Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH:11]([OH:13])[CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][C:15]1([CH3:39])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]([N:25]3[CH2:31][C:30]4[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:29]=4[O:28][CH2:27][CH2:26]3)[C:17]=2[CH2:16]1>>[CH3:14][C:15]1([CH3:39])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]([N:25]3[CH2:31][C:30]4[CH:32]=[C:33]([C:2]5[CH:3]=[C:4]6[N:10]=[C:9]([CH:11]([OH:13])[CH3:12])[NH:8][C:5]6=[N:6][CH:7]=5)[CH:34]=[CH:35][C:29]=4[O:28][CH2:27][CH2:26]3)[C:17]=2[CH2:16]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CC(O)c1nc2cc(Br)cnc2[nH]1
Product: CC(O)c1nc2cc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cnc2[nH]1

Procedure:
Prepared according to the method of example 5 by using 1-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)ethanol (reagent preparation 19) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.56 (br, 1H), 8.34 (s, 1H), 8.11 (br, 1H), 7.61 (s, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 5.11 (m, 1H), 4.73 (s, 2H), 4.37 (m, 2H), 3.95 (m, 2H), 2.79 (t, 2H), 2.48 (s, 2H), 1.68 (t, 2H), 1.64 (d, 3H), 0.88 (s, 6H); MS (EI) for C27H30N6O2: 471 (MH+).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH2:10][C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Br)cc1

Procedure:
The title compound was prepared in the same manner as for intermediate 66 using sodium metal (0.404 g, 17.58 mmol), 1-(4-bromophenyl)ethanone (3.5 g, 17.58 mmol), and diethyl ethanedioate (2.384 mL, 17.58 mmol). The product was collected as 5.1 g (97%). LCMS E-S (M+H)=299.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.37 (m, 3H), 4.25 (d, J=6.57 Hz, 2H), 7.72 (m, 2H), 7.92 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:28])[CH:19]([CH2:29][C:30]([OH:32])=O)[S:18]2)[CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:45][CH2:44][C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[NH:41][C:40]2=[O:50])[CH2:35][CH2:34]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:20](=[O:28])[C@H:19]([CH2:29][C:30]([N:33]3[CH2:34][CH2:35][CH:36]([N:39]4[CH2:45][CH2:44][C:43]5[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=5[NH:41][C:40]4=[O:50])[CH2:37][CH2:38]3)=[O:32])[S:18]2)[CH2:5][CH2:6]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CC(C)(C)CCN1C(=O)C(CC(=O)O)SC1c1cccc(F)c1NCCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)SC1c1cccc(F)c1NCCN1CCOCC1

Procedure:
2-(2-(2-(2-Morpholinoethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (420.8 mg, 0.9 mmol), 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (441 mg, 1.798 mmol), EDC (354 mg, 1.847 mmol), and HOBt (273 mg, 1.783 mmol) were stirred in DMF (5 mL) at RT. The mixture was transferred to a separatory funnel, then diluted with 100 mL EtOAc and washed with a saturated sodium bicarbonate solution. The aqueous layer was extracted 3× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by reverse phase chromatography to give 3-(1-(2-((5S)-2-(2-(2-morpholinoethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetyl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one. LC/MS: 695.33 (M+1) Rt=2.20 min (10-90% 3/5 min (grad/run) w/formic acid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([C:33]([O:35][CH3:36])=[O:34])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 30 mg, 0.076 mmol) in tetrahydrofuran (0.5 mL) is added to a suspension of sodium hydride (60% in mineral oil, 4 mg, 0.1 mmol) in dry tetrahydrofuran. After 20 min methyl chloroformate (6 μL, 0.078 mmol) is added, and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is a) extracted with dichloromethane. The combined organic layers are concentrated, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 2 mg; ESI mass spectrum [M+H]+=456; Retention time HPLC: 1.10 min (V011_S01).
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([SH:20])[NH:19][C:15]=2[CH:14]=1>>[Cl:12][C:13]1[CH:22]=[CH:21][C:16]2[NH:17][C:18]([S:20][CH2:2][C:3]3[C:4]4[N:5]([CH:9]=[CH:10][N:11]=4)[CH:6]=[CH:7][CH:8]=3)=[N:19][C:15]=2[CH:14]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: OCc1cccn2ccnc12
Product: Clc1ccc2[nH]c(SCc3cccn4ccnc34)nc2c1

