Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[C@H:17]([C:26]([OH:28])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C1C=CC2N(O)[N:46]=[N:45][C:43]=2[CH:44]=1.N1CC[O:52][CH2:51][CH2:50]1>C(Cl)Cl>[NH:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[C@H:17]([C:26]([OH:28])=[O:27])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1.[N:45]1([NH-:46])[CH2:43][CH2:44][O:52][CH2:51][CH2:50]1
Reactant: On1nnc2ccccc21
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Product: [NH-]N1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
9.08 g (44 mmol) of DCC are added to an ice-cooled suspension of 14.04 g (40 mmol) of Z-(L)-Tyr-OH in 750 ml of methylene chloride and the mixture is stirred for 20 min. Subsequently, 10.81 g (80 mmol) of HOBT and a solution of 5.23 g (60 mmol) of morpholine in 50 ml of methylene chloride are added. The mixture is stirred for 18 h at RT and then filtered. The filtrate is washed with sat. NaHCO3 solution, water and brine and the aqueous phases are extracted with 2 portions of methylene chloride. The organic phases are dried with Na2SO4, concentrated by evaporation and subjected to column chromatography (SiO2, ethyl acetate) to yield the title compound: TLC Rf (B)=0.39.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([NH:6][CH2:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:4]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:3]=1.[C:22](=[S:25])([O-:24])[CH3:23].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([O:24][C:2]1[CH:15]=[CH:14][C:5]([NH:6][CH2:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:4]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:3]=1)(=[S:25])[CH3:23]
Reactant: FS(F)(F)(F)(F)c1cc(Br)ccc1NCC1CCOCC1
Reactant: CC([O-])=S
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=S)Oc1ccc(NCC2CCOCC2)c(S(F)(F)(F)(F)F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 233C (456 mg) and potassium ethanethioate (197 mg) in dioxane (4 mL) was added tris(dibenzylideneacetone)dipalladium(0) (27 mg) and xantphos (33 mg) followed by N,N-diisopropylethylamine (0.5 mL). The mixture was purged with argon, sealed and stirred under microwave irradiation for 60 minutes at 120° C. The mixture was dissolved in ethyl acetate (300 mL) and water (100 mL). The organic phase was washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent followed by flash chromatography (20% ethyl acetate in hexane) provided the title compound.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: COc1cccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
6-(3-Methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 4 from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-methoxyphenyl boronic acid, as a yellow solid: mp 164-165° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.56 (m, 2H), 7.36 (t, 1H, J=7.89 Hz), 7.20 (m, 2H), 6.96 (d, 1H, J=8.88 Hz), 6.91 (dd, 1H, J=8.13, 2.35 Hz), 3.8 (s, 3H), 1.7 (s, 6H); MS (ESI) m/z 284 ([M+H]+, 30%); Anal. Calcd. For C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 70.58; H, 5.73; N, 4.67.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][CH:20]=[CH:19]4)=[CH:12][CH:11]=1)[CH2:2]2.CC(O)=O.[Br:29]N1C(=O)CCC1=O>CC#N>[Br:29][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([C:13]3[N:14]=[N:15][C:10]([O:9][C@@H:3]4[CH:4]5[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]5)[CH2:2]4)=[CH:11][CH:12]=3)[CH:17]=2)[NH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1
Solvent: CC#N
Solvent: CC(=O)O
Product: Brc1c[nH]c2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 9B (160 mg, 0.5 mmol) was dissolved in MeCN (10 mL) and treated with HOAc (Sigma, 60 mg, 1 mmol) for 10 min. N-bromosuccinimide (Aldrich, 110 mg, 0.6 mmol) in MeCN (Aldrich, 5 mL) was slowly added over 5 min. The mixture was stirred for 1 hour at ambient temperature and concentrated under vacuum. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.15) as a solid (70 mg, yield, 35%). 1H NMR (300 MHz, CD3OD) δ 1.55-1.62 (m, 1H), 1.70-1.96 (m, 2H), 2.05-2.20 (m, 1H), 2.29-2.43 (m, 1H), 2.74-3.13 (m, 5H), 3.42-3.66 (m, 1H, 5.24-5.46 (m, 1H), 7.27 (d, J=9.2 Hz, 1H), 7.38 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.82 (dd, J=8.5, 1.7 Hz, 1H), 8.05 (s, 1H), 8.11 (d, J=9.5 Hz, 1H) ppm. MS (DCI/NH3): 399 (M+H)+, 401 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6](C)=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OCC1OC=CC(=O)C=1OCC1C=CC=CC=1>>[CH3:1][O:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Agent: O=c1ccoc(CO)c1OCc1ccccc1
Product: COCc1occc(=O)c1OCc1ccccc1
Yield: 100 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using 2-hydroxymethyl-3-benzyloxy-pyran-4(1H)-one (2.32 g, 10 mmol, 1 eq.) yielded the title compound as an orange oil (2.5 g, ˜100%). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product as a bright yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)c1cccc(O)c1
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 2-(3-hydroxyphenyl)propanoate (2.51 g, 12.9 mmol) in acetic acid (20 mL) was added nitric acid (60-62%, 1.45 g, 13.8 mmol) at room temperature. The mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc. The organic layer was dried with MgSO4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=6/1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:29]([O:33][C:34]([NH:36][C:37]1[CH:38]=[C:39]([NH:47][C:48](=[O:53])[CH2:49][C:50](O)=[O:51])[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:29]([O:33][C:34]([NH:36][C:37]1[CH:38]=[C:39]([NH:47][C:48](=[O:53])[CH2:49][C:50]([NH:18][C@H:12]([C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[CH2:11][NH:10][C:9](=[O:19])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:51])[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)Nc1cc(NC(=O)CC(=O)O)cc(C(F)(F)F)c1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.4 %

Procedure:
