Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[CH2:4][CH:5]([N:7]([CH2:9][CH2:10][C:11]([O:13]C)=O)[CH3:8])[CH3:6].CCN(CC)CC.O>C(Cl)Cl.[Cl-].[Na+].O.Cl[Ti](Cl)(Cl)Cl>[CH3:8][N:7]1[CH2:9][CH2:10][C:11](=[O:13])[CH2:6][CH:5]1[CH3:4]
Reactant: COC(=O)CCN(C)C(C)CC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CC(=O)CCN1C
Temperature: -15 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A 1 M solution of TiCl4 in CH2Cl2 (23 mL, 23 mmol, 1.0 equiv) was added to a flask under Ar and cooled to −15° C. with a MeOH/ice water bath. 3-[(2-Methoxycarbonyl-ethyl)-methyl-amino]-butyric acid methyl ester (5 g, 23 mmol, 1.0 equiv) was added dropwise over a 25 min period as a solution in 75 mL of dry CH2Cl2 to give a dark red mixture that was difficult to stir with a magnetic stir bar. Stirring was continued an additional 1 h and then Et3N (5.1 g, 50.6 mmol, 2.2 equiv) was added dropwise over a 30 min period and then the reaction was stirred an additional 1.5 h at −15° C. The reaction mix was poured into 150 mL of brine and 150 mL of CH2Cl2 was added. After thorough mixing, the pH of the water was brought to 8-9 with Et3N. The mix was filtered and the gel-like solid was washed 3×100 mL CH2Cl2. The filtrate layers were separated and the aqueous layer was washed 3×50 mL CH2Cl2. All of the organic layers were combined and concentrated to a thick red oil. The residue was taken up in 150 mL of concentrated HCl and the solution was refluxed 4 h. The cooled reaction solution was evaporated to dryness and the residue was dissolved in 200 mL of saturated sodium bicarbonate solution. The product ketone was extracted with 2×100 mL of EtOAc. The organic layers were combined and dried over Na2SO4. The product was purified by flash chromatography on SiO2 using pure CH2Cl2 to 4% MeOH in CH2Cl2 as eluent. The product was isolated as an orange oil (1.23 g, 42%); MS, m/z 128=M+1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]([O:26][CH3:27])[O:24][CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:25][O:24][CH:23]([O:26][CH3:27])[C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Reactant: COC(OC)c1ccncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(OC)c1ccncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Yield: 98.7 %

Procedure:
Using analogous conditions as described for the preparation of Example 1A above, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-4-d: 505.4 mg, 2.3503 mmol) was reacted with 3-Bromo-4-dimethoxymethyl-pyridine (I-52a: 600 mg, 2.5854 mmol), 1,4-dioxane (20 mL), copper iodide (44.6 mg, 0.2348 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (80.9 mg, 0.7052 mmol) and potassium phosphate (1.49 g, 7.0507 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 850 mg of the product (98.8% yield).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:7][CH2:8][CH2:9][C:10](O)=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:6][C:10](=[O:11])[CH2:9][CH2:8][SH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: O=C(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCS)OC1CCCC1
Reaction time: 8 h

Procedure:
Into a 1 liter reaction flask equipped with heating mantle, stirrer, thermometer and reflux condenser are placed 172 grams of cyclopentanol; 265 grams of 3-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and reflux is continued for a period of 8 hours. At the end of the 8 hour period, the reaction mass is fractionally distilled on a 2" splash column yielding the following fractions:
Reaction SMILES: Cl[C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[NH:7][CH:8]1[CH2:10][CH2:9]1.[C:16]([O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1)([CH3:19])([CH3:18])[CH3:17].N12CCCN=C1CCCCC2>O.C(OCC)(=O)C>[CH:8]1([NH:7][C:6]2[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([F:15])=[C:2]([N:23]3[CH:24]=[CH:25][CH:26]=[C:22]3[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27])[CH:11]=2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1cccn1-c1cc(NC2CC2)c([N+](=O)[O-])cc1F
Yield: 13 %

Procedure:
5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (460 mg, 2 mmol) is heated to 80° for 40 hours with L-proline tert-butyl ester (342 mg, 2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (304 mg, 2 mmol). The reaction mixture is then dissolved in a water/ethyl acetate mixture (1:1, 100 ml). The ethyl acetate phase is washed with 10 percent sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel (eluent: hexane/ethyl acetate 8:2). The product is crystallized from ether/n-hexane. There are obtained 94 mg (13%) of tert-butyl rac-1-[5-(cyclopropylamino)-2-fluoro-4-nitro-phenyl]pyrrole-2-carboxylate with a m.p. of 142°-143°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1.[CH:17]1([C:20](=[S:22])[NH2:21])[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]([C:4]1[N:21]=[C:20]([CH:17]2[CH2:19][CH2:18]2)[S:22][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)c(F)c1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccc(C)c(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-4-methyl-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.06 min; [M+H]+=292.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-])=O)[CH:9]=2)[CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[NH2:18])[CH2:3]1
