Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:37][CH2:38][CH2:39][O:40][CH3:41]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[O:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: COCCOc1c(CCl)ccc2ccccc12
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2OCCOC)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86 (b)] with 2-chloromethyl-1-(2-methoxy-ethoxy)-naphthalene [Example 122 (h)] there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, from which by cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152 (e) there was obtained tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate. Subsequent alkylation with 3-phenyl-isoxazol-5-ylmethyl methanesulphonate analogously to Example 44 (e) gave tert-butyl (3RS,4RS)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-4-[4-(3-phenyl-isoxazol-5-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 665 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[C:11]([CH3:17])([CH3:16])[S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.CCN(CC)CC.[CH2:42]([NH2:45])[CH:43]=[CH2:44].Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:15])[NH:45][CH2:42][CH:43]=[CH2:44])[C:11]([CH3:17])([CH3:16])[S:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N1CSC(C)(C)[C@H]1C(=O)O
Agent: Cl
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCNC(=O)[C@H]1N(C(=O)OC(C)(C)C)CSC1(C)C
Temperature: 2 °C

Procedure:
(4R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (which can be prepared according to the methods of Ikunaka, M. et al., Tetrahedron Asymm. 2002, 13, 1201; Mimoto, T. et al., J. Med. Chem. 1999, 42, 1789; and Mimoto, T. et al., European Patent Application 0574135A1 (1993), 250 g; 0.957 mol) was added to an argon-purged 5-L flask and was dissolved in EtOAc (1.25 L). The solution was cooled to 2° C. and (PhO)2POCl (208 mL; 1.00 mol) was then added in one portion. NEt3 (280 mL; 2.01 mol) was added dropwise via addition funnel and the resulting suspension was then stirred at 0° C. Seven minutes later, allylamine (75.4 mL; 1.00 mol) was added dropwise. The ice bath was removed and the suspension was allowed to warm to room temperature. One-half hour later, 1 N HCl (750 mL; 0.750 mol) was added. The mixture was transferred to a 4-L separatory funnel using EtOAc (50 mL) for rinsing. The layers were separated. The organic fraction was washed with 7.2% aqueous Na2CO3 (2×1.25 L), and was then transferred to a 3-L distillation flask and was diluted with EtOAc (400 mL). The solution was dried azeotropically and concentrated to a volume of 800 mL by distillation of EtOAc at one atmosphere. After cooling to 25° C., the resulting clear yellowish EtOAc solution of (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester was carried on directly into the next step. An aliquot was removed and concentrated to give (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester as a white crystalline solid: mp=94–98° C., 1H NMR (300 MHz, CDCl3) δ 6.12 (br s, 1H), 5.88 (app ddt, J=10.2, 17.1, 5.6 Hz, 1H), 5.28 (app dq, J=17.1, 1.5 Hz, 1H), 5.18 (app dd, J=1.2, 10.2 Hz, 1H), 4.68 (s, 2H), 4.14 (br s, 1H), 3.95 (br t, J=5.4 Hz, 2H), 1.62 (s, 3H), 1.49 (s, 9H), 1.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.0, 154.0, 134.4, 116.9, 82.0, 73.3, 54.0, 48.7, 42.0, 30.6, 28.6, 24.6; MS (CI) m/z 301.1599 (301.1586 calcd for C14H25N2O3S, M+H+); elemental analysis calcd for C14H24N2O3S: C, 55.97; H, 8.05; N, 9.32; found: C, 56.11; H, 8.01; N, 9.11.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3]>C(O)C.[Pd]>[CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH2:2][CH3:3]
Reactant: C=CCN1Cc2cccc3c2C(C1)c1ccc(OC)c(OC)c1O3
Agent: [Pd]
Solvent: CCO
Product: CCCN1Cc2cccc3c2C(C1)c1ccc(OC)c(OC)c1O3
Reaction time: 3 h
Yield: 91.2 %

