Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:5]=2[N:6]=1.[CH3:15][N:16]=[C:17]=[O:18].[N-]=C=O>C(OCC)(=O)C>[CH3:13][C:8]1([CH3:14])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:17]([NH:16][CH3:15])=[O:18])[S:3][C:4]=2[C:10]([CH3:12])([CH3:11])[CH2:9]1
Reactant: CC1(C)Cc2nc(N)sc2C(C)(C)C1
Reactant: CN=C=O
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1nc2c(s1)C(C)(C)CC(C)(C)C2
Reaction time: 2 h

Procedure:
2-Amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazole (21 grams; 0.1 mole) was dissolved in ethyl acetate (100 ml) and the solution charged into a glass reaction vessel fitted with a mechanical stirrer and themometer. Methyl isocyanate (6.2 grams 0.11 mole) was added dropwise to this solution over a period of 30 minutes. The temperature of the reactants was at about 20°-25° C. during the addition. At the conclusion of the isocyanate addition, stirring was continued at room temperature for a period of about 2 hours. The desired product, 2-amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazole, a solid, was then filtered from the reaction mixture and air dried. Its melting point was greater than 250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:31][O:32][C:33]1[CH:38]=[C:37]([O:39][C:40]([F:43])([F:42])[F:41])[CH:36]=[CH:35][C:34]=1[S:44](Cl)(=[O:46])=[O:45]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:34]1[CH:35]=[CH:36][C:37]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:38][C:33]=1[O:32][CH3:31])(=[O:45])=[O:46])[C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:29])[CH3:30])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Product: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2OC)c2ccc(Cl)cc21
Yield: 44.7 %

Procedure:
With 303 mg of (2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide, which is the compound described in Preparation 3.49 (Isomer B) of the brochure Publication No. WO01/98295 and 245 mg of 2-methoxy-4-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 216 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20](=O)[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22]N(C)C)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]1([C:40]2[NH:41][C:42]([NH2:45])=[N:43][N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)(=O)C.C(O)C>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][N:43]4[N:44]=[C:40]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:41]=[C:42]4[N:45]=3)=[CH:18][CH:19]=2)[CH2:9][C:10]([OH:13])([CH3:12])[CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CC(C)(O)C2)cc1)c1ccccc1
Reactant: Nc1nnc(-c2ccccc2)[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(-c3nc4nc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1

Procedure:
A mixture of 2 (270 mg, 0.6 mmol) and 5-Phenyl-4H-[1,2,4]triazol-3-ylamine (96 mg, 0.6 mmol) in acetic acid (1 mL) and ethanol (4 mL) was heated under reflux for 6 hours.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[C:22]([Cu])#[N:23].O>CN(C=O)C>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([CH:16]=2)[C:22]#[N:23])=[CH:13][N:12]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Temperature: 120 °C
Yield: 43.3 %

Procedure:
A mixture of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.37 g, 0.925 mmol) and CuCN (0.12 g, 1.39 mmol) in DMF (5 ml) was heated at 120° C. for 3 hours. Water (100 ml) was added, and the precipitate was collected. The residue was triturated with methanolic dichloromethane (10% CH3OH in CH2Cl2 with 0.1% NH4OH) to release the product from its copper complex and filtered. The filtrate was concentrated and purified via flash chromatography (3% CH3OH in CH2Cl2 with 0.1% NH4OH) to give 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile as white solid (0.12 g, 44%): M+H 300.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:28]([NH2:30])[CH3:29]>O>[CH2:28]([NH:30][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:29]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCN
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: O
Product: CCNc1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
288 parts of β-naphthol, 6 parts of diphenyl phosphite and 115 parts of ethylamine gas are heated at 230° C in a pressure autoclave for 10 hours. The pressure is 35 atmospheres. The mixture is added to 2,000 parts of water and the batch is stirred for 30 minutes at 70° - 80° C. The lower oily phase is separated off and distilled. 314 parts of N-ethyl-β-naphthylamine boiling at 119° - 120° C/0.1 mm Hg are obtained, corresponding to a yield of 92% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6]C(C)=[CH:4][CH:3]=1.[C:9]([OH:12])(=[O:11])[CH3:10]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.[Br-].[Na+].C([O-])(=O)C.[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:10]([C:9]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(Br)cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=C(O)c1ccc(Br)cc1
Yield: 82.9 %

