Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[CH2:43]([NH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:62]([N:61]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 93.8 %

Procedure:
Lithocholic acid (81) (7.1 g, 18.8 mmol) was sissolved in anhydrous tetrahydrofuran (60 mL). Isobutylchloroformate (2.6 g, 2.6 mL, 18.8 mmol) was added followed by the addition of triethylamine (3.84 g, 5.3 mL, 38 mmol) and dioctadecylamine (9.8 g, 18.77 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL). The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 82 (15.5 g) in 93% yield. This was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)CC)C.[CH3:54][Si:55]([C:58]#[CH:59])([CH3:57])[CH3:56]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:59]#[C:58][Si:55]([CH3:57])([CH3:56])[CH3:54])[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH3:13])=[N:7]2
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was purged with nitrogen and charged with compound 138 (220 mg, 0.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (27.1 mg, 0.039 mmol), and anhydrous DMF (1 mL). Triethylamine (146 mg, 1.44 mmol) and (trimethylsilyl)acetylene (102 mg, 1.04 mmol) were added, and the reaction mixture was stirred for 10 h at 90° C. and an additional 8 h at 100° C. Evaporation of the reaction mixture to dryness followed by column chromatography purification afforded 63% yield of compound 139 as an off-white solid. 1H NMR (CD3OΔ)δ (ppm) 7.43-8.33 (m, 8H), 7.30 (d, 1H, J=6.6 Hz), 5.64 (s, 2H), 5.14 (bs, 1H), 3.68 (t, 2H, J=8.0 Hz), 2.81 (s, 3H), 1.59-1.64 (m, 3H), 0.94 (m, 2H), 0.32 (s, 9H), −0.09 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.C(Cl)(=O)C([Cl:16])=O>ClCCCl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([Cl:16])=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c[nH]c2ccccc12
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1H-indole-3-carboxylic acid (3.00 g, 18.6 mmol) was suspended in 1,2-dichloroethane (15 mL), and oxalyl chloride (2.42 mL, 25.38 mmol) was added dropwise. To this reaction liquor, a catalytic amount of DMF (one drop) was added, and the reaction liquor was stirred for one hour at room temperature. The solvent of the reaction mixture was distilled off under reduced pressure, to obtain 1H-indole-3-carboxylic acid chloride as a solid. The obtained acid chloride was suspended in 1,2-dichloroethane (20 mL), and (4-amino-2,5-dichlorophenyl)acetic acid ethyl ester hydrochloride (4.82 g, 16.92 mmol) was added thereto. The mixture was heated to ref lux for 18 hours with stirring. The reaction mixture was left to cool naturally to room temperature, and then the solvent was distilled off under reduced pressure. The obtained solids were dissolved in chloroform (100 mL), washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained solids were collected by filtration using hexane, to obtain [2,5-d]chloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic acid ethyl ester (5.95 g, 90%) as a solid. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: [Na+].[O:2]=[S:3]1(=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]([CH2:13][C:14]([O-])=[O:15])=[N:4]1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:2]=[S:3]1(=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]([C:13]2[C:14](=[O:15])[N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C@@H:28]3[C@H:23]([C:21]=2[OH:20])[C@@H:24]2[CH2:38][C@H:27]3[CH2:26][CH2:25]2)=[N:4]1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2ncccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3ncccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 6.9 %

Procedure:
The crude (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid sodium salt (˜0.928 mmol), (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.27 g, 0.928 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.494 g, 1.3 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (2 mL). The mixture was stirred at 25° C. for 1.5 h. Triethylamine (0.697 mL, 5 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with ethyl acetate (˜15 mL) and the product solidified. The solid was collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.03 g, 0.064 mmol, 6.9%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.92-1.05 (2H, m), 1.18-1.46 (4H, m), 2.26 (1H, d, J=3.1 Hz), 2.36 (1H, d, J=9.5 Hz), 2.45 (1H, d, J=3.0 Hz), 3.15 (1H, d, J=9.4 Hz), 4.13 (1H, d, J=15.6 Hz), 4.86 (1H, d, J=15.6 Hz), 7.01-7.05 (2H, m), 7.16-7.20 (2H, m), 7.39-7.42 (1H, m), 7.50 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 8.26 (1H, dd, J1=4.6 Hz, J2=1.5 Hz). LC-MS (ESI) calcd for C23H21FN4O4S 468.13, found 469.2 [M+H+].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[OH:27].O>CN(C=O)C.CCOC(C)=O>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3c2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracated with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].P(Cl)(Cl)([Cl:14])=O>[Cl-].C[N+](CC)(CC)CC.C(#N)C>[NH2:3][C:2]1[N:4]=[C:5]2[C:9]([NH:8][CH:7]=[N:6]2)=[C:10]([Cl:14])[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: CC[N+](C)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 58.1 %

