Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22](C)([CH3:26])C(O)=O)=[CH:19][N:20]=1.C1(S)C=CC=CC=1.C([O:45][C:46](=[O:56])CCSC1SC(N)=NC=1)C>>[CH3:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:13]([CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][CH2:22][CH2:26][C:46]([OH:56])=[O:45])=[CH:19][N:20]=2)[CH2:34][CH2:33]1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Agent: Sc1ccccc1
Product: C[C@H]1CC[C@H](N(CCCSc2ccccc2)C(=O)Nc2ncc(SCCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using thiophenol and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](O)(=O)[CH3:17]>O1CCCC1.C(OCC)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH2:16][CH3:17])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 25.1 g of 3-phenoxybenzaldehyde in 23 ml of an anhydrous tetrahydrofuran is added dropwise to 60 ml of 3-N-ethylmagnesium bromide in ethyl ether, cooled in an ice bath under a nitrogen atmosphere, over a period of about 1 1/2 hours. The reaction mixture is stirred overnight and warmed to room temperature, after which time it is poured over ice containing 12 ml of acetic acid. The organic and aqueous phases are separated and the aqueous phases extracted twice with ethyl ether. The ethereal extracts are combined and washed with a solution prepared from 3 g of sodium carbonate and 40 ml of water. The aqueous wash layers are extracted further with ethyl ether and the combined ethereal extracts are dried over anhydrous sodium sulfate and filtered. The ether is removed under reduced pressure to yield 29.45 g of 1-(3-phenoxyphenyl)propan-1-ol.
Reaction SMILES: CS(Cl)(=O)=O.CS([O:10][CH2:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)(=O)=O.C(N(CC)CC)C>ClCCl>[OH:10][CH2:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(CO)CCOCC1
Reaction time: 1 h

Procedure:
Intermediate 3 Ethyl 4-(Methanesulfonyloxy)methyltetrahydropyran-4-carboxylate Methanesulfonyl chloride (4.6 ml) was added to a solution of intermediate 2 (1 1.0 g) at 0° C. in dichloromethane (30 ml), followed by triethylamine (8.0 ml). The mixture was stirred for 1 h, then washed with citric acid (5% aq, 30 ml), saturated sodium bicarbonate and brine. The organic layer was separated, and then dried (MgSO4) and evaporated to give the title compound as colourless oil (15.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[N:35][N:34]([CH:42]([CH3:44])[CH3:43])[C:33]2=[O:45])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:33](=[O:45])[N:34]([CH:42]([CH3:44])[CH3:43])[N:35]=2)=[O:40])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)c1nn(C(C)C)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and 4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylic acid using the procedure for example 1. mp=216-218° C.; LCMS m/z=602 (M+1); 1H NMR (CDCl3) δ: 11.02 (s, 1H), 8.66 (d, 1H, J=8.5 Hz), 8.50 (d, 1H, J=5 Hz), 7.54 (s, 1H), 7.43 (s, 1H), 7.30-7.27 (m, 3H), 6.83 (dd, 1H, J=3.5, 10 Hz), 6.75 (d, 1H, J=2.5 Hz), 6.53 (d, 1H, J=5 Hz), 5.09 (m, 1H), 4.05 (s, 6H), 3.86 (s, 3H), 1.53 (d, 6H, J=6.5 Hz)
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:17])=[N-]>CCOCC>[CH3:17][O:13][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Solvent: CCOCC
Product: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Yield: 90 %

Procedure:
A solution of the acid (23) in ether (200 ml) at room temperature was treated with ethereal diazomethane until the yellow colour just persisted and tlc showed there to be no starting material present. The volatiles were then removed in vacuo leaving the product (24) as a light orange oil (17.89 g, 90%).
