,5-dione (46 mg, 38%) was prepared from 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (120 mg, 0.28 mmol) and 1-methyl-2-(tributylstannyl)imidazole (0.8 mL, containing 50% 1-methyl-imidazole) (Molloy, K. C.; Waterfield, P. C.; Mahon, M. F. J. Organonetallic. Chem. 1989, 365, 61.)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([O:21][CH2:22][CH2:23]O)[CH2:17][CH2:18][S:19][CH3:20])=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[C:12]([CH:16]([CH2:17][CH2:18][S:19][CH3:20])[O:21][CH2:22][CH2:23]2)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C(CCSC)OCCO)[nH]c(=O)c1OCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2CCSC
Yield: 52.4 %

Procedure:
To a solution of intermediate 20, ethyl 5-(benzyloxy)-2-(1-(2-hydroxyethoxy)-3-(methylthio)propyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (527 mg, 1.25 mmol) and Et3N (505 mg, 5 mmol) dissolved in 10 mL of CH2Cl2 was added a solution of CH3SO2Cl (288 mg, 2.5 mmol) dissolved in 2 mL of CH2Cl2. This was stir-red for 20 hrs then concentrated. The crude product was purified by chromatography on silica gel, using 10:1 CH2Cl2: ether as eluent, to give the title compound 265 mg (52% yield). (500 MHz, CDCl3) δ ppm: 7.31–7.55 (5H, m) 5.30 (2H, s) 4.75 (1H, dd, J=3.66 Hz) 4.32–4.40 (2H, q, J=7.17 Hz) 4.13–4.30 (2H, m) 3.75–3.97 (2H, m) 2.20–2.84 (4H, m) 2.06 (3H, s) 1.32 (3H, t, J=7.17 Hz); LC/MS m/z 405 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:42])[C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[C:40]([C:37]1[CH:36]=[CH:35][C:34]([C:33]([NH:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH:26]=2)[NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[O:42])=[CH:39][CH:38]=1)#[N:41]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1N
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Nc3cc(NC(=O)c4ccc(C#N)cc4)ccc3C)ncnc2cc1OCCCN1CCOCC1
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-4-cyanobenzamide to give the title compound in 52% yield; NMR: 2.15 (s, 3H), 2.3 (m, 2H), 3.0-4.1 (broad m, 10H), 3.95 (s, 3H), 4.3 (m, 2H), 7.35 (m, 2H), 7.65 (m, 1H), 7.88 (m, 1H), 8.02 (m, 2H), 8.14 (m, 3H), 8.53 (s, 1H), 10.65 (s, 1H), 12.1 (s, 1H); m/s: M+H+ 553.
Reaction SMILES: [NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C(OC(OCC)C[N:24]=[C:25]=[N:26][CH:27]1[CH2:32]CCCO1)C.CCOCC.Cl>C(Cl)Cl>[CH3:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:25]3[NH:24][CH:32]=[CH:27][N:26]=3)[C:17](=[O:18])[N:4]2[C:5]=1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CCOC(CN=C=NC1CCCCO1)OCC
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl 7-amino-3-methylceph-3-em-4-carboxylate (810 mg.) and 1-(2,2-diethoxyethyl)-3-(tetrahydropyran-2-yl)carbodiimide (726 mg.) in dry CH2Cl2 (8 ml.) under nitrogen at room temperature was dropwise added a 2N ether solution of HCl (1.5 ml.) in CH2Cl2 (4 ml.) over 30 minutes. The mixture was allowed to stand for a further 30 minutes and then evaporated to dryness. To a solution of the residue, t-butyl 7-[2-(2,2-diethoxyethyl)-3-(tetrahydropyran-2-yl)guanidino]-3-methylceph-3-em-4-carboxylate (1.7 g.) in acetonitrile (8 ml.) was added 3N aqueous HCl (1 ml.) and the mixture was heated at 50° for 2 hours, then evaporated to dryness at 30°. The residue was purified by chromatography on silica gel using CH2Cl2 /MeOH/HOAc 89:10:1 v/v/v as eluant to give, after precipitation from CH2Cl2 solution will ether, t-butyl 3-methyl-7-[5-hydroxy-1-(tetrahydropyran-2-yl)imidazolin-2-yl]aminoceph-3-em-4-carboxylate (900 mg.) as a mixture of diastereoisomers. A solution of this product in trifluoroacetic anhydride was allowed to stand at room temperature under nitrogen for 6 hours, and then evaporated to dryness. The residue was purified by chromatography on silica to give t-butyl 3-methyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylate. This compound was treated with trifluoroacetic acid to give the free acid, identical to the product obtained in Example 7.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][CH2:43][CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47]>C(#N)C>[Cl:42][CH2:43][CH2:44][CH2:45][S:46]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:48])=[O:47]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)CCCCl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 24.5 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0316 g, 0.0685 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.411 mmol) and 3-chloropropanesulfonyl chloride (0.0250 mL, 0.205 mmol) to obtain 4-(3-chloro-n-propanesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0101 g, yield 24%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]1=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.Cl>[OH-].[Na+]>[C:4]([C@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]1=[O:33])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](c2ccccc2)N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCc2ccccc2)C(=O)O)CSC[C@H]1c1ccccc1
Reaction time: 18 h
Yield: 43.8 %

