Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)C(C)C)(C)C.[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)=[O:17]>CN(C)C1C=CN=CC=1>[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:23])=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nccs1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(C(=O)Nc2nccs2)cc1
Yield: 54.6 %

Procedure:
In the same manner as that described in Example 2(1), a reaction was carried out using commercially available 2-aminothiazole (333 mg, 3.3 mmol), N,N-diisopropylethylamine (1.21 ml, 7.0 mmol), 4-formylbenzoyl chloride (468 mg, 2.8 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 2(1) to afford 4-formyl-N-(2-thiazolyl)benzamide (355 mg, yield 55%) as a pale yellow solid which was recrystallized from ethyl acetate-hexane to give pale yellow powdery crystals.
Reaction SMILES: CN(C)[CH2:3][CH:4]([CH3:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].S(=O)(=O)(O)O>>[F:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:5](=[O:6])[CH:4]([CH3:14])[CH2:3]2
Reactant: CC(CN(C)C)C(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC1Cc2cc(F)ccc2C1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 42 g. (0.20 mole) of 3-dimethylamino-4'-fluoro-2-methylpropiophenone and 100 ml. of concentrated sulfuric acid is warmed to 90°C over one hour and stirred at 90°C for two hours. The reaction is cooled and quenched in ice and the product extracted into toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]1([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH2:24][O:23][CH2:22]1>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:20][C:21]3([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH2:24][O:23][CH2:22]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)CC1(N)COC1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: CNC(=O)CC1(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-(3-aminooxetan-3-yl)-N-methyl-acetamide (example 231a) as starting materials and isolated (25 mg, 43%); MS (ESI, m/z): 402.6 (M+H+).
Reaction SMILES: C([O-])=O.[NH4+].C([NH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 90.2 %

Procedure:
10% Pd/C (wet, 1.1 g) and ammonium formate (2.87 g, 46 mmol) were added to a solution of tert-butyl cis(±)-4-(benzylamino)-3-(benzyloxy)piperidine-1-carboxylate obtained in Example (90c) (4.84 g, 11.4 mmol) in methanol (30 mL) in a nitrogen atmosphere, and the mixture was stirred at 70° C. for 40 minutes. The reaction solution was filtered to remove the Pd/C. Following concentration under reduced pressure, a 1 N aqueous sodium hydroxide solution was added to the residue, followed by extraction with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, to obtain 3.15 g of the crude title compound as a colorless oily substance (94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O>C1(C)C=CC=CC=1>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccccn1
Solvent: Cc1ccccc1
Product: c1ccc(CNc2ccccn2)nc1
Reaction time: 16 h

Procedure:
To a flask were added 4.7 g of 2-aminopyridine, 5.35 g of 2-pyridinecarboxaldehyde, and 75 ml toluene. The flask was equipped with a Dean-Stark trap and heated to reflux under nitrogen. After 16 hours, the toluene was removed and 100 ml ethanol were added followed by 2.1 g of sodium borohydride. The mixture was stirred at 22 C under nitrogen for 1 hour, and then 50 ml of water were added slowly. Following removal of the ethanol, aqueous ammonium chloride was cautiously added resulting in gas evolution. The product was extracted twice with 50 ml ethyl acetate and washed with 30 ml water. After solvent removal, the product was purified by silica gel chromatography using 5% methanol in ethyl acetate resulting in an orange oil.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]1[NH:27][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=2[N:26]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1cc(F)ccc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cc(F)ccc2F)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 78.2). Off-white solid. MS: m/e=336.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:25])[CH2:24][O:23][CH2:22]2)=[C:17]([O:26][CH3:27])[CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:25])[CH2:24][O:23][CH2:22]2)=[C:17]([O:26][CH3:27])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(O)COC4)c(OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1C1(O)COC1
Temperature: 70 °C
Yield: 17.5 %

