Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O.[CH2:13]([C:20]1[S:26][CH:25]2[CH:22]([C:23](=[O:44])[N:24]2[C:27](=[C:41]([OH:43])[CH3:42])[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CS(Cl)(=O)=O.N1CCOCC1.BrBr.Cl>O1CCCC1.CO.N1C=CC=CC=1.C(N(CC)CC)C>[C:14]1([CH2:13][C:20]([NH:21][CH:22]2[C:23](=[O:44])[N:24]3[C:27]([C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=4)=[O:29])=[C:41]([OH:43])[CH2:42][S:26][C@H:25]23)=[O:1])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: BrBr
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 0 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
Man adds triethylamine (5.68 ml) to a stirred suspension of p-nitrobenzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (9.06 g) in tetrahydrofuran (120 ml) under nitrogen atmosphere at -20° C. to give clear solution, adds methanesulfonyl chloride (1.65 ml) to the solution, stirs for 30 minutes at the same temperature, adds morpholine (1.92 ml), warms to 0° C., stirs for 5 hours, cools to -30° C. to -35° C., adds pyridine (1.54 ml) and bromine (3.12 g), stirs for 20 minutes, warms to ice-water temperatur, adds 5% hydrochloric acid (144 ml) and methanol (120 ml), stirs for 3 hours at room temperature, and lefts stand overnight at 0° C. Collection of the separated crystals in the reaction mixture by filtration gives p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (6.678 g). m.p. 201° C. Yield: 71%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:52])=[C:4]([NH:24][C:25]([NH:27][C:28]2[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([O:45][C:46](=[O:48])[CH3:47])[CH2:40][O:41][C:42](=[O:44])[CH3:43])=[O:36])[C:31]([I:49])=[C:30]([NH2:50])[C:29]=2[I:51])=[O:26])[C:5]([I:23])=[C:6]([C:9]([NH:11][CH2:12][CH:13]([O:19][C:20](=[O:22])[CH3:21])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:10])[C:7]=1[I:8]>C(OCC(Cl)=O)(=O)C>[I:52][C:3]1[C:2]([NH:1][C:39](=[O:45])[CH2:40][O:41][C:42](=[O:44])[CH3:43])=[C:7]([I:8])[C:6]([C:9]([NH:11][CH2:12][CH:13]([O:19][C:20](=[O:22])[CH3:21])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:10])=[C:5]([I:23])[C:4]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([O:45][C:46](=[O:48])[CH3:47])[CH2:40][O:41][C:42](=[O:44])[CH3:43])=[O:36])[C:31]([I:49])=[C:30]([NH:50][C:13](=[O:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:29]=1[I:51])=[O:26]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(NC(=O)Nc2c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c1I)OC(C)=O
Agent: CC(=O)OCC(=O)Cl
Product: CC(=O)OCC(=O)Nc1c(I)c(NC(=O)Nc2c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N,N'-bis[3-amino-2,4,6-triiodo-5-(2,3-diacetoxypropylaminocarbonyl)phenyl]urea (1.0 g, 0.71 mmol) was dissolved in acetoxyacetyl chloride (5 ml) and the solution was stirred at ambient temperature for 24 h. After heating to 60° C. for 2.5 h, the solution was evaporated to dryness and the residue was triturated with water (40 ml). The tan-colored precipitate was filtered off, washed again with water (20 ml) and dried. Yield: 0.92 g (81%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([N:30]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][C:32]([OH:34])=[O:33])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)(=O)C.[OH-].[Na+].OC1C=C(NCC(O)=O)C=C(OCCCCCCCCCCCCCCCCCC)C=1>O1CCOCC1.CO>[C:32]([CH2:31][N:30]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=[C:5]([OH:4])[CH:6]=1)[CH2:35][C:36]([OH:38])=[O:37])([OH:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OC(C)=O)cc(N(CC(=O)O)CC(=O)O)c1
Agent: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(NCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 60 h

