Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1.C(=O)(O)[O-].[Na+].[Na].[BH4-].[Na+].Cl.[H][H]>O>[SH:4][CH:5]([CH2:1][CH2:2][SH:3])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: O=C(O)CCCCC1CCSS1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Product: O=C(O)CCCCC(S)CCS
Reaction time: 0.33 h
Yield: 100 %

Procedure:
6,8-Bismercaptooctancoic acid: α-Lipoic acid (5.15 g, 25.0 mmol) was suspended in 125 mL of water and sodium bicarbonate (2.10 g, 25.0 mmol) added. The mixture was sonicated to generate the sodium salt. The resulting pale yellow solution was cooled in an ice bath and solid sodium borohydride (1.90 g, 50.0 mmol) added with stirring in small portions over 20 min. The solution was stirred at ice bath temperature another 30 min, and then at room temperature for 30 min. The cloudy solution was cooled in an ice bath, and the pH brought to about 1 by the slow addition of 2M hydrochloric acid. A vigorous evolution of hydrogen occurred as the excess sodium borohydride decomposed and an oily liquid separated. As much as possible the following operations were performed under nitrogen. The mixture was extracted with 3×50 mL of chloroform. The combined chloroform extracts were dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure at room temperature. The oil remaining was further dried under vacuum to remove the last traces of solvent. The 6,8-bismercaptooctanoic acid was isolated as a colorless oil weighing 5.2 g (100% yield). The product was stored at −20° under nitrogen.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:22][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH3:21])[N:11]=1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cl)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 37.8 %

Procedure:
5.0 g of methyl 2,6-dichloronicotinate was dissolved in ml of dimethylformamide, and 4.39 g of (S)-(−)-1-(4-fluorophenyl)ethylamine, 6.27 g of diisopropylethylamine and 150 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at 60° C. for 24 hours. The reaction solution was cooled, and then diluted with ethyl acetate, and washed in turn with water and brine, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 2.83 g of the objective compound as white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[Li+].[OH-]>C1COCC1>[F:22][C:21]1[C:20]([O:23][CH3:24])=[CH:19][C:18]([O:25][CH3:26])=[C:17]([F:27])[C:16]=1[C:13]1[C:12]2[N:11]=[CH:10][CH:9]=[N:8][C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Yield: 85.4 %

