Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH2:3][CH2:2]1.P(O)(O)O>>[CH:7]1([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1=C(N2CCOCC2)CCCC1
Agent: OP(O)O
Product: C1CCC(N2CCOCC2)CC1
Yield: 91 %

Procedure:
1-morpholinocyclohexene (32.3 g; 0.19 mole) and phosphorous acid (15.9 g; 0.19 mole) were heated together with stirring to 100° and maintained for 1 hour. Dilution with water, basification with NaOH and extraction with chloroform gave 29.7 g (91% of N-cyclohexylmorpholine after evaporation of the solvent. ##STR17##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]1([F:20])[F:19])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][C:7]1([F:19])[F:20])[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1(F)F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1(F)F
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a suspension of tert-butyl 4-(2-ethoxy-2-oxoethylidene)-3,3-difluoropiperidine-1-carboxylate (462 mg, 1.51 mmol) and Pd/C (10%, 70 mg) in dry EtOH (8 mL) was stirred at rt under a H2 atmospheric pressure until completion of the reaction. The mixture was then filtered, washed with EA/EtOH, and the filtrate concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 1:0→1:1) and the title compound obtained as a colorless oil. LC-MS-conditions 08: tR=0.89 min; [M-CH3+H]+=293.29.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:18]#N)[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.[OH2:39]>C(Cl)Cl>[Cl:21][C:6]1[C:7]([CH3:20])=[C:8]([CH:18]=[O:39])[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=1
Reactant: O
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cc(F)cc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile (2.43 g, 7.95 mmol) in methylene chloride (50 mL) was added 1.0 M diisobutylaluminum hydride in hexane (19.9 mL, 19.9 mmol) at −78° C. The reaction was warmed to rt over 2 h with stirring. 5.0 M Hydrogen chloride in water (70 mL) was added slowly, and stirring was continued for 1 h. The resultant mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dry. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.4 g, 97%). LCMS calculated for C16H12ClF2O (M-OH)+: m/z=293.1; Found: 293.1.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.Cl.[NH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[NH:1]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:2]([C:15]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Yield: 69.8 %

Procedure:
Boc-D-Trp(CHO)-OH (10.0 g), HCl.H-βAla-OMe (4.41 g) HOBt (4.47 g), WSCD (5.14 g) and DMF (100 ml) were reacted in a similar manner to that of Preparation 1-1) to give Boc-D-Trp(CHO)-βAla-OMe (8.77 g). mp: 134°-135° C. Rf: 0.54 (CHCl3 :MeOH=9:1)
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:99]=[C:100]1[CH:104]=[CH:103][C:102](=[O:105])[N:101]1[CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][C:111]([NH:113][NH2:114])=[O:112]>CN(C=O)C>[O:105]=[C:102]1[CH:103]=[CH:104][C:100](=[O:99])[N:101]1[CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][C:111]([NH:113][NH:114][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:112]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.8 mg (6.3 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3S)-1-(benzyloxy)-1-oxo-3-phenylbutan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 943 μl of DMF and then admixed with 3.6 mg (19 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2.9 mg (19 μmol) of 1-hydroxy-1H-benzotriazole hydrate, 2.2 μl of N,N-diisopropylethylamine and with 6.6 mg (25 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT overnight and then concentrated under high vacuum. The remaining residue was purified by means of preparative HPLC. Thus, 4.5 mg (64% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].[CH3:35][N:36]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[N:37]1>ClCCl>[CH3:35][N:36]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH2:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:14]2=[O:13])=[N:37]1
Reactant: Cn1ccc(CN)n1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cn1ccc(CNC(=O)CN2CCC(c3ccccc3)(c3ccccc3)C2=O)n1
Reaction time: 8 h