Procedure:
To a mixture of methyl 6-chloro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carboxylate (100 mg, 0.258 mmol) in methanol (3 mL) and sodium hydroxide (1 M, 1.0 mL, 1.0 mmol) was heated to 70° C. for 24 hours. The reaction was concentrated under reduced pressure and the reaction was acidified with 1 M hydrochloric acid aqueous to pH=2 then diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate two additional times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure yielding 83 mg of the crude desired product. A portion of the crude material (60 mg) was purified by prep-HPLC (Phenomenex HILIC (Diol) 250×21.2 mm 5 μm; Mobile phase A: heptane; Mobile Phase B: Ethanol, gradient 95% A/5% B hold for 1.5 minutes, linear gradient to 0% A/100% B in 8.5 minutes, Hold at 0% A/100% B for 1 minutes; flow rate: 28 ml/min) to afford the title compound (16.9 mg, 17.5%) as a solid. MS (ES−) 372.0 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.13 (br. s, 1 H), 11.96 (br. s, 1 H), 8.10 (d, J=2.2 Hz, 1 H), 7.98 (s, 1 H), 7.65 (s, 1 H), 7.29 (d, J=7.8 Hz, 1 H), 7.05 (d, J=1.5 Hz, 1 H), 6.99 (dd, J=7.6, 1.5 Hz, 1 H), 5.89 (s, 1 H), 5.02 (d, J=6.8 Hz, 2 H), 4.67 (d, J=6.8 Hz, 2 H), 3.81 (s, 3 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Nc1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Nc1cccc(Cl)c1)C(=O)OCC
Reaction time: 3 h
Yield: 28.8 %

Procedure:
m-Chloroaniline (12.8 g) and diethyl bromomalonate (9.6 g) were dissolved in dry toluene (20 ml). The solution was heated under reflux with stirring for 3 hours. The reaction mixture was washed with dilute hydrochloric acid and then three times with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was washed with n-hexane to give 3.3 g (yield 29%) of diethyl m-chloroanilinomalonate having the following NMR data.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: C1CON(C2CCC3(CC2)OCCO3)C1
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2CCCO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(1,4-dioxaspiro[4.5]decan-8-yl)isoxazolidine (350 mg, 1.64 mmol) from above step A, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (x4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)Cc1ccc(OCCCBr)c(F)c1

Procedure:
A solution of methyl 3-fluoro-4-hydroxyphenylacetate (25.545 grams) in 2-butanone (300 mL) was treated with 1,3-dibromopropane (48.79 mL) and potassium carbonate (50.859 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was chromatographed over silica gel with hexane/methylene chloride (2:1) to afford the title compound. This compound was taken forward without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].[Li+].CC([N-]C(C)C)C.CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:34][CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[Si:38]([O:37][CH2:36][CH2:35][CH2:34][CH2:8][C:6]1[O:5][C:4](=[O:9])[C:3]([C:10](=[O:13])[CH2:11][CH3:12])=[C:2]([OH:1])[CH:7]=1)([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CCC(=O)c1c(O)cc(C)oc1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1c(O)cc(CCCCO[Si](C)(C)C(C)(C)C)oc1=O
Reaction time: 1 h