Procedure:
A mixture of 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (885 mg, 2.37 mmol) (Step 185.2), a 2N aqueous solution of LiOH (8 mL) and THF (8 mL) was stirred for 16 h at rt. THF was removed under vacuum. The resulting mixture was diluted with Et2O/H2O. The aqueous layer was separated and extracted with Et2O. The aqueous layer was acidified to pH 6 by addition of a 2N aqueous solution of HCl. The resulting yellow precipitate was collected by vacuum filtration and dried to provide 701 mg of the title compound: ESI-MS: 347 [M+H]+; tR=3.16 min (System 1)
Reaction SMILES: O[CH:2]([CH2:25][OH:26])[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C(OC)(OC)(OC)C.C(Br)(=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:23][O:22][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:24])[N:4]([CH2:3][CH:2]1[CH2:25][O:26]1)[C:13]([C:14]#[N:15])=[C:12]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(=O)n(CC(O)CO)c(C#N)c(-c3ccccc3)c2c1
Agent: CC(=O)Br
Agent: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: COc1ccc2c(=O)n(CC3CO3)c(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a room temperature suspension of diol 89 (352 mg, 1 mmol) and PPTS (12 mg, 0.05 mmol) in CH2Cl2 (10 mL) was added trimethyl orthoacetate (0.153 mL, 1.2 mmol). A clear solution resulted within 2 minutes. After stirring at RT for 3.5 h the reaction mixture was concentrated. The residue was dissolved in CH2Cl2 (10 mL) and acetyl bromide (0.089 mL, 1.2 mmol) added. After stirring at RT for 1.5 h the reaction mixture was concentrated. The residue was taken up in 2 mL MeOH (2 mL) to give an orange-brown suspension. K2CO3 (153 mg, 1.1 mol) was added and the resulting mixture stirred at room temperature for 2 h. It was then partitioned between sat NH4Cl and CH2Cl2. The aqueous phase was washed once more with CH2Cl2. The extracts were dried (MgSO4) and concentrated. The product 99 was purified by automated flash chromatography (40-80% EA/Hex).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(O)=O.CN.Cl.[BH3-][C:20]#[N:21].[Na+]>CO>[CH3:20][NH:21][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCC2(CC1)OCCO2
Reaction time: 2 h
Yield: 54 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (10.0 g, 64.10 mmol, 1.0 eq.) was dissolved in MeOH (100 ml); AcOH (0.1 ml) and CH3NH2.HCl (8.65 g, 128.21 mmol, 2.0 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (10.0 g, 160.256 mmol, 2.5 eq.) was added in portions at 0° C. and the mixture was then stirred for 16 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Alox, 5% MeOH in DCM). Yield: 54% (6.0 g, 35.08 mmol)
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].[N+](C1C=CC([O:25][C:26](=O)[O:27][CH2:28][N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][N:47]([C:50]5[C:58]6[CH:57]=[CH:56][S:55][C:54]=6[CH:53]=[CH:52][CH:51]=5)[CH2:46][CH2:45]4)[CH:37]=3)[CH:32]=[CH:31][C:30]2=[O:59])=CC=1)([O-])=O.O>C1COCC1>[CH2:1]([O:13][C:26](=[O:25])[O:27][CH2:28][N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][N:47]([C:50]4[C:58]5[CH:57]=[CH:56][S:55][C:54]=5[CH:53]=[CH:52][CH:51]=4)[CH2:46][CH2:45]3)[CH:37]=2)[CH:32]=[CH:31][C:30]1=[O:59])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCOC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Reaction time: 1 h
Yield: 39.5 %