Procedure:
To solution of 1.0 g (1.87 mmol) of N-[3-(acetyloxy)-5-(octadecyloxy)phenyl-N-(carboxymethyl)glycine in 30 ml of dioxane and 70 ml of methanol was added 1.6 mol (9.6 mmol) of 6N NaOH The solution was kept at room temperature for 60 hours. The solvent was removed at reduced pressure and the residue wa acidified with 3N HCl. The resultant solid was filtered to give 0.546 g, mp 143°-146°, of pure N-carboxymethyl)-N-[3-hydroxy-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)C.C1COCC1.[OH-].[Na+]>CCO>[CH3:22][N:21]1[C:17]([CH2:16][O:15][C:13]2[CH:12]=[CH:11][C:10]3[C:6]([CH2:5][C:4]([OH:27])=[O:3])=[CH:7][S:8][C:9]=3[CH:14]=2)=[CH:18][C:19]([C:23]([F:25])([F:26])[F:24])=[N:20]1
Reactant: CCOC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1COc1ccc2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a mixture of ethyl(6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (129.8 mg), THF (2.0 mL) and EtOH (2.0 mL) was added 1N NaOH (0.98 mL) at room temperature. The mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The mixture was concentrated. The residue was neutralized with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The solid was crystallized from EtOAc-hexane to give the title compound (106 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[NH2:33])[C:27]([OH:29])=[O:28].Cl>C(O)(C)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:32]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:23][CH3:22])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 53 °C
Reaction time: 60 h

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (2.542 kg, 8.05 mol), 3-methoxy-4-aminobenzoic acid (1.50 kg) in t-butyl alcohol (23 L) and heat to about 53° C. Add conc. HCl (951 g) over about 10 minutes, heat to 80° C. and stir for 60 hours. The temperature was adjusted to 15° C. and stirred for 40 hours to give a solid which was collected by filtration, rinsed with isopropyl alcohol/water (1:1, 2×2.5 L) and dried under a stream of nitrogen for about 1.5 hours, then in a vacuum oven at 40° C. for 4 days to give 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.Cl.[CH3:21][O:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[O:22][CH3:21])[CH2:28]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: O=C(O)c1nc(-c2cccnc2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3cccnc3)nc3ccccc13)C2
Yield: 7 %

Procedure:
Reaction of 2-(3-pyridinyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 86 (7% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.73 and 2.99 (2t, 2H), 3.51 and 4.03 (2t, 2H), 3.68-3.81 (4s, 6H), 4.44 and 4.94 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.59-8.22 (m, 5H), 8.76-8.83 (m, 2H), 9.61-9.66 (m, 1H); MS (ESI) m/z 427 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([CH2:13][C:14]#[N:15])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>[Pd].C1COCC1.C(O)(=O)C>[NH2:1][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][C:14]#[N:15])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: N#CCc1nc2c([N+](=O)[O-])cccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CCc1nc2c(N)cccc2o1
Reaction time: 15 h
Yield: 62.9 %

Procedure:
The mixture of 4-nitro-2-benzoxazoleacetonitrile (27.22 g, 0.13 mole) and Palladium on carbon (3 g) in THF (320 ml) and acetic acid (5 ml) in a Parr bottle was hydrogenated at 50 psi for 15 h. It was filtered over a patch of celite (1.5 cm) covered with activated carbon (0.5 cm) and washed with isopropyl ether. The filtrate was evaporated and the residue was triturated with isopropyl ether and propyl acetate and filtered to give 4-amino-2-benzoxazoleacetonitrile (14.16 g, 61%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[N:19]=1)[C:13]([O:15][CH3:16])=[O:14].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26](B(O)O)[CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.ClCCl.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([F:31])=[C:24]([C:10]2[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:23]=1
Reactant: COC(=O)c1cc(C)nc(Br)c1
Reactant: OB(O)c1cc(Cl)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)nc(-c2cc(Cl)ccc2F)c1
Yield: 30.6 %

Procedure:
Potassium phosphate tribasic (13.84 g, 65.2 mmol), palladium acetate (0.390 g, 1.739 mmol), methyl 2-bromo-6-methylisonicotinate (5 g, 21.73 mmol), 5-chloro-2-fluorophenylboronic acid (5.68 g, 32.6 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (1.521 g, 3.26 mmol) were combined in toluene (70 mL) and water (14 mL) and heated at 110° C. in an oil bath for 1 hour. The reaction was then cooled and diluted with water (30 mL), filtered through Celite® and the layers were separated. The aqueous layer was extracted with ether and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was dissolved in ethyl acetate/dichloromethane and absorbed onto silica gel before chromatography on silica eluting with 10% ethyl acetate in hexanes to give an off white powder which was dissolved in dichloromethane, dried onto silica gel and further purified by chromatography on silica using a step gradient (0-10% ethyl acetate/hexanes) to give methyl 2-(5-chloro-2-fluorophenyl)-6-methylisonicotinate (1.86 g, 30.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64-2.68 (3H, m) 3.91-3.95 (3H, m) 7.45 (1H, dd, J=11.12, 8.84 Hz) 7.59 (1H, ddd, J=8.84, 4.29, 2.78 Hz) 7.75-7.81 (1H, m) 8.01 (1H, dd, J=6.57, 2.78 Hz) 8.06 (1H, s). ESI-MS: m/z 280.1 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:21]([Cl:20])=[O:23])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 54F (73 mg, 0.28 mmol) in dichloromethane (2.5 mL) was added triphosgene (32 mg, 0.106 mmol), and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with dichloromethane (10 mL) and washed by 10% aqueous NaHCO3 solution (5 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:32]=[CH:31][C:22]([C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].Br[CH2:34][CH:35]([OH:38])[CH2:36][OH:37]>>[OH:38][CH:35]([CH2:36][OH:37])[CH2:34][N:28]1[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:32][CH:31]=2)[CH2:30][CH2:29]1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Reactant: OCC(O)CBr
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CC(O)CO)CC3)cc2)CC1
Yield: 71 %

