Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:16][CH:17]([OH:19])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A solution of (S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (12 mg, 0.028 mmol) in 3:1 THF/MeOH (4 mL) was cooled to 0° C. NaBH4 (2.1 mg, 2 equiv) was added. After 15 min, the mixture was warmed to rt slowly. After stirring 1.5 h, LC-MS found the reaction completed. The mixture was quenched by water (2 mL), concentrated, and purified by preparative HPLC to afford (6S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one (4.4 mg, 36%). LC-MS (3 min) tR=1.68 min, m/z=458, 460 (M+Na). 1H NMR (CDCl3) 7.36-7.21 (m, 3H), 7.12-6.96 (m, 4H), 6.83 (m, 1H), 5.63 (m, 1H), 2.93 (m, 1H), 1.51 (d, 3H), 1.17 (d, 3H).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:11]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCCCCCCCO
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOCCCCCCCO

Procedure:
3-(7-Decyloxyheptylthio)-propanol (m.p. 28°-32° C.), obtained by reacting heptane-1,7-diol with 1-bromodecane to give 7-decyloxyheptanol, bromination thereof to give 7-decyloxyheptyl bromide, reaction with methyl β-mercaptopropionate to give methyl β-(7-decyloxyheptylthio)-propionate and reduction with lithium aluminium hydride, is reacted in the manner described in Example 20C to give the desired choline ester in a yield of 17% of theory. The water-soluble, white crystals sinter at 53° C. and melt at 224° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](Cl)[N:12]2[N:16]=[CH:17][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>C(O)C.CCOC(C)=O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:28][CH:25]2[CH2:27][CH2:26]2)[N:12]2[N:16]=[CH:17][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: N#CCCCCc1cnn2c(Cl)nc(SCc3ccccc3)nc12
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CCCCCc1cnn2c(NC3CC3)nc(SCc3ccccc3)nc12
Yield: 65 %

Procedure:
A solution of compound (5) and cyclopropylamine (1.2 g. 17.7 mmol) in anhydrous ethanol (10 mL) was stirred for 0.5 h at ambient temperature. The mixture was then diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 and brine and dried over anhydrous Na2 SO4. Removal of the solvent provided 5-(2-benzylsulfanyl-4-cyclopropylamino-pyrazolo[1,5-a][1,3,5]triazin-8-yl)-pentanenitrile (6) (4.3 g. 65% in two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2OC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
To a solution of ethyl 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylate (D104) (38.7 mg, 0.071 mmol) in Tetrahydrofuran (THF) (10 mL), Ethanol (2 mL) and Water (1 mL) was added sodium hydroxide (56.9 mg, 1.423 mmol). The reaction mixture was stirred at room temperature overnight (16 h). Sodium hydroxide (56.9 mg, 1.423 mmol) was added again. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with 2N HCl solution till pH ˜6.0. The organic solvent was removed. Then the mixture was extracted with EA/THF. The combined organic layers were concentrated. The residue was re-dissolved in THF/water and then purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylic acid (E73) (10 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.78 (2H, m), 1.94 (1H, m), 2.12 (2H, d), 2.55 (1H, m), 3.08 (4H, m), 3.29 (3H, m), 3.49 (3H, m), 3.66 (2H, d), 4.87 (1H, dt), 7.29 (1H, t), 7.40 (1H, d), 7.49 (1H, m), 7.93 (1H, m), 8.04 (1H, dd), 8.16 (1H, d), 9.51 (1H, br. s.), 12.59 (1H, br. s.). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C28H34ClN3O3S requires 515.2. found 516.2 (M+H+).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=1[CH:15]([OH:19])[CH:16]=[CH:17][CH3:18].C(Cl)Cl>O>[CH3:6][C:7]12[O:3][C:8]1([CH:15]([OH:19])/[CH:16]=[CH:17]/[CH3:18])[C:9]([CH3:13])([CH3:14])[CH2:10][CH2:11][CH2:12]2
Reactant: CC=CC(O)C1=C(C)CCCC1(C)C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C12OC1(C)CCCC2(C)C

Procedure:
21 g. of 40 % percetic acid and 0.6 g. of sodium acetate were added under nitrogen to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene (19.4 g.) and 12 g. of sodium acetate in 35 ml. of CH2Cl2 at 20°. The reaction mixture was left 2 more hours with stirring and it was then poured into 250 ml. of water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:29][CH2:30][S:31]([CH2:34][CH2:35]Br)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:35][CH2:34][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(=O)(CCBr)CCBr
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CS(=O)(=O)CCN1CCC(N2N=C(c3ccc(OC)c(OC)c3)[C@H]3CC=CC[C@H]3C2=O)CC1
Reaction time: 18 h