Reaction SMILES: [I-].[C:2]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)([O:4][CH2:5][CH3:6])=[O:3].Br[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([C:10]2[CH:11]=[CH:12][C:7]([C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(C#N)cc2)cc1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
4-Carbethoxyphenylzinc iodide (2.16 mmol, in about 10 mL THF) was transferred via a cannula to a THF solution of 5 mole-% Pd(PPh3)4 (0.127 g, 0.11 mmol) and 4-bromobenzonitrile (0.400 g, 2.19 mmol) at room temperature under an argon atmosphere. The solution was then stirred for 3 hours. The reaction product was isolated by a procedure similar to that described in Example 3. Ethyl 4-(4-cyanophenyl)benzoate (Entry 4 in Table VIII, 0.433 g, 1.73 mmol) in 80% yield was obtained as a crystalline solid: mp 114-115° C.; 1H NMR (360 MHz) δ 7.60-8.21 (m, 8H), 4.42 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H); 13C NMR δ 165.9, 144.2, 143.1, 132.5, 130.4, 130.1, 127.7, 127.0, 118.5, 111.6, 61.0, 14.2; IR (CCl4) ν 2981, 2231, 1722, 1608, 1276, 1109 cm-1. HREI calcd. for C16H13NO2 m/e 251.0947, found 251.0949. Anal. calcd. for C16H13NO2 : C, 76.48; H, 5.21; N, 5.57, Found: C, 76.25; H, 5.17; N, 5.31.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[CH:14]=O)[CH3:2].[C:16]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17].N1CCCCC1>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2/[CH:14]=[CH:17]/[C:16]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:18])[CH3:2]
Reactant: CC(=O)c1ccncc1
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: CCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Yield: 85.6 %

Procedure:
5-Ethoxy-2-methylindole-3-carboxaldehyde 409a (188 mg, 0.93 mmol) was dissolved in anhydrous methanol (12 mL). 4-Acetylpyridine (168 mg, 1.38 mmol) and piperidine (118 mg, 1.38 mmol) were added and the solution was heated at reflux for 24 h. A precipitate slowly formed which was collected, washed with ice-cold MeOH (30 mL) and dried at 40° C. in a vacuum desiccator for 24 h to yield a bright yellow powder (244 mg, 86%): mp 255-257° C. TLC Rf 0.30 (80% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.88 (s, 1H), 8.80 (m, 2H), 8.09-8.06 (d, 1H, J=15.3 Hz), 7.93-7.92 (m, 2H), 7.41 (d, 1H, J=2.22 Hz), 7.34-7.32 (d, 1H, J=15.3 Hz), 7.30-7.29 (d, 1H, J=8.64 Hz), 6.84-6.82 (dd, 1H, J1=8.7 Hz, J2=2.28 Hz), 4.14-4.11 (q, 2H, J=6.96 Hz), 2.57 (s, 3H), 1.37-1.36 (t, 3H, J=6.96 Hz). 13C NMR (150 MHz, d6-DMSO) δ 188.1, 154.4, 150.6, 145.8, 145.1, 139.6, 131.0, 126.6, 121.4, 112.82, 112.24, 111.3, 109.3, 104.4, 63.6, 14.9, 12.2. Elemental analysis calculated for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.30; H, 6.02; N, 9.04.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([OH:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:22]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([O:19][CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(I)c(O)c12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(I)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To 748 mg (2 mmol) of 5-iodo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 1.42 g (10 mmol) of iodomethane, 553 mg (4 mmol) of K2CO3 and 10 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo gave 790 mg (100% yield) 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a pale brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O[CH2:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][OH:33])[CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][OH:33])[CH:27]=[CH:28][CH:29]=2)=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: OCCCc1cccc(CO)c1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(CCCO)c3)cc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (312 mg), 3-(3-(hydroxymethyl)phenyl)propan-1-ol (199 mg) and triphenylphosphine (522 mg) in THF (10 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (790 μL) at 0° C., and the mixture was stirred at 0° C. for 5 min and at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (277 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCC[CH2:22]1>C[Mg]Br>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16]([C:15]([CH3:22])=[CH:14][CH2:13][CH2:12]2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2cc(OCc3ccccc3)ccc21