Procedure:
1-Dodecanol (0.10 g) was dissolved in anhydrous THF (5 ml) under a nitrogen atmosphere and sodium hydride (about 55% oil) (25 mg) was added under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 30 min under a nitrogen atmosphere, and then the mixture was ice-cooled. To the mixture was added a solution (5 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester 4-nitrophenyl ester obtained in Example 133 (0.33 g) in anhydrous THF using a cannula. Under a nitrogen atmosphere, the reaction mixture was stirred with ice-cooling for 2 hr, and at room temperature for 1 hr. Water was added to the reaction mixture to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated by filtration. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (0.14 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.N1C=CC=CC=1.[CH2:37]=[C:38]1[O:41][C:40](=[O:42])[CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:23][C:40](=[O:42])[CH2:39][C:38](=[O:41])[CH3:37])([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (28 mg, 0.07 mmol), prepared as described in Procedure 3, 4, 5 and 6, in DCM (1 mL) was added pyridine (0.01 mL, 0.12 mmol). The reaction was cooled to 0° C., followed by the addition of 4-methyleneoxetan-2-one (0.01 mL, 0.13 mmol). The reaction mixture was stirred at rt for 2 h and concentrated. The residue was purified by preparative HPLC (Axia luna column, 30×75 mm, 40-100% ACN/H2O with 0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide (Example 251) as colorless oil (23 mg, 58% yield). LCMS: RT=3.71 min [M+H] 510.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (1H, s), 7.04-7.20 (5H, m), 6.96-7.02 (2H, m), 6.87-6.92 (3H, m), 6.61 (2H, d, J=7.07 Hz), 5.87 (1H, t, J=2.78 Hz), 3.94 (1 H, d, J=12.88 Hz), 3.71 (1H, d, J=12.88 Hz), 3.43 (2H, s), 2.24 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[CH:5][C:3]=1[OH:4].[C:11](O)(=[O:25])[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]>ClCCCl>[CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[C:5]([C:11](=[O:25])[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])[C:3]=1[OH:4]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: Cc1c(O)ccc(O)c1C
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)c1cc(O)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
93 g of 2,3-dimethyl-hydroquinone and 168 g of myristic acid were dissolved with stirring in 300 ml of 1,2-dichloroethane and heated to 80° C. Boron trifluoride was bubbled through for 4 h and stirring was continued at 80° C. for 2 h. The reaction mixture was poured into 1800 ml of water containing 200 g of dissolved sodium acetate. The organic layer was separated, washed with water and the solvent evaporated in a rotary evaporator. Any precipitate formed during washing should be filtered off and be recrystallized together with the residue after evaporation. The crystallization was effected from a mixture of 1,2-dichloroethane and benzine (1:1 by volume). Yield: 126 g. Melting point: 100° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[Br:9])[NH2:5].[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([Br:10])[C:8]=1[Br:9]
Reactant: Nc1cc(Br)c(Br)c(Br)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)c(Br)c(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Tribromoaniline was obtained by the procedure of L. F. Tietze and T. Eicher (L. F. Tietze, T. Eicher. Reaktionen und Synthesen im organisch-chemischen Praktikum und Forschungslaboratorium. (1991) Georg Thieme Verlag, Stuttgart, New York). 7.8 g (24 mmol) of 3,4,5-tribromoaniline were stirred with a solution of 6.5 mL of concentrated hydrochloric acid and 6.5 mL of water. The mixture was cooled to about −10° C. and at this temperature the solution of 2.76 g of NaNO2 in 11 mL of water was added for 20 min with intensive stirring. The reaction mixture was stirred for 30 min at −10° C. Then the cooled solution of 16.2 g of SnCl2·2H2O in 17 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water. The residue was resuspended in 50 mL of water and concentrated aqueous solution of NaOH was added to get alkaline medium. The 3,4,5-tribromophenylhydrazine was extracted with ether. Organic layer was dried with MgSO4 and ether was evaporated. Yield: 5.5 g (67%). 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.09 (2H, s, arom.), 7.34 (1H, s, NH), 4.19 (2H, d, NH2).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[O:19][CH:18]([CH2:20][OH:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.O.S(=O)(=O)(O)[OH:24]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[CH3:1][C:2]1[C:3]2[O:19][CH:18]([C:20]([OH:24])=[O:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1
Reactant: Cc1cc2c(-c3ccccc3)noc2c2c1OC(CO)C2
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc2c(-c3ccccc3)noc2c2c1OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A portion (4.5 g) of the 7,8-dihydro-5-methyl-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 9 was dissolved in 150 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (5.9 g), water (12 ml) and concentrated sulfuric acid (8.3 g) was added dropwise over time, and the resulting mixture was stirred for 2 hours at room temperature. After leaving the mixture to stand overnight, the insolubles were filtered off by suction. After distilling off the acetone, water was added and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water to yield 2.9 g of 7,8-dihydro-5-methyl-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7carboxylic acid. m.p. 210°-213° C. This compound exhibited a mass spectrum haivng a molecular ion peak at m/e 295.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]3[C:23](=[O:25])[N:22]([CH2:26][CH3:27])[CH2:21][C:20]([CH3:29])([CH3:28])[O:19][C:18]=3[N:17]=[C:16](S(C)(=O)=O)[N:15]=2)=[CH:10][C:9]=1[F:34])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C@H:37]1[CH2:42][O:41][CH2:40][CH2:39][NH:38]1>O1CCOCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]3[C:23](=[O:25])[N:22]([CH2:26][CH3:27])[CH2:21][C:20]([CH3:29])([CH3:28])[O:19][C:18]=3[N:17]=[C:16]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][C@@H:37]3[CH3:36])[N:15]=2)=[CH:10][C:9]=1[F:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1COCCN1
Reactant: CCN1CC(C)(C)Oc2nc(S(C)(=O)=O)nc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)c2C1=O
Solvent: C1COCCO1
Product: CCN1CC(C)(C)Oc2nc(N3CCOC[C@@H]3C)nc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)c2C1=O
Temperature: 100 °C
Yield: 35.5 %

