Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]([CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:5]([N:7]1[CH2:11][CH2:10][S:9][CH2:8]1)=[O:6])=[N+]=[N-].C(NC(C)C)(C)C.[I:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[I:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:14]2[CH2:15][CH2:16][CH:12]([C@H:4]([NH2:1])[C:5](=[O:6])[N:7]3[CH2:11][CH2:10][S:9][CH2:8]3)[CH2:13]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)N1CCSC1)C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCSC1)C1CCN(S(=O)(=O)c2ccc(I)cc2)C1
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 28 mg (0.1 mmol) of 3-[(2S)-2-azido-2-pyrrolidin-3-ylethanoyl]-1,3-thiazolidine in methylene chloride (1 mL) was added 0.030 mL of diisopropylamine and 29 mg (0.12 mmol ) of 4-iodobenzenesulfonyl chloride. The mixture was stirred for 18 h and subjected directly to preparative TLC on silica gel (eluent: 60% ethyl acetate in hexanes) to give the desired sulfonamide (40 mg) as an off white solid. This solid was dissolved in wet THF (10%) and 25 mg (0.1 mmol) of triphenyl phosphine was added and stirred at 60° C. for 5 h and concentrated. A mixture of diastereomers were separated by preparative TLC on silca gel (10% methanol in CH2Cl2). Diastereomer I (faster moving isomer) 1H NMR (500 MHz, CDCl3) δ 7.9 (d, 2H, J=8.1 Hz), 7.52 (d, 2H, J=8.1 Hz), 4.65–4.47 (m, 2H), 3.86 (m, 1H), 3.78 9 (dd, 1H, J=6 and 8 Hz), 3.43 (m, 1H), 3.25–3.02 (m, 4H), 2.4 (m, 1H), 1.95 (m, 2H). Diastereomer II (slower moving isomer) 1H NMR (500 MHz, CDCl3) δ 7.91 (d, 2H, J=8.2 Hz), 7.56 (d, 2H, J=8.2 Hz), 4.63–4.41 (m, 2H), 3.86 (m, 1H), 3.79 (m, 0.5H), 3.64 (m, 0.5H), 3.37 (m, 3H), 3.25 (dd, 1H, J=10 and 14 Hz), 3.12 (m, 2H), 3.01 (t, 1H, J=4.4 Hz), 2.4 (m, 1H), 1.94 (m, 1H), 1.61 (m, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[CH2:2][CH2:3][CH3:4].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][O:25][CH2:26][C:27]([NH2:29])=[NH:28])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:29][C:27](=[NH:28])[CH2:26][O:25][CH2:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: N=C(N)COCCc1cccc(Cl)c1
Reactant: CCCCc1cnc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cccc(Cl)c2)c1

Procedure:
In analogy to the procedure described in example 78.3, 5-butyl-2-chloro-nicotinic acid was reacted with 2-[2-(3-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 79.2) in the presence of TBTU and DIPEA to give 5-butyl-2-chloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as yellow oil. MS: m/e=408.3 [M+H+].
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH:40][C:41]2[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=2[F:48])=[O:33])[CH2:28][CH2:27]1.O>CS(C)=O>[F:48][C:42]1[CH:43]=[C:44]([I:47])[CH:45]=[CH:46][C:41]=1[NH:40][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][C:34]=1[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=2)[CH2:27][CH2:28]1)=[O:33]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: NC1CCN(C(=O)c2ccncc2Nc2ccc(I)cc2F)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(CC(=O)NC2CCN(C(=O)c3ccncc3Nc3ccc(I)cc3F)CC2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 109.2 %