Procedure:
170 mg of α-{6(R)-[(R)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-3(R)-phenylperhydro-1,4-thiazepin-4-yl}acetic acid (prepared as described in Example 4) were dissolved in 0.8 ml of a 1% w/v aqueous solution of sodium hydroxide, and the resulting solution was allowed to stand for 18 hours at room temperature. 0.8 ml of 1N hydrochloric acid was added dropwise to this reaction product, and the pH of the mixture was adjusted to the value of 2.0. The title compound was precipitated as a powder following the dropwise addition; this was separated and washed with a small amount of water and ethyl acetate, to yield 70 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([O:24]CC)=[O:23])[O:13][C:12]1([CH3:31])[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CCCCCC.C(OCC)(=O)C.[OH-].[K+]>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:14]([CH:20]=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([OH:24])=[O:23])[O:13][C:12]1([CH3:31])[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CC(C)C[C@H]1[C@H](C=C(C(=O)O)C(C)C)OC(C)(C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
199 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoate was dissolved in 1.16 ml of an ethanol/water (10/1) solution of 2N potassium hydroxide, and the mixture was stirred overnight at room temperature. The mixture was cooled to 0° C. and adjusted to pH 2 with 1N hydrochloric acid, and then 12 ml of water was added thereto. The mixture was extracted 3 times with 10 ml of ethyl acetate. The organic solvent layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoic acid as a colorless oily substance.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2)[CH3:2].[O:14]1CCOCC1>O>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH:13]=[O:14])[CH:9]=[CH:8]2)[CH3:2]
Reactant: C1COCCO1
Reactant: CCc1cccc2ccc(C)nc12
Solvent: O
Product: CCc1cccc2ccc(C=O)nc12
Temperature: 25 °C
Yield: 85.8 %

Procedure:
A solution of 8-ethyl-2-methylquinoline (3.34 g, 19.5 mmol) in dioxane (150 mL) and water (1.5 mL) was added SeO2 (2.60 g, 23.4 mmol) and the mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:1 hexane/DCM) to give 8-ethylquinoline-2-carbaldehyde (3.1 g, 85.8%) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17]CC3C=CC=CC=3)[C:11]=2[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=2[NH:10][C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-benzyl-4-benzyloxy-1,3-dihydro-benzoimidazol-2-one (0.875 g, 2.64 mmol) in 100 ml of 1:1 ethyl acetate:THF was added palladium hydroxide (0.270 mg, 1.923 mmol). The reaction mixture was purged with hydrogen gas at 1 atm., allowed to stir at room temperature for 2 hours, and then filtered through celite. The filtrate was concentrated in vacuo to give 640 mg (2.64 mmol. quantitative) of 1-benzyl-4-hydroxy-1,3-dihydro-benzoimidazol-2-one as a white solid. MS: 241 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH3:24])=[O:5])[CH3:2].[Br:25]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH2:24][Br:25])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1CBr
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution of 4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.150 g, 0.451 mmol) in DMF (5 mL) was added N-bromosuccinimide (0.084 g, 0.474 mmol). After stirring for 30 minutes, the reaction mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield a yellow residue. Purification by flash column chromatography (methylene chloride) gave 0.122 g (66%) of a yellow residue.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:38])[NH:32][CH2:33][CH:34]([OH:37])[CH2:35][NH2:36])([CH3:29])([CH3:28])[CH3:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:13]([NH:36][CH2:35][CH:34]([OH:37])[CH2:33][NH:32][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:38])=[O:15])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
44 mg (0.12 mmol) of the compound from Example 97A and 40 mg (0.21 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are dissolved in 1 ml of DMF and cooled to 0° C., and 40.3 mg (0.21 mmol) of EDC and 5.51 mg (0.04 mmol) of HOBt are successively added. The mixture is allowed to warm to room temperature and is stirred overnight. After concentration in vacuo, purification by chromatography on silica gel (dichloromethane/methanol 20:1) results in the title compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[C:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)(C)(C)C>C1COCC1>[O:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH:42]1[O:41][CH2:40][CH2:39][CH2:38][CH2:37][C:36]#[C:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][OH:24]
Reactant: CC(C)(C)[Si](OCCCCCCCCCCC#CCCCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCCCCCCCCC#CCCCCOC1CCCCO1
Reaction time: 5 h
Yield: 89.9 %

