Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([NH:12]C(=O)OCC)=S)[CH:3]=1.Cl.NO.CC[N:23](C(C)C)C(C)C>CO.CCO>[Cl:8][C:6]1[N:5]2[N:23]=[C:10]([NH2:12])[N:9]=[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(Cl)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2cc(Cl)cc(Cl)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Ethyl [(4,6-dichloropyridin-2-yl)carbamothioyl]carbamate (2.9 g, 9.9 mmol) was added to a stirred suspension of hydroxylamine hydrochloride (1.1 g, 16 mmol) and DIEA (1.9 g, 15 mmol) in MeOH/EtOH (1:1, 40 mL) portion-wise as a solid. This mixture was stirred at rt for 2 h and then heated at 80° C. for 18 h. The reaction mixture was concentrated in vacuo and the resultant reside treated with water yielding a cream solid, which was filtered and dried in a vacuum oven at 40° C. for 18 h to give the desired product (1.2 g, 60%). 1H NMR (DMSO) δ 7.58 (d, J=2.0 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.44 (s, 2H). m/z [M+H]+=203.15.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[OH:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][C:28](=[O:29])[CH2:27][NH:26][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C(=O)O)cc1O
Reaction time: 4 h

Procedure:
A solution of 9.75 g of 4-amino-3-hydroxybenzoic acid and 9.75 ml of triethylamine in 90 ml of dimethylformamide is heated to 80° C. 20 g of the N-hydroxysuccinimide ester of N-tert.-butoxycarbonylglycine are added and the reaction mixture is kept at 80° C for 4 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)CCC.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2
Reactant: Brc1cnc2c(c1)CCCN2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1cnc(-c2cnc3c(c2)CCCN3)cn1
Temperature: 110 °C
Yield: 55.9 %

Procedure:
To a solution of 6-bromo-1,2,3,4-tetrahydro-[1,8]naphthyridine (350 mg, 1.6 mmol) in 14 mL of toluene/DMF 1:1 mixed solvents are added 2-tributylstannanyl-pyrazine (670 mg 1.8 mmol) and Cs2CO3 (1.6 g, 4.9 mmol). Then Pd(dppf)Cl2 (120 mg, 0.16 mmol) is added under N2 atmosphere. The mixture is heated at 110° C. for 16 hrs and the solvent is removed under vacuum. The residue is purified by flash column chromatography to give 190 mg of 6-pyrazin-2-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:14].[N:1]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: BrCCNCCBr
Reactant: Nc1cccc2c1NC(=O)CC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cccc(N3CCNCC3)c2N1
Reaction time: 9 h
Yield: 16.6 %

Procedure:
8-Amino-3,4-dihydrocarbostyril (7.5 g, 46.2 mmols) and bis(β-bromoethyl)amine hydrobromide (15.9 g, 50.8 mmols) were suspended in methanol and the suspension was heated under reflux while stirring for 9 hours. After adding 2.5 g of sodium carbonate, the reaction mixture was further heated under reflux for 8 hours while stirring, and stirred on an ice bath for 1 hours. Crystals which precipitated were collected by filtration. The crude crystals thus obtained were recrystallized from methanol-ether to give 2.4 g of 8-(1-piperazinyl)-3,4-dihydrocarbostyril hydrobromide, m.p. above 300° C., colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2.[ClH:14]>C(O)(=O)C.CO.[Pd]>[ClH:14].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH2:12])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=NO)CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc2c1C(N)CC2
Yield: 75 %

Procedure:
7-methoxyindan-1-one oxime (2.92 g, 16 mmol) was dissolved in acetic acid (150 mL) and hydrogenated on the H-Cube: 1 mL/min flow rate, 80° C., 100 bar with 10% Pd/C. The reaction mixture was evaporated, the residue was dissolved in methanol and 1 equivalent of hydrochloric acid in methanol was added. The solvent was evaporated and the residue was triturated with diethyl ether to give 7-methoxy-1-aminoindane hydrochloride (2.38 g, 12 mmol, 75%). ESMS m/z 147 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1.[Li]CCCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:13][C:9]=2[CH:10]=1)[CH2:29][CH2:30][CH3:31]
Reactant: ClCCOc1ccc2occc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cc(OCCCl)ccc2o1

