Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]=[C:2]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([O-:25])=[O:20].[S:1]=[C:2]([NH:13][CH2:14][C:15]([F:16])([F:17])[F:18])[C@H:3]([NH3+:5])[CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=S)NCC(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]([NH3+])C(=S)NCC(F)(F)F
Product: O=C([O-])C(F)(F)F
Reaction time: 18 h

Procedure:
To a stirred solution of (R)-tert-butyl 1-thioxo-1-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate (200 mg, 0.69 mmol) in CH2Cl2 (5 mL) was added TFA (0.5 mL) dropwise and the reaction mixture was stirred for 18 h. The volatiles were evaporated and the residue was triturated with pentane to give the title compound as colorless gum, which was taken to next step without further purification (200 mg): 1H NMR (300 MHz, DMSO-d6) δ 10.99 (bs, 1H), 8.23 (bs, 2H), 4.62-4.55 (m, 2H), 4.23-4.19 (m, 1H), 1.43 (d, J=8.4 Hz, 3H); ESIMS m/z 186.2 ([M+H]+); IR (thin film) 3445, 2967, 1168 cm−1.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:43](O)/[CH:44]=[CH:45]/[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[C:46]1([CH:45]=[CH:44][CH2:43][O:2][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: OC/C=C/c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)OCC=Cc1ccccc1
Yield: 38.3 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (65 mg, 0.17 mmol), 4-N,N-dimethylaminopyridine (12.5 mg, 0.10 mmol, 0.6 eq), 1,3-dicyclohexylcarbodiimide (64 mg, 0.31 mmol, 1.8 eq) in dichloromethane (5.0 mL) was treated with trans cinnamyl alcohol (29 uL, 0.22 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 32 mg (38%) of L-isoleucine, N-[1-(2-(3-phenyl-2-propen-1-oxy)-2 -oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[C:6]([OH:13])[CH:5]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([OH:13])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(CC)c(O)c1
Reaction time: 24 h
Yield: 97 %

Procedure:
1-(4-Ethoxy-2-hydroxy-phenyl)-ethanone was dissolved in MeOH (40 mL), treated with 10 wt % Pd/C (1.4 g, Degussa type) and stirred under a balloon of H2 for 24 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to give the product as an oil (3.12 g, 97%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3H), 1.39 (t, J=7.1 Hz, 3H), 2.56 (d, J=7.6 Hz, 2H), 3.98 (d, J=7.1 Hz, 2H), 4.79 (s, 1H), 6.37 (d, J=2.5 Hz, 1H), 6.44 (dd, J=8.3, 2.5 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])=[CH:5][C:4]=1C)#N.[OH-:16].[Na+].[CH2:18]([OH:21])[CH2:19]O>CCOCC.O>[CH3:3][C:4]1[CH:5]=[C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:19]=1[C:18]([OH:21])=[O:16]
Reactant: OCCO
Reactant: [OH-]
Reactant: Cc1cc(S(F)(F)(F)(F)F)ccc1C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(S(F)(F)(F)(F)F)ccc1C(=O)O
Temperature: 130 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A mixture of 4-cyano-3-methylphenylsulfur pentafluoride (41.2 g, 169.4 mmol), NaOH (20.4 g, 510 mmol) and water (60 ml) in ethylene glycol (160 ml) was heated to 130° C. and stirred at this temperature for 4 h. It was then cooled to room temperature and diluted with MTB ether (150 ml) and water (250 ml), and the mixture was filtered with suction. The phases of the filtrate were separated, and the aqueous was acidified with concentrated aqueous HCl solution, and the precipitated solid was filtered off with suction. 41.1 g (93%) of 2-methyl-4-pentafluorosulfanylbenzoic acid were obtained as colorless crystals, m.p. 138-139° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]2)[CH:3]=1.C1C(=O)N([Br:36])C(=O)C1>CC#N.CO>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]2)[C:3]=1[Br:36]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(N2CCC(C(=O)O)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CC#N
Solvent: CO
Product: Nc1c(Br)c(N2CCC(C(=O)O)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Reaction time: 1 h

Procedure:
To a solution of 1-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-3-carboxylic acid (17 mg, 0.033 mmol) in a 2:1 mixture of CH3CN/MeOH (1.0 mL) was added NBS (6.2 mg, 0.033 mmol). The mixture was stirred at it for 1 h then concentrated in vacuo. The residue was purified by prep-LC to afford the title compound. LC/MS RT=3.27 min. Mass calculated for, M+H 453.07, observed 453.07
