Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=[O:12].O[C:41]1[CH:42]=[CH:43][C:44]([O:60][CH3:61])=[C:45]([N:47]([CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[S:48]([CH3:51])(=[O:50])=[O:49])[CH:46]=1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:36][CH2:37]2)[CH:24]=1)[O:10][C:11]([O:13][C:41]1[CH:42]=[CH:43][C:44]([O:60][CH3:61])=[C:45]([N:47]([CH2:52][CH2:53][N:54]2[CH2:55][CH2:56][O:57][CH2:58][CH2:59]2)[S:48]([CH3:51])(=[O:50])=[O:49])[CH:46]=1)=[O:12]
Reactant: COc1ccc(O)cc1N(CCN1CCOCC1)S(C)(=O)=O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 39.2 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine I-oxide (prepared in an analogous manner to that described in Scheme 3, Step 1) (0.250 g, 0.427 mmol) and DMAP (0.052 g, 0.427 mmol) in dry DMF (5 ml), N-(5-hydroxy-2-methoxyphenyl)-N-(2-morpholinoethyl)methanesulfonamide (0.180 g, 0.545 mmol) was added, and the resulting mixture was stirred at RT for 7 hours. The reaction mixture was treated with water and extracted with DCM (3×). The combined organic layers were washed with brine and dried over Na2SO4; the solvent was removed under vacuum and the crude was purified by flash chromatography on silica gel column (DCM:acetone=6:4) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)phenoxy)carbonyloxy)-ethyl)pyridine 1-oxide (0.130 g, 0.167 mmol, 39.2% yield, LC-MS purity (BPI): 100%, MS/ESI+ 776.34 [MH]+, [δD]−27.42, c=0.542, DCM).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[N+](C(Br)C1C=CC=CC=1)([O-])=O.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:27]1[C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[C:23]1=[O:33])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: O=[N+]([O-])C(Br)c1ccccc1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cc1cccc([N+](=O)[O-])c1

Procedure:
A process wherein from m-nitrobenzaldehyde is derived nitrobenzylbromide, which is then reacted with potassium phthalimide to obtain N-(m-nitrobenzyl)-phthalimide which is then subjected to a two-stage reduction to obtain m-aminobenzylamine (yield: Ca. 20%) (N. Kornblum et al., J.Am. Chem. Co., 71, 2137(1949)).
Reaction SMILES: F[B-](F)(F)F.N1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]1[C:33]([NH2:52])=[N:34][CH:35]=[C:36]([C:38]2[C:39]([CH2:49][O:50][CH3:51])=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[CH:42]=2)[CH:37]=1.[CH3:53][N:54]([CH3:59])[CH2:55][C:56](O)=[O:57].CN1CCOCC1>CN1C(=O)CCC1>[NH2:52][C:33]1[N:34]=[CH:35][C:36]([C:38]2[C:39]([CH2:49][O:50][CH3:51])=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:56](=[O:57])[CH2:55][N:54]([CH3:59])[CH3:53])[CH2:45][CH2:44]3)[CH:42]=2)=[CH:37][C:32]=1[C:24]1[O:23][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=1
Reactant: COCc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: COCc1nn(C2CCN(C(=O)CN(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
Benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium tetrafluoroborate (115 mg) was added to a stirred suspension of 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-piperidin-4-ylpyrazol-4-yl]pyridin-2-amine] (121 mg), 2-(dimethylamino)acetic acid (32.4 mg) and 4-methylmorpholine (0.066 ml) in NMP (1.5 ml) at 25° C. The mixture was stirred at 25° C. for 5 hours and purified by preparative HPLC using a Waters OBD reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to provide the title compound (101 mg, 69.0%). NMR Spectrum: (DMSOd6) 1.73-1.85 (m, 1H), 1.87-1.98 (m, 1H), 2.04-2.16 (m, 2H), 2.21 (s, 6H), 2.72-2.82 (m, 1H), 3.08 (d, 1H), 3.13-3.22 (m, 2H), 3.41 (s, 3H), 4.15-4.23 (m, 1H), 4.41 (s, 2H), 4.41-4.51 (m, 2H), 7.40-7.48 (m, 2H), 7.66 (bs, 2H), 7.78 (dd, 1H), 7.84 (dd, 1H), 8.23 (s, 1H), 8.43 (d, 1H), 8.50 (d, 1H); Mass spectrum: M+H+ 490.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:10]2)[CH3:2].[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@@H:38]([C:52](O)=[O:53])[CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@H:38]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)[C:52]([N:17]3[CH2:16][CH2:15][N:14]([CH:9]4[CH2:10][CH:11]5[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH:7]([CH2:13][CH2:12]5)[CH2:8]4)[CH2:19][CH2:18]3)=[O:53])=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1
Reactant: CCOC(=O)CN1C2CCC1CC(N1CCNCC1)C2
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C2CCC1CC(N1CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
113 mg (0.40 mmol) ethyl(3-piperazin-1-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-acetate (Example A12d) were added to a mixture of 200 mg (0.45 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 128 mg (0.40 mmol) TBTU and 56 μL (0.40 mmol) triethylamine in 2 mL DMF and the reaction mixture was stirred for 2 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined and evaporated down i. vac.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].CC1C=CN=CC=1C1C=CC=C2C=1C=NN2>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: Cc1ccncc1B(O)O
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cnccc1C