Procedure:
Tetra-n-butylammonium fluoride (3.14 g, 12.5 mL of a 1 M soln in THF, 12.50 mmol) was added to a solution of the above crude tert-butyldiphenyl-[16-(tetrahydropyran-2-yloxy)hexadec-11-ynyloxy]silane (6 g, 10.42 mmol) in THF (150 mL) under an argon atmosphere. After 5 h, the reaction mixture was quenched with sat. aq. NH4Cl (5 mL), washed with water (100 mL), and brine (75 mL). The aqueous layer was back-extracted with ether (2×75 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by SiO2 column chromatography using 5-10% EtOAc/hexanes as eluent to give 16-(tetrahydro-2H-pyran-2-yloxy)hexadec-11-yn-1-ol (3.17 g, 80% overall) as a colorless oil. TLC: 40% EtOAc/hexanes, Rf≈0.4; 1H NMR (CDCl3, 300 MHz) δ 4.57-4.59 (m, 1H), 3.82-3.90 (m, 1H), 3.71-3.79 (m, 1H), 3.64 (t, 2H, J=6.8 Hz), 3.46-3.53 (m, 1H), 3.36-3.44 (m, 1H), 2.10-2.22 (m, 4H), 1.20-1.80 (m, 26H).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][CH:9]2[C:20](=[O:21])[NH:19][CH2:18][CH2:17][NH:16][C:15](=[O:22])[CH2:14][N:13](C(=O)C(F)(F)F)[C:12](=[O:29])[CH2:11][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>>[N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][CH:9]2[C:20](=[O:21])[NH:19][CH2:18][CH2:17][NH:16][C:15](=[O:22])[CH2:14][NH:13][C:12](=[O:29])[CH2:11][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CN(C(=O)C(F)(F)F)C(=O)CNC(Cc2ccc([N+](=O)[O-])cc2)C(=O)NCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C1CNC(=O)CNC(Cc2ccc([N+](=O)[O-])cc2)C(=O)NCCN1

Procedure:
The aforementioned free amino acylation affords 3-(4-nitrophenyl)-2-hydroxy-N-(trifluoroacetylglycylglycyl-2-aminoethyl)propionamide. The hydroxyl group of 3-(4-nitrophenyl)-2-hydroxy-N-(trifluoroacetylglycylglycyl-2-aminoethyl)propionamide is tosylated with TsCl in pyridine to give 3-(4-nitrophenyl)-2-(p-toluenesulfonyl)-oxy-N-(trifluoroacetylglycylglycyl-2-aminoethyl)-propionamide. The trifluoroacetylamide group of 3-(5-nitrophenyl)-2-(p-toluenesulfonyl)-oxy-N-(trifluoroacetylglycylglycyl-2-aminoethyl)propionamide is deprotonated with sodium hydride and cyclized to give 2-(4-nitrobenzyl)-3,8,11-trioxo-N-trifluoroacetyl-1,4,7,10-tetraazadodecane. The trifluoroacetyl group of 2-(4-nitrobenzyl)-3,8,11-trioxo-N-trifluoroacetyl-1,4,7,10-tetraazacyclododecane is cleaved with sodium hydroxide to afford a triamide product, 2-(4-nitrobenzyl)-3,8,11-trioxo-1,4,7,10-tetraazacyclododecane. The triamide is reduced with borane to give 2-(p-nitrophenyl)-1,4,7,10-tetraazacyclododecane. Conversion of this product to nitro-benzyl-DOTA is accomplished via the procedure discussed in the Rennet al. article referenced above or as discussed in subsections A and C set forth above.