Reaction SMILES: N[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:17].N([O-])=O.[Na+]>O>[Cl:17][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: Nc1cccc2c1nnn2C1CCCCC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc2c1nnn2C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 11.4 g. of the 4-amino-1-cyclohexylbenzotriazole in 75 ml. of concentrated hydrochloric acid and 75 ml. of water kept at 5° C. is slowly added 4.1 g. of sodium nitrite in 15 ml. of water. On completion of the addition, the reaction mixture is allowed to stir an additional 1/2 hour at 0°-5° C. and then is added slowly to an excess of freshly prepared cuprous chloride in 120 ml. of concentrated hydrochloric acid also at 0°-5° C. On completion of the addition, the reaction is allowed to stir and come to room temperature over a 21/2 hour period. Then 1000 ml. of water is added to the reaction mixture and the crude product is collected by filtration, washed with water and air dried. The product is purified by column chromatography, yield: 6.2 g, m.p. = 141°-144° C, analytical sample, m.p.=146°-147° C., is recrystallized from CHCl3 /Et2O.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Mg]>O1CCCC1.Cl[Ni]Cl>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCCc1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl[Ni]Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(-c3ccc(OC)cc3)nn2)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
3-Chloro-6-(4'-propylphenyl)-pyridazine prepared according to a method disclosed in a known literature (m.p.: 127.6°-129.6° C.) (60.0 g) was dissolved in tetrahydrofuran (THF) (700 ml), followed by adding NiCl2 (dppp) (2.5 g) as a catalyst, agitating the mixture at -10° C. for 15 minutes, dropwise adding therto a Grignard reagent obtained by reacting p-bromoanisole (96.5 g) with magnesium in THF, agitating the mixture in an ice bath for one hour, removing the ice bath, agitating it at room temperature for 3 hours, allowing it to stand overnight, adding toluene (500 ml), further adding 6N-hydrochloric acid, separating the resulting organic layer, washing it with water, then with an alkali and further with water till the washing water became neutral, drying with MgSO4, distilling off toluene, purifying the residue according to column chromatography using activated alumina (300 g) and toluene as an eluent, concentrating, and recrystallizing from ethyl acetate (700 ml) to obtain 3-(4'-methoxyphenyl)-6-(4'-propylphenyl)-pyridazine (70 g). This product had a m.p. of 155.9° C., exhibited nematic phase and formed an isotropic liquid at 254° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([C:28]2[N:37]3[C:31]([CH2:32][NH:33][C:34]4[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=4[CH2:36]3)=[CH:30][CH:29]=2)=[O:27])[CH:19]=1.C(N(CC)C(C)C)(C)C>ClCCl.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[CH2:36][N:37]3[C:28]([C:26]([NH:25][CH2:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[O:27])=[CH:29][CH:30]=[C:31]3[CH2:32]2)=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)Cl)cc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
A stirred solution of 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid of Step A (0.790 g, 3.5 mmol) in dichloromethane (15 mL) was treated under nitrogen with a catalytic amount of N,N-dimethylformamide followed by dropwise addition of 2N oxalyl chloride in dichloromethane (2.8 mL). After the gas evolution ceased the mixture was refluxed for 4 hours, cooled, and evaporated. The residue was azeotroped twice with benzene and dried in vacuo to provide 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride. The crude 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride (0.856 g, 3.5 mmol) was dissolved in dichloromethane (7 mL) and added dropwise to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12 (0.450 g, 1.41 mmol) in anhydrous tetrahydrofuran 10 mL) containing N,N-diisopropylethyl amine (0.860 mL). The mixture was stirred for 18 hours at room temperature and evaporated to dryness. The residue was dissolved in dichloromethane, the solution washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed over silica gel Merck-60 eluting with a gradient from 0 to 4% methanol in 1:1 hexane-ethyl acetate to provide the title compound (0.452 g) as a white solid after trituration with hexane, m.p. 216-218° C. (dec).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]=[CH:17][C:18]#[N:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([CH2:30][N+:31]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[CH3:33]S(C)=O.[H-].[Na+]>O.CCOCC>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:17]([C:30]#[N:31])=[CH:18][NH:19][CH:33]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CS(C)=O