Procedure:
N-Allyl amine 10a (1.033 g; 3.2 mmol) was dissolved in 50 ml of ethanol. Palladium on charcoal (10% dry; 0.103 g) was then added. The mixture was shaken on a Parr hydrogenator under 60 psi H2 for 3 hours. After TLC showed no more starting material, the mixture was filtered through Celite and concentrated to give 0.95 g (91%) of an oil that was used without further purification: 1H NMR: (300 MHz, CDCl3): 7.15 (t, 1H, J=7.2 Hz); 7.04 (d, 1H, J=8.1 Hz); 6.84 (t, 2H, J=7.5 Hz); 6.65 (d, 1H, J=8.4 Hz); 4.07 (m, 2H); 3.95 (s, 3H); 3.86 (s, 3H); 3.71 (q, 1H, J=5.1 Hz); 3.42 (d, 2H, J=15.6 Hz); 2.62 (m, 2H); 2.471 (t, J=10.5 Hz); 1.69 (h, 2H, J=7.2 Hz); 0.98 (t, 3H, J=7.5 Hz). CIMS m/z: 326 (M+H+, 100%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1.O>CN(C=O)C>[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][N:15]=1)([O-:19])=[O:18]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
8.1 Phenol (25 mmol) is dissolved in DMF (30 ml) and NaH (1.1 eq., 60% suspension in liquid paraffin) is added at 0° C. 5-Bromo-2-nitro-pyridine (1.0 eq.) in DMF (20 ml) is added and stirred 16 h at RT. The reaction solution is poured into water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 2-Nitro-5-phenoxy-pyridine is obtained after column chromatography (heptan/ethyl acetate) as a brown oil in a yield of 78%; HPLC (method A): 1.95 min; LC-MS: 1.678 min, 217.15 (M+H+).
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[C:10]([O:16]C)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[C:18](Cl)(=[O:20])[CH3:19].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCCl.CC(O)C.CC(O)=O>[C:18]([C:13]1[S:12][C:11]2[C:10](=[O:16])[C:9]3[C:4]([C:3](=[O:2])[C:15]=2[CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: COc1c2ccccc2c(OC)c2sccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)c1cc2c(s1)C(=O)c1ccccc1C2=O
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To 4 (1.5 g) in 1,2-dichloroethane (120 mL) were added acetyl chloride (4.3 mL, 55 mmol) and AlCl3 (7.3 g, 55 mmol). The resulting mixture was stirred at 5±2° C. for 4 h and then poured into ice water and acidified with conc. HCl. The organic layer was washed with water, dried over anhydrous MgSO4 and evaporated. CrO3 (0.5 g, 50 mmol) and HOAc (12 mL) were added to the residue. The mixture was stirred at room temperature for 8 h, and then i-PrOH (30 mL) was added, and the resulting solution extracted with CHCl3. The organic layer was washed with saturated NaHCO3, dried over anhydrous MgSO4 and evaporated. Column chromatography (silica gel, CHCl3) gave compounds 5, 6, and 7 in 20, 11, and 9% yields, respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cn2)CC1
Yield: 56.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (380 mg) described in Preparation Example 151 and oxazolidin-2-one (91 mg), the title compound (217 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17]Cl)=[N:15][N:16]=2)[CH:3]=1.[CH3:19][CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:25]3[CH2:26][CH2:27][N:22]([CH:20]([CH3:21])[CH3:19])[CH2:23][CH2:24]3)=[N:15][N:16]=2)[CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: Cn1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Product: CC(C)N1CCN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)CC1
Temperature: 90 °C
Yield: 93.1 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-methyl-1H-indazole (260 mg, 0.794 mmol) and 1-(1-methylethyl)piperazine (1.5 ml, 0.794 mmol) were added to a microwave vial. The reaction mixture was heated under microwave irradiation at 90° C. for 15 mins. The reaction mixture was evaporated under a stream of nitrogen, dissolved in DCM (20 ml) and washed with a 10% solution of 2M hydrochloric acid in water. The layers were separated by hydrophobic frit and the aqueous layer was neutralised to pH=7 with 2M sodium hydroxide then extracted with DCM (20 ml). The organic layer was collected and the solvent removed in vacuo to give the title compound as an orange solid (310 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]1([CH3:15])[C:7]([C:12](Cl)=[O:13])=[CH:8][CH:9]=[CH:10][CH:11]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:6]1([CH3:15])[C:7]([C:12]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:13])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(O)CN
Reactant: Cc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)NCC(C)O
Yield: 58 %

Procedure:
To 100 ml of a solution of 5.83 g of 1-amino-2-propanol in toluene, 18.0 ml of triethylamine was added, and 10 ml of a solution of 10.00 g of o-toluoyl chloride in toluene was added dropwise slowly with stirring under ice-cooling. After 30-minute-stirring, the ice-bath was removed, and the mixture was stirred for additional 1 hour at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid, ice-cold water and saturated aqueous sodium hydrogen carbonate solution sequentially, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was crystallized by addition of diethyl ether to provide 7.25 g of the objective compound as colorless crystals. M.p. 78–81° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([O:16][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:38])[F:39])=[CH:37][CH:36]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cccc(-c2nc(O)c3c(n2)CCN(Cc2ccccc2)C3)c1
Product: O=[N+]([O-])c1cccc(-c2nc3c(c(OCc4ccc(C(F)(F)F)cc4)n2)CN(Cc2ccccc2)CC3)c1