Procedure:
Intermediate 20A was prepared from Intermediate 1A and methyl 2-bromo-5-nitrobenzoate by the procedure described for the preparation of Intermediate 1C. MS (ES): m/z=273.1 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:34]=[CH:33][C:10]([O:11][C:12]2[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=2)[C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])=[CH:9][CH:8]=1)=O.O.[NH2:37]N>C(O)C>[CH3:31][O:30][CH2:29][C@H:28]([CH3:32])[O:27][C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C:10]2[CH:33]=[CH:34][C:7]([C:5]3[CH:4]=[CH:3][NH:2][N:37]=3)=[CH:8][CH:9]=2)[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)/C=C/N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3cc[nH]n3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
A mixture of 3-{4-[(2E)-3-(dimethylamino)prop-2-enoyl]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.209 mmol) and hydrazine hydrate (0.204 mL, 4.18 mmol) in ethanol (3 mL) was heated to 100° C. for 5 minutes in a ‘Smith Creator’ microwave. The volatiles were removed in vacuo to give the product as a colourless foam (92 mg).
Reaction SMILES: I[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.[NH:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:12]([C:11]1[CH:10]=[N:9][C:8]2[NH:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:2]=1[N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCCN2
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCCN3)C1
Temperature: 140 °C
Yield: 91.1 %

Procedure:
A mixture of 5-iodo-6-nitro-1,2,3,4-tetrahydro-1,8-naphthyridine (0.50 g, 1.6 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (0.39 g, 2.0 mmol), DIPEA (0.64 g, 5.0 mmol) and 1-butanol (6 mL) was heated at 140° C. for 14 h, then allowed to cool. The solvent was removed under reduced pressure, then the residue was diluted with EtOAc and washed with aq. Na2CO3 solution. The organic layer was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 10 to 90% EtOAc in hexanes, to give the sub-title compound (0.55 g, 89%). LCMS calc. for C18H28N5O4 (M+H)+: m/z=378.2. Found: 378.1.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[F:16].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:17])=[C:8]([F:16])[CH:9]=2)=[O:13])[CH2:30][CH2:31]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)c(F)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 57.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-fluorobenzoic acid (272 mg) described in Preparation Example 26 and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (258 mg) was obtained.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]2[N:44]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[O:11])[C:5]=3[N:43]=2)[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: CN(C)C=C1CCCC(C(=O)N2CCCC2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C(=O)N2CCCC2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-(pyrrolidine-1-carbonyl)-cyclohexanone (58 mg, 0.23 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (64 mg, 0.17 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (55 mg, 73%). MS ISP (m/e): 433.3 (100) [(M+H)+]. mp 94-95° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[SH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].C1(C2C=C(SCC(O)=O)C3C(=CC=CC=3)N=2)C=CC=CC=1>N1C=CC=CC=1>[C:12]1([C:4]2[CH:3]=[C:2]([S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CCS
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Agent: O=C(O)CSc1cc(-c2ccccc2)nc2ccccc12
Solvent: c1ccncc1
Product: O=C(O)CCSc1cc(-c2ccccc2)nc2ccccc12
Yield: 54.9 %

