Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 69 %

Procedure:
A solution of 5-chloro-3-methylbenzothiophene-2-sulfonyl chloride (50 mg, 0.178 mmol) and methyl 3-aminobenzoate (17 mg, 0.112 mmol) in aqueous dioxane (900 μL, 8:1 dioxane/water) was stirred at room temperature for 4 days. The reaction mixture was diluted with MeOH (1 mL) and the crude product was purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 69% yield (30.5 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 2.49 (s, 3 H) 3.85 (s, 3 H) 7.35 (ddd, J=8.12, 7.31, 0.56 Hz, 1 H) 7.38 (ddd, J=8.12, 2.20, 1.58 Hz, 1 H) 7.46 (dd, J=8.65, 2.05 Hz, 1 H) 7.74 (dt, J=7.31, 1.58 Hz, 1 H) 7.82 (ddd, J=2.20, 1.58, 0.56 Hz, 1 H) 7.84 (dd, J=8.65, 0.56 Hz, 1 H) 7.85 (dd, J=2.05, 0.56 Hz, 1 H). MS (ESI+) m/z 396 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:74]=[CH:73][C:65]([CH2:66][N:67]2[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:74]=[CH:73][C:65]([CH2:66][N:67]4[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68]4)=[CH:64][CH:63]=3)[CH3:59])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.036 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-ol dihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([OH:30])[C@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:31][S:32]([O:30][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:11]([NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of tert-butyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)-propylcarbamate (14.50 g, 32.3 mmol) in 50 mL DCM at −15° C. were added TEA (4.57 g, 45.2 mmol), N,N-dimethylpyridin-4-amine (0.197 g, 1.61 mmol), and methanesulfonyl chloride (3.26 mL, 41.9 mmol). The mixture was allowed to warm to room temperature. Distilled water (200 mL) was added, and the aqueous phase was extracted into DCM (2×200 mL). The combined organic layers were washed with cold 5% HCl, saturated sodium bicarbonate, and water. The resulting product was then chromatographed eluting with 15% EtOAc in hexane. After removing the solvent, the product was obtained as a colorless oil (15 g, yield=88%). 1H NMR (400 MHz, CD3OD) δ ppm 0.11 (d, J=3.91 Hz, 6 H) 0.93-0.98 (m, 9 H) 1.44 (s, 9 H) 2.84 (s, 3H) 3.80-3.87 (m, 2H) 4.84-4.86 (m, 1H) 5.13 (d, J=5.28 Hz, 1H) 7.58 (d, J=8.02 Hz, 2H) 7.69 (d, J=8.22 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: C1CCCNCC1
Product: O=Cc1c(N2CCCCCC2)n(-c2ccccc2)c2ccccc12
Yield: 42 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with azepane as described in Example 2 to give the title compound (42% yield). NMR (CDCl3) 10.25 (1H, s), 8.23 (1H, d), 7.58 (2H, m), 7.51 (1H, m), 7.39 (2H, d), 7.25 (1H, m), 7.15 (1H, t), 6.98 (1H, d), 3.50 (4H, m), 2.55 (4H, m), 2.33 (3H, s), 1.78 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1)=[O:41]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:49][C:46]1[CH:45]=[CH:44][C:43]([NH:42][C:40](=[O:41])[CH3:39])=[CH:48][CH:47]=1)=[N:6]2
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: CC(=O)Nc1ccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc1
Yield: 31.2 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 4-aminoacetanilide (26 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-{4-[(5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-yl)amino]phenyl}acetamide (19 mg) as a yellow solid. MS m/z 359 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH2:20]2>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH2:20]2
Reactant: Brc1cccc2c1CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2c(Br)cccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:12]1([NH:18][C:19](=[O:32])[CH:20]([O:23][C:24]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:25]=2[Cl:31])[CH2:21][CH3:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>O>[Cl:31][C:25]1[CH:26]=[CH:27][C:28]([N:30]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:29][C:24]=1[O:23][CH:20]([C:19](=[O:32])[NH:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:21][CH3:22]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: CCC(Oc1cc(N)ccc1Cl)C(=O)Nc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.52 g. of cyclohexane-1,2-dicarboxylic anhydride, 3.05 g. of N-phenyl-α-(5-amino-2-chlorophenoxy)butyramide (melting point of 78° to 80° C.) and 10 ml. of acetic acid was refluxed with stirring for 2 hours and the reaction mixture was cooled to room temperature and water was added to obtain a crude crystal. The product was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 3.86 g. of Compound No. 294 shown in Table 1.