Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=[N:7][C:5]=2C=1.CCN=C=NCCCN(C)C.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C@@H:35]([CH3:36])[CH2:34][N:33]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][N:43]=[C:42]([C:46]([OH:48])=O)[CH:41]=3)=[O:38])[C@H:32]([CH3:49])[CH2:31]2)=[CH:26][C:25]=1[C:50]([F:53])([F:52])[F:51])#[N:23].CN>CN(C=O)C.O>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C@@H:35]([CH3:36])[CH2:34][N:33]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][N:43]=[C:42]([C:46](=[O:48])[NH:7][CH3:5])[CH:41]=3)=[O:38])[C@H:32]([CH3:49])[CH2:31]2)=[CH:26][C:25]=1[C:50]([F:52])([F:51])[F:53])#[N:23]
Reactant: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)Nc1ccnc(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(NC(=O)N2C[C@H](C)N(c3ccc(C#N)c(C(F)(F)F)c3)C[C@H]2C)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
Under ice-cooling, 332 mg of HOBT and 519 mg of WSC were added in that order to a suspension of 1.10 g of (2R,5S)-4-{[4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carbonyl]amino}pyridine-2-carboxylic acid synthesized in Example 12-1 in 30 ml of DMF, and then the mixture was warmed up to room temperature and stirred for 1.5 hours. This was again ice-cooled, 10 ml of 40% aqueous methylamine was added thereto in one portion and then the mixture was stirred overnight. This was mixed with purified water and extracted with ethyl acetate, and the thus obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to a silica gel column chromatography to obtain 674 mg of the title compound from methanol-ethyl acetate (1:9, v/v) eluate.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Reactant: CCCC=C1CCNCC1
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)CSc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 59.6 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.432 g, 1.25 mmol) and 4-butylidenepiperidine (111MF05) (0.208 g, 1.49 mmol) in MeCN ( 1/2 mL) were reacted according to GP10 shaking at 60° C. for 4 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM50-47) (0.267 g, 60%). 1H NMR (CDCl3) δ 7.35 (d, J=7.5 Hz, 1H), 7.26-7.18 (m, 2H), 6.98 (t, J=7.5 Hz, 1H), 5.10 (t, J=7.4 Hz, CH), 4.17-4.03 (m, 2H), 3.36 (s, CH2), 2.43-2.33 (m, 2H), 2.30-2.08 (m, 8H), 2.00-1.90 (m, 3H), 1.28-1.38 (m, 2H), 0.90-0.80 (m, 6H); 13C NMR (CDCl3) δ 166.0, 139.2, 136.4, 128.8, 127.1, 124.8, 123.5, 122.7, 118.8, 63.4, 56.4, 55.6, 47.7, 36.4, 32.1, 29.5, 29.4, 28.6, 23.4, 16.7, 14.0; HPLC-MS (ammonium acetate) [M+H]+=359.3.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8](=[O:9])[NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)=[CH:3][N:4]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ccc(CC(=O)O)cc3)s2)c(C(=O)C2CCCC2)c1
Yield: 28.2 %