Reactant: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#Cc1c[nH]cc1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 10.7 g (40 mmole) of 3-(2-benzoyl-4-chlorophenyl)-2-propenenitrile, 5.3 g (38 mmole) of tosylmethyl isocyanide, 75 ml of dimethyl sulfoxide and 150 ml of ether was added dropwise to a suspension of 3.7 g (77 mmole) of 50% sodium hydride in mineral oil and 170 ml of ether. When the addition was complete stirring was continued for 2 hr. The mixture was diluted with water and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate; and concentrated at reduced pressure to give a dark green oil. Purification by column chromatography (800 g silica gel; eluent 5% ether in methylene chloride) gave end product as off-white prisims, mp 175°-177°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O>C(O)(=O)C.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cc(Br)ccc1N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)ccc2[nH]1
Yield: 85 %

Procedure:
A solution of the compound of Example 49A in glatial acetic acid (75 mL) was warmed at 60° C. for 3 h. The mixture was cooled and diluted with toluene and concentrated in vacuo. The remainder of the acetic acid was removed by azeotroping with toluene (2×) and the residue was chromatographed over a 360 g silica gel cartridge, eluting with 25-75% ethyl acetate in dichloromethane. These procedures afforded the product (10.0 g, 85%) as a light beige rigid foam.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11].S(O)(O)(=O)=O.[CH2:20]([S:27]SCC[C@H](N)C(O)=O)C[C@H](N)C(O)=O>>[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[CH3:20][SH2+:27].[CH3:9][SH2+:10]
Reactant: O=S(=O)(O)O
Reactant: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: C[SH2+]
Product: O=S(=O)([O-])[O-]

Procedure:
The reaction solution was analyzed by liquid chromatography. As a result, it was found that 0.13 g (0.67 mmol) of L-methionine sulfate, 2.64 g (7.22 mmol) of L-homocystine sulfate and 4.25 g (13.72 mmol) of L-methionine-S-methylsulfonium sulfate were formed. The conversion ratio was 98% and the selectivity was 43%.
Reaction SMILES: S(=O)(=O)(O)O.FC(F)(F)C(O)=O.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.N([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+]>O>[N:18]([C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(F)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Prepared in analogy to J. Org. Chem. (1989) 54:5938-5945. To a solution of sulfuric acid (40 mL) and trifluoroacetic acid (200 mL) was added 4-fluoroaniline (22.1 mL, 0.23 mol) dropwise. Then under ice-cooling a solution of sodium nitrite (20.6 g, 0.3 mol) in water (200 mL) was added over 30 min at 15-18° C. The solution was then stirred for 30 min while kept in the ice bath. A solution of sodium azide (25.42 g, 0.39 mol) in water (150 mL) was added dropwise over 30 min. Mixture was foaming and temperature went up to 10° C. while cooling with an ice bath. Reaction mixture was stirred without cooling for 1 h, then extracted with diethyl ether. The combined organic layers were washed with water two times. Then the combined organic layers were diluted with saturated aqueous sodium carbonate solution (500 mL) until the mixture became basic. The organic phase was separated and washed with brine, extracted again with diethyl ether. The organic layers were dried over sodium sulfate and evaporated at 40° C., minimum 50 mbar (already distillation of product), to afford the title product (30.42 g, 96%) as a brown liquid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (1.0 g; 6.02 mmol), 0.502 ml (6.62 mmol) of 3-amino-propan-1-ol and 1.15 ml (6.62 mmol) of diisopropylethylamine in 5 ml THF is stirred at rt for 1 hr (temperature raises somewhat at the beginning). After concentration in vacuo the residue is dissolved in 50 ml of ethyl acetate, washed with 50 ml of 4% aqueous sodium hydrogen carbonate and brine, dried and concentrated. 1.32 g of pure title compound as a solid are thus obtained (99% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15]C1CCCCO1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C.O>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:2]([CH3:1])([CH3:22])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCC(C)(C)CCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)CCC(C)(C)CCCCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4,4-dimethyl-9-(tetrahydro-2H-pyran-2-yloxy)nonanoate (example 285, step e) (0.86 g) in methanol (10 mL) was added p-toluenesulfonic acid monohydrate (52 mg) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and water and the phases separated. The aqueous layer was extracted with ethyl acetate (×2) and the combined organic phase was washed with 10% citric acid, saturated aqueous sodium bicarbonate solution and brine then dried over magnesium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0-50% ethyl acetate in cyclohexane to afford the subtitled compound as colourless oil. Yield 0.44 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C.[CH3:19][O:20][C:21](OC)(OC)OC>CO.[OH-].[Na+].O>[CH3:19][O:20][C:21]1[NH:1][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[C:11]=2[N:12]=1