Procedure:
The test described in Example 1 was repeated using 300 g of p-bromotoluene, 700 g of acetic acid, 50 g of water, 6 g of cobalt acetate tetrahydrate, 5 g of sodium bromide and 5 g of sodium acetate. In a reaction time of 170 minutes, 292.4 g of p-bromobenzoic acid was obtained (80% of the theory).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:10][CH:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[P-](F)(F)(F)(F)F.[N:31]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1.N12CCCN=C1CCCCC2.O>O1CCCC1>[N:31]1([O:1][C:2]2[C:3]3[O:10][CH:9]=[C:8]([CH:11]4[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2coc3c(O)ncnc23)CC1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2coc3c(On4nnc5ccccc54)ncnc23)CC1
Yield: 84.7 %

Procedure:
Under an argon atmosphere, tert-butyl 4-(4-hydroxyfuro[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.06 g, 3.22 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (1.81 g, 3.49 mmol) were dissolved in anhydrous tetrahydrofuran (17 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (656 mg, 4.31 mmol) was added to the solution, and then the resultant solution was stirred at room temperature for 40 minutes. Water was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]furo[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate (1.19 g, 83%) as a white amorphous.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[Cr]([O-])([O-])(=O)=[O:19]>C(O)(=O)C>[CH3:15][C:5]1([CH3:16])[C:6]2[C:14](=[CH:13][C:12]3[CH2:11][C:10](=[O:19])[CH2:9][C:8]=3[CH:7]=2)[C:2]([CH3:17])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCC3
Reactant: O=[Cr](=O)([O-])[O-]
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)CC(=O)C3
Temperature: 70 °C
Yield: 94.2 %

Procedure:
A round bottom flask fit with a mechanical stirrer, condenser, thermometer, addition funnel, and nitrogen inlet was charged with 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indane (43.0 g, 0.0.19 mol) and 84 mL glacial acetic acid and heated to 70° C. While stirring chromate (56.7 g, 0.57 mol, Aldrich) was added slowly maintaining the temperature at about 110° C. After complete addition (30 minutes) the reaction was allowed to cool to room temperature for an additional 2½ hours. The reaction was quenched with 5% HCl/ice and extracted with diethyl ether. The combined ether extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of the solvents by rotary evaporation gave 43.0 g of greenish solids which were washed with chilled acetone to give 16.0 g (98% pure by GC) of solids. The acetone wash was concentrated to give 15.0 g of more solids which were washed with hexane to give 8.7 g (79% pure by GC) of solids. The 16.0 g solids from the acetone wash and 8.7 g solids from the hexane wash were combined to give the crude 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indan-2one (total of 24.7 g). 1HNMR (CDCl3, 500 MHz) 6 7.75 (s, 1H); 7.43 (s, 1H); 3.08 (t, J=3.5 Hz, 2H); 2.66 (t, J=6 Hz, 2H); 1.71 (s, 4H); 1.32 (s, 6H); 1.30 (s, 6H).
Reaction SMILES: CN=C=O.[C:5]1([C:11]2[C:19]([CH:20]=[N:21]O)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:5]1([C:11]2[C:19]([C:20]#[N:21])=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: ON=Cc1c(-c2ccccc2)nn2ccccc12
Agent: CN=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#Cc1c(-c2ccccc2)nn2ccccc12
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A solution of methyl isocyanate (0.19 g) in methylene chloride (2ml) was added dropwise to a mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (0.52 g) in chloroform (4 ml) with stirring and ice-cooling. The mixture was stirred at room temperature for 2 hours and allowed to stand at room temperature overnight. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (20 g) with methylene chloride as an eluent. The fractions containing the object compound were combined (20 ml) and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbonitrile (0.21 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[N-:29]([C:32]#[N:33])[C:30]#[N:31].[Na+]>CN(C)C=O.Cl>[C:30]([N:29]=[C:32]([NH2:33])[NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:19][CH:20]=3)=[CH:14][CH:15]=2)=[CH:8][C:2]=1[F:1])#[N:31]
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN=C(N)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Yield: 31 %