Procedure:
(4-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-yl sulfanyl}-phenyl)-acetic acid (140 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and (4-mercapto-phenyl)-acetic acid (336 mg, 2 mmol) following the general procedure Y.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.Cl.Cl.[CH3:19][NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH3:19][NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(C)c1
Temperature: 95 °C
Reaction time: 15 h
Yield: 39.7 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (75.00 mg, 0.348 mmol), N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (133 mg, 0.436 mmol) and (cyanomethyl)trimethylphosphonium iodide (136 mg, 0.558 mmol) in Propiononitrile (Volume: 2.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.425 mL, 2.439 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide N,3-dimethyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0594 g, 0.138 mmol, 39.6% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3 H) 2.53-2.66 (m, 4 H) 2.75 (d, J=4.55 Hz, 3 H) 2.86-2.96 (m, 4 H) 3.64 (s, 2 H) 6.71-6.76 (m, 1 H) 7.03 (d, J=8.34 Hz, 1 H) 7.07 (dd, J=3.66, 1.64 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.59-7.66 (m, 2 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.19 (q, J=4.29 Hz, 1 H) 8.36 (d, J=1.52 Hz, 1 H) 11.58 (s, 1 H). ESI-MS: m/z 431.4 (M+H)+. mp=264.0-266.3° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2)(=[O:15])=[O:14])[C:9]([NH2:11])=O)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2)(=[O:14])=[O:15])[C:9]#[N:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCCc2cccc3ncccc23)c1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@H](C#N)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of (S)-3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-succinamic acid tert-butyl ester (0.24 g, 0.40 mmol) in dry THF (10 mL) at 0° C. was added Et3N (0.14 mL, 1.0 mmol). A solution of trifluoroacetic anhydride in THF (0.5 M, 0.50 mmol) was added to the solution dropwise. After 30 min of stirring at 0° C., the ice bath was removed. The reaction mixture was allowed to warm up to room temperature over 4 h. The reaction mixture was worked up by addition of EtOAc (100 mL) then followed by washing the organic phase with saturated NaHCO3. Drying and removal of solvents under vacuum gave 0.20 g (92%) of (S)-3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid tert-butyl ester as a tan solid. MS (APCI) m/z 539.1 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:19][C:18]=2[CH:30]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:21]2[C:17]3[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:30][C:18]=3[S:19][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of p-anisoyl chloride (1.54 g, 9.00 mmol) stirring at ambient temperature in anhydrous methylene chloride (100 ml) was added 6-methoxy-2-(4-methoxyphenyl)benzo [b]thiophene (1.62 g, 6.00 mmol). The resulting mixture was cooled to 0° C. and aluminum chloride (1.20 g, 9.00 mmol) was added in small portions over a five minute period. After 1 hour, the reaction mixture was poured into ice water (150 mL) and extracted with methylene chloride. The combined organic extracts were washed with 1N sodium hydroxide, water, brine, dried (magnesium sulfate), filtered, and concentrated. The resulting material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexanes) giving 2.25 g (93%) of a the desired product as a light yellow solid. The product was further purified by recrystallization from acetone/methanol to give 2.11 g (87%): 1H NMR (300 MHz, DMSO-d6) δ 7.64-7.69 (m,3H), 7.29-7.32 (m, 3H). 6.86-7.00 (m, 5H), 3.83 (s, 3H) 3.76 (s, 3H); 13C NMR (75.5 MHz, DMSO-d6) δ 192.0, 163.6, 159.5, 157.4, 141.0, 139.4, 133.2, 131.8, 130.0, 129.6, 125.2, 123.3, 115.0, 114.4, 114.1, 105.1, 55.5, 55.1; IR (CHCl3) 3020, 3015, 2970, 2940, 2840, 1600, 1475, 1253, 1218, 1167; MS (FD) 404 (M+); Anal. Calcd for C24 H20O4S: C, 71.27; H, 4.98; S, 7.93; O, 15.82. Found: C, 71.50; H, 5.00; S, 7.98; O, 15.77.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:20]=1[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(#N)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:3]2[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=[C:2]2[NH:1][CH2:21][C:20]2[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:19]=2[F:18])=[CH:12][CH:13]=1
Reactant: O=Cc1c(F)ccc(F)c1F
Reactant: COC(=O)c1cnc(N)n1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)c1cnc(NCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
Methyl 2-amino-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (67) (200 mg, 0.85 mmol), 2,3,6-trifluorobenzaldehyde (163 mg, 1.02 mmol), sodium triacetoxyborohydride (450 mg, 2.13 mmol) and catalytic amounts of acetic acid in acetonitrile (5 mL) was heated under microwave radiation for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford methyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)amino)-1H-imidazole-5-carboxylate (68).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21](O)=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30].[N+](=[CH2:37])=[N-]>CO.C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([O:31][CH3:37])=[O:30])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OC

Procedure:
The tripeptide acid of Example 1 (4.6 g) is dissolved in methanol and treated with an ethereal solution of diazomethane until a persistent yellow color is obtained. After 0.5 hour a few drops of acetic acid are added to discharge the yellow color; the solvent is removed in vacuo and replaced with ethyl acetate. This solution is washed sequentially with 0.1 N HCl, water, saturated sodium bicarbonate and water. The organic phase is dried over magnesium sulfate and concentrated to dryness to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:32]=[CH:33][C:34]=3[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Example 23 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:39]=[CH:38][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]2[S:28][CH:29]([CH2:32][C:33](OCC)=[O:34])[CH2:30][N:31]=2)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[BH4-].[Li+].O>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:39]=[CH:38][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]2[S:28][CH:29]([CH2:32][CH2:33][OH:34])[CH2:30][N:31]=2)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCC4CCOCC4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.8 %

Procedure:
Ethyl (2-{5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (310 mg) was dissolved in tetrahydrofuran (15 mL), lithium borohydride (24 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 2.5 hr, and then at 50° C. for 2.5 hr. Lithium borohydride (24 mg) was added to the reaction mixture, and the mixture was stirred at 50° C. for 30 hr. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80 to 100:0, volume ratio), and the obtained amorphous solid was washed with diethyl ether to give the title compound (123 mg, yield 55%) as a pale-yellow solid. melting point 104-105° C. MS 531 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]1[CH2:17][NH:16][C@@H:15]([CH3:18])[CH2:14][NH:13]1>C(#N)C>[CH3:11][C@H:12]1[CH2:17][NH:16][C@H:15]([CH3:18])[CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1