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and (1-methyl-1H-pyrazol-3-yl)methanamine (0.021 g, 0.186 mmol) were combined and stirred together in dichloromethane (0.5 mL) at room temperature. After stirring overnight, the reaction was loaded directly onto a SF10-8 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 0.4% to 7.5% methanol/dichloromethane over 20 minutes (flow=20 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.23-7.34 (m, 11H), 6.40 (t, J=6.0 Hz, 1H), 6.06 (d, J=2.2 Hz, 1H), 4.38 (d, J=5.3 Hz, 2H), 4.05 (s, 2H), 3.82 (s, 3H), 3.50 (t, J=6.4 Hz, 2H), 2.82 (t, J=6.4 Hz, 2H); MS (ESI−) m/z 387 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[C:22](O)(=O)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>P(Cl)(Cl)(Cl)=O>[CH3:15][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:5]=[C:4]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:3]=[C:2]3[C:7]=2[NH:8][C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[N:1]3)[CH2:10][CH2:11]1
Reactant: CN1CCN(c2nc(-c3ccccc3)nc(N)c2N)CC1
Reactant: O=C(O)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(c2nc(-c3ccccc3)nc3nc(-c4ccncc4)[nH]c23)CC1
Yield: 52.6 %

Procedure:
To 80 ml of phosphorus oxychloride are added 4 g of 4,5-diamino-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine and 1.7 g of isonicotinic acid, and the mixture is refluxed with heating for 6 hours under stirring. The reaction solution is concentrated and 700 ml of water is added to the residual oil. The solution is neutralized with an ammonia solution and the crystals precipitated are filtered, and then washed with water. Recrystallization from a mixture of chloroform and methanol (2:1) gives 2.7 g of 6-(4-methyl-1-piperazinyl)-2-phenyl-8-(4-pyridyl)purine, melting at 333°-337° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:19]2[N:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:26][CH2:25][C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[N:24]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(N2CCCC2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(N4CCCC4)n3)ccc12
Yield: 9.1 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (200 mg, 0.770 mmol), (6-pyrrolidin-ylpyrid-2-yl)methylamine (150 mg, 0.848 mmol), Pd2(dba)3 (71 mg, 0.077 mmol), rac-BINAP (153 mg, 0.246 mmol) and NaOtBu (190 mg, 1.977 mmol) in DMA (6 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-[(6-pyrrolidin-1-yl-pyridin-2-ylmethyl)-amino]-2H-phthalazin-1-one (25 mg) as a white solid. 1H (400 MHz, d6-DMSO) δ: 2.12 (m, 4H), 3.39 (m, 4H), 4.32 (d, 2H), 6.30 (d, 1H), 6.51 (d, 1H), 6.91 (s, 1H), 7.18 (dd, 1H), 7.42 (t, 1H), 7.61 (t, 1H), 7.93 (d, 1H), 12.33 (s, 1H) ppm; m/z (M+1) 356.21.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH2:21]([O:20][P:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1)(=[O:19])[O:23][CH2:24][CH3:25])[CH3:22]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Fc1ccc(Br)c2ccccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(F)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A solution of 1-bromo-4-fluoronaphthalene (500 mg, 2.22 mmol) in tetrahydrofuran (5 mL) was added dropwise to stirred solution of t-BuLi (1.4 M in pentane, 3.17 mL, 4.44 mmol) in tetrahydrofuran (5 mL) at −78° C. The reaction mixture was stirred for 1 hour at −78° C., after which diethyl chlorophosphate (0.96 mL, 6.66 mmol) was added dropwise. The reaction mixture was left to warm to rt and concentrated. The residue was suspended in 2 M NaOH (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated to give crude (4-fluoronaphthalen-1-yl)phosphonic acid diethyl ester (139MBT60-8C, 512 mg, 60% pure by NMR) as a yellow oil. 139MBT60-8C (200 mg, 0.425 mmol) was dissolved in pyrrolidine (0.5 mL) and stirred 2 hours at rt. The reaction mixture was concentrated and re-dissolved in dichloromethane (20 mL). The organic phase was washed with 2 M NaOH (20 mL) and dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (0-5% methanol in dichloromethane) to give the title compound (89 mg, 30%) as a white solid.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([CH:7]=[O:8])=[O:6].P([O-])([O-])([O-])=[O:14].[K+].[K+].[K+]>O>[CH2:1]([OH:12])[C@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([C:7]([OH:14])=[O:8])=[O:6]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=CC(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [K+]
Solvent: O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The reaction mixture containing 100 ml of cell free extract of UV-10, FERM BP-1267 (total enzyme activity, 115 units), as prepared by the manner as described in steps (1) to (2) of Example 1, 50 ml of 0.5M potassium phosphate buffer (pH 7.0), 50 ml of 10% L-sorbosone solution and 300 ml of water was incubated at 30° C. with gentle shaking. As a result, 2-keto-L-gulonic acid was formed with the rate of 700 mg/hr.
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O.C(O)CCC>C(OCC)(=O)C>[OH:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:7][CH:6]=1
Reactant: CC(=O)NC(C)Cc1ccc(OC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A 0.2 mole preparation of rac. N-(4-acetoxy-alpha-methylphenethyl)acetamide was prepared as described above except that a more concentrated sodium hydroxide solution was used: i.e., 16 g. of NaOH in 50 ml. of water. Overnight, the oil partially crystallized. The mixture was warmed to 60°-70° C. and 110 ml. of 10% NaOH solution added in portions until a permanent pH of 9 was obtained. The mixture was cooled to 25° C., 125 ml. of n-butanol was added; the two phase mixture transferred to a separatory funnel, and the layers separated. Three more extractions with n-butanol were made and the combined extracts dried with anhydrous MgSO4. After removal of the drying agent by filtration, the solvent was distilled in a rotary evaporator. The traces of n-butanol that remained were removed by the addition of 100 ml. of water and reevaporation in a rotary evaporator, whereupon the residue crystallized on cooling; yield 46 g. The product was recrystallized from 450 ml. of boiling water and 26 g. of crystalline material, m.p. 154.4°-158.5° was obtained. An analytical sample was obtained by recrystallization from hot ethyl acetate, m.p. 160.5°-163.5°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]([CH3:11])[C:7](=[O:12])[CH:6]=1)=O.O.[NH2:14][NH2:15]>C(O)C.C(OCC)C>[CH3:11][N:8]1[CH:9]=[CH:10][C:5]([C:3]([NH:14][NH2:15])=[O:2])=[CH:6][C:7]1=[O:12]
Reactant: NN
Reactant: COC(=O)c1ccn(C)c(=O)c1
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cn1ccc(C(=O)NN)cc1=O
Temperature: 78 °C
Yield: 78 %