Procedure:
A solution of 20 g (0.12 mole) of 3-chloro-6-nitroaniline in 350 ml of methanol was hydrogenated over 5% palladium on carbon to yield 24.9 g of the corresponding diamino compound. Reaction of the diamino compound with potassium ethylxanthate using the method described in Example 10 yielded 19 g of 5-chloro-2-mercaptobenzimidazole, as confirmed by elemental analysis. The title compound (1.14 g) was prepared by the method of Example 6 using 8-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt (701 mg, 3.8 mmole) and using 701 mg (3.8 mmole) of 5-chloro-2-mercaptobenzimidazole instead of 2-mercapto-5-methoxybenzimidazole. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2.I[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:14]([CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[NH:7][C:6]1=[O:12])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CI
Reactant: COc1cccc2c1CC(=O)N2
Product: COc1cccc2c1C(CC(C)C)C(=O)N2
Yield: 80 %

Procedure:
3-Isobutyl-4-methoxy-1,3-dihydro-indol-2-one is prepared from 4-methoxyoxindole (3.1 mmol) and 1-iodo-2-methylpropane (3.1 mmol) substantially as described above for Epoxide 1 and Epoxide 2. The compound is purified by flash chromatography (SiO2, 25% ethyl acetate:hexane) to obtain 180 mg (27%) of the desired compound. MS (ESI+) 220.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>[Cu]I.CC(O)C>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:8]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[CH:3]=[C:2]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccccc1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3s2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CN1CCC(OC(c2cccc(NCc3ccccc3)c2)c2nc3ccccc3s2)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A screw-capped tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 41, 190 mg), copper(I) iodide (4 mg), ethylene glycol (45 μL), potassium carbonate (173 mg), benzylamine (54 μL), and propan-2-ol (1 mL). The tube is evacuated, filled with argon and sealed. After stirring at 80° C. for 15 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5). The base is converted into its dioxalate salt in acetone to give {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine, dioxalate melting at 75° C.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:26])[CH2:22][C@@H:23]([OH:25])[CH3:24].N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:26])[CH2:22][C@@H:23]([O:25][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:24]
Reactant: COC(=O)C[C@H](C)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl(chloro)diphenylsilane (15.282 g, 55.6 mmol) was added dropwise to an ice-cooled and stirred solution of (S)-3-hydroxybutanoic acid methyl ester (5.473 g, 46.3 mmol) and 1H-imidazole (6.939 g, 102 mmol) and DMAP (0.566 g, 4.63 mmol) in DMF (250 mL). After 10 min., the cloudy reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was taken up in EtOAc, then washed successively with H2O (3×), 1N HCl and a sat. NaHCO3 solution. The organic phase was dried (Na2SO4), filtered and concentrated to give a viscous colourless oil.
Reaction SMILES: C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].Cl.[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>O1CCCC1.C(Cl)(Cl)Cl>[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Yield: 88.4 %