Procedure:
Treatment of 5-(2-chloroethoxy)-1-benzofuran with n-BuLi for 16 h followed by the addition of tributyltin chloride at −50° C. gave tributyl (5-(2-chloroethoxy)benzofuran-2-yl)stannane upon warming to room temperature.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:34]=[CH:33][C:15]([C:16]([NH:18][C:19]3[C:20](=[O:32])[N:21]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[CH:23][CH:24]=3)=[O:17])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38][CH2:37]1>O>[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:34]=[CH:33][C:15]([C:16]([NH:18][C:19]4[C:20](=[O:32])[N:21]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH:22]=[CH:23][CH:24]=4)=[O:17])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:37]1
Reactant: O=C(Nc1cccn(-c2ccc(F)cc2)c1=O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc(C(=O)Nc4cccn(-c5ccc(F)cc5)c4=O)cc3)c3nccn3n2)CC1
Reaction time: 12 h

Procedure:
To 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide (0.011 g, 0.023 mmol) from 1a was added trans-1,4-diaminocyclohexane (0.5 g, 57.0 mmol). The mixture was allowed to melt at 160° C. for 12 hours. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was then concentrated in vacuo to give 0.020 g of crude product. Purification was done via preparative HPLC providing 0.006 g of the title compound as a TFA salt. 1H NMR (400 MHz, MeOD) δ ppm 8.56 (1H, dd, J=7.38, 1.78 Hz), 7.92-8.10 (3H, m), 7.88 (1H, d, J=2.03 Hz), 7.42-7.61 (3H, m), 7.39 (1H, dd, J=7.12, 1.53 Hz), 7.30 (2H, t, J=8.65 Hz), 6.77 (1H, s), 6.54 (1H, t, J=7.12 Hz), 3.97 (1H, s), 3.66-3.84 (1H, m), 3.03-3.24 (1H, m), 2.26 (2H, m), 2.00-2.20 (2H, m), 1.44-1.68 (2H, m), 1.22-1.46 (2H, m). LC/MS, m/e 533 (M+1). HPLC Rt, 2.14 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH:11]([NH:20][C:21](=[O:31])[CH2:22][NH:23]C(=O)OC(C)(C)C)[C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2]>Cl.CO.N1C=CC=CC=1>[OH:31][C:21]1[N:20]=[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:23][CH:22]=1
Reactant: CC(C)n1nc(C(NC(=O)CNC(=O)OC(C)(C)C)C(=O)c2ccccc2)ccc1=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)n1nc(-c2nc(O)cnc2-c2ccccc2)ccc1=O
Temperature: 82.5 °C
Yield: 29.1 %

Procedure:
A solution of tert-butyl (2-{[1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]amino}-2-oxoethyl)carbamate (310 mg) in 10% hydrogen chloride in MeOH (3 ml) was stirred at 20-25° C. for 18 hours and the mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in pyridine (1.5 ml) and heated at 80-85° C. for 10 hours. After evaporation of pyridine, the mixture was dissolved in CHCl3, washed with 1N HCl, sat. aq. NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure to give syrup. The syrup was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give 6-(6-hydroxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (65 mg).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22].O>ClCCl>[CH3:19][N:20]([CH3:24])[C:21]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)=[O:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)N(C)C)CC1
Reaction time: 18 h

Procedure:
Ethyl isonipecotate (31.44 g, 200 mmol) and triethylamine (50.2 ml, 360 mmol) were dissolved in dichloromethane (200 ml), and under ice cooling, to the solution was added dropwise N,N-dimethylcarbamoyl chloride (27.6 ml, 300 mmol). The mixture was stirred for 18 hours while the temperature was elevating to room temperature. To the reaction mixture was added water (100 ml) under ice cooling, and the organic layer was taken by separatory funnel. The aqueous layer was extracted with dichloromethane (50 ml×2) and the extracts were mixed with the organic layer. The combined organic layer was washed with 1N-hydrochloric acid (100 ml×3), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (51.30 g, It was proved that N,N-dimethyl carbamoyl chloride is contained about 10 wt % by 1H NMR.) as a pale brown oily substance.
Reaction SMILES: N[C@H: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.[BrH:19].N([O-])=O.[Na+].[Cl-].[Na+]>O.C(O)C>[Br:19][C@H: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
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](N)[C@H]2SC1
Reactant: Br
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2SC1
Temperature: 0 °C
Yield: 50 %

