Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:32]([N:36]=[C:37]=[O:38])([CH2:34][CH3:35])[CH3:33]>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:37]([NH:36][CH:32]([CH2:34][CH3:35])[CH3:33])=[O:38])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: CCC(C)N=C=O
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and sec-butyl isocyanate (29 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (81 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C1(C)C(S([C:26]2([C:37]3C=CC=C[CH:38]=3)[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])(=O)=O)=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:38][CH2:37][C:26]4([C:2]5[CH:16]=[CH:15][CH:5]=[CH:4][CH:3]=5)[C:34](=[O:35])[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]4=[O:36])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1ccccc1S(=O)(=O)C1(c2ccccc2)C(=O)c2ccccc2C1=O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)C1(CCN1CCC(c2noc3cc(F)ccc23)CC1)c1ccccc1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.2 g, 10 mmol), K2O3 (1.6 g, 11.6 mmol) and 2-toluenesulfonyl-2-phenyl-1,3-indandione (4.2 g, 10 mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator. The residue was purified twice using a flash chromatography column (SiO2, 45 g and 40 g; eluted with DCM). The product thus purified was recrystallized from ethanol (30 ml) and isopropyl ether, yield: 2.8 g, m.p. 149°-150° C.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCNC(=O)[C@H]1CCCCN1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(R)-(+)-1-(tert-Butoxycarbonyl)-2-piperidinecarboxylic acid n-octyl amide (8) (1.00 g; 2.94 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added and the solution is stirred for 7 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3 times, 50 mL each). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (23) as a solid. ISMS: MH+ 240.8
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[O:26]=[C:20]([NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a mixture of quinolin-2-amine (200 mg, 1.4 mmol) and triethylamine (210 mg, 2.1 mmol) in dichloromethane (10 mL) was added dropwise ethyl 2-chloro-2-oxoacetate (227 mg, 1.67 mmol). After stirring for 1 hour at room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1% ethyl acetate in petroleum ether to afford ethyl 2-oxo-2-(quinolin-2-ylamino)acetate as yellow solid (210 mg, 62%). (ES, m/z): [M+H]+ 245.1; 1H NMR (400 MHz, CDCl3): δ 9.65 (br s, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.74-7.69 (m, 1H), 7.53-7.49 (m, 1H), 4.46 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[Si](C)(C)C.[BH4-].[Li+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH2:17][C:18]#[N:19]>O1CCCC1.CO>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[C:11]([CH2:17][CH2:18][NH2:19])[CH:12]=1
Reactant: COc1ccc(Cl)cc1CC#N
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1CCN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Chlorotrimethylsilane (2 mL, 16 mmol) was added dropwise to lithium borohydride (2M in tetrahydrofuran, 4 mL, 8 mmol). A solution of 2-methoxy-5-chlorophenylacetonitrile (312 mg, 4 mmol) in tetrahydrofuran (2 mL) was then added at 0° C. and the mixture was allowed to stir for 24 hours, whilst warming to room temperature. The mixture was then diluted with methanol (20 mL) and concentrated in vacuo. The residue was taken up in 20% potassium hydroxide solution (20 mL), extracted with dichloromethane (3×20 mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using an Isolute® SCX-2 cartridge, eluting with methanol followed by 1M ammonia in methanol, to give an oily residue. The oil was triturated with diethyl ether to afford the title compound, 485 mg.
Reaction SMILES: [N:1]1[NH:2][C:3]([NH:6][C:7]([C:9]2[C:14]([NH2:15])=[N:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11](Br)[N:10]=2)=[O:8])=[CH:4][CH:5]=1.[NH:21]([CH2:25]CO)[CH2:22]CO>CN(C=O)C>[N:1]1[NH:2][C:3]([NH:6][C:7]([C:9]2[C:14]([NH2:15])=[N:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([N:21]([CH3:25])[CH3:22])[N:10]=2)=[O:8])=[CH:4][CH:5]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1ccn[nH]1
Reactant: OCCNCCO
Solvent: CN(C)C=O
Product: CN(C)c1nc(C(=O)Nc2ccn[nH]2)c(N)nc1C(F)(F)F
Temperature: 100 °C