Procedure:
A mixture of guanine (22.7 g, 0.15 mol), methyltriethylammonium chloride (TEMAC) (45.5 g, 0.3 mol), phosphorus oxychloride (82.6 ml, 0.9 mol) and acetonitrile (67 ml) was heated at 60° C. with stirring for 6 hours and then cooled to 10° C. The solid material was filtered off and suspended in water (300 mls). The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide to achieve dissolution and powdered carbon (6.8 g) added. The mixture was stirred for 1 hour and then filtered to remove the carbon. Acetone (72 mls) was added and then the pH reduced to 7 with dilute hydrochloric acid. The product was filtered off, washed with acetone/water (50:50 mixture, 50 mls), water (50 mls), acetone/water (50:50 mixture, 50 mls) and acetone (50 mls) and then dried to give 2-amino-6-chloropurine as a cream coloured solid (14.77 g, 54 % yield).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].C(O)(=O)C.Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O>C(O)C>[C:1]([O:4][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
78.5 g (0.80 mol) of potassium acetate, 5.0 g (0.08 mol) of acetic acid and 123.7 g (0.80 mol) of 2-chloroacetophenone was heated under reflux in 500 ml of ethanol for 6 hours. After the completion of heating, the reaction solution was cooled to room temperature, precipitated potassium chloride was filtered off, and ethanol was evaporated off under reduced pressure, giving an oily and caramel-like substance. The obtained oily substance was poured into 1 liter of water and the precipitated yellowish-brown crystalline solid was filtered off, followed by recrystallization from methanol, giving 113.1 g (0.635 mol, 79.3% yield) 2-acetoxyacetophenone.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
N-Bromosuccinimide (8.1 g) and azo(bisisobutyronitrile) (130 mg) were added to a solution of compound (B) (9.3 g) in carbon tetrachloride (300 ml). The mixture was heated under reflux for 4 hours and then cooled to ambient temperature. Insoluble material was removed by filtration and the filtrate concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v) to give methyl 4'-(bromomethyl)biphenyl-2-carboxylate (C) as a solid (10.9 g), m.p. 48°-50° C.; NMR: 3.65(s,3H), 4.55(s,2H), 7.25-7.60 complex (m,7H), 7.85(d,1H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]([N:38]=[C:39]=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([NH:38][C:39]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 49 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.28 g, 1.9 mmol) was added to stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitnile (50 ml). After stirring for 1 hour, t-butylisocyanate (0.21 g, 2 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (70 ml) and washed with 0.1 N HCl (20 ml), water (20 ml), brine (20 ml) and dried. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol/isopropyl ether to give 0.36 g (51%) of the product: mp 186-188° C.; 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 7.77-7.59 (m, 3H), 6.17 (t, J=6.2 Hz, 1H), 5.86 (s, 1H), 5.08-5.01 (dd, J=5.4 and 12.4 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 2.82-2.73 (m, 1H), 2.54-2.40 (m, 2H), 1.98-1.94 (m, 1H), 1.12 (s, 9H); 13C NMR (DMSO-d6) δ 172.33, 169.39, 167.11, 166.59, 156.85, 140.72, 134.20, 132.99, 131.06, 126.54, 121.20, 48.69, 48.37, 37.89, 30.46, 28.88, 21.53; Anal. Calcd. For C19H22N4O5+0.2 water: C, 58.51; H, 5.79; N, 14.37. Found: C, 58.86; H, 6.15; N, 14.24.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 15 °C
Reaction time: 19 h