Reactant: CN1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Oc2cc(N)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
Add Pd/C (10%, 400 mg) to the solution of 1-methyl-3-(3-nitro-5-(trifluoromethyl) phenoxy)pyrrolidine (1.54 g, 5.31 mmol) in methanol (10 mL). Stir the mixture under hydrogen atmosphere at room temperature for 15 hrs. Filter off the solid and concentrate the filtrate to give crude product. Purify by flash chromatography (silica gel, EtOAc:PE=1:1) to afford the target compound (900 mg, 65%). MS: (M+1): 261.1.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([I:13])[C:5]=1[OH:14])(=[O:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([I:13])[C:5]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(C#N)c(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(C(C)=O)cc(C)c(C#N)c1I
Temperature: 60 °C
Yield: 93.3 %

Procedure:
The 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile (5.0 g, 17 mmol) was dissolved in N,N-dimethylformamide (50 mL) and the potassium carbonate (4.6 g, 33 mmol) and methyl iodide (2.1 mL, 33 mmol) were added. The reaction was heated to 60° C. and monitored by LC/MS. After heating for 2 hrs the reaction was complete. This was allowed to cool, diluted with ethyl acetate (300 mL) and filtered to remove the remaining solids. The organic layer was washed with water (3×), brine, dried over magnesium sulfate and concentrated to give the crude product as a dark solid. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-3-methoxy-2-iodo-6-methylbenzonitrile as a pale yellow crystalline solid (5.0 g, 96%). LCMS calculated for C11H11INO2 (M+H)+: m/z=315.9; found: 316.0.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].Cl.[NH2:33]O.Cl>CO.CO.O.O.C(OCC)(=O)C>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:9]2)[O:7][NH:33]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A solution of trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)-piperidine-1-carboxylate (1.8 g, 4.33 mmol) (from example 107, step 1) in MeOH (7 mL) was added to a solution of NaOH (225 mg, 5.63 mmol) in MeOH/H2O (8 mL/0.5 mL) at −30° C. After 10 min hydroxylamine hydrochloride (0.602 g, 8.67 mmol) and NaOH (347 mg, 8.67 mmol) were added in MeOH (7 mL) and H2O (7 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (60 mL) at 80° C. and heated for 30 min. The reaction mixture was dissolved between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Purification using prepLC (pH=3, large column 25-55% MeCN over 20 min) Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.06 g, 63.6%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.49-2.17 (m, 4H), 2.80-3.22 (m, 4H), 3.34-3.76 (m, 3H), 4.07-4.40 (m, 1H), 4.52-4.84 (m, 1H), 5.65 (s, 1H), 7.28-7.54 (m, 4H). MS m/z 385 (M+H)+
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CN1C(=O)CCC1>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(O)cc2s1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1nc2ccc(Oc3ccnc4ccccc34)cc2s1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 79.7 %

Procedure:
To the reaction mixture of 2-(methylthio)benzo[d]thiazol-6-ol (750 mg, 3.79 mmol) in 10 ml of NMP was added Cesium Carbonate (3.2 g, 9.5 mmol) and stirred at RT for 3 minutes. To this mixture was added 4-chloroquinoline (682 mg, 4.17 mmol). The reaction mixture was stirred at 110° C. for 24 hours. The reaction was worked up by adding 250 ml ethyl acetate and washed with 75 ml of saturated NaHCO3, 2×60 ml water, 1×50 ml saturated NaCl, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting solid residue was purified by silica gel column chromatography, eluted with (40% EtOAc: 60% Hexanes) and concentrated in vaccuo to give 2-(methylthio)-6-(quinolin-4-yloxy)benzo[d]thiazole as solid (980 mg). ES/MS m/z 325.1 (MH+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH2:38]([O:45][CH2:46][N:47]1[N:51]=[N:50][C:49]([Sn](CCCC)(CCCC)CCCC)=[N:48]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:49]3[N:50]=[N:51][N:47]([CH2:46][O:45][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:48]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4nnn(COCc5ccccc5)n4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and (2-benzyloxymethyl-2H-tetrazol-5-yl)tri-n-butyltin (see Tetrahedron Lett. (2000) 2805) were treated in a manner similar to Example 128-(5) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzene as colorless solid. APCI-Mass m/Z 727/729 (M+H). (2) A mixture of 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzene (247 mg), 6M aqueous hydrochloric acid solution (2 ml) and methanol (20 ml) was refluxed overnight. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene (172 mg) as colorless powder. ESI-Mass m/Z 437/439 (M−H).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC(C(O)=O)=N1.N1C=CC=CC=1.[NH2:36][C:37]1[C:45]([CH3:46])=[CH:44][C:43]([Cl:47])=[CH:42][C:38]=1[C:39](O)=[O:40]>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:39](=[O:40])[C:38]3[CH:42]=[C:43]([Cl:47])[CH:44]=[C:45]([CH3:46])[C:37]=3[N:36]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Agent: O=C(O)c1cc[nH]n1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 5, Step 1D) (3.02 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 1 Step A) (1.86 g, mmol) and pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with more acetonitrile (5 mL). The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise over 5 minutes at a temperature of −5 to 0° C. The reaction mixture was stirred minutes more at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (20 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and dried under nitrogen to afford the title product as a light yellow powder, 4.07 g (90.2% crude yield), melting at 203-205° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 95.7% of total chromatogram peak area.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[CH2:6][CH:5]([C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[C:11]=3[CH:10]=2)[CH2:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[C:11]=3[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1C(=O)CC(c2ccc3oc4c(c3c2)CCCC4)CC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CN1CCC(c2ccc3oc4c(c3c2)CCCC4)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.97 g (0.01 mol) of N-methyl-3-(6,7,8,9-tetrahydro-2-dibenzofuranyl)-glutarimide are added in portions to a suspension of 7.6 g (0.020 mol) of lithium aluminium hydride in 50 ml of anhydrous ester in the course of 10 minutes at room temperature. The reaction mixture is stirred at room temperature for 3 hours and thereafter cooled to 0° and excess reducing agent is decomposed by adding 0.74 ml of water, 0.74 ml of 2 N sodium hydroxide solution and thereafter 22.4 ml of water. After 30 minutes, the mixture is filtered through diatomaceous earth, and the filtrate is dried over sodium sulfate and evaporated to dryness under a waterpump vacuum. The crude 1-methyl-4-(6,7,8,9-tetrahydro-2-dibenzofuranyl)-piperidine thereby obtained is dissolved in methanol and, by addition of an ethereal solution of hydrogen chloride, its hydrochloride is precipitated in the form of white crystals melting at 279°-281°.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[CH:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([S:33]([NH:36][C:37]2[S:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])[CH:27]=1.N1C=CC=CC=1>C(Cl)Cl>[S:41]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:36][S:33]([C:28]1[CH:27]=[CH:26][C:31]([NH:32][C:15](=[O:17])[CH2:14][O:13][C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)=[CH:30][CH:29]=1)(=[O:35])=[O:34]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C(O)COc1ccnc2c(C(F)(F)F)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(COc1ccnc2c(C(F)(F)F)cccc12)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
(8-Trifluoromethylquinolin-4-yloxy)-acetic acid (0.50 g, 1.84 mmol) was suspended in 20 mL DCM with rapid stirring. At rt, oxalyl chloride (0.19 mL, 1.2 equiv) was added dropwise and stirring continued for 4 h. Solvent and excess oxalyl chloride were removed in vacuo, the white residue was re-suspended in DCM, and the mixture cooled to 0° C. N′-(2-thiazolyl)sulfanilamide (0.47 g, 1.0 equiv) was added followed by pyridine (0.30 mL, 2.0 equiv). The mixture was allowed to warm to rt overnight. The solid was collected and rinsed with fresh DCM. Further purification was effected by suspending the solid in 20 mL methanol, stirring vigorously for 4 h, and filtration. After drying under vacuum, white solid 0.65 g (69%) was obtained. 1H-NMR (DMSO-d6) 5.11 (s, 2H), 6.79 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 7.22 (d, J=4.8 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.85 (d, J=5.2 Hz, 1H), 13C-NMR (DMSO-d6) δ8.0, 103.6, 108.8, 120.0, 122.0, 124.8 (q, J=270 Hz), 125.1, 125.4, 126.4 (q, J=33 Hz), 127.7, 127.8, 129.2, 137.7, 142.1, 145.6, 153.2, 161.2, 166.5, 169.4 LC/MS (10-99%) M/Z: M+1 obs=509.5; tR=3.13 min.