A solution of (2S, 3S)-(2-amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (225 mg, prepared as in WO PCT 0250019) in 3:1 CH2Cl2/DMF (12 mL) was charged successively with N,N-diisopropylethylamine (0.54 mL), 3-(3-(tert-butoxycarbonyl)amino-5-(trifluoromethyl)phenylamino)-3-oxopropanoic acid 235 mg), and HATU (283 mg). The reaction was stirred for 14 h at RT before being partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography provided benzyl (2S,3S)-2-(3-(3-(tert-butoxycarbonyl)amino-5-(trifluoromethyl)phenylamino)-3-oxopropanamido)-3-hydroxyhex-4-ynylcarbamate (92 mg). MS found: (M+Na)+=629.4.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:14][OH:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.C(N(CC)CC)C.CO>[C].[Pd].O1CCCC1>[C:8]1([C:5]2[N:4]=[C:3]([CH2:14][OH:15])[CH:2]=[CH:7][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1nc(-c2ccccc2)ccc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 3-chloro-6-phenyl-2-pyridylmethanol (2.20 g), 5% palladium-carbon (1.10 g), triethylamine (1.4 ml), methanol (20 ml) and tetrahydrofuran (20 ml) was stirred at room temperature under a hydrogen atmosphere. After palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 6-phenyl-2-pyridylmethanol (1.76 g, yield 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:5, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([N:34]=[C:35]=[S:36])[CH2:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:35]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[S:36])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Reactant: CCCCN=C=S
Product: CCCCNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(n-butylaminothiocarbonylaminosulfonyl)-7-methoxychroman is prepared analogously to Example 4 from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and n-butyl isothiocyanate. Melting point: 167° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH3:2].C1C(=O)N([Br:30])C(=O)C1>ClCCl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:15]=2
Reactant: CCOCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-{[2-(ethyloxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.8 g, 25.4 mmol) in dichloromethane (100 ml) and NBS (5 g, 27.9 mmol) added with stirring. After 2 h, the solvent was removed. The product was purified through a silica column using petroleum ether: ethyl acetate 2:1 as eluent, which was a pale yellow solid (7.8 g, 79.6%).
Reaction SMILES: [F:1][C:2]([F:18])([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[CH3:26][S:27]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:18])([F:1])[C:8]([F:16])([F:17])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 5,5,6,6,7,7,8,8,8-nonafluorooctan-1-ol (7.8 g, 26.70 mmol) in dichloromethane (150 ml) was cooled to 0° C. Triethylamine (9.29 ml, 66.75 mmol) and methanesulfonyl chloride (2.48 ml, 32.04 mmol) were added dropwise to the solution, followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give 1-methanesulfonyloxy-5,5,6,6,7,7,8,8,8-nonafluorooctane (8.5 g, Yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([N:13]([CH2:17][CH2:18]Cl)[CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([N:13]([CH2:17][CH2:18][N:31]1[CH2:30][CH2:29][CH:28]([C:26]2[NH:25][C:24]3[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=3[N:27]=2)[CH2:33][CH2:32]1)[CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12]
Reactant: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: CC(C)N(CCCl)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Product: CC(C)N(CCN1CCC(c2nc3cc(F)ccc3[nH]2)CC1)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared using the procedure described in Example 1 using D7 and 4-(5-fluoro-1H-benzimidazol-2-yl)piperidine (D17). MH+ 547/549/551/553.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][CH2:11][CH2:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC1C(=O)C(=O)C(Cl)=C(Cl)C=1Cl>>[CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8](=[CH:7][CH:6]=1)[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12]2)([CH3:3])[CH3:2]
Reactant: CC1=CCCc2cc(OC(C)C)ccc21
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Product: Cc1cccc2cc(OC(C)C)ccc12

Procedure:
Using general procedure A (Exp. 1.2.), 7-isopropoxy-4-methyl-1,2-dihydro-naphthalene was reacted with 3,4,5,6-tetrachloro-1,2-benzoquinone to give 6-isopropoxy-1-methyl-naphthalene as a pale yellow oil. MS: 201.3 ([M+H]+).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([C:28](=O)[CH2:29][CH3:30])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH2:29][CH3:30])=[CH2:1])[CH:23]=1)[CH3:20]
Reactant: [Li]CCCC
Reactant: CCC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=C(CC)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
Methyl triphenylphosphonium bromide (0.72 g; 2.01 mmol) was added to benzene (15 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.3 ml; 2.03 mmol) was added dropwise. The mixture was stirred for 5 minutes, and Compound 23 (0.40 g; 1.34 mmol) in benzene (5 ml) was added dropwise thereto, followed by heating under reflux for 2 hours. The mixture was brought to room temperature, and poured into ice/water, followed by extraction with benzene (100 ml). The organic layer 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 (n-hexane:ethyl acetate=20:1), to thereby yield 0.20 g of the target compound as pale yellow oily matter (yield: 50.5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:34][C:35]([NH:37][CH3:38])=[O:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:66])(=O)=O)CCCCCCCCCCCCCCC>>[I:66][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:34][C:35]([NH:37][CH3:38])=[O:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(=O)NC

Procedure:
3-(3-chloropropylsulfonylamino)-2-(3-methylureido)-1-octadecylcarbamoyloxypropane IIIf1 is allowed to react and worked up by the same procedure as described in (5). m.p. 87°-89° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:36]([CH3:35])(=[O:38])=[O:37])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and methanesulfonyl chloride in N,N-dimethylformamide, to give the desired product as a colorless foam (35%).