Procedure:
To an ice-cooled mixture of t-butyl 7α-amino-3-methyl-3-cephem-4-carboxylate (1.3 g, 0.0048 mol), ethanol (30 ml), water (8.5 ml), hydrobromic acid (48%, 5.83 ml), sodium nitrite (0.48 g, 0.00696 mol) was added portionwise over 15 minutes and the mixture was stirred at ice-temperature (-5° C.) for 3 hours, saturated with sodium chloride, extracted with ethyl acetate (3 times). The combined ethyl acetate extract was washed with water, brine, dried and concentrated to give 800 mg (50%) of pure t-butyl 7α-bromo-3-methyl-3-cephem-4carboxylate.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](Cl)[N:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(SC1C(C(OC)=O)=C(SCC2C=CC=CC=2)N=C(Cl)N=1)C1C=CC=CC=1.[OH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:52]2[CH2:53][CH2:54][CH:49]([OH:48])[CH2:50][CH2:51]2)[N:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1SCc1ccccc1
Agent: COC(=O)c1c(SCc2ccccc2)nc(Cl)nc1SCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(SCc2ccccc2)nc(Cl)nc1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-benzylthio-5-methoxycarbonyl-2,6-dichloropyrimidine and 4,6-dibenzylthio-5-methoxycarbonyl-2-chloropyrimidine (prepared in the above (3)) 97 mg, 4-hydroxypiperidine 29 mg, triethylamine 29 mg and toluene 2.5 mg is stirred at room temperature for 4 hours. Further, 4-hydroxypiperidine 3 mg and triethylamine 3 mg are added thereto, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidine-1-yl)-2-chloropyrimidine as a colorless caramel, 120 mg.
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([N:7]2[C:11]([S:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCCCCCCCBr
Reactant: Sc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCCCCCCCCCSc1nnnn1-c1ccccc1
Yield: 77 %

Procedure:
1-Phenyl-1H-tetrazole-5-thiol, 12-bromododecan-1-ol and anhydrous potassium carbonate were mixed together in acetone for 18 hrs at room temperature to provide 12-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-dodecan-1-ol in 77% yield following work up and recrystallisation. Ammonium molybdate (VI) tetrahydrate in 35% H2O2 were added to a stirred solution of the solid in THF IMS (500 ml) at 10° C. and stirred at room temperature for 20 hrs. Work-up and crystallisation gave a white solid (m.p.: 56-58° C.), 12-(1-phenyl-1H-tetrazol-5-sulfonyl)-dodecan-1-ol in 95% yield. N-Bromosuccinimide was added to a solution of the alcohol and triphenylphosphine in dichloromethane and the reaction stirred at room temperature for 75 min. Work-up and purification by chromatography provided a white solid (m.p.: 63-65° C.), 5-(12-bromo-dodecane-1-sulfonyl)-1-phenyl-1H-tetrazole in 72% yield.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=3)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: CC(C)(C#N)c1ccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C#N)c1ccc(-c2ccc3[nH]nc(-c4nc5ccccc5[nH]4)c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
TFA (0.25 mL, 3.245 mmol) was added to a solution of 2-(4-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenyl)-2-methylpropanenitrile (7 mg, 0.015 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound in a 55% yield. 1H NMR (400 MHz, CD3OD): δ 8.66 (bs, 1H), 7.87-7.80 (m, 6H), 7.66 (m, 2H), 7.56 (m, 2H), 1.78 (s, 6H); ESI-MS [M+H]+: 378.3.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([F:22])[C:20]=1F>CN(C=O)C.O>[F:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([F:22])[C:20]=1[NH:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)CNc1c(F)cc([N+](=O)[O-])cc1F
Temperature: 80 °C
Yield: 65.9 %

Procedure:
To a stirred solution of glycinamide hydrochloride (45 g, 407 mmol) in DMF (500 mL) was added successively triethylamine (197 mL, 1.43 mol) followed by 3,4,5-trifluronitrobenzene (72 g, 407 mmol) at room temperature over 15 min. The reaction mixture was heated to 80° C. overnight and then allowed to cool to room temperature. Ice pieces suspended in water were added to the reaction mixture and the solid obtained was filtered. The solid was dried to afford title compound (62 g, 67%) that was taken up directly for the next step without further purification. Mp 160–162° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][CH:9]1C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C1(NC(=O)C(O)C(N)CCC)CC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CC2CCCCC21
Agent: CCCC(N)C(O)C(=O)NC1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2CCCCC21