Reaction SMILES: [OH:1][CH:2]([CH2:19][OH:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=O.C=CCCCCCCCCCCCCCCCC>>[CH2:19]([OH:20])[CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)CCCCCCCCCCCCCC(O)CO
Agent: C=CCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCC(O)CO

Procedure:
The bioconversion of 1,2-hexadecanediol was tested following the procedures set forth in Example 24. This substrate was tested to demonstrate the ability to form a (ω,ω-1)-dihydroxy fatty acid. Recovery was 0.138 g from 0.253 g starting material (54.5% recovery). NMR shows the 1,2-diol to be unchanged, as expected from olefin studies. But, interestingly, CH3 oxidation to the 15,16-dihydroxyhexadecanoic acid was lower than seen with octadecene, because the starting material was solid. Conversion was only about 30%. Some fatty unsaturation and minor polypropylene glycol were also seen. Since the NMR results were fairly convincing, no GC/MS analysis was performed.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][CH2:10][C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cnc(CCc2c(-c3ccc(F)cn3)noc2C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid methyl ester (1.27 g, 3.66 mmol) in THF (9 mL) was added a solution of lithium hydroxide monohydrate (307 mg, 7.31 mmol) in water (9 mL) and the resulting mixture stirred at room temperature for 2 h. The mixture was then evaporated to half volume and then acidified to pH 1 with HCl (1 N) and cooled to 0° C. for 15 min. A solid precipitated and was filtered off and dried to afford the title compound (707 mg, 58%) which was obtained as an off white solid after recrystallization from ethyl acetate. MS: m/e=332.3 [M−H]−.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH:7]([CH2:9][C:10]([NH2:12])=[O:11])[CH3:8].C(=O)(O)[O-].[Na+].Cl>C1C=CC=CC=1.O>[Cl:1][CH2:2][C:3]([N:7]([CH2:9][C:10]([NH2:12])=[O:11])[CH3:8])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CN(CC(N)=O)C(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
A solution of chloroacetyl chloride (0.1 mole, 11.3 g) in benzene (40 ml) was added over 30 min to a mixture of sarcosinamide hydrochloride (0.1 mole, 12.45 g) and sodium bicarbonate (0.25 mole, 20.0 g) in 40 ml of water. The mixture was vigorously stirred for 3 h at room temperature. The aqueous phase was acidified with 5M hydrochloric acid to pH 5 and extracted with ethyl acetate (3×400 ml). The combined extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The solid residue obtained was recrystallized from ethanol-ether to give 8.5 g (52%) of the title compound. Mp 85°-86° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11].C(=O)(O)[O-].[Na+]>>[NH2:1][C:2]1[C:7]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cnc(N)c(S(=O)(=O)Cl)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
Solid 2-amino-5-picoline (10.8 g, 0.10 mol) was added portionwise to chlorosulfonic acid (66 mL, 1.0 mol) at ambient temperature over 5 minutes. When the addition was complete, the mixture was warmed to 140° C. and stirred at that temperature for 2 hours. During the heating period gas evolution was initially rapid and ceased completely after 2 hours. The mixture was then cooled to room temperature and poured onto 2 liters of ice. Solid sodium bicarbonate was added to the resulting solution to adjust the pH to about 7.0. The solid product that precipitated was collected and rinsed with a small amount of cold ethanol. The solid was then dissolved in one liter of hot chloroform, the resulting solution was dried (magnesium sulfate), and the solution was concentrated to a volume of about 100 mL. The solid product that formed was collected, the mother liquor was concentrated to 20 mL and a second crop was collected. The solid products were combined to give the title compound (14.4 g, 70 %); m.p. 16°-166° C.