Procedure:
The title compound from example 30.1 (4 g, 24 mmol) was dissolved in ethanol and stirred at 78° C. Hydrazine hydrate (5.8 mL, 120 mmol) was added via a syringe and the reaction was stirred for 3 h at 78° C., at which time the starting material was no longer visible by TLC. The reaction mixture (clear solution) was then cooled to room temperature, and diluted with diethyl ether to precipitate the product which was collected by vacuum filtration to yield the title compound as a pale yellow solid (3.13 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14]CC)=[O:13])=[CH:8][NH:9]2)=[N:4][CH:3]=1.[OH-].[Na+].C>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c2cc(Br)cnc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2cc(Br)cnc2c1O
Reaction time: 0.03 h

Procedure:
Ethyl 7-bromo-4-oxo-1,4-dihydro-1,5-naphtyridine-3-carboxylate (1 g, 3 mmol) and 2.5 M NaOH (10 mL) were refluxed for 1 h in a RBF fitted with a reflux condenser. The hot, heterogeneous mixture was diluted with boiling water at which point a tan precipitate dissolved. Charcoal was added to the solution, which was swirled for 2 min and then the mixture was filtered. Glacial acetic acid was added to the filtrate and a white precipitate started to form (pH adjusted to 4). The precipitate was filtered off upon cooling, washed with water and dried to provide the desired product as a white solid.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][C:22]=3[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[OH-].[Na+]>C(O)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][C:22]=3[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CCc2sccc2S(C)(=O)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccsc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Yield: 83.3 %