Procedure:
The title compound was prepared from 6-benzyl-2-(3-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 9) and 4-(trifluoromethyl)benzyl bromide according to Method A; LC retention time 2.95 min; MS: m/z (ESI) 521 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH2:8][NH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:45])(=O)=O>CN(C=O)C>[Cl:45][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2=CC=C(CO)CN2)C(OCc2ccc3ccccc3c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCl)cn2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A solution of 70 mg (0.156 mmol) of tert-butyl (3'RS,4'RS)-5-hydroxymethyl-3'-(naphthalen-2-ylmethoxy)-3',4',5',6-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate in 2 ml of absolute DMF was cooled to -10° C. and treated with 26 μl (19 mg, 0.187 mmol) of triethylamine. 13 μl (20 mg, 0.172 mmol) of methanesulphonyl chloride and 2 mg of N,N-dimethylaminopyridine (DMAP) were added at -10 to -15° C. and subsequently the mixture was stirred at 0° C. for 1 hour. For the working-up, the mixture was partitioned between 25 ml of ethyl acetate and 25 ml of aqueous 5% ammonium chloride solution and the organic phase was separated. The aqueous phase was extracted three times with 10 ml of ethyl acetate each time. The combined ethyl acetate phases were dried over magnesium sulphate and finally evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 22 mg (35% of theory) of tert-butyl (3'RS,4'RS)-5-chloromethyl-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate as a light yellow oil; MS: 467, 469 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C=O)C>[Si:13]([O:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C1CC(O)CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Temperature: 0 °C

Procedure:
4-Hydroxy-2-pyrrolidone (1.00 g, 9.89 mmol) was suspended in DMF (25 mL) and cooled to 0° C. Imidazole (1.01 g, 14.84 mmol) and TBS—Cl (1.57 g, 10.39 mmol) were added and the reaction was then warmed to room temperature. After 30 minutes the reaction was poured into water (˜50 mL) and the resulting white precipitate was collected by filtration, dried in an oven, and used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]O.P(Br)(Br)[Br:13]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9][Br:13]
Reactant: BrP(Br)Br
Reactant: CC1(C)CCC(C)(C)C1CO
Solvent: c1ccccc1
Product: CC1(C)CCC(C)(C)C1CBr
Temperature: 0 °C

Procedure:
2,2,5,5-Tetramethyl-1-cyclopentylmethanol is dissolved in benzene and stirred at 0° C. under argon. A solution of phosphorus tribromide in benzene is added and the mixture is stirred for 2 hours and then heated to 60° C. for 4 hours. The mixture is cooled, poured into ice and extracted with ether. The organic layer is washed with saturated NaHCO3, dried over MgSO4 and evaporated to yield 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide.
Reaction SMILES: CC(NC(C)C)C.C([Li])CCC.[C:13]1([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:29][C:30]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](OCC)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])[CH3:31]>C1COCC1.CCCCCC.O>[C:13]1([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:42]([CH:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:35])[CH2:37][CH2:38]2)=[O:43])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: c1ccc(Cn2cnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
A mixture of N-(1-methylethyl)-2-propanamine (16.7 g) in THF (600ml) was stirred at −70° C. under N2 flow. Butyllithium in hexane (63 ml; 2.5 M) was added portionwise and the temperature was allowed to rise to −40° C. and stirring was continued for 15 minutes. The mixture was cooled to −70° C. and a suspension of 1-(phenylmethyl)benzimidazole (31.3 g) in THF was added dropwise. After stirring for 1 hour at −70° C., 4-(ethoxy-carbonyl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (42.5 g) was added dropwise and stirring at −70° C. was continued for 1.5 hours. The temperature was allowed to rise to RT and the mixture was decomposed with water, and further extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was crystallized from acetonitrile, yielding 54 g (85.8%) of (1,1-dimethylethyl) 4-[[1-(phenylmethyl)-1H-benzimidazol-2-yl]carbonyl]-1-piperidinecarboxylate (interm. 1; mp. 121.5° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1)=O>O1CCOCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]2[N:7]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[O:23][CH:22]=[N:21][CH:20]=4)=[CH:15][CH:14]=3)[N:1]=2)[CH:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=C(CBr)c1ccc(-c2cnco2)cc1
Solvent: C1COCCO1
Product: Brc1cnc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 86.1 %