Procedure:
A mixture of p-tolyl acetic acid (0.027 g, 0.180 mmol) and CDI (0.036 g, 0.222 mmol) in dry DMSO (2 mL) was heated to 50° C. for 2 h prior to addition of 4-[(4-aminopiperidin-1-yl)carbonyl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine hydrochloride (described above) (0.052 g, 0.109 mmol). The contents were then stirred at room temp. After 6 h, HPLC indicated near-complete reaction. The contents were poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organics were washed with brine (2×30 mL), dried over sodium sulfate and concentrated to a yellow oil. The oil was further dried under high vacuum for 2 h at 40° C. to provide the desired product as a yellow semi-solid (0.068 g, 0.119 mmol, 66%). LC/MS [8.92 min; 573 (M+1)]
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=CC2C=CC=CC=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]=[O+][O-]>ClCCl.CO>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:19]([OH:35])[CH2:18][O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:9](=[O:34])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: O=[O+][O-]
Reactant: O=C(N[C@H]1CC[C@H](OCC(=Cc2ccccc2)c2ccccc2F)CC1)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](OCC(O)c2ccccc2F)CC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of 41 g of trans-[4-(2-(2-fluorophenyl)-3-phenyl-allyloxy)-cyclohexyl]-carbamic acid benzyl ester in 750 mL of dichloromethane and 250 mL of methanol cooled to −78° C. was dispersed a stream of ozone from an ozone generator until a blue color persisted. The excess ozone was purged with nitrogen until the blue color dissipated, and 7.8 g of sodium borohydride was added. After warming to room temperature over 30 min, the solution was diluted with 50 mL of water and concentrated under reduced pressure. The residue was treated with 500 mL of 3N hydrochloric acid and extracted into 3×500 mL of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-30% ethyl acetate in hexane gave 30 g of product as a white crystalline solid: MS (m+1)=388.4; 1H NMR (400 MHz, CDCl3) 7.53 (m, 1H), 7.33 (m, 5H), 7.25 (m, 1H), 7.14 (m, 1H), 7.0 (m, 1H), 5.15 (d, 1H), 5.07 (s, 2H), 4.6 (m, 1H), 3.7 (d, 1H), 3.5 (br m, 1H), 3.4 (t, 1H), 3.3 (m, 1H), 2.9 (s, 1H), 2.0 (m, 4H), 1.2 (q, 2H), 1.15 (q, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[N:1]1([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1
Reactant: C1=CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Into a solution of 1,2,3,6-tetrahydropyridine (1.00 g, 12.0 mmol) and triethylamine (3 mL) in CH2Cl2 (30 mL), benzoyl chloride (1.69 g, 12.0 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hrs and washed with saturated Na2CO3 (20 mL×3) and brine solution (20 mL), dried over Na2SO4 and concentrated under vacuum to afford crude product. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (10/3, v/v) to afford target product as a colorless oil (2.27 g, 100%). 1H NMR (CDCl3): δ 2.16-2.25 (m, 2H), 3.46-4.20 (m, 4H), 5.53-5.91 (m, 2H), 7.29-7.53 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:9][Br:11])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1C
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1C(=O)CBr
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
A solution of 13.42 g of ortho-methylacetophenone in 15 ml of acetic acid was treated with 15.98 g of bromine in 15 ml acetic acid. After being kept at ca 100° C. for 90 minutes, the mixture was poured into 300 ml water and extracted with ether. Removal of solvent from the dried (MgSO4) extract provided 19.70 g of residual oil, which by GLC was 75% pure. This crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH3:31])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH3:31])[C:42](=[O:43])[O:44][CH3:45])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 18 h
Yield: 17 %

Procedure:
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials, 217 mg) and DIPEA (0.2 ml) were stirred in DCM (20 ml). Methyl chloroformate (0.043 ml) was added slowly and the resulting solution was stirred for 18 hours. The solution was evaporated and the residue purified by chromatography, eluting with increasing concentrations of methanol in ethyl acetate (5-10%). The appropriate fractions were evaporated to give an oil, which was triturated with acetonitrile to give the title compound as a solid (43 mg, 17%); NMR spectrum (DMSO-d6 @ 373K) 2.88 (s, 3H), 3.30 (s, 3H), 3.75-3.85 (t, 2H), 4.35-4.55 (bs, 2H), 5.30 (s, 2H), 7.10-7.30 (m, 2H), 7.30-7.40 (m, 2H), 7.50-7.60 (m, 2H), 7.70-7.78 (t, 1H), 7.80-7.95 (m, 2H), 8.43 (bs, 1H), 8.75-8.80 (d, 1H), 9.60-9.80 (bs, 1H); Mass spectrum MH+ 494.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:11][CH:10]=1
Reactant: COc1ccc(O)cc1
Reactant: BrCCCCBr
Product: COc1ccc(OCCCCBr)cc1
Yield: 82 %