Procedure:
A solution of 10 mmol of compound 5c, 10 mmol of 1-bromo-2-(2-bromo-ethanesulfonyl)-ethane and 30 mmol of potassium carbonate in 30 ml of dimethylformamide is stirred at RT. After 18 h, the mixture is poured into water (150 ml) and subsequently extracted with ethyl acetate. Crystallisation from diethyl ether. M. p. 165-166° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CS(C)=O>[C:24]([O:23][C:21](=[O:22])[CH2:20][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
To a solution of 49 g of N-hydroxyphthalimide in 25 ml of dimethyl sulfoxide at 5° C., was added portionwise 27.6 g of potassium carbonate. After 10 minutes of stirring the reaction mixture was present as a red slurry to which 75 g of tert-butyl chloroacetate was added dropwise over 1 hour at 5° C. The resulting reaction mixture was stirred for 18 hours and poured into ice water. The solid product was filtered, dissolved in methylene chloride and washed with water. The methylene chloride phase was dried over magnesium sulfate, filtered and stripped and recrystallized from ethanol to give 77.5 g of 2-(2-tertbutoxy-2-oxoethoxy)-1H-isoindole-1,3(2H)-dione; m.p. 146°-7° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:33](O)(=[O:36])[CH:34]=[CH2:35]>C1COCC1.O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH:25][C:33](=[O:36])[CH:34]=[CH2:35])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)O
Reactant: C[C@H](Nc1cncc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1ccc2ncn(-c3cncc(N[C@@H](C)c4ccccc4)n3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine (67 mg, 0.2 mmol) in anhydrous THF (2 mL) under N2 was added triethylamine (67 μl, 0.48 mmol), EDACHCl (46 mg, 0.24 mmol), 4-(1-pyrrolidino)pyridine (cat.) and acrylic acid (17 mg, 0.24 mmol). The resulting mixture then stirred at RT overnight and was the diluted with H2O (10 mL) and the mixture extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous Na2CO3, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane-methanol (98:2-94:6) as eluant to separate the pure product (25 mg).
Reaction SMILES: COC1C=CC(C[N:8]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=4[C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18][O:17][C:16]=3[CH:31]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:33]1[CH:34]=[CH:35][N:36]=[C:32]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:20]([C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18][O:17][C:16]=2[CH:31]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
To a solution of methyl 2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoate (From example 254, step 1; 1.2 g, 2.784 mmol) in DCM (40 mL) was added TFA (2.0 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 5 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and the aqueous layer was extracted with DCM (2×20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-50% ethyl acetate in hexane) to get methyl 2-(7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoate as a yellow solid (400 mg, 42.7%).
Reaction SMILES: [OH-].C[Sn+](C)C.[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:23])[N:15]2[CH2:18][C:19]([O:21]C)=[O:20])=[CH:10][CH:9]=1)#[N:7]>ClCCCl.ClCCl>[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:23])[N:15]2[CH2:18][C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1)#[N:7]
Reactant: COC(=O)Cn1c(=O)ccc2ccc(C#N)cc21
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: N#Cc1ccc2ccc(=O)n(CC(=O)O)c2c1
Yield: 88.9 %