Procedure:
2-Amino-5-bromopyrimidine (348 mg) and 2-bromo-1-[4-(1,3-oxazol-5-yl)phenyl]-1-ethanone (532 mg) were suspended in 1,4-dioxane (20 mL), followed by refluxing under heating overnight. Immediately after refluxing, the reaction mixture was filtered without being cooled, followed by washing with heated 1,4-dioxane and drying, to thereby yield the title compound (587 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O>N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:11][CH2:10][CH2:9]2
Reactant: COc1cccc(CCNC(=O)c2ccccc2)c1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN=C2c1ccccc1
Temperature: 0 °C
Yield: 108.9 %

Procedure:
A solution of N-[2-(3-methoxyphenyl)ethyl]benzamide (1.530 g, 5.99 mmol) in phosphorous oxychloride (10 ml, 107.3 mmol) was refluxed under N2 for 24 hours. The cooled reaction mixture was then slowly added to ice-water (50 ml) with stirring, and basified to pH 10 with concentrated ammonia (60 ml). This was extracted with CHCl3 (4×25 ml), and the combined organic extracts were dried over MgSO4 then concentrated in vacuo to give 1.548 g (100% yield) of yellow oil.
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:15][CH2:16][CH2:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9]1[O:13][CH:12]([CH3:14])[CH2:11][O:10]1)[CH2:2][CH3:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][CH2:32][C:33](Cl)=[O:34]>O>[CH2:16]([O:15][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][N:7]([CH2:8][CH:9]1[O:13][CH:12]([CH3:14])[CH2:11][O:10]1)[C:33](=[O:34])[CH2:32][Cl:31])[CH2:17][CH3:18]
Reactant: CCCOC(CNCC1OCC(C)O1)OCCC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCOC(CN(CC1OCC(C)O1)C(=O)CCl)OCCC

Procedure:
N-(2,2-Dipropoxyethyl)-N-(4-methyl-1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]1.N1CCCC1.O>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:14]1([CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCCOC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Yield: 79.4 %

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (8.2 g, 38.13 mmol), dihydro-pyran-3-one (4.96 g, 49.57 mmol) and pyrrolidine (4.12 mL, 49.57 mmol) in toluene (80 mL) was stirred at 50° C. for 1 h. The temperature was increased to reflux, and the reaction was refluxed for 22 h. Additional dihydro-pyran-3-one (0.5 g 5 mmol) was added and the mixture was refluxed for an additional 24 h. The mixture was allowed to reach r.t., and then water (50 mL) followed by EtOAc (100 mL) was added. The organic layer was concentrated and the residue was purified by flash chromatography using a gradient of heptane to 40% EtOAc in heptane to give the title compound (9 g, 79% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.57 (m, 1 H), 1.72 (ddd, 1 H), 1.96 (m, 1 H), 2.12 (m, 1 H), 2.71 (m, 2 H), 3.51 (d, 1 H), 3.58 (m, 1 H), 3.86 (m, 2 H), 6.96 (d, 1 H), 7.57 (dd, 5 H), 7.97 (d, 4 H); MS (ES+) m/z 297 [M+H]+.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](/[CH:17]=[CH:18]/[N+:19]([O-])=O)=[CH:13][NH:14]2)=[CH:10][CH:9]=1.C(OCC)(=O)C>O1CCCC1>[F:7][C:8]1[CH:16]=[C:15]2[C:11](=[CH:10][CH:9]=1)[C:12]([CH2:17][CH2:18][NH2:19])=[CH:13][NH:14]2
Reactant: O=[N+]([O-])/C=C/c1c[nH]c2cc(F)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCc1c[nH]c2cc(F)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Aluminum lithium hydride (1.36 g) was suspended in tetrahydrofuran (72 ml), 6-fluoro-3-[(E)-2-nitrovinyl]-1H-indole (1.48 g) was dissolved in tetrahydrofuran (20 ml) and added dropwise under ice-cooling, and the mixture was stirred at 60° C. for 1 hr. Under ice-cooling, excess aluminum lithium hydride was decomposed with ice water, ethyl acetate was added, and the mixture was filtered through a celite (trademark) filter. A 1N aqueous sodium hydroxide solution was added to the filtrate, pH was adjusted to not less than 11, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a brown oil. The oil was purified by amine coating silica gel column chromatography (elution solvent:ethyl acetate-ethyl acetate-methanol (10:1)) to give 6-fluorotryptamine (1.24 g, yield 97%).