Procedure:
Triethylamine (50.0 mL, 358 mmol) and potassium carbonate (40 g, 290 mmol) were added to a solution of 4-chloro-3-nitroquinoline (49.6 g, 238 mmol) in tetrahydrofuran (THF) (100 mL) and chloroform (250 mL). Ethyl 4-aminobutyrate hydrochloride (43.8 g, 262 mmol) was added in portions over a period of five minutes during which time an ice bath was used to cool the reaction. The reaction was stirred with cooling for 30 minutes, allowed to warm to ambient temperature, and stirred overnight. An analysis by thin layer chromatography (TLC) indicated the presence of 4-chloro-3-nitroquinoline. Additional ethyl 4-aminobutyrate hydrochloride (8.0 g, 48 mmol) was added, and the reaction was stirred at ambient temperature for one hour and then heated at reflux for two hours. Additional triethylamine (20 mL) was added, and the reaction was heated at reflux for one hour, cooled to ambient temperature, washed with water (3×100 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 63.8 g of ethyl 4-(3-nitroquinolin-4-ylamino)butyrate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:22].[H][H]>[Pd].C(O)C.CO.C(Cl)Cl>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]([CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1])[C:10](=[O:22])[CH2:11][CH2:12]2
Reactant: CN1CCCC1CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CN1CCCC1CCN1C(=O)CCc2cc(N)ccc21
Yield: 73 %

Procedure:
A suspension of 1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (2.25 g, 7.42 mmol) and palladium on activated carbon (10%, 100 mg, 0.09 mmol) in 50 mL ethanol was stirred under a balloon of hydrogen for 2 days. The suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL ethanol and the filtrate was concentrated to give a viscous oil. The crude product was subjected to Biotage flash chromatography on silica gel using 0-5% 2M NH3 in MeOH/CH2Cl2 to give a yellow foam (1.48 g, 72.9%). 1H-NMR (CDCl3) δ: 6.82 (d, J=8.4 Hz, 1H), 6.55 (dd, J=3.0, 8.4 Hz, 1H), 6.52 (d, J=3.0 Hz, 1H), 4.09-3.99 (m, 1H), 3.86-3.76 (m, 1H), 3.54 (br s, 2H), 3.04-3.01 (m, 1H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.29 (s, 3H), 2.17-1.60 (m, 8H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[C-:16]#[N:17].[K+]>CN(C=O)C>[C:16]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:17]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CC#N)CC1

Procedure:
A solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2 g) in DMF (20 mL) was treated with potassium cyanide (0.672 g) and the resultant mixture stirred at 20° C. for 4 days. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 60% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.18 g.
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([F:14])=[CH:7][C:6]=1[Cl:15].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:15][C:6]1[C:5]([Cl:4])=[CH:10][C:9]([NH2:11])=[C:8]([F:14])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(Cl)c(Cl)cc1F

Procedure:
Tin (II) chloride dehydrate (27.0 g, 119.6 mmol) was dissolved in ethanol and 1,2-dichloro-4-fluoro-5-nitrobenzene (5.0 g, 23.8 mmol) was added dropwise. Temperature rose to near reflux during the addition and was complete upon cooling. The reaction mixture was carefully added to saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The organic phase was washed several more times with water, dried, filtered and concentrated to give the title compound as a yellow solid: 1H NMR (CDCl3): δ 7.17 (d, 1H), 6.84 (d, 1H), 3.78 (br s, 2H).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH2:19]1[O:22][CH:20]1[CH3:21]>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:19][CH:20]([OH:22])[CH3:21])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: CC1CO1
Agent: [Na]
Solvent: CCO
Product: CC(O)CSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
4.8 (20 mmoles) of 5-benzyl-benzimidazoline-2-thione and 0.46 g sodium dissolved in ethyl alcohol and 2 ml of 1,2-propylenoxide are refluxed for 5 hours. The reaction mixture is evaporated and 50 ml of benzene and 20 ml of 1N sodium hydroxide solution are added. The aqueous phase is extracted twice with 10 ml of benzene, the combined benzene phases are evaporated and the residue is crystallized from nitromethane. The title product thus obtained melts at a temperature of 115° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC)=[N+:2]=[N-:3].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 68.9 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.262 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.242 g, 2.39 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)dodecanamide (0.220 g, 69%). 1H NMR (300 MHz, CDCl3) δ 6.11 (s, 1H), δ 3.40 (d, 2H), δ 3.37 (d, 2H), δ 2.17 (t, 2H), δ 1.59 (q, 2H), δ 1.22 (s, 14H), δ 0.84 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.8, 51.1, 39.1, 36.8, 32.1, 29.8, 29.7, 29.6, 29.5, 29.5, 29.2, 25.9, 22.9, 14.3 ppm; HRMS (ESI) calcd for C14H28N4O (M+) 268.2263, found 268.2259.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([OH:38])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].Cl>O.CN(C)C=O>[C:15]([O:14][C:13]([N:12]([CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]2[C:37]3[C:32](=[C:33]([O:38][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]2=[O:39])[CH2:22][CH2:21]1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(O)cccc32)CC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 166 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 65 mg of potassium carbonate and 43 μL of ethyl bromoacetate were added, and stirred at room temperature for 2 hours. After water was added to the reaction mixture and acidified with hydrochloric acid, the mixture was extracted with a mixture of ethyl acetate: toluene=5:1. The extracts were washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 196 mg of ethyl (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate as a pale brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:45])=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[N:27]=2)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Cl-].[NH4+]>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:45][C:8]2[CH:7]=[CH:6][C:5]([S:10]([NH:13][C:14]3[S:18][N:17]=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:36][CH2:37]3)[N:27]=2)[CH:25]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3Oc3ccc(S(=O)(=O)Nc4ncns4)cc3C#N)n2)CC1
Temperature: 25 °C