Procedure:
To 4-hydroxy-6-methyl-3-propionyl-2H-pyran-2-one (XII; 7 g, 38.5 mmol) in 60 ml anhydrous THF at −72° C. under argon, was added freshly prepared LDA (18.5 ml DIPEA in 150 ml THF with 52 ml 2.5 M n-butyllithium, Aldrich) in 150 ml anhydrous THF, and 20 ml HMPA (Aldrich). The reaction mixture was stirred for 1 h. 3-bromopropoxy-t-butyldimethylsilane (7 ml g; 27.7 mmol; Aldrich) in 50 ml anhydrous THF was added over 30 min, and stirred for an additional 5 min. The reaction mixture was quenched with saturated NH4Cl, extracted with 3×150 ml EtOAc, dried with brine and anhydrous Na2SO4, and evaporated to a yellowish oil. The product was purified via silica flash chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[N:18]1[C:25](Cl)=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>CC(C)=O.O>[Cl:20][C:19]1[N:18]=[C:25]([NH:8][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)[N:24]=[C:22]([NH:8][CH:6]2[CH2:7][C:2]([CH3:11])([CH3:1])[NH:3][C:4]([CH3:10])([CH3:9])[CH2:5]2)[N:21]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
62.4 g of 2,2,6,6-tetramethyl-4-amino-piperidine in 200 ml of acetone and, at the same time, 42.4 g of sodium carbonate dissolved in 100 ml of water are added to a finely dispersed suspension of cyanuric chloride, prepared by adding 36.9 g of the latter in 200 ml of boiling acetone to 400 ml of ice water. The temperature is kept at 0°-5° C. by means of external cooling. After the addition is complete, the reaction mixture is allowed slowly to warm to room temperature and is stirred at this temperature for 3 hours. Filtering and recrystallisation of the product from ethyl acetate/hexane gives 46.3 g of a white crystalline product, melting point 270° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:34])[CH2:20][CH2:21][N:22]([CH3:33])[C:23]1[S:24][C:25]2[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:32][C:30]3[CH:29]=[CH:28][C:26]4[N:27]=[C:23]([N:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:34])[CH3:33])[S:24][C:25]=4[CH:31]=3)=[O:15])=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(OCC2CCCCC2)cc1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(OCC4CCCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following Method A, using 4-cyclohexylmethoxy-benzoic acid (Crooks, S. L.; Merrill, B. A.; Wightman, P. D. WO 9603983 A1.) (0.20 g, 0.86 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.17 g, 0.68 mmol) to afford 0.12 g (38%). LC/MS: Retention time=5.67 min; (m/z): calcd for C26H34N4O2S (M+H)+: 467.7; found: 467.0.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:15])[C:10]=2[Br:14])[CH:5]1[CH2:16][C:17]([O:19]C)=O)(=[O:3])[CH3:2].C([N:24]1C=CC2C(=CC=C(F)C=2Br)C1CC(OC)=O)(=O)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Br:14][C:10]1[C:9]([F:15])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:24][C:17](=[O:19])[CH:16]=[C:5]12
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2C=CN1C(C)=O
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. A stirred solution of methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate (70.6 g, 206 mmol), triethylsilane (176 g, 1517 mmol) and trifluoroacetic acid (121 mL, 1568 mmol) in 1,2-dichloroethane (500 mL) was stirred at 80° C. for 3.5 h. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. The remaining volatile components were evaporated under high vacuo and 40° C. bath temperature. To the resulting yellow residue saturated aqueous NaHCO3 (500 mL) was added while stirring and the mixture was extracted with DCM (3×400 mL). The organic layer was washed with saturated aqueous NaHCO3 (250 mL) and brine (200 mL). The organic layer was treated with charcoal, then dried with sodium sulfate, filtered through a pad of Hyflo and the solvent was removed under reduced pressure. The crude product was crystallized from diethyl ether (200 mL) to yield the title compound as white crystals (47.6 g). UPLC-MS: MS 344.1/346.1 (M+H+); UPLC rt 0.95 min.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([OH:30])(=[O:29])[CH:26]([CH3:28])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH:26]([C:25]([OH:30])=[O:29])[CH3:28])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)C(=O)O
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCC2CCCCC2)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-(8-cyclohexyloctylamino)-benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated Å Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][C:30](O)=[O:31])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].S.[S:36](=O)(=O)(O)O>C(Cl)Cl>[N+:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:31])=[S:36])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.4 g (40 mmol) of triethylamine and a solution of 2.8 ml (2 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise, in succession, to a solution, cooled to -10°, of 5.36 g (20 mmol) of 3-p-nitrobenzyloxycarbonylaminopropionic acid in 100 l of dry methylene chloride. The reaction mixture is stirred for one hour at -18°, then for 11/2 hours a strong current of hydrogen sulphide is passed through and the mixture allowed to heat up to room temperature. After acidifying with 2 N sulphuric acid, again in the cold, the organic phase is separated, dried and concentrated in vacuo. The 3-p-nitrobenzyloxycarbonylaminothiopropionic acid obtained can be used without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].Cl>C(O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([O-:19])=[O:18]