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[C@@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.I[CH2:37][C:38]#[N:39].C(#N)C>O1CCCC1>[C:38]([CH2:37][N:5]1[C@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:33])=[O:34])[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][C:8]=2[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[C:4]1=[O:3])#[N:39]
Reactant: N#CCI
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC#N
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 50 mg, 105 μmol) in tetrahydrofuran (3.0 mL). After 20 min, 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. After 2 h, a second portion of 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. After 2 h, a third portion of 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. The mixture is stirred over night, treated with acetonitrile and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 8 mg; ESI mass spectrum [M+H]+=515; Retention time HPLC: 1.01 min (Z018_504).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:19])[CH2:17][CH3:18])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CCC(=O)Cl
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CCC(=O)NCC(C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and propionyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[N:5]=1)[CH3:2].C(N(CC)CC)C.[NH2:25][CH:26]([CH2:28][CH3:29])[CH3:27]>C(O)C>[CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH:25][CH:26]([CH2:28][CH3:29])[CH3:27])[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Reactant: CCC(C)N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNc1nc(C(F)(F)F)nc(NC(C)CC)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 73.2 %

Procedure:
5.4 g (0.02 mol) of 4-ethylamino-6-chloro-5-nitro-2-trifluoromethyl-pyrimidine are dissolved in 100 ml of abs. ethanol. The solution is treated with 2.3 g of triethylamine (0.023 mol) and 1.7 g (0.023 mol) of 2-amino-butane and the mixture is stirred overnight. After the mixture has been evaporated, the product is taken up in water and extracted with ether to yield 4.5 g of 4-ethylamino-5-nitro-6-(2-butylamino)-2-trifluoromethyl-pyrimidine; nD20 = 1.5209.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30](Br)[C:31]([OH:33])=[O:32])=[CH:29][C:24]=2[O:23][CH2:22]1>CN(C)C=O>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([C:4]3[C:5]4[C:10](=[CH:9][C:8]([C:11]([O:13][CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[O:12])=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)[C:31]([OH:33])=[O:32])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=C(O)C(Br)c1ccc2c(c1)OCO2
Reactant: Cn1ccc2ccc(C(=O)OCc3ccccc3)cc21
Solvent: CN(C)C=O
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2ccc(C(=O)OCc3ccccc3)cc21
Temperature: 90 °C
Yield: 60.9 %

Procedure:
Benzyl 1-methyl-1H-indole-6-carboxylate (from (b), 9.8 g) and 2-(1,3-benzodioxol-5-yl)-2-bromoacetic acid (from Preparation 1, 10.5 g) were stirred together in dimethylformamide (100 ml) and a steady stream of nitrogen was passed through the solution which was warmed to 90° C. After 4 h the reaction mixture was cooled to room temperature and the dimethylformamide removed in vacuo. The oily residue was partitioned between ethyl acetate (300 ml) and 2M hydrochloric acid and the organic phase was washed with more 2M hydrochloric acid (3×50 ml) and brine (50 ml). The organic phase was dried (MgSO4) and decolourising charcoal was added. The slurry was filtered and concentrated to give an orange oil. Flash column chromatography (gradient elution from 100% CH2Cl2 to 95% CH2Cl2/5% MeOH) gave 9.97 g of the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:25])=O>O1CCCC1>[Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:25])=[O:5]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)Oc1cccc(C(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethoxy)benzoic acid (278 mg, 1.16 mmol) produced in Example C70(iii) in tetrahydrofuran (2.5 mL) were added N,N-dimethylformamide (25 μL) and oxalyl chloride (125 μL, 1.46 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-chloro-3-(1-cyano-1-methylethoxy)benzoyl chloride as a pale-yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[O:13]