Procedure:
4-Chloro-2-phenylquinoline (4.8 g) and 3-mercaptopropionic acid (2.54 g) in pyridine (50 cc) are heated under reflux for 11 hours. After a treatment similar to that described in Example 54 for 2-[(2-phenyl-4-quinolyl)thio]acetic acid, 3-[(2-phenyl-4-quinolyl)thio]propionic acid (3.4 g) is isolated, the proton NMR spectrum of which, in deuterated chloroform, has the following characteristics:
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]3[CH:10]=[CH:11][S:12][C:6]=23)[CH2:15][CH2:16]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol (0.21 g, 0.72 mmol) (Example 3, Step 1) and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) in methylene chloride (2 mL) was added methanesulfonyl chloride (0.083 mL, 1.1 mmol). The reaction was stirred at room temperature for 2 h. After dilution with sat. aq. NaHCO3 solution, the resulting mixture was extracted with dichloromethane. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.24 g, 90%). LCMS calculated for C14H18N3O5S2 (M+H)+: m/z=372.1. Found: 372.0.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[C:17]([NH2:23])=[C:16]([F:24])[C:15]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[F:33].C(OC(=O)C)=O>C1COCC1>[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[C:17]([NH:23][CH:1]=[O:3])=[C:16]([F:24])[C:15]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[F:33]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C(C)=O)c(N)c(F)c1Nc1ccc(Br)cc1F
Agent: CC(=O)OC=O
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To acetic anhydride (1.30 equiv.) is added formic acid (1.60 equiv.) at room temperature. The resulting mixture is stirred at 65 OC under N2 atmosphere for 2 hours, cooled to room temperature, and diluted with THF. To a solution of 5-acetyl-4-amino-2-(4-bromo-2-fluorophenylamino)-3-fluorobenzoic acid methyl ester (1.00 equiv.) in THF at 0° C. is added the above solution of acetic formic anhydride in THF. After stirring 30 minutes at 0° C., the reaction is quenched with MeOH. The reaction mixture is concentrated under reduced pressure to give the crude material that is purified by trituration or flash column chromatography to yield the desired product as necessary.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][S:17][S:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:21]([OH:23])=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>CN(C=O)C>[CH2:41]([O:14][C:13](=[O:15])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][S:17][S:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:21]([O:23][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(N[C@H](CSSC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)C(=O)O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H](CSSC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-2-carboxyethyl]disulfanyl}propanoic acid LXVI (5.6 g; 11 mmol) and anhydrous potassium carbonate (6.08 g; 44.0 mmol) in DMF (50 mL) cooled to 0° C. was added benzyl bromide (7.8 mL; 66.0 mmol). The mixture was stirred overnight at r.t. Water (150 mL) was added, and solution was extracted once with DCM (40 mL). The solvent was evaporated under reduced pressure and the residue was dissolved in diethyl ether (60 mL). The ether was washed with 10% aq Na2S2O3 until all the DMF was removed and once with water. The organic phase was dried over anhydrous MgSO4, evaporated and the residue purified on a silica gel column (100% CHCl3→200:3 CHCl3:MeOH). Benzyl (2S)-3-{[(2S)-3-(benzyloxy)-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl]disulfanyl}-2-{[(benzyloxy)carbonyl]amino}propanoate LXVII was obtained as a light-green viscous oil (5.9 g; 8.56 mmol; 77.8% yield). 1H NMR (CDCl3) 3.04-3.18 (m, 4H), 4.62-4.76 (m, 2H), 5.12 (s, 2H), 5.17 (s, 2H), 5.62-5.76 (m, 2H), 7.28-7.40 (m, 20H); ESIMS found for C36H36N2O8S2 m/z 689.5 (M+H).
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[CH2:53][C:54]([O-])=[O:55].[Na+]>C1COCC1.C(Cl)Cl>[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[CH2:53][C:54]([NH:11][C@H:8]1[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:22])[CH2:6][C@H:7]1[CH2:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15])=[O:55]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: O=C([O-])Cc1nc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)Cc2nc3ccccc3s2)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 60.2 %