Procedure:
By the same procedure as described in the example 23, synthesis was carried out starting with 1-[4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoyl]piperazine and using 3-bromo-1,2-propanediol. Then, the product was recrystallized using isopropanol and isopropyl ether to give the desired compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C(O)C>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)CCN
Reactant: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Solvent: CCO
Product: COC(=O)c1cccc2nc(-c3cccc(CNCCN(C)C)c3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 141.5 %

Procedure:
Methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (70 mg, 0.2 mmol) and N,N-dimethylethane-1,2-diamine (140.8 mg, 1.6 mmol) were added to ethanol (30 mL) and the mixture was stirred at room temperature for 1 hr and evaporated under reduced pressure to obtain methyl 2-(3-((2-(dimethylamino)ethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (100 mg, yield 85%). LC-MS (ESI) m/z 354 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:32]3[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:29][CH2:30][CH2:31]3)=[O:10])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1ccc2c(c1)NCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cc(Cl)cnc1C(=O)N1CCOc2ccccc21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 56.2 %

Procedure:
To a mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (112 mg, 0.244 mmol), 100 mg (0.70 mmol) of 3,4-dihydro-2H-benzo[1,4]oxazine, and 0.174 mL (1.0 mmol) of DIEA in CH2Cl2 (2.5 mL) was added 0.19 mL 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate). After 3 h the reaction mixture was directly purified via flash column (50% EtOAc in hexane) to afford 79 mg of 4-chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as a white powder. MS m/z: 576.38 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:7]=1)=O.NC1C=CC=C2C=1N=CC=C2C1C=CC=CC=1.[As](=O)(O)(O)O.[N+:41]([C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[N:52]=[CH:51][CH:50]=[C:49]2[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([O-])=O>P(=O)(O)(O)O>[C:54]1([C:49]2[C:48]3[C:53]([N:52]=[CH:51][CH:50]=2)=[C:44]2[C:45]([C:4]([C:6]4[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:7]=4)=[CH:3][CH:2]=[N:41]2)=[CH:46][CH:47]=3)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=[N+]([O-])c1cccc2c(-c3ccccc3)ccnc12
Reactant: O=C(CCCl)c1ccc(CCCCCCO)cc1
Agent: Nc1cccc2c(-c3ccccc3)ccnc12
Agent: O=P(O)(O)O
Agent: O=[As](O)(O)O
Product: OCCCCCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1