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCN)C(=O)c2cccc(Cl)c2)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCNS(C)(=O)=O)C(=O)c2cccc(Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(2-Amino-ethyl)-3-chloro-N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-benzamide (80 mg, 0.16 mmol, 1 eq), methanesulfonyl chloride (0.015 ml, 0.19 mmol, 1.2 eq), TEA (0.07 ml) in THF (1 ml) was stirred at room temperature overnight. It was purified with HPLC to give the desired product. LCMS observed for (M+H)+: 527.2
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:5][CH:4]([CH2:13][CH3:12])[CH2:3][CH2:2][CH2:15][CH3:14])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)[CH3:20]
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc2c(c1)C(=O)c1ccc(OCC(CC)CCCC)cc1C2=O
Temperature: 90 °C
Yield: 128.3 %

Procedure:
2,6-Dihydroxyanthraquinone (100.0 g, 0.42 mol) and 2-ethylhexyl bromide (165.0 g, 0.86 mol) were dissolved in 1 L of DMF. To this solution was added anhydrous K2CO3 (120.0 g, 0.87 mol). The reaction was heated at 90° C. overnight. Most of DMF was removed and 500 mL of water was added. The reaction was extracted with ether (3×400 mL), washed with brine (1×200 mL), and dried over MgSO4. Solvent was removed and the crude product was recrystallized from methanol to give yellow powdery product 125.21 g (65% yield). 1H NMR (CDCl3) δ (Ppm): 0.92-0.98 (m, 12H, CH3), 1.34-1.54 (m, 16H), 1.75-1.81 (m, 2H, CH(CH3)), 4.02 (d, J=5.5 Hz, 4H, OCH2), 7.19 (d, J=8.4 Hz, 2H), 7.70 (s, 2H), 8.19 (d, J=8.5 Hz, 2H); 13C NMR (CDCl3): 11.12, 14.06, 23.04, 23.88, 29.08, 30.51, 39.34, 71.34, 110.64, 120.84, 127.00, 129.62, 135.88, 164.29, 182.27. M.p. 49-51° C.; FD-MS: m/z 464 (M+).
Reaction SMILES: [NH2:1][C@@H:2]([CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].C([N:42]=[C:43]=[S:44])(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2.N1CCCCC1>C(Cl)Cl>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:3](=[O:4])[C@@H:2]([NH:1][C:43]([NH2:42])=[S:44])[CH:22]([CH3:24])[CH3:23])=[N:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)[C@H](NC(N)=S)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-amino-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methylbutan-1-one (1.530 g, 3.91 mmol) in CH2Cl2 (10 mL) was added O-(9H-fluoren-9-yl)methyl carbonisothiocyanatidate (1.100 g, 3.91 mmol) as a solid in one portion. The mixture was allowed to stir at room temperature for 12 h. Piperidine (2 mL) was added to the mixture and it was allowed to stir at room temperature for 1 h. A further portion of piperidine (2 mL) was added and the solution allowed to stir 1 h. The solution was concentrated to dryness and the residue was purified by column chromatography (biotage, eluting with 5:4.5:0.5 hex:EtOAc:MeOH, and then 5% MeOH in EtOAc). The title compound as obtained as a light yellow glass (1.30 g, 74%). 1HNMR (300 MHz, DMSO-d6) δ 11.81 (s, H), 7.65 (d, J=8.8 Hz), 7.63-7.71 (m, overlap with previous peak, 2H total), 7.42-7.56 (m, 2H), 7.10-7.14 (m, 1H), 5.06 (dd, J=7.0, 3.0 Hz, 1H), 4.94 (app t, J=8.0 Hz, 1H), 4.72-4.76 and 4.56-4.62 (m, 1H, rotamers, 1:1 ratio), 3.77-3.90 (m, 1H), 2.07-2.14 (m, 2H), 1.90-1.98 (m, 3H), 0.93 (d, J=7.0 Hz, 3H), 0.84 (d, J=7.0 Hz, 3H). LCMS: Anal. Calcd. for C19H24BrN5OS: 449, 451; found: 450, 452 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C:16](=[O:21])[N:17]3[CH3:20])=[CH:12][CH:11]=2)=[O:8])=[C:5]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)[CH:4]=1.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CO.C=O>[ClH:2].[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C:16](=[O:21])[N:17]3[CH3:20])=[CH:12][CH:11]=2)=[O:8])=[C:5]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH3:32])[CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCC3CCCCN3)cc21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCC3CCCCN3C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
