Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:10]([NH:12][CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])=[O:11])=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[NH2:8][C@@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:10]([NH:12][CH2:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of (2S)-2-(tert-butoxycarbonylamino)-N-[2-[4-(4-chlorophenyl)-1-piperazinyl]-2-oxoethyl]-3-(2-pyridyl)-propanamide (42 g) in methanol (84 ml) was added 4N hydrogen chloride in ethyl acetate (209 ml) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and diluted with ethyl acetate. The resulting solid was collected by filtration and washed with ethyl acetate. The solid was poured into aqueous sodium hydrogencarbonate solution and the mixture was extracted with chloroform. The aqueous layer was extracted twice with chloroform. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a crude product of the title compound (27 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.N1C=CC=CC=1>[CH:26]1([C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:25][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]5[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)C4CCCCC4)ncc3[nH]2)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCC4)cc3)[nH]c2cn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a stirring solution of 10 (0.080 g, 0.24 mmol) in dry THF/Pyridine (10 ml/0.300 ml) cyclohexane carbonyl chloride (0.060 ml, 0.38 mmol) was added and stirred at room temperature for 4 h. The reaction mixture was quenched with water and stirred for 30 min. The yellow solid was filtered, dried, and purified through a bed of SiO2 gel. Elution with ethyl acetate afforded the desired product 11 as light yellow solid 0.055 g (51%). Mp. 235° C.; 1HNMR (DMSO-d; 500 MHz): δ 12.99 (1H, brs, NH), 10.27 (1H, brs, NH), 10.07 (1H, brs, NH), 8.61 (1H, brs), 8.27 (1H, brs), 8.07 (2H, d, J=8.0 Hz), 7.79 (2H, d, J=9.0 Hz); 2.52 (1H, m), 2.36 (1H, m), 1.83-1.17 (20H, m); EIMS m/z: 446.5 (M+1) 444.6 (M−1); Anal. (C26H31N5O2.0.91H2O) C, H, N
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([CH3:17])([CH3:16])[CH2:5]1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[C:6]([CH3:17])([CH3:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
1.46 g of 10% palladium on charcoal, 8.8 g of 1-acetyl-3,3-dimethyl-6-nitroindoline obtained in stage e) below and 110 mL of ethanol are placed in a hydrogenation reactor. After reacting for one hour 10 minutes at 3 bar at a temperature of 25° C., the reaction medium is filtered through paper and concentrated under reduced pressure to give 6.9 g of 1-acetyl-3,3-dimethylindolin-6-amine in the form of a brown solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:14]([NH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COC(=O)CCNS(=O)(=O)c1ccccc1

Procedure:
N-(phenylsulfonyl)-β-alanine, methyl ester (23) was prepared from methyl β-alaninate and phenylsulfonyl chloride on a 32 mmol scale in the manner described above in Example 13 to yield 6.76 g (86%) product. Analysis calculated for C10H13NO4S (M.W. 243.28): C, 49.37; H, 5.39; N, 5.76; S, 13.18. Found: C, 49.06; H, 5.46; N, 5.78; S, 12.95.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:22][C:23](=[S:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[S:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80.9 %