Procedure:
Trimethyl tin hydroxide (0.388 g, 2.14 mmol) was added to a solution of methyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate (0.104 g, 0.429 mmol) in 1,2-dichloroethane (5 mL) and the resulting suspension was stirred at reflux for 4 h. The reaction mixture was diluted with dichloromethane and washed with 1N aqueous HCl. Filtration of the organic phase provided 87 mg (89%) of 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetic acid. Retention time (min)=0.987, method [1], MS (ESI) 229.1 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)[N:11]=1>O>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: Clc1nc(Nc2ccc(-c3ccccc3)cc2)c2ncn(C3CCCC3)c2n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(-c4ccccc4)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
342 mg of trans-1,4-diaminocyclohexane is taken to approximately 150° C. then 234 mg of the product obtained in Stage 1 above is added, the reaction medium is maintained under agitation at 140° C. for 9 hours 30 minutes then left to return to ambient temperature. Then 10 ml of water is added, followed by extracting with dichloromethane, drying and evaporating the solvent. The residue is chromatographed on silica (eluent: MeOH/NH4OH 98/2), followed by taking up in 5 ml of an ethanolic solution of hydrochloric acid, evaporating the solvents, impasting the residue in ether and drying under reduced pressure at 60° C. 93 mg of expected product is recovered.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[F:26][C:27]([F:37])([F:36])[CH2:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH:21][CH:32]3[CH2:31][CH2:30][N:29]([CH2:28][C:27]([F:37])([F:26])[F:36])[CH2:34][CH2:33]3)=[CH:16][N:15]=2)=[N:6]1
Reactant: O=C1CCN(CC(F)(F)F)CC1
Reactant: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1NC1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 237 mg (1.312 mmol) of 1-(2,2,2-trifluoroethyl)piperidin-4-one were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-(2,2,2-trifluoroethyl)piperidin-4-one, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added to the reaction mixture, which was stirred vigorously for 10 min. Subsequently, the reaction mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 269 mg of the title compound were obtained (90% of theory).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:10]([O-])=[O:11].[Na+].N>CCCCCCC.O.CO>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:10]=[O:11])=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: CNc1ccccc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Solvent: CO
Product: CNc1ccc(N=O)cc1
Temperature: 0 °C
Yield: 51 %

Procedure:
Initially, 107 g (1.0 mol) of N-methylaniline was added dropwise to a methyl alcohol solution containing 40% HCl with stirring at a temperature between 5° and 10° C. for one and a half hours. Thereafter, 80 g (1.12 mol) of sodium nitrite, of a purity of 97%, was added to the solution obtained at 5° C. After stirring at a temperature between 15° and 25° C. for 15 hours, the solution was poured in 2 l of ice water and the water solution was neutralized to pH 8 with aqueous ammonia after stirring for 15 minutes. Thereafter, 500 ml of heptane was added to the solution. After stirring at a temperature between 10° and 20° C. for 2 hours, the crystals obtained were filtered, washed sufficiently on the filter paper and thereafter dried with hot-air at 50° C. for 48 hours. 69.5 g of N-methyl-p-nitrosoaniline of a melting point of 115°~117° C. was obtained. The yield was 51.1%.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@H:10]([O:11][C:12]([O:14][CH3:15])=[O:13])[C@@H:9]([CH3:16])[O:8][C@H:7]1[N:17]1[CH:24]=[C:23]([F:25])[C:21]([NH2:22])=[N:20][C:18]1=[O:19])=[O:4].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:34].Cl>ClCCl>[CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@H:10]([O:11][C:12]([O:14][CH3:15])=[O:13])[C@@H:9]([CH3:16])[O:8][C@H:7]1[N:17]1[CH:24]=[C:23]([F:25])[C:21]([NH:22][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:34])=[N:20][C:18]1=[O:19])=[O:4]
Reactant: CCCCCOC(=O)Cl
Reactant: COC(=O)O[C@@H]1[C@H](OC(=O)OC)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](OC(=O)OC)[C@H]2OC(=O)OC)cc1F
Temperature: -2.5 °C
Yield: 91.1 %

Procedure:
35.8 g (0.099 mole) of the compound obtained in Example 2 was mixed with 163 ml of dichloromethane and 11 ml (0.136 mole) of pyridine, and stirred. After cooling the resulting mixture to −5 to 0° C., 15.7 ml (0.109 mole) of n-pentyl chloroformate was added dropwise thereto while maintaining the temperature of the reaction mixture at less than 0° C., followed adding the resulting mixture was warmed to room temperature and stirred for 2 hrs, 1 N HCl thereto. The organic layer was separated, successively washed with 163 ml of saturated sodium bicarbonate and 163 ml of water, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure, to obtain 42.9 g of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.COCCOC[O:12][CH:13]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:14][CH2:15][S:16]([C:19]1[S:23][C:22]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>O.CO>[OH:12][CH:13]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:14][CH2:15][S:16]([C:19]1[S:23][C:22]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: COCCOCOC(CCS(=O)(=O)c1ccc(S(N)(=O)=O)s1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: NS(=O)(=O)c1ccc(S(=O)(=O)CCC(O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To a solution of sulfuric acid (76.7 ml) in water (76.7 ml), cooled to 0° C. was added a solution of compound from Step F (5.2 g, 11.5 mmol) in methanol (76.7 ml) and the reaction mixture was stirred at room temperature for 1 hour. Water was added, extracted with ethyl acetate and the organic layers were washed with saturated NaaHCO3 solution and brine. Drying and solvent evaporation gave an oil (4.4 g) and column chromatography (silica gel, 40% ethyl acetate-hexane) gave a solid product (2.3 g, 56%); m.p. 119°-121° C.
Reaction SMILES: [OH:1][P:2]([O-:5])([O-:4])=[O:3].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.CC(OC([NH:33][C@@H:34]1[C:37](=[O:38])[O:36][CH2:35]1)=O)(C)C.FC(F)(F)C(O)=O.N[C@H]1COC1=O>CN(C=O)C.O>[P:2]([O:5][CH2:35][C@@H:34]([C:37]([OH:38])=[O:36])[NH2:33])([OH:4])([OH:1])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1COC1=O
Reactant: O=P([O-])([O-])O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N[C@H]1COC1=O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: N[C@@H](COP(=O)(O)O)C(=O)O
Reaction time: 72 h
Yield: 87.2 %