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Product: CC1=CCCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the obtained 6-(benzyloxy)-3,4-dihydronaphtalen-1(2H)-one (34.5 g) in tetrahydrofuran (300 mL), methyl magnesium bromide (3M diethyl ether solution, 55 mL) was added at 0° C., followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and poured into ice-saturated aqueous ammonium chloride solution. After adding 2N hydrochloric acid, the mixture was stirred at room temperature for 3 hours. Then, the resultant was extracted with ethyl acetate and the organic layer was successively washed with water and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to thereby give the title compound (24.8 g) having the following physical properties.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:23]=[C:22]3[S:32][C:33]([CH3:42])([CH3:41])[C:34]([O:36]C(C)(C)C)=[O:35])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>ClCCl>[CH:8]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3[C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:24][N:23]=[C:22]3[S:32][C:33]([CH3:42])([CH3:41])[C:34]([OH:36])=[O:35])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(-c2ccccc2)n1-c1ccc(C2CC2)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nnc(-c2ccccc2)n1-c1ccc(C2CC2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-phenyl-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (25 mg, 0.051 mmol) in dichloromethane (2 mL) and the mixture stirred at room temperature for 20 hours. The mixture was then concentrated, dissolved in ethyl acetate (5 mL) and washed with water (2×5 mL). The combined aqueous layers were washed with ethyl acetate (5 mL) and the combined organic extracts were dried over sodium sulfate, filtered concentrated and purified by column chromatography (1% AcOH/40% EtOAc/hexanes) to give 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-phenyl-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as a brown paste (14 mg, 64%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[C:8]([F:20])[CH:7]=2)[CH2:2]1.[C:21]1([C:27]2[O:31][C:30]([C:32](OCC)=[O:33])=[N:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:20][C:8]1[CH:7]=[C:6]([O:5][CH:3]2[CH2:4][N:1]([C:32]([C:30]3[O:31][C:27]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:28][N:29]=3)=[O:33])[CH2:2]2)[CH:19]=[CH:18][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN1CCN(Cc2ccc(OC3CNC3)cc2F)CC1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Product: CN1CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2F)CC1
Yield: 41.2 %

Procedure:
Using a similar protocol as described in Example 10 employing 29D (0.10 g, 0.36 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.10 g, 0.46 mmol) as starting materials afforded 67 mg (41%) of 29 as a foam. 1H NMR (500 MHz, DMSO-d6): δ 2.10 (s, 3H), 2.12-2.50 (bm, 8H), 3.43 (s, 2H), 4.05-4.16 (m, 1H), 4.50-4.70 (m, 2H), 5.03-5.23 (m, 2H), 6.68-6.84 (m, 2H), 7.25-7.37 (m, 1H), 7.57-7.75 (m, 3H), 8.00-8.13 (m, 2H), MS (APCI+) m/z 452 [M+H]+, LC purity: 97%.
Reaction SMILES: O.[CH3:2][C:3]([C:6]1[CH:7]=[C:8]([S:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[S:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)([CH3:5])[CH3:4].O.[OH-].[Li+].Cl>CO>[CH3:15][C:12]([C:10]1[CH:9]=[C:8]([S:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[S:23][CH2:24][C:25]([OH:27])=[O:26])[CH:7]=[C:6]([C:3]([CH3:2])([CH3:4])[CH3:5])[CH:11]=1)([CH3:13])[CH3:14]
Reactant: COC(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Water was added to a solution of the compound of Example 4 (9.2 g, 0.0255 moles) in methyl alcohol (100 ml) until the solution became cloudy. Lithium hydroxide hydrate (1.75 g, 0.0675 moles) was added, and the reaction mixture was stirred at room temperature. Periodically, water was added to make the solution cloudy. After 6 hours, the solution was made acidic with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, filtered, and concentrated to give the crude product as an oil. The product was purified by silica gel chromatography. The structure assignment was supported by NMR and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].[CH:13]1([CH2:19]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:8]=[CH:7]2
Reactant: Clc1cccc2cc[nH]c12