Procedure:
3-Cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 43.6 mg, 0.154 mmol), tert-butyl 4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate (Preparation 873, 50.0 mg, 0.128 mmol) and potassium carbonate (53 mg, 0.38 mmol) in dimethyl sulfoxide (1 mL, 10 mmol) was stirred at 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude intermediate, tert-butyl 4-[4-(5-chloro-2-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate, as a yellow solid. Trifluoroacetic acid (300 uL, 4 mmol) was added to a solution of tert-butyl 4-[4-(5-chloro-2-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate (83 mg, 0.154 mmol) in methylene chloride (2.9 mL, 46 mmol). After 1 hour, the reaction mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the product as a white solid (trifluoroacetic acid salt, 36 mg, 51%).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O.[CH3:44][NH:45][CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][CH2:52][C:53]([F:59])([F:58])[C:54]([F:57])([F:56])[F:55].O>CN(C=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:9]=[CH:8][C:7]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[CH:6][C:5]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:45]([CH3:44])[CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][CH2:52][C:53]([F:59])([F:58])[C:54]([F:55])([F:56])[F:57]
Reactant: Cc1ccc(S(=O)(=O)OCCCCC[C@@H]2Cc3cc(OC4CCCCO4)ccc3[C@@H]3[C@@H]2[C@@H]2CCC(=O)[C@@]2(C)C[C@@H]3F)cc1
Reactant: CNCCCSCCCC(F)(F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCCSCCCC(F)(F)C(F)(F)F
Reaction time: 6.5 h

Procedure:
2.0 g of 11β-fluoro-3-(tetrahydropyran-2-yloxy)-7α-(5-p-toluenesulphonyloxypentyl)oestra-1,3,5(10)-trien-17-one in 44 ml of DMF are stirred at 80° C. with 1.2 g of methyl-[3-(4,4,5,5,5-pentafluoropentylthio)propyl]-amine. After 6.5 h, the reaction mixture is treated with water. The mixture is extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo. After chromatographing the crude product on silica gel using a methylene chloride-methanol gradient, 1.3 g of 11-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]-pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one are obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]1[CH:35]=[CH:34][C:29](/[CH:30]=[CH:31]/[CH:32]=O)=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:32](/[CH:31]=[CH:30]/[C:29]2[CH:34]=[CH:35][C:26]([F:25])=[CH:27][CH:28]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C/C=C/c1ccc(F)cc1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 66 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and trans-4-fluorocinnamaldehyde [Arch. Pharm. 316 574 (1983)] to obtain the title compound, a major product as an oil in a yield of 66%.