Procedure:
In a sealed glass tube suitable for microwave heating, the compound 2-fluoro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.1 g, 0.27 mmol) and sodium dicyanamide (37 mg, 0.4 mmol) in 2.5 ml of dimethylformamide and 0.5 ml of hydrochloric acid 1N are heated at 75° C. in a microwave oven (Biotage, Emrys Optimiser) for 900 seconds. The reaction medium is evaporated to dryness. After passing the residue obtained through a silica column (eluent dichloromethane/ethanol 93/7), a solid in the form of white powder is obtained with a yield of 31%.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=[C:26]2[N:28]=N[N:30](O)[C:25]2=[CH:24]C=1.O.CCN=C=NCCCN(C)C.Cl.Cl.NC(C)C#N.CN1CCOCC1>CN(C=O)C>[C:26]([CH:25]([NH:30][C:13](=[O:15])[C@H:12]([N:9]1[C:8](=[O:19])[C:7]2=[CH:20][NH:21][C:5]3[C:6]2=[C:11]([C:2]([F:1])=[CH:3][N:4]=3)[CH2:10]1)[CH:16]([CH3:18])[CH3:17])[CH3:24])#[N:28]
Reactant: On1nnc2ccccc21
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CC(N)C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C#N)NC(=O)[C@@H](C(C)C)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 2-Aminopropanenitrile hydrochloride (8.23 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. Following reaction, the product was purified by preparative HPLC (10-55% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (11 mg, 62%). 1H NMR (500 MHz, DMSO-d6) δ 1.20-1.26 (m, 3H), 1.32-1.39 (m, 3H), 1.77-1.82 (m, 3H), 2.76-2.84 (m, 1H), 5.06-5.22 (m, 1H), 5.36-5.44 (m, 2H), 5.77 (dd, J=19.0, 2.0 Hz, 1H), 8.38 (dd, J=10.5, 2.0 Hz, 1H), 8.65 (t, J=3.0 Hz, 1H), 9.47 (d, J=2.0 Hz, 1H), 12.78 (br d, J=7.5 Hz, 1H). [M+H] calc'd for C17H18FN5O2, 344; found, 344.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(S)c(C)c1
Reactant: Fc1ccc(I)c(Br)c1
Product: Cc1ccc(Sc2ccc(F)cc2Br)c(C)c1

Procedure:
Prepared from 2,4-dimethyl-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: ClC(Cl)OC.[CH3:6][C:7]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[CH3:28])[N:8]=1.[CH:29]1([CH2:32]O)[CH2:31][CH2:30]1>>[CH3:6][C:7]1[C:11]([CH2:12][C:13]([O:15][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[O:14])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[CH3:28])[N:8]=1
Reactant: OCC1CC1
Reactant: Cc1ccncc1-n1nc(C)c(CC(=O)O)c1-c1ccccc1
Agent: COC(Cl)Cl
Product: Cc1ccncc1-n1nc(C)c(CC(=O)OCC2CC2)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
0.296 g (2.575 mmol) of dichloro(methoxy)methane was added to 0.175 g (0.569 mmol) [3-methyl-1-(4-methylpyridin-3-yl)-5-phenyl-1H-pyrazol-4-yl]acetic acid, and the mixture was stirred at 60° C. for 2 h. Excess dichloro(methoxy)methane was removed under reduced pressure, 0.660 g (9.153 mmol) of cyclopropylmethanol was added to the residue and the mixture was stirred at 20° C. for 0.5 h. The solvent was removed under reduced pressure, a mixture of 10 ml of dichloromethane, 1.5 ml of diisopropylethylamine and 10 ml of water was added to the residue and the aqueous phase was extracted with 15 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.123 g (59% of theory) of a colorless solid of m.p. 87° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:9][O:8][S:7](=[O:10])[N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:19].[Na+]>C(#N)C.O.O.[Ru](Cl)(Cl)Cl>[C:1]([C@H:5]1[CH2:9][O:8][S:7](=[O:19])(=[O:10])[N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)[C@H]1COS(=O)N1Cc1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a solution of (4S)-4-(tert-butyl)-3-(phenylmethyl)-1,2,3-oxathiazolidine-2-oxide (6.26 g, 24.71 mmol) in acetonitrile (30 mL) and water (30 mL) at 0° C. was added ruthenium chloride hydrate (5.13 mg, 0.025 mmol), followed by sodium periodate (7.93 g, 37.1 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 h, diluted with water, extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, filtered then concentrated to give the title compound (6.22 g) as an off-white solid. LCMS m/z=270.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.00 (s, 9H), 3.25-3.30 (m, 1H), 4.31-4.40 (m, 2H), 4.47 and 4.55 (dd, J=15.2 Hz, 2H), 7.30-7.48 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([O:20][C:22]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:28])[CH2:15]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCCC(O)C1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)OC1CCCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)C1
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A solution of 5-chloro-3-(3-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) in dry pyridine (2.5 ml) and dry tetrahydrofuran (50 ml) was cooled. To the solution was dropwise added a solution of succinic anhydride (1.1 g) in dry tetrahydrofuran (5 ml) under stirring. The mixture was refluxed for two hours and then left overnight. The solvent was evaporated off under vacuum from the reaction mixture. The residue was dissolved in 5% aqueous sodium bicarbonate (20 ml). The resultant solution was cooled and adjusted to pH 2 with 1% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and then recrystallized from isopropyl alcohol to yield the title compound as colorless crystals (2.0 g). m.p. 131°-133° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13]>CO.[Pd]>[OH:18][CH2:17][CH2:16][NH:15][S:12]([C:3]1[CH:2]=[CH:7][CH:6]=[C:5]([CH2:8][C:9](=[O:11])[CH3:10])[CH:4]=1)(=[O:14])=[O:13]
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)NCCO)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Cc1cccc(S(=O)(=O)NCCO)c1