Reaction SMILES: C(OC([N:11]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:22][O:21][CH2:20]2)[CH2:15][C:12]21[CH2:14][CH2:13]2)=O)C1C=CC=CC=1>[Pd]>[O:21]1[CH2:22][CH:19]([N:16]2[CH2:15][C:12]3([CH2:13][CH2:14]3)[NH:11][CH2:18][CH2:17]2)[CH2:20]1
Reactant: O=C(OCc1ccccc1)N1CCN(C2COC2)CC12CC2
Agent: [Pd]
Product: C1CN(C2COC2)CC2(CC2)N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 7-oxetan-3-yl-4,7-diazaspiro[2.5]octane-4-carboxylic acid benzyl ester in IMS (3 mL) was added 10% Pd/C (60 mg) and the resulting mixture stirred under an atmosphere of H2 at r.t. for 20 h. The reaction mixture was filtered through Celite® and the filtrate loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (90 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 4.63-4.63 (2H, m), 3.50-3.42 (2H, m), 3.00-2.98 (2H, m), 2.35-2.25 (2H, m), 2.15 (2H, s), 2.05-2.03 (2H, m), 0.68-0.63 (2H, m), 0.52-0.51 (2H, m)
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH3:28][C@H:29]1[NH:34][CH2:33][CH2:32][N:31]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:30]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:26][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][C@H:13]([CH2:12][N:34]4[CH2:33][CH2:32][N:31]([C:35]5[CH:44]=[CH:43][C:42]6[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=6)[N:36]=5)[CH2:30][C@H:29]4[CH3:28])[O:27][C:17]3=2)[N:22]=1
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)CCN1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4ccccc4n2)C[C@H]1C)O3
Temperature: 50 °C
Yield: 47.3 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (238 mg, 0.528 mmol) and (R)-2-(3-methyl-piperazin-1-yl)-quinoline (350 mg, 1.58 mmol) in anhydrous dimethylsulfoxide (6 mL) was heated at 50° C. overnight. The cooled reaction was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica gel (2/2/96 methanol/2 M ammonia in methanol/methylene chloride) afforded 110 mg (47%) of the title compound as an off-white solid: mp 78–82° C.; MS (ES) m/z441 [M+H]+; [α]D −33.0° (c 1.0, DMSO)
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.CC(C)=O.C(OCC)(=O)C>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([S:16][C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Oc1cccnc1Br
Reactant: Sc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Oc1cccnc1Sc1cccc(Br)c1
Yield: 77.5 %

Procedure:
2-Bromo3-pyridinol (44 g, 250 mmol) and 3-bromothiophenol (30 g, 160 mmol) are dissolved in tetrahydrofuran (hereinafter, occasionally referred to as THF) (100 ml) and dimethylformaldehyde (hereinafter, referred to as DMF) (100 ml), and the mixture is heated under reflux for 5 hours. After being allowed to cool, ethyl acetate (1000 ml) is added to the mixture, and the mixture is washed with 5% aqueous sodium hydroxide solution (50 ml×2) and a saturated brine (100 ml×2), and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give the title compound (35 g) as colorless crystals, m.p. 125-126° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]([CH3:19])[CH2:13]1.C1COCC1>[Ni].O>[CH3:18][CH:16]1[CH2:15][CH:14]([CH3:19])[CH2:13][N:12]([C:3]2[C:4]([F:11])=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH2:17]1
Reactant: CC1CC(C)CN(c2c(F)cc([N+](=O)[O-])cc2F)C1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: CC1CC(C)CN(c2c(F)cc(N)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,6-Difluoro-4-nitrophenyl)-3,5-dimethylpiperidine (14.01 g, 51.8 mmol) and THF (240 mL) were added to Raney-nickel 2800, water slurry (14.01 g, 239 mmol) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 8 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane and concentrated to give the title compound.