Procedure:
To a stirring solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2H-pyrazol-3-yl)-amide (Ex. 7)(50 mg, 0.142 mmol) in dry DMF (5 ml), diethanolamine (37.4 mg, 0.356 mmol) was added. The resulting solution was heated at 100° C. using microwave radiation for 66 hours. The reaction mixture was partitioned between EtOAc (20 ml) and water (20 ml), and the phases separated. The organic phase was washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo to give an orange solid. Purification of the crude product by chromatography on silica eluting with iso-hexane/EtOAc (gradient of 0 to 50% EtOAc) yielded the title compound as a yellow solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].Cl.[CH3:11]O>>[OH:3][C@@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:1]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](O)CC(C)C
Temperature: 25 °C

Procedure:
To a solution of L-leucic acid (1.33 g, 10 mmol) in methanol (20 mL) was added 12 N HCl (0.2 mL, 2.4 mmol) and the solution was refluxed for 3 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to afford methyl (2S)-2-hydroxy-4-methylpentanoate as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[N:4][N:3]=[N:2]1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl>N1C=CC=CC=1>[C:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[NH:1][N:2]=[N:3][N:4]=1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccccc1-c1nnn[nH]1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccccc1-c1nnn[nH]1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-(1H-Tetrazol-5-yl)phenol (4.86 g) was dissolved in pyridine (20 ml), and pivaloyl chloride (7.2 g) was added to the solution at room temperature. After being stirred for 15 h, the mixture was poured into ice water and acidified with dilute hydrochloric acid. The resulting crystals were collected by filtration and dried to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24]([C:29](=[O:31])[CH3:30])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[CH2:40]1[O:48][C:47]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=2[O:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:45]3[CH:44]=[CH:43][C:42]4[O:41][CH2:40][O:48][C:47]=4[CH:46]=3)[CH:25]=[C:24]([C:29](=[O:31])[CH3:30])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(C)=O)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Yield: 72.7 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-acetyl-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (303 mg, 0.5 mmol), 3,4-methylenedioxyphenylboronic acid (166 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (326 mg, 1.0 mmol) to obtain 4-[3-[6-(3-acetyl-5-benzo[1,3]-dioxol-5-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (235 mg, 73%) as a colorless oil: ES(+)-HRMS m/e calcd for C38H46O9 (M+Na)+ 669.3034. found 669.3031.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)c3ccccc3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and benzoyl chloride.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]=1[N+:16]([O-:18])=[O:17]>O1CCOCC1>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH:14]=[O:2])=[N:11][C:10]=2[C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[Se]=O
Reactant: COc1ccc2sc(C)nc2c1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc2sc(C=O)nc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h

Procedure:
12.8 g (0.115 mol; 6 equivalents) of selenium dioxide is added to 4.34 g (19.3 mmol) of 5-methoxy-2-methyl-4-nitro-1,3-benzothiazole in solution in 180 ml of anhydrous dioxane. The reaction mixture is stirred at 80° C. for 18 hours then the insoluble matter is filtered and the solvent is evaporated off under reduced pressure. The expected aldehyde is obtained in the form of a yellow oil and purified on a silica column (eluent:ethyl acetate/heptane:gradient of 30% to 70%). Melting point: 154-155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH2:11]([C:18]1[C:23]([Cl:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=1[Cl:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:15]2[CH:16]=[CH:17][C:12]([CH2:11][C:18]3[C:19]([Cl:28])=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][C:23]=3[Cl:24])=[CH:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cc2ccccc2)c(Cl)c1
Reactant: Cc1ccc(C(=O)Cl)cn1
Product: Cc1ccc(C(=O)c2ccc(Cc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2)cn1
Yield: 14.8 %