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-methoxyphenyl)-2-(phenylthioacetylamino)pyrazine (c-17) (114 mg, 267 μmol) was dissolved in anhydrous dichloromethane (2 mL), and then cooled to 0° C. To this was added 1.0 M solution of boron tribromide in dichloromethane (1.35 mL, 1.35 mmol) and stirred for 3.5 h after warming to room temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction and concentrated under reduced pressure with a rotary evaporator to remove dichloromethane. The suspension was filtered and the residue was dried to give 105 mg of the crude product as a red solid, which was purified by silica gel chromatography (8.2 g, n-hexane/ethyl acetate=3/2) to give 3-benzyl-5-(4-hydroxyphenyl)-2-(phenylthioacetylamino)pyrazine (h-coelenterathioamide) (c-14) as an orange solid (88.9 mg, 80.9%). Rf=0.21 (n-hexane/ethyl acetate=3/2). Mp. 195-198° C. UV (MeOH) λmax (log ε) 336.5 (4.24), 297 (4.18), 273.5 (4.26). UV (pH 7.4 PB) λmax (log ε) 336.5 (4.12), 270 (4.20). 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 2H), 4.13 (s, 2H), 6.84-6.90 (AA′BB′, 2H), 6.99 (d, J=7.1 Hz, 2H), 7.10-7.24 (m, 3H), 7.26 (t, J=7.1 Hz, 1H), 7.36 (t, J=7.1 Hz, 2H), 7.50 (d, J=7.1 Hz, 2H), 7.93-7.99 (AA′BB′, 2H), 8.91 (s, 1H), 9.94 (s, 1H), 12.17 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 39.4, 51.6, 115.9 (2C), 126.1, 126.3, 127.0, 128.3 (2C), 128.36 (2C), 126.44 (2C), 128.9 (2C), 129.0 (2C), 136.9, 137.6, 138.1, 144.6, 150.0, 152.0, 159.5, 204.5. IR (KBr, cm−1) 702, 839, 1140, 1169, 1207, 1234, 1283, 1319, 1360, 1435, 1450, 1472, 1491, 1522, 1607, 3069, 3478. HRMS (FAB+) m/z 412.1490 (M+H, C25H22N3OS requires 412.1484).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[NH3:12]>O.CO>[ClH:11].[ClH:1].[CH3:2][O:3][C:4]1[C:9]([CH2:10][NH2:12])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: N
Reactant: COc1ncccc1CCl
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ncccc1CN
Temperature: 35 °C
Reaction time: 1 h

Procedure:
15.1 g of 2-methoxy-3-picolyl chloride hydrochloride (77.76 mmol) were slowly added dropwise to a mixture of 600 ml of 30% strength ammonia solution in water and 250 ml of methanol at 35° C. while continuously passing in gaseous ammonia. After the solution had been stirred at 35° C. for 1 h it was concentrated under reduced pressure in a rotary evaporator, the residue was made alkaline with 20% strength NaOH solution (water phases were kept small) and extracted several times with DCM, and the org. phases were dried over magnesium sulfate and concentrated under reduced pressure in a rotary evaporator. The residue was taken up in ether and, after addition of ethereal hydrochloric acid, filtration with suction and washing of the precipitate with ether, 11.0 g (67%) of 2-methoxy-3-picolylamine.2HCl were obtained as white crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[C:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:29]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][NH:28][C:2]2[N:10]=[C:9]([NH:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: Clc1nc(NCCN2CCCCC2)nc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(CNc2nc(NCCN3CCCCC3)nc3[nH]cnc23)c2ccccc2)cc1

Procedure:
A mixture of Intermediate 38 (5.000 g, 17.8 mmol), 2,2-diphenylethylamine (5.200 g, 27 mmol) and N,N-diisopropylethylamine (6.2 ml, 36 mmol) in isopropanol (100 ml) was heated to reflux overnight. Upon cooling the solvent was removed in vacuo and the residue was purified using flash column chromatography with a Biotage column (90 g, SiO2) eluting with 5% methanol/chloroform/1% ammonia gave the title compound as an off white solid (4.500 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C=O)=[N:4][C:3]=1[CH2:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]C=O)=[CH:14][CH:13]=1.Cl.CO>O1CCCC1>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([CH2:10][S:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:4]=1
Reactant: O=CNc1ccc(SCc2nc(NC=O)sc2Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(SCc2nc(N)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
A solution of 5-chloro-2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (3.5 g) in a mixture of concentrated hydrochloric acid (9 ml), methanol (30 ml) and tetrahydrofuran (30 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8 using aqueous sodium bicarbonate with stirring under ice cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-(4-aminophenylthiomethyl)-5-chlorothiazole (2.3 g, yield: 79.3%). mp: 158°-163° C. (dec.)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH-:12].[Cs+]>C(OCC)(=O)C.CCCCCCC>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:12]
Reactant: [OH-]
Reactant: Brc1ccc2ccccc2c1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Oc1ccc2ccccc2c1
Yield: 88 %