Procedure:
The procedure followed was similar to that of Case and Strohm (Case, F. H.; Strohm, P. F. J. Org. Chem, 1962, 27, 1641-1643). 3-Chloro-1-[4-(6-hydroxyhexyl)phenyl]propan-1-one (0.73 g), 8-amino-4-phenylquinoline (0.27 g), arsenic acid (0.99 g) and 85% phosphoric acid (10 mL) were reacted as described in the procedure for the synthesis of 8-nitro-4-phenylquinoline. However during precipitation of the crude product, a pH of 6-8 was maintained in order to ensure that the alcohol functionality remained protonated. The crude product was re-crystallized with a 50:50 mixture of petroleum ether and chloroform. Further purification of the desired product was achieved using preparatory TLC with 2% methanol and 98% chloroform.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7](=O)C)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: NO
Reactant: CC(=O)[C@@H]1COC(C)(C)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](C=NO)O1
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a solution of (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanone (10.5 g, 72.8 mmol) in 150 (mL) THF: 60 mL was added hydroxylamine hydrochloride (5.06 g, 72.8 mmol), and the reaction was stirred for 20 minutes. Na2CO3 (3.78 g, 35.7 mmol) was added and the reaction was stirred overnight. The reaction was extracted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated to afford (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde oxime (10.3 g, 71.0 mmol, 97.4% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.C1C2C(COC([N:62]3[CH2:67][C@@H:66]([C:68](=[O:88])[N:69]([CH:85]4[CH2:87][CH2:86]4)[CH2:70][C:71]4[C:79]5[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=5)[N:73]([CH2:80][CH2:81][CH2:82][O:83][CH3:84])[CH:72]=4)[CH2:65][C@@H:64]([NH2:89])[CH2:63]3)=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[CH:85]1([N:69]([CH2:70][C:71]2[C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[N:73]([CH2:80][CH2:81][CH2:82][O:83][CH3:84])[CH:72]=2)[C:68]([C@H:66]2[CH2:65][C@@H:64]([NH:89][C:7]([CH:3]3[C:4]([CH3:5])([CH3:6])[C:2]3([CH3:1])[CH3:10])=[O:9])[CH2:63][NH:62][CH2:67]2)=[O:88])[CH2:86][CH2:87]1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C3C(C)(C)C3(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid (50 mg, 0.35 mmol), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (145 mg, 0.35 mmol), N-ethyldiisopropylamine (171 μL, 1 mmol) in CH2Cl2 (3 mL) is stirred for 10 min at RT. After the addition of (3R*,5S*)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (121.4 mg, 0.2 mmol) (Starting Material 6), stirring is continued for 14 h. The mixture is diluted with CH2Cl2, the organic layer washed with saturated NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellowish solid. MS: 509.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.68 min.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].CO[CH:22](OC)[CH2:23][CH:24](OC)OC>C(O)C.CO>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:3]1[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]2[CH:24]=[CH:23][CH:22]=[N:1][C:2]=12
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)c(N)[nH]1
Reactant: COC(CC(OC)OC)OC
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1nc(Cc2ccccc2F)c2ncccn12

Procedure:
50 mg (0.19 mmol) of ethyl 5-amino-4-(2-fluorobenzyl)-1H-imidazole-2-carboxylate from example 9A are heated in 0.5 ml of ethanol to reflux and a solution of 34 mg (0.21 mmol) of 1,1,3,3-tetramethoxypropane in 1.0 ml of methanol is added dropwise. The mixture is then stirred under reflux for 45 min. The product is purified directly by preparative HPLC. 37 mg (65% of theory) of the desired compound are obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=O)[CH2:12][CH2:13][N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:9]=2[CH:8]=[CH:7]1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[N:21][OH:22])[CH2:12][CH2:13][N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:9]=2[CH:8]=[CH:7]1
Reactant: NO
Reactant: CN1CCC(=O)c2c(ccn2CCCCCl)S1(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(=NO)c2c(ccn2CCCCCl)S1(=O)=O
Yield: 72.5 %

Procedure:
A suspension of 152 mg (0.5 mmol) of Compound 18, 174 mg (2.5 mmol) of hydroxylamine hydrochloride and 205 mg (2.5 mmol) of sodium acetate in 20 ml of ethanol was refluxed for 20 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of water to the residue. The resulting mixture was extracted with chloroform (3 times). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=3/97), whereby 116 mg of the title compound were obtained (yield: 73%).
Reaction SMILES: O[CH2:2][CH2:3][S:4]([CH:7]([CH:14]=[CH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5].N1C=CC=CC=1.S(Cl)([Cl:24])=O>O1CCCC1.[N+](C1C=CC=C([N+]([O-])=O)C=1)([O-])=O>[Cl:24][CH2:2][CH2:3][S:4]([CH:7]([CH:14]=[CH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: C=CC(c1ccccc1)S(=O)(=O)CCO
Agent: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(c1ccccc1)S(=O)(=O)CCCl
Temperature: 0 °C
Yield: 85 %

Procedure:
To a solution of 50 g (0.221 moles) of vinylbenzyl 2-hydroxyethyl sulfone, 19.2 g (0.243 moles) of pyridine, and 1 g of m-dinitrobenzene in 500 ml of tetrahydrofuran at 0° to 5° C. was added dropwise 28.9 g (0.243 moles) of thionyl chloride. After the addition was complete, the mixture was refluxed for 2 hours, cooled to 0° to 5° C., and the pyridine hydrochloride was removed by filtration. The solvent was then evaporated to leave an oil which was added to one liter of ice water to crystallize the product. The solid was collected by filtration and recrystallized from 1.6 liters of 50 percent water, 50 percent ethanol to give 46 g (85.2 percent) of the desired product (mp 62° to 84° C.).