Procedure:
6.09 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(3-methylsulfonyl-2-thienyl)ethyl]piperidine obtained in Example 43 and 2 ml of thionyl chloride were dissolved in 50 ml of ethanol, and the mixture was heated under reflux for 2 hours. The reaction mixture was basified by adding a 1N aqueous sodium hydroxide thereto, and then extracted with dichloromethane. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by NH form silica gel column chromatography (ethyl acetate), to give 4.89 g of the title compound as colorless crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[C:31](=[O:32])[C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:29][N:28]([CH2:40][CH3:41])[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)=[CH:15][C:14](C2C=CC(OC)=C(OC)C=2)=[CH:13][N:12]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.NC1C=CC(C2C(N)=NC=C([Br:92])C=2)=CC=1>CN(C=O)C.O>[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[C:31](=[O:32])[C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:29][N:28]([CH2:40][CH3:41])[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)=[CH:15][C:14]([Br:92])=[CH:13][N:12]=1
Reactant: CCn1cc(C(=O)Nc2ccc(-c3cc(-c4ccc(OC)c(OC)c4)cnc3N)cc2)c(=O)c(-c2ccc(F)cc2)c1
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2ccc(-c3cc(Br)cnc3N)cc2)c(=O)c(-c2ccc(F)cc2)c1
Reaction time: 0.17 h
Yield: 242 %

Procedure:
DIPEA (120 μl) was added to a solution of the compound obtained in Step of Example 3 (80 mg) and COMU (192 mg) in DMF (1.5 ml) at room temperature, and the mixture was stirred for 10 minutes. The compound obtained in Step 1 of Example 1 (100 mg) was added at room temperature. The mixture was stirred for four hours, followed by the addition of water. The precipitated solid was collected by filtration to give 174 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[CH:4]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc(C)c(C(Br)c2ccccc2)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(c1ccccc1)c1cc(C)ccc1C
Yield: 98.9 %

Procedure:
A solution of 2,5-dimethylbenzhydryl bromide (64.2 g, 233 mmol) prepared according to Example 3, was heated at 155° C., under N2, in triethyl phosphite (60.0 mL, 350 mmol), for 16 hours. The excess triethyl phosphite was removed by distillation to give 76.6 g of a pale yellow oil. The crude product was chromatographed on a silica gel column. Elution with ethyl acetate/hexane (1:1) afforded analytically pure product as a pale yellow oil, 57.36 g (74.0%). 300 MHz 1H NMR (CDCl3): δ, 4.64 (d,1H, J=26.0 Hz, PCH), 2.33 (s, 3H, PhCH3), 2.28 (s, 3H, PhCH3). MS: 333 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][NH:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:17]([N:8]1[C:7](=[O:10])[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:9]1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=O
Reactant: Cc1ccc2s[nH]c(=O)c2c1
Product: CCCCNC(=O)n1sc2ccc(C)cc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6t (98% yield) was synthesized from 5-methyl-benzo[d]isothiazol-3-one and n-butyl isocyanate as a white solid. IR(KBr) 3268, 1708, 1650, 1534 cm−1; 1H-NMR (CDCl3) δ0.96 (t, J=7.3 Hz, 3H), 1.38-1.48 (m, 2H), 1.60-1.67 (m, 2H), 2.46 (s, 3H), 3.41-3.47.(t, 2H), 7.46 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 8.88 (br s, 1H); ESIMS m/e 265 (M++1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH3:11])[C:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)=[O:4].Cl.[OH:13][C@@H:14]([C@@H:23]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](O)=[O:25])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>>[O:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:3]([C@@H:2]([NH:1][C:24](=[O:25])[C@@H:23]([C@H:14]([OH:13])[C:15]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)=[O:16])[CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][CH3:11])=[O:4]
Reactant: O=C(O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Reactant: CC[C@H](N)C(=O)c1ncco1
Agent: Cl
Product: CC[C@H](NC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1)C(=O)c1ncco1

Procedure:
It is similarly prepared according to the general procedure for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one; hydrochloride as the amino component and (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid as the acidic component but without further oxidation.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[I-:16].[K+]>CC(C)=O>[I:16][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: [I-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCI
Temperature: 25 °C
Reaction time: 96 h
Yield: 78.9 %

Procedure:
A solution of 50.0 g (0.187 mol) of N-(3-bromopropyl)phthalimide in 1.2 L of acetone was treated with 208.5 g of potassium iodide and stirred at room temperature for 4 days. The reaction was filtered and the filtrate was diluted with 4 L of ether. This was then filtered through CELITE. The filtrate was concentrated under reduced pressure to a yellow solid. This was recrystallized from hexane to yield 46.5 g (79%) of off-white solid.