Procedure:
2.5 g of [4-(6-ethyl-2-methanesulfonyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl)-2-fluorophenyl]carbamic acid tert-butyl ester (19.66 mmol) in 20 ml of dioxane are placed in 4 microwave tubes, respectively. One quarter of (S)-3-methylmorpholine (98.32 mmol) is added to each tube, respectively. The tubes are heated for 2 hours at 100° C. in a Biotage microwave machine. The reaction media are filtered and rinsed with MeOH. The solid is washed with water, with acetonitrile and then with pentane. 3.7 g of {4-[6-ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]-2-fluorophenyl}carbamic acid tert-butyl ester are obtained. The DMSO/MeOH phase is evaporated to dryness. The residue is taken up in water and filtered, rinsed with acetonitrile and then with pentane. This product is chromatographed on silica gel with a gradient of MeOH in DCM ranging from 0 to 5%. 1.7 g of {4-[6-ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]-2-fluorophenyl}carbamic acid tert-butyl ester are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:26])=[CH:22][CH:21]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2cncc(Cl)c2)cc1C(CC(C)C)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(-c2cncc(Cl)c2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A solution of 4-({1-[5-(5-chloropyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (199 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (225 mg, 93%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:23]([O:25]CC)=[O:24])[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:23]([OH:25])=[O:24])[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:23]([OH:25])=[O:24])[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCCN(CC)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCCN(CC)C2)cc1

Procedure:
3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidinecarboxylic acid 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidinecarboxylic acid was prepared starting from ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidinecarboxylate (3.2 g, 8.0 mmol) dissolved in THF:Methanol (15:25 ml) and NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 1 (step 7). Yield 2.11 g (71%), white solid: mp 159.2° C.; MS (ES): m/z 366.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.[I:38]I>C1C=CC=CC=1.S([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][I:38])=[CH:8][C:7]=1[CH3:14]
Reactant: II
Reactant: COC(=O)CCc1ccc(CO)cc1C
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(CI)cc1C
Temperature: 25 °C

Procedure:
A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (0.62 g, 2.98 mmol), triphenyl phosphine (0.86 g, 3.27 mmol) and dichloromethane (10 mL) is stirred at room temperature. A solution of iodine (0.83 g, 3.27 mmol) in benzene (5 mL) is added and the black mixture is stirred at room temperature 2 hr. The brown mixture is diluted with 10% aqueous sodium hydrogen sulfite (5 mL) and the resulting clear mixture is washed with ethyl acetate (3×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified via silica chromatography eluting with 9:1 hexanes:ethyl acetate to afford the title compound as a crystalline ivory solid, 0.68 g, 72%. MS M++1 319. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)[C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.S(OCC)(O[CH2:33][CH3:34])(=O)=O>O.CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16]/[C:17](/[N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[C:18](/[O:23][CH2:33][CH3:34])\[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)(C)C(=O)C(Oc1ccc(-c2ccc(Cl)cc2)cc1)n1ccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCO/C(=C(/Oc1ccc(-c2ccc(Cl)cc2)cc1)n1ccnc1)C(C)(C)C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
6 g of potassium hydroxide, dissolved in a little water, are added dropwise to 36.85 g (0.1 mole) of 1-(4'-chloro-4-biphenylyloxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one in 50 ml of dimethylsulphoxide. The mixture is subsequently stirred for a short time and 16 g (0.11 mole) of diethyl sulphate are then added dropwise. During this addition, the temperature of the reaction mixture is kept at about 40° C. and thereafter it was kept at 80° C. for 1/2 hour. It was allowed to cool, water is added and the crystalline precipitate is filtered off and recrystallised from petroleum ether. 22 g (50% of theory) of (E)-1-(4'-chloro-4-biphenylyloxy)-3,3-dimethyl-2-ethoxy-1-(imidazol-1-yl)-1-butene of melting point of 112°-113° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>C1COCC1>[CH3:35][C:32]([NH:31][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)([CH3:36])[CH2:33][OH:34]
Reactant: CC(C)(N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(C)CO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 72 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and 2-amino-2-methyl-1-propanol (94 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a light-yellow amorphous solid. mp 106-112°, LC MS m/z=437 (MH+) Retention time=1.94 min.