Procedure:
1-Fluoro-4-nitrobenzene (6 g, 42.52 mmol) and (2R,5S)-2,5-dimethylpiperazine (21.9 g, 191.34 mmol) were heated in acetonitrile (20 ml) at 100° C. for 11 h. The solution was concentrated in vacuo, then the residue was partitioned between DCM and water+sat. sodium hydrogen carbonate. The organic extract was washed with water (4 times), brine, dried and concentrated. Chromatography on silica gel with MeOH: DCM (1:99 to 5:95) gave the title compound as an oil which solidified on standing overnight (8.32 g, 83%). NMR (400 MHz) 1.08 (d, 3H), 1.16 (d, 3H), 2.55 (dd, 1H), 3.18 (m, 2H), 3.34 (m, 2H), 3.95 (m, 1H), 6.91 (d, 2H), 8.03 (d, 2H); m/z 236.
Reaction SMILES: S(=O)(=O)(O)O.OC[CH:8]1[CH:13]([CH3:14])[CH:12]2[CH2:15][CH:9]1[CH2:10][CH2:11]2.C=[C:17]1[CH:22](C)[CH:21]2C[CH:18]1[CH2:19][CH2:20]2.[CH3:25]C1C2CC(C=1C)CC2>C1C=CC=CC=1>[CH:17]1([C:13]2([CH3:14])[CH2:8][CH:9]3[CH2:15][C:12]2([CH3:25])[CH2:11][CH2:10]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1=C(C)C2CCC1C2
Reactant: CC1C2CCC(C2)C1CO
Reactant: C=C1C2CCC(C2)C1C
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC12CCC(C1)CC2(C)C1CCCCC1

Procedure:
In a 3 L four-necked flask were placed 820 g of benzene and 53 g of concentrated sulfuric acid, to which 428 g of the dehydration product of 2-hydroxymethyl-3-methylbicyclo[2.2.1]heptane containing 2-methylene-3-methylbicyclo[2.2.1]heptane and 2,3-dimethylbicyclo[2.2.1]hept-2-ene as main ingredients was added dropwise over 3 hours to perform alkylation. The reaction mixture was washed with a dilute aqueous NaOH solution and with a saturated aqueous sodium chloride solution. After the removal of unreacted benzene by distillation, the washed mixture was placed in a 2 L autoclave together with 18 g of a nickel/diatomaceous earth hydrogenation catalyst (N-113, manufactured by Nikki Chemical Co., Ltd.) and was hydrogenated (hydrogen pressure: 2 MPa, reaction temperature: 250° C., reaction time: 8 hours). After completion of the reaction, the catalyst was removed by filtration and the filtrate was distilled under reduced pressure to obtain 210 g of the desired cyclohexyl-dimethylbicyclo[2.2.1]heptane (Fluid D). The results of the measurements of the properties and the traction coefficient are shown in Table 1, from which it will be appreciated that the traction coefficient is low.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.[Br:33]N1C(=O)CCC1=O>CN(C=O)C>[Br:33][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Yield: 30 %

Procedure:
Following General Procedure I, tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (1.0 g, 2.2 mmol) was reacted with N-bromosuccinimide (0.45 g, 2.5 mmol) in DMF (10 mL) to afford the desired product (0.35 g, 29%) as a brown solid: ESI MS m/z 529 [C25H25BrN2O4S+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>COCCOC.O>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)N1CCC(N(Cc2ccccc2)Cc2ccccc2)C(OC)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of racemic ethyl 4-amino-3-methoxypiperidine-1-carboxylate (1 part by mole) in DME were added benzyl bromide (about 2.2 part by mole), potassium carbonate (about 2.4 part by mole) and potassium iodide (about 0.2 part by mole) respectively. The reaction was heated to about 80° C. (in the specification, delta, or “A,” refers to heat). After about 6 hours, the reaction was slowly diluted with water (about 12 parts by volume) and extracted with, for example, ethyl acetate. The organic layer was washed with brine and then dried over anhyh. Na2SO4. Subsequent filtration and concentration of the solvent provided the 1 as the yellow-orange oil (1 part by mole).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:11][CH2:12][CH2:13][CH2:14][C:15]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:16]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)CCCCl
Product: O=C(CCCCl)N1CCc2ccccc2C1

Procedure:
from 3,4-dihydro-1H-isoquinoline and 4-chlorobutanoyl chloride
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=O)=[CH:7][CH:6]=1.[OH2:15].[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:17][C:18]([O:19][CH2:20][CH3:16])=[O:15])=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1CCc2ccc(OC)cc21
Yield: 64 %

Procedure:
To a suspension of 60% sodium hydride (1.84 g, 46.0 mmol) in THF (200 ml) was added dropwise, under ice-cooling, triethyl phosphonoacetate (10.3, g, 46.0 mmol). The mixture was stirred until the reaction mixture became a homogeneous solution. To the solution was added a suspension of 6-methoxy-1-indanone (7.10 g, 43.8 mmol) in THF (30 ml). The mixture was stirred for 2 hours at room temperature and for further 12 hours at 70° C. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was dissolved in ethanol (200 ml), to which was added 5% Pd-C (50% hydrous, 2.5 g). The mixture was stirred for 1.5 hours at 50° C. under hydrogen atmosphere. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (hexane/ethyl acetate, 97:3→4:1) to give 6.55 g (yield 64%) of the above-titled compound as an oily product.