Procedure:
Following general operating mode B, 2-bromonaphthalene (207 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a white solid with a yield of 88% (eluent: ethyl acetat/heptane 20:80).
Reaction SMILES: C([O:3][C:4](=[O:25])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[C:17]=2[F:23])=[CH:12][C:11]1=[O:24])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+]>O1CCCC1>[Br:22][C:18]1[C:17]([F:23])=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:25])=[O:3])[C:11](=[O:24])[CH:12]=1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(Br)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(Br)c2F)=CC1=O
Temperature: 15 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
To a solution containing (S)-2-[4-(3-bromo-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.260 g, 0.63 mmol) in tetrahydrofuran (8 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 3 mL, 1.5 mmol). The mixture was stirred at 15° C. for 3 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-bromo-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid, (0.250 g, 100%), as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH2:8]([O:10][C:11]([C:13]1[C:14](=[O:36])[C:15]2[CH:20]=[N:19][C:18](S(C)(=O)=O)=[N:17][C:16]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[C:14](=[O:36])[C:15]2[CH:20]=[N:19][C:18]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[N:17][C:16]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=[O:12])[CH3:9]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN(C)C)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(Step F) the title compound was prepared from N1,N1-dimethyl-propane-1,3-diamine (4.6 μL, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 15 mg, 0.036 mmol). 9.7 mg of 2-(3-dimethylamino-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.46 (s, 1H), 7.34 (d, 1H), 7.23 (s, 1H), 7.13 (d, 1H), 6.77 (br, 1H), (m, 2H), 2.99 (m, 4H), 2.19 (m, 10H), 1.60 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H29N5O3: 436.23 (M+H). Found: 436.4.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[S:4][CH:3]=1.Cl.[NH2:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:15](=[O:16])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:9])[S:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)c1cc(Br)cs1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Br)cs1

Procedure:
Compound a was prepared by coupling commercially available 3-bromothiophene-5-carboxylic acid with 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) using the method described in Example 128 to afford a tan solid. HPLC Ret time=3.01 min. LCMS [M+H]+ 379.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:19][C:20]([OH:22])=O)[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[C:20](=[O:22])[CH2:19][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)(=[O:10])=[O:9])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCNCc1cccc(C)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C)cn2)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cn1

Procedure:
prepared by reaction of [(5-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14](=[O:17])[NH:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[OH:16][NH:15][C:14]([C:11]1([S:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:23][CH:24]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:17]
Reactant: CC#CCOc1ccc(SC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC#CCOc1ccc(SC2(C(=O)NO)CCNCC2)cc1

Procedure:
4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1-carboxylic acid tert-butyl ester, prepared by the method outlined in Example 14 (Step 3) (0.175 g, 0.4 mmol), was treated with 4N hydrochloric acid in dioxane (5 mL) at 25 ° C. for 1 h 15 min. The reaction mixture was concentrated in vacuo, diethyl ether was added and the resulting precipitate isolated by filtration to give 4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide as a white solid (0.12 g). Electrospray Mass Spectroscopy: ((M+H)+=321)
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]([CH:37]3[CH2:38][CH2:39]3)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(c1cccc(CBr)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OC(C)(C)C)c2)c1)C1CC1
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2-(tert-butoxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (96.1 mg) in DMF (3.31 mL) were added ethyl 3-(3-(bromomethyl)phenyl)-3-cyclopropylpropanoate (124 mg) and potassium carbonate (91 mg) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was 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) to give the title compound (142 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@H:5]([C:7](Cl)=[O:8])[C@@H:4]([CH3:10])[O:3]1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([NH:19][C:7]([C@@H:5]1[C@@H:4]([CH3:10])[O:3][C:2]([CH3:11])([CH3:1])[O:6]1)=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: C[C@H]1OC(C)(C)O[C@@H]1C(=O)Cl
Solvent: C1CCOC1
Product: C[C@H]1OC(C)(C)O[C@@H]1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A flask was charged with 70 mL dry tetrahydrofuran, 3.17 g (17.7 mmol) (4S,5R)-2,2,5-trimethyl[1,3]dioxolane-4-carbonyl chloride, and the solution was cooled in a 0° C. bath. To this solution, 3.48 mL (31.9 mmol) benzyl amine was slowly added, and a precipitate formed immediately. The reaction mixture was stirred for 1 hour at 0° C. and 1 hour at room temperature. The reaction mixture was filtered through Celite to remove salts, and the tetrahydrofuran was removed under reduced pressure giving 4.41 g (100%) of the title compound as a yellow oil. No further purification was necessary. MS (APCI) (m+1)/z 250.1.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]1[O:12][C:11](=[O:19])[C:10]([N:20]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[N:21]3)=[CH:9][C:8]2=1.Cl.CO>O1CCCC1>[OH:19][CH2:11][CH:10]([N:20]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[N:21]1)[CH2:9][C:8]1[C:7]2[C:16](=[CH:17][CH:18]=[C:5]([O:4][CH3:3])[CH:6]=2)[N:15]=[CH:14][C:13]=1[OH:12]
Reactant: COc1ccc2ncc3oc(=O)c(-n4cc([N+](=O)[O-])cn4)cc3c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc(O)c(CC(CO)n3cc([N+](=O)[O-])cn3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Sodium borohydride (179 mg, 4.73 mmol, 8.0 eq) is added at 0° C. to a stirred solution of 6-methoxy-3-(4-nitro-pyrazol-1-yl)-1-oxa-9-aza-phenanthren-2-one (200 mg, 0.59 mmol, 1.0 eq) in tetrahydrofuran (50 mL). After 2 hours stirring at 0° C., the reaction mixture is cautiously acidified to pH=1 with a 4N hydrochloric acid aqueous solution. Tetrahydrofuran is evaporated and the residue is extracted with ethyl acetate (3×40 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ethyl acetate:methanol, 20:1, v/v) to afford 4-[3-hydroxy-2-(4-nitro-pyrazol-1-yl)-propyl]-6-methoxy-quinolin-3-ol as a white solid (170 mg, 84% yield).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Li].[CH3:24][N:25]([CH3:31])[N:26]=[C:27]([CH2:29][CH3:30])[CH3:28]>>[CH3:24][N:25]([CH3:31])[N:26]=[C:27]([CH2:28][CH:14]([OH:15])[CH:13]([O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:21])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:16])[CH2:29][CH3:30]
Reactant: CC(C=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCC(C)=NN(C)C
Agent: [Li]
Product: CCC(CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)=NN(C)C