Procedure:
To a stirred suspension of 4-imidazole carboxaldehyde (from Maybridge Chemicals, United Kingdom) (35.0 g, 364 mmol) and triethylamine (55.8 mL; 400 mmol) in dichloromethane (2 L), was added a solution of triphenylmethyl chloride in dichloromethane (600 mL) while maintaining the reaction temperature at approximately 15° C. with a cooling bath. The resultant solution was warmed to room temperature and stirred for 19 h. Washed the reaction solution with a solution of saturated brine and water (1:3.5; 3×600 mL), followed by brine (1×800 mL). Dried over sodium sulfate; filtered to remove drying agent; and removed solvent under vacuum to obtain the desired tritylated product (7) as an off-white solid. MP 186.5-194° C. [Trituration of this product with ether yielded a cream-colored powder with mp 195-197° C.]
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C(N(CC)CC)C>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:34](=[O:35])[C@H:32]([CH3:33])[NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 12.9 g of glycine benzyl ester tosylate in 200 ml acetonitrile cooled to 0° C., was added dropwise triethylamine (5.3 ml), followed by addition of 12 g of N-tert-butyloxycarbonylalanine N-hydroxysuccinimide ester (prepared by reaction of N-tert-butyloxycarbonylalanine with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide). The resulting solution was stirred at 0° C. for one hour and then at room temperature for 18 hours. At the end of reaction, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and the extract was washed with 5% acetic acid, water and saturated aqueous solution of sodium chloride in that order, giving 16 g of crude product. Purification of this crude product by silica gel chromatography (chloroform:methanol=40:1) afforded 12.6 g of pure N-tert-butyloxycarbonyl-L-alanyl-glycine benzyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15]Cl)[CH:14]=1>>[Br:8][C:9]1[CH:14]=[C:13]([CH2:15][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[CH:12]=[N:11][CH:10]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=C1CCCCN1
Product: O=C1CCCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], piperidin-2-one has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a colorless oil. MS: 269.2, 271.2 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][C:12]2=[O:11])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(C2CCCC2O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cccc(C2CCCC2=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of oxalic chloride (9.0 ml) in methylene chloride (200 ml) was added dimethyl sulfoxide (9.6 ml) at -78° C. After 10 minutes, to the solution was added a solution of 1-hydroxy-2-(3-methoxyphenyl)cyclopentane (13 g) in methylene chloride (20 ml) at the same temperature. After 15 minutes, to the mixture was added triethylamine at -78° C. and the mixture was warmed at 0° C. for 1 hour. The reaction mixture was washed with water and brine and dried over magnesium sulfate. The organic solution was concentrated and the residue was purified by column chromatography on silica gel to give 2-(3-methoxyphenyl)cyclopentanone (8.9 g).
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Na+].[I-].C[Si](C)(C)[C:22]([F:25])(F)[F:23].C1COCC1>C(Cl)Cl>[F:23][C:22]1([F:25])[CH2:3][CH:2]1[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a sealed tube was added tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate 11B (280 mg, 1.16 mmol), NaI (112 mg, 0.74 mmol), trimethyl(trifluoromethyl)silane (0.6 mL) and THF (10 mL), The tube was sealed, and then the mixture was stirred at 80° C. overnight. The resulting mixture was diluted with DCM, filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which was used for next step without further purification. LC-MS: m/z 292.3 (M+H)+
Reaction SMILES: CC(N(C)C)=O.CC(C)([O-])C.[Na+].[CH2:13]([C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:26])[C:24]=1[CH3:25])=[CH:21][C:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:19]([CH3:39])[CH:18]=2)[CH3:14].Cl[C:41]([O:43][CH3:44])=[O:42]>O>[C:41](=[O:42])([O:43][CH3:44])[O:26][C:23]1[C:22]2[C:17](=[CH:18][C:19]([CH3:39])=[C:20]([O:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=3)[CH:21]=2)[N:16]=[C:15]([CH2:13][CH3:14])[C:24]=1[CH3:25]
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Reactant: COC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Dimethylacetamide (694 ml), 35.2 g of sodium t-butoxide, and 131 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one were added into a 1000-ml glass flask equipped with a stirring device, a thermometer, and a reflux condenser under a nitrogen atmosphere, and the mixture was stirred at room temperature. Methyl chloroformate (34.4 g) was added dropwise thereto, and a reaction was allowed to proceed at room temperature for one hr. The reaction mixture was poured into 1735 ml of water contained in a 5-L plastic container, and the mixture was stirred at room temperature for two hr. The precipitated solid was collected by filtration through a suction filter and was washed with water. The solid was dried under the reduced pressure to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (149.5 g, yield: 98.8%). The results of 1H-NMR analysis showed that the compound thus obtained was No. 120 described in a brochure of International Publication No. 2006/013896.
Reaction SMILES: CS(C)=O.I[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12].O=[C:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu-]=O.O>[CH3:21][C:14]1[NH:12][C:7]2[C:6]([C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Nc1ccccc1I
Reactant: CCOC(=O)CC(C)=O
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c(C)[nH]c2ccccc12
Temperature: 100 °C
Reaction time: 9 h
Yield: 15.1 %

Procedure:
To a mixed solution of dimethyl sulfoxide and water (20 mL), 2-iodobenzenamine (3.0 g, 13.7 mmol), ethyl 3-oxobutanoate (2.0 g, 15.1 mmol), copper(I) oxide (0.2 g, 1.4 mmol) and cesium carbonate (4.5 g, 13.7 mmol) was added. The mixture was stirred at 100° C. for 9 hours under nitrogen gas atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic phase was concentrated in vacuo, and then the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give ethyl 2-methyl-1H-indole-3-carboxylate as a light yellow solid (0.42 g, 15%). 1H NMR (300 MHz, CDCl3): δ 8.12-8.09 (m, 1H), 7.31-7.16 (m, 3H), 4.40 (q, J=6.9 Hz, 2H), 2.77 (s, 3H), 1.45 (t, J=6.9 Hz, 3H).