4-Chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-[(piperidin-2-ylmethyl)amino]benzamide hydrochloride (100 mg) was dissolved in a mixed solution of acetic acid (3 mL) and methanol (2 mL), and 1 ml of formaldehyde aqueous solution (36%) was added thereto. Sodium triacetoxyborohydride (252 mg) was added to this solution at 0° C., followed by stirring at room temperature for 30 minutes. After concentration under a reduced pressure, this was made basic by adding a saturated sodium bicarbonate aqueous solution, followed by extraction with chloroform. After drying the organic layer with magnesium sulfate, the solvent was evaporated under a reduced pressure. By purifying the residue by silica gel column chromatography (chloroform:methanol, 10:1) and treating the resulting free base with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-{[(1-methylpiperidin-2-yl)methyl]amino}benzamide hydrochloride (45 mg) was obtained as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:29])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][CH2:4][O:5][C:6]1[O:10][C:9]([C:11](O)=[O:12])=[CH:8][CH:7]=1.S(Cl)([Cl:32])=O>>[CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:29])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][CH2:4][O:5][C:6]1[O:10][C:9]([C:11]([Cl:32])=[O:12])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)Cl)o1

Procedure:
A mixture of 57.2 g (0.14 mole) of 5-(3,7,11,15-tetramethylhexadecyloxy)-2furoic acid in 300 ml of thionyl chloride is heated to reflux for 1 hour, and the excess thionyl chloride is removed by distillation to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furancarboxylic acid chloride with is combined with 2.8 g of 2% palladium-BaSO4 catalyst, 0.6 g of quinoline-sulfur in 800 ml of xylene. A slow stream of hydrogen gas is passed through the mixture until hydrogen chloride is no longer evolved (about 8 hours). After cooling, the catalyst is removed by centrifuging, and the solvent is removed under reduced pressure. The residue is distilled to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furancarboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])O>CS(C)=O>[CH3:34][O:35][C:36](=[O:40])[CH:37]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[C:4]([F:16])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1)[CH3:39]
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 24 g (0.1 mol) of 4-(5-chloro-3-fluoropyridin-2-yloxy)-phenol in 80 ml of dimethylsulfoxide is added dropwise to a stirred solution of 13.8 g (0.1 mol) of potassium carbonate in 50 ml of dimethylsulfoxide. When everything is added, the mixture is stirred for 2 hours at room temperature and then a solution of 25.8 g (0.1 mol) of (S)(-)-lactic acid-methylester tosylate is added dropwise over 30 minutes. The mixture is heated to 60° and stirred at that temperature for 20 hours, then poured onto ice/water and the organic material is extracted three times with ether. The ether-layer is washed with water and saturated salt solution, dried over magnesium sulfate, filtered and evaporated. The residue is passed for purification through a silicagel column with a hexane/ethyl acetate 3:1 solvent. After distillation of the solvent, 26 g of a clear oil of the above ester is obtained ([α]D20 =+38.8°±0.5°2% in acetone).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)(Cl)=O.[CH2:26](OC1C=CC(CO)=CC=1)[CH2:27]CCCCCCCCCCCC>C(Cl)Cl>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Reactant: CCCCCCCCCCCCOc1ccc(CCl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CCl)cc1

Procedure:
This one was synthesized following the same general procedure as that for the preparation of 4-dodecyloxybenzyl chloride; thionyl chloride (7.45 g, 63.1 mmol), 4-tetradecyloxybenzyl alcohol (18.4 g, 57.4 mmol), CH2Cl2 (150 mL). 16.28 g (84%) white solid which decomposes upon melting.