Procedure:
Octahydro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 89 (Bachem, 1.6 g, 1.0 eq) in DMF (20 mL) was treated with PyBOP (3.41 g, 1.1 eq) and NMM (1.97 mL, 3.0 eq). To this was added 3-amino-2-hydroxy-hexanoic acid cyclopropylamide 90 (1.22 g, 1.1 eq, prepared according to the procedure of U. Schoellkogf et al., Justus Liebigs Ann. Chem. GE, pp. 183-202 (1976) and J. Semple et al., Org. Letters, 2, pp. 2769-2772 (2000) and NMM (1.97 mL, 3.0 eq) in DMF (3 mL) and the mixture stirred at rt overnight. The mixture was evaporated in vacuo, diluted with ethyl acetate, the organic phase washed with 0.5N HCl, sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give 2-[1-cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indole-1-carboxylic acid tert-butyl ester 91 which was used without further purification. 1H NMR (CDCl3) δ 6.92 (bs, 1H), 6.80 (bs, 1H), 3.80-4.20 (m, 3H), 2.75 (m, 1H), 2.25 (m, 1H), 2.10 (m, 1H), 1.90-2.00 (m, 2H), 1.5-1.75 (m, 7H), 1.45 (s, 9H), 1.10-1.40 (m, 5H), 0.90 (m, 3H), 0.75 (m, 2H), 0.50 (m, 2H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:34][CH3:35])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:26][C:24]1[CH:25]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:34][CH3:35])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:22][C:23]=1[CH3:27]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 109.9 %

Procedure:
7-Benzyloxy-4-(5,6-dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinoline (compound 331) (958 mg) was dissolved in trifluoroacetic acid (9.5 ml) to prepare a solution. Methanesulfonic acid (0.95 ml) was added to the solution, and the mixture was stirred at 70° C. for one hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (848 mg, yield 100%).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CO.O>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]3[N:29]=[N:30][N:31]=[C:2]3[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c3nnnn23)cc1OC
Yield: 78.9 %

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (1.0 g) in a mixture of methanol (9 ml) and water (1.5 ml) was added sodium azide (0.163 g). The mixture was stirred at 50° to 55° C. for an hour. After removal of the solvent, the residue was washed with water and collected by filtration to give 4,5-dihydro-7-(3,4-dimethoxyphenyl)-4-methyl-5-(2,4,6-trimethylphenylimino)tetrazolo[1,5-a]pyrimidine (0.80 g).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14]O>OS(O)(=O)=O>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:14])=[O:10])=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
To a solution of 4-(aminosulfonyl)benzoic acid (16 g, 79.6 mmol) (Step 1) in methanol (600 ml), conc. H2SO4 (1.2 ml) was added and the mixture was heated at reflux for 4 days. The solvent was removed and washed with ether. The white solid (16.5 g, 96%) was used in the next reaction without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=CC=2F)=NOC=1C)=O)C>>[F:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2F)noc1C
Agent: CCOC(=O)c1c(-c2ccccc2F)noc1C
Product: Cc1ccc(-c2noc(C)c2CO)c(F)c1
Yield: 99.7 %

Procedure:
As described for example 84d, 3-(2-fluoro-4-methyl-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (18.5 g, 70.3 mmol) was converted, instead of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (15.5 g, 100%) which was obtained as a light yellow oil. MS: m/e=280.1 [M+OAc]−.
Reaction SMILES: C(=C(O)[C@@H](O)[C@@H](O)C=[O:8])(C)C.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:8])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)=C(O)[C@@H](O)[C@@H](O)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 50 %

Procedure:
For example, alcohol 4 was prepared with a 50-65 percent yield by coupling 2,3,-isopropylidene-D-erythrose with the known Wittig reagent (4-carbethoxybutyl) triphenylphosphonium bromide and KN(SiMe3)2 in THF at -78 degrees C. to 0 degrees C. The alcohol 4 was then treated with p-toluenesulfonyl chloride to furnish the corresponding p-toluenesulfonate. This p-toluenesulfonate was treated with sodium azide NaN3 in dimethyl formamide (DMF) (CH3)2NCHO at about 70 degrees C. to 100 degrees C. to produce the imino ester 6 having the structure ##STR11## wherein R is (C1 -C8) alkyl;