Procedure:
K2HPO4 (0.446 g, 3.28 mmol, dried 4 h at 130° C.) and 18-crown-6 ether (0.867 g, 3.28 mmol) were stirred 16 h in anhydrous DMF (10 mL). BOC-L-serine β-lactone (169 mg, 0.902 mmol) was deprotected to (S)-3-amino-2-oxetanone trifluoroacetic acid salt and added as a solution in DMF (3 mL). The mixture was stirred 3 days, diluted with H2O (to 50 mL), and applied to a column of AG1-X8 (trademark) (80 mL, 3 cm dia., OH- form). Elution (2 mL/min) with a linear gradient (0 to 3M over 10 L) of formic acid afforded O-phospho-L-serine 145.6 mg) in 87% yield after lyophilization: mp 170°-171° C. (dec) (lit. mp 175°-176° C. (dec)); [α]D 25 +7.2° (c 1.0, H2O) (lit. [α]D 25 +7.2° (c 1.0, H2O)); IR (KBr disk) 3420 (w, br), 3180 (w), 2700 (w), 2400-2260 (w), 1620 (w), 1560 (m), 1260 (m), 1089 (s), 1045 (s), 1000 (s), 970 (s), 740 (m), 810 (m) cm-1 ; 1H NMR (300 MHz, D2O+DC1)δ 4.37-4.27 (m, 2H, CH-CHH), 4.26-4.16 (m, 1H, CHH)31 ; 31p NMR (161.96 MHz, D2O+DC1) -0.45 (br (s). Anal. Calc. for C3H3NO6P: C, 19.47; H, 4.35; N, 7.57. Found: C, 19.27; H, 4.29; N, 7.82; POSFAB-MS (glycerol/HC1 ) 186 (MH+), 371 (M2H+); Rf 0.43 (System A).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: [H][H]
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)CNc1c(N)cnc2cccnc12

Procedure:
A catalytic amount of 5% platinum on carbon was added to a solution of N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (1.0 g, 4.1 mmol) in ethyl acetate (50 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum to provide N4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6]1.Br[CH2:30][CH2:31][CH2:32][OH:33]>>[CH3:1][O:2][CH2:3][CH2:4][C@H:5]1[CH2:6][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:23])([F:24])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:8][CH2:9][N:10]1[CH2:30][CH2:31][CH2:32][OH:33]
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Reactant: OCCCBr
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1CCCO

Procedure:
Using the method of Example 351, using (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene and 3-bromo-propan-1-ol, 15 hours at reflux after the addition of alcohol, and two purifications by flash chromatography: the first, eluting with a gradient of a 3% solution of methanol in ethyl acetate (0-100%), and then with a gradient of methanol: ethyl acetate (3%-5% methanol in ethyl acetate); and the second, eluting with a gradient of solutions of 2M ammonia in methanol, in ethyl acetate (4%-5% over 40 minutes), gives the title compound: mass spectrum (APCI, m/e): 470 (M+1); NMR (1H, 300 MHz, DMSO-d6): δ 8.47 (s, 1H), 6.96-6.81 (m, 3H), 6.70 (m, 1H), 4.42 (m, 1H), 3.54-3.37 (m, 6H), 3.37-3.18 (m, 2H), 3.15 (s, 3H), 2.68 (m, 2H), 2.58-2.45 (m, 1H), 2.35 (m, 2H), 1.68 (m, 2H), 1.55 (m, 2H).