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
To 250 ml of an aqueous solution containing 73.5 g of phenol and 31.2 g of sodium hydroxide was added 50.0 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide, followed by reflux for 5 hours. To the ice-cooled reaction solution were successively added 50 ml of 36% hydrochloric acid and 200 ml of ethanol with stirring. The precipitate was collected by filtration, successively washed with ethanol and water, and air-dried to give 52.2 g of N-(5-nitro-2-phenoxyphenyl)methanesulfonamide as yellow prisms.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4](=[O:15])(=[O:14])[N:3]1[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:4](=[O:15])(=[O:14])[N:3]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:32][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[O:23])=[CH:24][CH:25]=1
Reactant: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(C(=O)O)cc1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 4-[[(3S)-3-methyl-1,1-dioxo-6-phenyl-thiazinan-2-yl]methyl]benzoic acid Stereoisomer A (75 mg, 0.21 mmol), tetrahydropyran-4-amine (64 mg, 0.63 mmol) and triethylamine (0.12 mL, 0.83 mmol) in N,N-dimethylformamide (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg, 0.31 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was then partitioned between dichloromethane and saturated sodium bicarbonate in water. The organic layer was separated, concentrated and purified by preparative HPLC to give 4-(((3S)-3-methyl-1,1-dioxido-6-phenyl-1,2-thiazinan-2-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide Stereoisomer A (66.4 mg, 0.15 mmol, 72% yield). 1H NMR (400 MHz, DMSO) δ 8.27-8.19 (d, J=7.7 Hz, 1H), 7.85-7.77 (m, 2H), 7.50-7.43 (m, 4H), 7.43-7.34 (m, 3H), 4.64-4.53 (m, 1H), 4.47-4.33 (m, 2H), 4.18-4.06 (m, 1H), 4.06-3.93 (m, 1H), 3.91-3.81 (m, 2H), 3.46-3.33 (m, 2H), 2.48-2.37 (m, 1H), 2.17-2.08 (m, 1H), 1.92-1.69 (m, 3H), 1.70-1.50 (m, 3H), 1.11-1.02 (d, J=6.9 Hz, 3H); LCMS [M+1]+=443.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22])[CH3:5].[CH3:24][NH2:25]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:25][CH3:24])[S:7]1(=[O:22])=[O:23]
Reactant: CN
Reactant: CC(CCBr)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Product: CNCCC(C)N1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.04 g, 0.09 mmol) was dissolved in 2 mL of MeNH2 solution (8M in EtOH). The solution was irradiated in a microwave cuvette at 100° C. for 3 minutes. The reaction mixture was concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-10% 7M ammonia/MeOH solution in dichloromethane) to afford 44 mg of 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:12]=2[CH2:14]O)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:21][O:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)=[O:24]>>[CH3:21][O:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]2[N:29]([CH2:14][C:12]3[CH:11]=[C:10]([O:16][C:17]([F:20])([F:19])[F:18])[CH:9]=[C:8]4[C:13]=3[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7]4)[CH:30]=[N:31][C:27]=2[CH:26]=1)=[O:24]
Reactant: CC(C)Cn1ncc2cc(OC(F)(F)F)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Product: COC(=O)c1ccc2c(c1)ncn2Cc1cc(OC(F)(F)F)cc2cnn(CC(C)C)c12
Yield: 65 %

Procedure:
Compound 40 was prepared following general method 3A, using compound 21 as a starting material and 1H-benzoimidazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 65%.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11].[OH-].[Li+].Cl>O1CCOCC1.O>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCCCCCCCF
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCCCCCF
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of methyl 9-fluorononanoate (17.1 g, 90 mmol) in 1,4-dioxane (45 mL) was treated drop-wise with a solution of lithium hydroxide (2.4 g, 100 mmol) in water (15 mL). The reaction mixture was stirred at ambient temperature until no starting material remained by thin layer chromatography. The reaction mixture was acidified to pH 1.0 with 2N hydrochloric acid and extracted with diethyl ether. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, through a short pad of silica gel, and the filtrate evaporated in vacuo to yield 9-fluorononanoic acid (12.75 g, 72 mmol) as a clear, colorless oil, which solidified on standing in the refrigerator. The product was used without further purification.