Procedure:
2-Chloro-N-(2-hydroxy-ethyl)-5-(2-oxo-propyl)-benzenesulfonamide (43b) (1.22 g, 4.18 mmol) in methanol (150 ml) is stirred under an atmosphere of hydrogen in the presence of 10% Palladium on carbon (1 g) for 5 hours at room temperature. Filtration through celite and removal of the solvent affords the titled compound which is purified by chromatography on silica eluting with ethyl acetate-hexane (2:1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[S:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NCc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCc1ccsc1
Yield: 93.1 %

Procedure:
Using the same reaction conditions as those of Example 4, 3-(aminomethyl)thiophene hydrochloride (4 mmol), triethylamine (4.4 mmol) and dodecanoyl chloride (4.0 mmol) were reacted to give N-(3-thienylmethyl)dodecanamide (1.1 g, 92%) M.p. 83°-84° C. (Found: C, 68.9; H, 10.2; N, 4.8; S, 10.8. Calculated for C17H29NOS: C, 69.1; H, 9.8; N, 4.7; S, 10.9%); EI m/e Intensity (%): 295 (18, M+), 97 (46, C4H3S.CH2+); δH(CDCl3) 7.01-7.30 (3H, m), 5.80 (1H, br,s), 4.46 (2H, d), 2.20 (2H, t), 1.80 (2H, m), 1.25 (16H, m), 0.87 (3H, t);
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[N:16]=[CH:17][S:18][CH:19]=3)[N:14]=1)[N:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:52][O:53][C:54](=[O:58])[CH2:55][CH2:56][NH2:57].CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl.C1COCC1.CO>[CH3:52][O:53][C:54](=[O:58])[CH2:55][CH2:56][NH:57][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[N:16]=[CH:17][S:18][CH:19]=3)[N:14]=1)[N:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)CCN
Reactant: COC(=O)c1nc(-c2cscn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCNC(=O)c1nc(-c2cscn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-thiazol-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (64 mg, 0.14 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight. The mixture was concentrated to approximately one-third of its original volume, and the resulting mixture was acidified to pH about 3-4 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (30 mg, 0.22 mmol), CH2Cl2 (3 mL), and EDC (47 mg, 0.25 mmol), and the resulting mixture was stirred for 10 min. β-Alanine methyl ester HCl salt (31 mg, 0.22 mmol) and Hunig's base (0.1 mL, 0.49 mmol) were added, and the mixture was stirred for 16 h. EtOAc (30 mL) was added, and the mixture was washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH) to give 24 mg of the title compound. MS: (+) m/z 541.31 (M+1).
Reaction SMILES: CCCCCCC.[N+:8]([CH2:11][C@:12]1([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:18][C@@H:17]2[C@H:13]1[CH2:14][CH2:15][CH2:16]2)([O-:10])=[O:9].O1CCCC1.[OH-].[Na+]>O>[N+:8]([CH2:11][C@:12]1([CH2:19][C:20]([OH:22])=[O:21])[CH2:18][C@@H:17]2[C@H:13]1[CH2:14][CH2:15][CH2:16]2)([O-:10])=[O:9]
Reactant: CCOC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Reaction time: 16 h
Yield: 96.9 %

Procedure:
The n-heptane from the organic solution of the nitro ester of Example 7 (1.08 Kg; 4.49 mol) was replaced with tetrahydrofuran by azeotropic distillation at atmospheric pressure and constant volume. The solution was cooled to +25° C. and a solution of sodium hydroxide (0.359 Kg; 8.98 mol) in demineralised water (4.5 L) was added and the reaction stirred for 16 hours. n-Heptane (4.5 L) was added and the phases were separated. The aqueous phase was adjusted to pH 2–4 by the addition of concentrated hydrochloric acid (0.8 L) giving a suspension. The aqueous phase was extracted with ethyl acetate (9.6 L) to give the title product (0.928 Kg) in 97% yield as an organic solution which is used directly in the next step.