Procedure:
The title compound was prepared as pale yellow crystals at yield of 14.8%, in a similar manner as in Reference Eample 1, by the reaction of 6-methylnicotinoylchloride and 4-benzyl-3,5-dichloronitrobenzene.
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][N:11]2[C:12](=[O:30])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[C:20]1([NH:19][C:16]2[CH:17]=[C:18]3[C:13]([C:12](=[O:30])[N:11]4[CH2:31][CH2:32][NH:8][CH2:9][C@H:10]43)=[C:14]([C:26]([F:28])([F:29])[F:27])[CH:15]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Nc4ccccc4)cc3C(F)(F)F)[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(cc(Nc3ccccc3)cc2C(F)(F)F)[C@@H]2CNCCN12
Reaction time: 0.33 h
Yield: 50 %

Procedure:
The product from Step A was dissolved in trifluoroacetic acid (3 mL); after 20 min, the solution was concentrated and purified by preparative LC/MS chromatography (C18 column; 10-90% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (16 mg, 50%) as a pale yellow solid upon lypholization. MS (ESI) 348 (M−CF3CO2).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=1)[CH2:7][CH2:6]2.Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][CH2:21]3)=[CH:18][CH:19]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN(c1ccc(N3CCCN(C)CC3)cc1)C2=O
Agent: Br
Product: CN1CCCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2)CC1

Procedure:
6-Methoxy-2-[4-(4-methyl-[1,4]diazepan-1-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one was reacted with 48% HBr according to Method L1. In this way the product was obtained with molecular weight 351.45 (C21H25N3O2); MS (ESI): 352 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH3:27])[CH3:26]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 2-bromopropane (0.008 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 299 (M+, 3), 285 (15), 284 (bp), 205 (6) 133 (4).
Reaction SMILES: [Cl-:1].[NH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(O[Cl:20])(C)(C)C>CO.O>[Cl-:20].[Cl:1][N:2]([Cl:20])[C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(N)CC[N+]1(C)CCCCC1
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C)(CC[N+]1(C)CCCCC1)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-amino-3-methylbutyl)-1-methylpiperidinium chloride (1.00 g, 3.80 mmol) in a mixture of methanol (6 mL) and water (6 mL) was cooled in an ice bath for 15 min. t-BuOCl (1.3 mL, 3.0 equiv, 11.4 mmol) was added in one portion via syringe to the colorless solution to give a deep yellow solution. The reaction mixture was stirred for 30 min at 0° C. Then the methanol was removed under reduced pressure and the crude solid was purified via reverse phase chromatography on a Shimadzu Prep-LC utilizing water/methanol and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. Fractions were pooled and concentrated under reduced pressure at 25° C. to give a white solid, (0.92 g, 83%). 1H NMR (D2O, 400 MHz): δ 1.46 (s, 6H), 1.52-1.55 (m, 2H), 1.70-1.95 (m, 4H), 2.20-2.28 (m, 2H), 3.05 (s, 3H), 3.35-3.48 (m, 6H). LRMS (ESI+) for C11H23Cl2N2+ (253.1); Found: 253, 255 (M+, M2H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23](OS(C)(=O)=O)[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CN(C)C=O>[C:30]([S:32][CH:23]1[CH2:22][N:21]([C:18]2[S:19][CH:20]=[C:16]([C:14](=[O:15])[NH:13][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:11][CH3:12])[N:17]=2)[CH2:24]1)(=[O:33])[CH3:31]
Reactant: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.02 g, 2.20 mmol) (obtained as described in Reference Example 34(5)) in dimethylformamide (50 ml) was added potassium thioacetate (1.51 mg, 13.2 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→2:1) as the eluant to afford 3-acetylthio-1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (618 mg, yield 63%) as a pale brown oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].[H][H]>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:12][CH:10]([CH2:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7])[CH3:11]
Reactant: [H][H]
Reactant: CC(=O)C=CCC(C)CC(C)C
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CC(C)CC(C)CCCC(C)O
Temperature: 170 °C
Reaction time: 3 h