Procedure:
Condensation of 1,4-dibromobutane with 4-methoxyphenol according to A. M. Ismaiel et al. (J Med Chem (1993) 36, 2519-25) gives an 82% yield of 1-(4-methoxyphenoxy)-4-bromobutane. By condensing 670 mg (2.58 mmol) of this derivative with 700 mg (2.35 mmol) of N-methyl-N-[4-piperidyl]-4H-3,1-benzothiazin-2-amine, obtained in Example 16-2, in 8 ml of dry DMF in the presence of 630 mg (5.8 mmol) of 98 Na2CO3 /02 KI according to the procedure of Example 16-3, the compound of formula 22 is prepared in a yield of 58%: ##STR46##
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10]>>[Cl:1][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=1[OH:10]
Reactant: ClCl
Reactant: Oc1ccccc1F
Product: Oc1c(F)cccc1Cl

Procedure:
4 g (56 mmol) of chlorine is introduced at this temperature. Then 60.5 g (540 mmol) of 2-fluorophenol are dropped in the solution over about 2 hours, while at the same rate 42 g (590 mmol) more chlorine is Introduced. After that 4 g more chlorine are introduced to complete the chlorination.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:9]([C:10]#[N:11])=[CH:8][C:7]([C:12](=[O:18])[CH2:13][NH:14][CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[Br:19]>O1CCCC1.O>[NH2:3][C:4]1[C:9]([C:10]#[N:11])=[CH:8][C:7]([CH:12]([OH:18])[CH2:13][NH:14][CH:15]2[CH2:16][CH2:17]2)=[CH:6][C:5]=1[Br:19]
Reactant: N#Cc1cc(C(=O)CNC2CC2)cc(Br)c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(O)CNC2CC2)cc(Br)c1N
Reaction time: 1 h

Procedure:
3 gm of sodium borohydride were added at room temperature to a solution of 7.5 gm of 4'-amino-3'-bromo-5'-cyano-2-cyclopropylamino-acetophenone in 200 ml of tetrahydro-furan and 100 ml of water, and the mixture was stirred for one hour. Thereafter, the excess sodium borohydride was destroyed by addition of acetone. The insoluble part of the mixture was filtered off, and the solvents were distilled out of the filtrate in vacuo. The residue was dissolved in hot isopropanol, and the hydrochloride of 1-(4'-amino-3'-bromo-5'-cyano-phenyl)-2-cyclopropylanino-ethanol was precipitated by addition of isopropanolic hydrochloric acid, and recrystallized from isopropanol. M.p. 190°-193° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([SH:10])=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=O>>[CH2:20]([S:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[C:18]#[CH:17]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCSc1ccc([N+](=O)[O-])cn1

Procedure:
7 g of 5-nitro-pyridine-2-thiol are suspended in acetone, and 5 g of potassium carbonate are added. There are then added 6 g of 3-bromopropine-1, and, after the exothermic reaction has finished, the reaction mixture is refluxed for about 30 minutes. The solution obtained is poured onto ice, and the precipitate occurring is filtered off. The crude product is purified by recrystallisation from methanol to yield 2-propargylthio-5-nitropyridine, m.p. 98°-99.5° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:10][CH:11]=1)C.[OH-].[K+].Cl>C(O)C.C(OCC)(=O)C>[CH2:12]([C:9]1[S:10][CH:11]=[C:7]([CH2:2][C:1]([OH:4])=[O:3])[N:8]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCc1nc(CC)cs1
Reactant: CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCc1nc(CC(=O)O)cs1