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc2ccn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of 7-chloroindole (4.91 g, 32.4 mmol) in dimethylformamide (60 ml) at 0° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 1.43 g, 35.6 mmol). The mixture was stirred for 1 h at room temperature. Cyclohexylmethyl bromide (5.0 ml, 35.6 mmol) was added at 0° C. The mixture was stirred for 18 h at room temperature. To the reaction mixture was added sodium hydride (60% dispersion in mineral oil, 358 mg, 8.94 mmol). After stirring for 15 mins, cyclohexylmethyl bromide (1.25 ml, 8.96 mmol) was added. The mixture was heated at 70° C. with stirring for 1.5 h. After cooling to room temperature, the mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 0-5% (v/v) ethyl acetate in n-heptane to afford 7-chloro-1-cyclohexylmethylindole (8.1 g, 32.0 mmol).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:20]([CH3:22])[CH3:21])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([OH:19])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH:20]([CH3:21])[CH3:22])[C:10]([C:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:23])[CH2:7][CH2:6]2)=[O:9])=[CH:18]3)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(O)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.6 %

Procedure:
To a cold (0° C.) mixture of (1,1-dioxo-1λ6-thiomorpholin-4-yl)-(5-hydroxy-1-isopropyl-1H-indol-2-yl)-methanone (890 mg, 1.0 eq.), 1-tert-butyloxycarbonyl-4-hydroxy-piperidine (659 mg, 1.2 eq.) and triphenylphosphine (858 mg, 1.2 eq.) in tetrahydrofuran (6 mL) was added dropwise a solution of di-tert-butyl-azodicarboxylate (746 mg, 1.0 eq.) in tetrahydrofuran (4 mL). The reaction mixture was stirred for 15 h at room temperature, concentrated in vacuo, then purified on silica eluting with a gradient of cyclohexane/ethyl acetate. One fraction was isolated to yield 434 mg (31.6%) of the desired product as white oil. MS (m/e): 520.7 (MH+, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=3[CH:52]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCOCCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.500 g of tertbutyl 3-hydroxy-4-(4-{2-[2-(2-methoxyphenyl)-ethoxy]ethoxy}phenyl)piperidine-1-carboxylate and 0.314 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2b) are reacted. The title compound is obtained as an opaque oil. Rf=024 (1:1 EtOAc-heptane); Rt=5.82.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+](=[CH2:22])=[N-]>>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:22])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: COC(=O)c1ccc(-c2ccc(OC(C)=O)cc2)cc1

Procedure:
In 400 ml of dioxane was dissolved 30 g of 4-methoxy-4'-acetoxy biphenyl. To this solution was dropped an aqueous solution composed of 84 g of sodium hydroxide, 400 ml of water and 30 ml of bromine and maintained at 40° C., and the solution was stirred for 30 minutes. Thereafter, 200 g of sodium hydrogen sulfate and 1 l of water were added to the solution, and the resultant reaction solution was concentrated under a reduced pressure, methyl bromide and dioxane were evaporated from the reaction solution, an aqueous concentrated hydrochloric acid solution was added to the solution and the solution was then allowed to stand to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried to obtain 28 g of crude 4-methoxy-4'-biphenylcarboxylic acid. In 1.2 l of acetic acid was dissolved 28 g of this crude 4-methoxy-4'-biphenylcarboxylic acid. Thereafter, 240 ml of hydrogen bromide (48% concentration) was added to this solution and the mixed solution was refluxed for 10 hours. To this solution, 3 l of ice water was added, thereby forming a precipitate. The precipitate was recovered by filtration, washed with water, and then dried. The dried product was dissolved in a mixture of 50 ml of acetic anhydride and 25 ml of pyridine, and the solution was dropped in 200 ml of ice water to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried. Recrystallization of the dried precipitate from acetic acid yielded 18 g of 4-acetoxy-4'-biphenylcarboxylic acid. 18 g of the 4-acetoxy-4'-biphenylcarboxylic acid was reacted with 20 g diazomethane to obtain methyl 4-acetoxy-4'-biphenylcarboxylate. The methyl 4-acetoxy-4'-biphenylcarboxylate was dissolved in 500 ml of tetrahydrofuran and an equimolar amount of a 1N aqueous lithium hydroxide solution was added to the resultant solution thereby to hydrolyze the methyl 4-acetoxy-4'-biphenylcarboxylate. The reaction mixture was extracted with ether to obtain 13 g of methyl 4-hydroxy-4'-biphenylcarboxylate.