Procedure:
64 g of the foregoing ketone are hydrogenated in a stirring autoclave in the presence of 6 g of copper chromite and under 40 bar hydrogen pressure. The temperature is firstly brought to 140° C. When the hydrogen absorption slows down (after 3 hours), the autoclave is heated to 170° C. and held for 3 hours between 165° C. and 170° C. After cooling down to 25° C., the catalyst is filtered off under suction and the filtrate is distilled. There are obtained 56 g (85.4%) of chemically pure 2,4-dimethyl-nonan-8-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][O:16][C:15](=[O:18])[C@H:14]([CH2:19]C(O)=O)[C@@H:13]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C@H:12]([CH3:29])[O:11][C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[SH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N+:48]=1[O-].[Al]>C1COCC1>[C:24]([O:23][C@@H:13]1[C@@H:14]([CH2:19][S:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[C:15](=[O:18])[O:16][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:10](=[O:30])[O:11][C@H:12]1[CH3:29])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: [O-][n+]1ccccc1S
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Al]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CSc1ccccn1
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
To a solution of 2-((3S,7R,8R,9S)-3-(tert-butoxycarbonylamino)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)acetic acid (500 mg, 1.2 mmol) in anhydrous THF (7 mL) at −15° C. was added N-methylmorpholine (127 μL, 1.2 mmol) and isobutylchloroformate (152 μL, 1.2 mmol). The mixture was stirred for 5 min and then treated with a solution of 2-mercaptopyridine N-oxide (177 mg, 1.4 mmol) and TEA (162 μL, 1.2 mmol) in THF (2 mL). The reaction was stirred at −15° C. in the dark (covered with aluminum foil) for 1 h. The reaction was then filtered, concentrated, and the resulting bright yellow residue dissolved in CH2Cl2 (5 mL) and irradiated for 1 hr. The crude reaction mixture was concentrated and purified by flash chromatography (SiO2, 10% EtOAc/hexanes) to furnish the title compound (169 mg, 29%) as a fluffy white solid: mp 54-58° C.; IR (neat) 3370, 2980, 2939, 2878, 1753, 1718 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=4.9 Hz, 1H), 7.48-7.41 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.00-6.94 (m, 1H), 5.32 (bs, J=12.9 Hz, 1H), 5.21-5.07 (m, 2H), 4.87 (dt, J=16.1, 6.4 Hz, 2H), 3.66-3.60 (m, 1H), 3.59 (bs, 1H), 3.15-3.00 (m, 2H), 2.68 (dq, J=14.2, 7.1 Hz, 1H), 1.43 (s, 9H), 1.33-1.25 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 176.11, 171.91, 171.33, 157.67, 155.07, 149.73, 136.35, 122.89, 120.10, 81.00, 75.34, 74.76, 66.22, 51.66, 51.26, 34.68, 28.74, 28.64 (3), 19.38, 19.23, 18.14; ESIMS m/z 519 ([M+Na]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Na+].[OH-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.Cl>O.C(OCC)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:10]2[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)=[CH:26][CH:25]=1
Reactant: O=S(=O)([O-])c1ccc(NCc2ccc(F)cc2)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(O)c1ccc(N(Cc2ccc(F)cc2)Cc2ccc(Cl)cc2)cc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A mixture of 16.0 g (0.053 mole) of sodium 4-(((4-fluorophenyl)methyl)amino)benzenesulfonate in 200 ml of water, 4.5 g (0.053 mole) of 50 percent sodium hydroxide and 9.75 g (0.06 mole) of 4-chlorobenzyl chloride was stirred at about 85° C. for 20 hours. The reaction mixture was cooled and then treated with diethyl ether. The aqueous layer was heated and acidified with concentrated hydrochloric acid. A light tan powder precipitated. Recrystallization gave the product 4-(((4-chlorophenyl)methyl)((4-fluorophenyl)-methyl)amino)benzenesulfonic acid having a melting point greater than 250° C.