Procedure:
Following the procedure of Example 1, 2-[4-(4-trifluoromethylphenoxy)phenoxy]propanal is reacted with the lithium salt of 2-butanone N,N-dimethylhydrazone to give 5-hydroxy-6-[4-(4-trifluoromethylphenoxy)phenoxy]-3-heptanone N,N-dimethylhydrazone (cpd. 9, Table A). This hydrazone is then hydrolyzed to 5-hydroxy-6-[4-(4-trifluoromethylphenoxy)phenoxy]-3-heptanone (cpd. 9, Table B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:24](=[O:38])[CH2:25][NH:26][C:27](=[O:37])[CH2:28][NH:29]C(OCCCC)=O)[C:7]=2[CH:39]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:24](=[O:38])[CH2:25][NH:26][C:27](=[O:37])[CH2:28][NH2:29])[C:7]=2[CH:39]=1
Reactant: CCCCOC(=O)NCC(=O)NCC(=O)N[C@H]1CCc2cc(OC)c(OC)c(OC)c2-c2ccc(OC)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@H](NC(=O)CNC(=O)CN)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 65 %

Procedure:
A solution of N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]-2-[2-(butoxycarbonylamino)acetylamino]acetamide (0.9 g; 0.64 mmol) in dichloromethane (6 ml) was treated with TFA (6 ml) at ambient temperature for 0.5 hour. After evaporation to dryness, the residue was neutralised to pH 6.5 with solid sodium hydrogen carbonate and purified on reverse phase silica eluting with a gradient of 30-40% methanol/ammonium carbonate buffer (2 g/1, pH 7). The appropriate fractions were evaporated to dryness and triturated in ether to give the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][N:8]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([OH:37])[CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34]>>[CH:19]1([N:8]([CH3:7])[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:37][C:29]3[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[CH:28]=3)=[CH:12][CH:11]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C(=O)c1ccc(CBr)cc1)C1CCCCC1
Reactant: COc1cc(O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(OCc2ccc(C(=O)N(C)C3CCCCC3)cc2)cc(OC)c1OC

Procedure:
The reaction and workup were carried out in the same manner as for Example 21 using K2CO3 (576 mg, 4.17 mmol), 4-bromomethylbenzoic acid N-methyl-N-cyclohexyl amide (1.124 g, 3.62 mmol) and 3,4,5-trimethoxyphenol (648 mg, 3.52 mmol). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 115.53° C. (DSC).