Procedure:
A solution of (1R,3R,4S)-N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)-cyclohexane-1,4-diamine (see 30b) (70 mg, 0.216 mmol), EDCI (50 mg, 0.260 mmol), HOBT (35 mg, 0.260 mmol), and sodium 2-(benzo[d]thiazol-2-yl)acetate (56 mg, 0.260 mmol) in THF (5 mL) was stirred overnight at room temperature. The mixture was dilute with CH2Cl2 (25 mL) and washed with water, brine and evaporated. The residue was chromatographed on silica gel (6% NH4OH/MeOH/CH2Cl2) to give the product (65 mg). MS found: (M+1)+: 500.49.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:17]([OH:19])=[O:18])=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:1][C:2]1[O:3][C:4]([C:17]([O:19][CH3:25])=[O:18])=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1
Reactant: CO
Reactant: Cc1nc(-c2ccc3c(c2)CCCC3)c(C(=O)O)o1
Agent: O=S(=O)(O)O
Product: COC(=O)c1oc(C)nc1-c1ccc2c(c1)CCCC2
Yield: 76 %

Procedure:
To a solution of [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]carboxylic acid (6.0 g) in methanol (120 mL) was added conc. sulfuric acid (6.0 mL) and the mixture was stirred with heating under reflux for 18 hrs. The reaction mixture was concentrated and the residue was diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give methyl [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]carboxylate (4.75 g, yield 76%) as crystals. Recrystallization from ethanol gave colorless crystals. melting point: 96–97° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[OH:32][CH:33]([CH:58]([OH:65])[CH:59]([OH:64])[CH:60]([OH:63])[CH2:61][OH:62])[C:34](=[O:57])[CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][C:54](O)=[O:55])=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:54](=[O:55])[CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][C:34](=[O:57])[CH:33]([OH:32])[CH:58]([OH:65])[CH:59]([OH:64])[CH:60]([OH:63])[CH2:61][OH:62])=[CH:18][CH:17]=1
Reactant: NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Reactant: O=C(O)COCCOCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCCOCC(=O)NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO

Procedure:
29 is prepared similarly to 18 starting from 62 mg of 4-(3-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one 15, 76 mg of {2-[2-({2-[2-(3,4,5,6,7-pentahydroxy-2-oxoheptyloxy)ethoxy]ethylcarbamoyl}methoxy)-ethoxy]ethoxy}acetic acid 26, 57 μl of diisopropylcarbodiimide and 40 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 29:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]#[N:8])([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 90.3 %

Procedure:
A solution of 3-nitro-4-hydroxybenzonitrile (10 g, 61 mmol) in a mixture of 40 mL of dimethylformamide and 100 mL of acetonitrile was stirred as anhydrous potassium carbonate (10.1 g, 73.2 mmol) and benzyl bromide (10.4 g, 61 mmol) were added. The reaction was heated at 60° C. for about 4 h. The reaction was filtered and the solid was washed with ethyl acetate. The filtrate was washed with water. The organic layers were washed with water and brine, dried and concentrated. The solid was recrystallized from acetone/hexane to give 14 g (90%) of 3-nitro-4-(benzyloxy)benzonitrile, as a white solid.