Reactant: COC(OC)(OC)OC
Reactant: COC(=O)c1ccc(OC)c(N)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(OC)c2nc(OC)[nH]c12
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl 2,3-diamino-4-methoxybenzoate [0.5 g, Reference Example 8(a)] acetic acid (0.15 ml) and tetramethoxymethane (0.53 ml) was stirred at 80° C. for 40 minutes. After cooling to room temperature the reaction mixture was diluted with a mixture of methanol (3.6 ml), 1N sodium hydroxide (2.55 ml) and water (8 ml). The resulting precipitate was filtered and then passed through a short filtration silica gel column to give the title compound (0.49 g) as a tan coloured solid. M+236. NMR (CDCl3): δ 3.93(s,3H), 4.05(s,3H), 4.23(s,3H), 6.69(d,J=8 Hz,1H), 7.74(d,J=8 Hz,1H). 9.48(bs,1H)]
Reaction SMILES: CCC1C=CC(=O)[C:5]2=C[C:7]3[CH2:25][N:24]4[C:10](=[CH:11][C:12]5[C@@](O)(CC)C(=O)OC[C:13]=5[C:22]4=O)[C:8]=3[NH:9][C:4]=12.[CH2:30]([Cl:32])Cl.C(N)(=[O:35])C.N1C=CC=CC=1>C(N(CC)CC)C>[N:24]1([CH:25]2[CH2:5][CH2:4][N:9]([C:30]([Cl:32])=[O:35])[CH2:8][CH2:7]2)[CH2:22][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCc1ccc(=O)c2cc3c([nH]c1-2)-c1cc2c(c(=O)n1C3)COC(=O)[C@]2(O)CC
Reactant: ClCCl
Reactant: CC(N)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Cl)N1CCC(N2CCCCC2)CC1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
In a suitable vessel were charged 7-Ethyl-10-hydroxycamptothecin (20 g), methylene dichloride, acetamide (3 gm) and pyridine (60 ml) under nitrogen atmosphere. A solution of [1,4′]bipiperidinyl-1′-carbonyl chloride (17.6 g), methylene dichloride and triethylamine (20 ml) was prepared and added to the above suspension and stirred at 30-40° C. for 2 hours. The solvent was distilled out under reduced pressure at 50° C. and hexane was added under stirring as an antisolvent to isolate crystalline compound. The crystalline compound was filtered, washed with hexane and dried under reduced pressure at 50° C. The yield was 28.4 g (95%). HPLC Purity—99.9%
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH:13][CH3:14].O>C1COCC1>[CH3:12][N:13]([CH3:14])[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzyl bromide (25.0 g), and to the mixture was added 50% dimethylamine solution (29 ml) at 0° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give dimethyl-4-nitrobenzylamine (20.7 g) as orange oil.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:38])=[C:11]2[C:16](=[C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[N:18]=1)[N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14](=[O:31])[C:13]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:12]2)=[O:8].[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:24]([N:15]1[C:16]2[C:11](=[C:10]([OH:38])[C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:8])=[N:18][C:17]=2[C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH:12]=[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:14]1=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CCNC(=O)c1nc(-c2nccs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1nc(-c2nccs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
A mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-thiazol-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-propionic acid methyl ester (28 mg, 0.052 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3-4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 11 mg of the title compound. MS: (+) m/z 527.33 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[NH2:10])[C:5]#[N:6].[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH:21]=O.II>CO>[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([CH3:11])[C:9]=2[N:10]=1
Reactant: COc1nccc(I)c1C=O
Reactant: Cc1cc(C#N)cc(N)c1N
Agent: II
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(C#N)cc2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a solution of 3,4-diamino-5-methyl-benzonitrile (2.00 g, 13.6 mmol) in MeOH (40 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (3.6 g, 13.6 mmol) in MeOH (20 mL) at 0° C. The resulting slurry was stirred at 0° C. for 1 h. Iodine (1.73 g, 8.8 mmol) in MeOH (10 mL) was added dropwise via a dropping funnel to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 14 h. After removal of MeOH, the residue was diluted with saturated Na2S2O3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4. The crude product was purified by flash column chromatography (3% MeOH/CH2Cl2) to yield the title compound (1.81 g, 46%). 1H NMR (300 MHz, CDCl3) δ 7.90 (1H, s), 7.49 (1H, d, J=5.4 Hz), 7.46 (1H, s), 7.41 (1H, d, J=5.3 Hz), 3.78 (3H, s), 2.68 (3H, s). LCMS (M+H)+ m/z 391 (t=1.27 min.).