Procedure:
Ethyl-2-tridecyl-thiazole acetate (2.13 g, 6.35 mmol) and potassium hydroxide (0.39 g, 6.98 mmol) were refluxed overnight in ethanol (200 mL). The mixture was then acidified with 1M HCl and the precipitate filtered to give a solid which was dissolved in ethyl acetate and washed with brine, dried (MgSO4), filtered concentrated, and triturated with hexanes. The solid was filtered and air dried to yield 0.75 g, 37%. %C,H,N(found): C, 66.16; H, 9.50; N 3.99.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(=O)([O-])O.[Na+]>O1CCCC1>[OH:12][C:11]1[C:3]([NH:2][C:21](=[O:23])[CH3:22])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: Nc1ccc2c(c1O)C(=O)CC2
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1O)C(=O)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
6-Amino-7-hydroxyindan-1-one hydrobromide (800 mg, 3.28 mmol) was suspended in tetrahydrofuran (20 mL), triethylamine (571 μL, 4.10 mmol) and acetic anhydride (387 μL, 4.10 mmol) were added, and the mixture was stirred at room temperature for 1.5 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=60/40→100/0) to give the title compound (481 mg, yield 71%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:19]([C:15]1[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Fc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cccnc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.1 %

Procedure:
To a freshly prepared solution of lithium diisopropylamide (22 mmol) in dry THF (20 mL) under nitrogen and cooled to −78° was added a solution of 2-fluoropyridine (1.94 g, 20 mmol) in dry THF (10 mL). The reaction was stirred for 2.5 h at −78° before adding a solution of N-methoxy-N-methyl benzamide (3.47 g, 21 mmol) in THF (8 mL). The reaction mixture was allowed to warm to room temperature over 1.5 h and stir at room temperature for 1 h. The reaction was quenched with water (50 mL), extracted with EtOAc (2×50 mL), the extracts dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (5–20% EtOAc in isohexane) to give the title compound as a colourless oil (1.05 g, 26%). δH (CDCl3) 8.44 (1H, ddd, J 4.9, 2.0, 1.1 Hz), 8.06 (1H, ddd, J 9.3, 7.4, 2.0 Hz), 7.84 (2H, dm, J 8.4 Hz), 7.66 (1H, tt, J 7.4, 1.3 Hz), 7.52 (2H, tm, J 7.8 Hz), 7.38 (1H, ddd, J 6.8, 4.9, 1.9 Hz). LCMS (ES+) RT 3.27 minutes, 202 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:22][C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCCCCC(=O)C(CC(=O)OCC)NC(=O)c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCc1oc(-c2ccc(Cl)cc2)nc1CC(=O)OCC
Yield: 84.3 %

Procedure:
2.0 g of ethyl 3-(4-chlorobenzoylamino)-3-caproylpropionate, 10 ml of dimethylformamide and 1.0 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.6 g of ethyl 2-[2-(4-chlorophenyl)-5-n-pentyl-4-oxazolyl]acetate are thereby obtained. Yield: 84.2%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:44]=1)[CH2:8][C:9]1([CH2:19][CH2:20][CH2:21][S:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14](=[O:15])[O:13]C(C)(C)[O:11][C:10]1=[O:18])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:44]=1)[CH2:8][C:9]([CH2:19][CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:10]([OH:18])=[O:11])[C:14]([OH:15])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CC2(CCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC(C)(C)OC2=O)cc(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)C(=O)O)cc(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 5-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2,2-dimethyl-5-[3-[(triphenylmethyl)thio]propyl]-[1,3]dioxane-4,6-dione X (11 g, 16.5 mmol) in 1,4-dioxane (15 ml) was added a solution of sodium hydroxide (4.63 g, 115.5 mmol) in H2O (15 mL) at 25° C., and the mixture was stirred at 100° C. for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and a 10% aqueous KHSO4 solution. The organic layer was dried over MgSO4, concentrated. The crude material was recrystallized from ethyl acetate/hexane mixture to afford 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2-[3-[(triphenyl-methyl)thio]propyl]malonic acid XI (9.0 g, 90%) as a white solid: 1H NMR (CD3OD) δ 1.4 (s, 9H), 1.4 (m, 2H), 1.6 (m, 2H), 2.1 (t, J=8.0 Hz, 2H), 3.2 (s, 2H), 7.1-7.4 (m, 16H), 7.7 (s, 1H), 7.9 (s, 1H); 13C NMR (CD3OD) δ 24.8, 31.8 (3C), 32.4, 33.3, 35.6, 39.0, 59.5, 67.7, 126.2, 127.7, 128.9, 129.6, 130.7, 131.5, 132.9, 137.8, 146.2, 152.6, 170.1, 174.5.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:28]([CH:29]=3)=[C:27](F)[CH:26]=[CH:25][C:24]=4[CH3:31])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.C1OCCOCCOCCOCCOC1>C1COCC1.CS(C)=O>[CH:1]1([O:6][C:27]2[CH:26]=[CH:25][C:24]([CH3:31])=[C:23]3[C:28]=2[CH:29]=[C:20]([NH:19][CH:16]2[CH2:17][CH2:18][C:13]4([O:12][CH2:11][CH2:10][O:9]4)[CH2:14][CH2:15]2)[N:21]=[CH:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Cc1ccc(F)c2cc(NC3CCC4(CC3)OCCO4)ncc12
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(OC2CCCC2)c2cc(NC3CCC4(CC3)OCCO4)ncc12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
In a dry box, in a microwave test tube cyclopentanol (600.0 mg, 7.0 mmol) was dissolved in 5 ml of THF. To this solution was added the NaH (273.0 mg, 11.4 mmol) at room temperature and the mixture was stirred for 30 min. N-1,4-dioxaspiro[4.5]dec-8-yl-5-fluoro-8-methylisoquinolin-3-amine (1.8 g, 5.7 mmol) mixed with 15-crown-5 ether (0.13 g, 0.57 mmol) in 15 ml of DMSO was added to above solution. The microwave test tube was capped and moved out from the dry box. The tube was placed into Microwave apparatus and heated to 140° C. for 2 hours. The crude product was purified using a silica gel column to give 263.0 mg (yield 53%). 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.89 (m, 1H), 1.17-1.40 (m, 2H), 1.57-2.02 (m, 10H), 2.05-2.29 (m, 2H), 2.47-2.63 (m, 3H), 3.54-3.78 (m, 1H), 3.90-4.06 (m, 4H), 4.64-5.02 (m, 2H), 6.46-6.77 (m, 1H), 6.79-6.98 (m, 2H), 7.20-7.43 (m, 1H), 8.91 (s, 1H). MS m/z, (APCI); 383.2 ([M+H]+).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9](OCCC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:11][CH2:10][N:9]([CH2:32][CH2:31][O:30][C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(OCCc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylic acid ethyl ester (2.5 g, 5.76 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (56%); off white powder; mp 204° C.; MS: 462.5 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:18]([O:36][CH3:37])=[C:19]([NH:21][C:22]([C:24]3[N:25]=[N:26][C:27]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:28][CH:29]=3)=[O:23])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:38]([C:17]1[C:18]([O:36][CH3:37])=[C:19]([NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([NH:30][CH2:31][C:32]([F:35])([F:33])[F:34])=[CH:28][CH:29]=2)=[O:23])[CH:20]=[C:15]([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: COc1c(NC(=O)c2ccc(NCC(F)(F)F)nn2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)nn2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
step 3—To a solution of 314 (0.029 g, 0.1 mmol) in MeOH (5.0 mL) and EtOAc (4.0 mL) was added Pd(OH)2 (0.005 g). The solution was stirred under 1 atm of H2. After 18 h the mixture was filtered through a pad of CELITE and the filtrate concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (1% to 10% MeOH) to 0.018 g (74%) of I-248 as an oil: MS (CI) mz/=476 (M+H).