Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([NH:16][CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[CH3:20]S(O)(=O)=O.O1CCCOO1>ClCCl>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]2[NH:12][S:13](=[O:15])(=[O:14])[N:16]([CH:17]([CH3:18])[CH3:19])[CH2:20][C:10]=2[CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)O
Reactant: CCS(=O)(=O)c1ccc(NS(=O)(=O)NC(C)C)cc1
Agent: C1COOOC1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(4-Ethylsulfonylphenyl)-N′-(1-methylethyl)sulfamide (5 g, 0.016 mol) was dissolved in dry dichloromethane (150 ml) and methanesulphonic acid (18.87 ml, 0.303 mol). The solution was cooled at 0° C. before the addition of trioxan (0.480 g, 0.005 mol) in dichloromethane (15 ml). After stirring at 0° C. for 1 hr, the reaction mixture was poured onto ice-water (250 ml), the layers separated, dried (MgSO4) and concentrated in vacuo to yield 3,4-dihydro-6-(ethylsulfonyl)-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as a white solid. δ(1H NMR, DMSO, ppm): 1.10 (9H, m), 3.30 (2H, q), 4.10 (1H, m), 4.80 (2H, s), 6.95 (1H, d), 7.75 (1H, dd), 7.80 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[CH:7]=[C:8]([C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:15](=[O:17])[CH3:16])=[CH:7][C:6]=1[O:5][C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Oc2cccc(Cl)c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(N)c(Oc2cccc(Cl)c2)c1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A mixture of 3'-(3-chlorophenoxy)-4'-nitroacetophenone (2.4 g), iron powder (2.4 g) and ammonium chloride (0.24 g) in ethanol (32 ml) and water (16 ml) was refluxed with stirring for 1 hour. The insoluble was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), washed with water (20 ml), dried, and concentrated to give an oil of 4'-amino-3'-(3-chlorophenoxy)acetophenone (2.3 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:20])=[N:10]2.S(=O)(=O)(O)O.[N+:26]([O-])([OH:28])=[O:27].[OH-].[Na+]>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:20])=[N:10]2
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CF)[C@H]2CS1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (9.10 g, 0.03 mol, 1.0 equiv.) was dissolved in trifluoroacetic acid (36.4 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 12.0 mL) was added, followed by fuming nitric acid (6.9 mL) dropwise while maintaining the temperature below 5° C. After stirring at 0-5° C. for 4 h, the reaction mixture was slowly charged into a vigorously stirred solution of aq.NaOH (43.3 g in 273 mL water) while maintaining a temperature below 20° C. The mixture was extracted with CH2Cl2 (1×94 ml, and 2×64 mL), and the combined organic phases were washed with sat. aq. NaCl (46 mL). Celite (15.0 g) was added to the organics, and the mixture was filtered rinsing with CH2Cl2 (40 mL). The solvents were evaporated to afford the title compound (8.3 g) which was used in the subsequent step without purification. 1H NMR (500 MHz, DMSO) δ ppm 8.41-8.30 (m, 1H), 8.22-8.13 (m, 1H), 6.36 (s, 2H), 4.70-4.46 (m, 2H), 4.43-4.31 (m, 1H), 4.35 (d, J=8.7 Hz, 1H), 3.69 (dd, J=8.5, 1.6 Hz, 1H), 3.04-2.91 (m, 2H), 2.86-2.76 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 152.36 (dd, JCF=246.8, 12.3 Hz), 151.13, 150.32 (dd, JCF=238.2, 12.2 Hz), 143.25 (dd, JCF=7.9, 2.5 Hz), 134.70 (d, JCF=9.5 Hz), 121.28, 113.02 (d, JCF=22.3 Hz), 83.74 (d, JCF=170.1 Hz), 79.44 (d, JCF=18.3 Hz), 78.02 (d, J=3.9 Hz), 36.96, 23.28.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)CC=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
A mixture of diphenylacetaldehyde (19.6 g), malonic acid (10.9 g) and piperidine (0.4 mL) in pyridine (20 mL) was heated at reflux until the evolution of gas had subsided (1.25 h). The solution was cooled and poured into a stirred mixture of ice (100 g) and 2N hydrochloric acid (150 mL). The resulting solid was recovered by filtration, washed with water and dried to provide 23.1 g of 4,4-diphenyl-3-butenoic acid, mp 109°-111° C. A portion was crystallized from ethyl acetate-hexane to give the pure acid of 4,4-diphenyl-3-butenoic acid, mp 112.5°-114° C.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([O-])(=O)C.[Na+].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[CH:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCO
Agent: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: CCCCCCCCCC=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
6.08 g (38.4 mmol) of 1-decanol were dissolved in 58 ml of methylene chloride in a 200 ml sulphonation flask. 3.3 g (40.2 mmol) of sodium acetate and 3.6 g (15.5 mmol) of trichloroisocyanuric acid were added thereto. The mixture was cooled to 0° C. while stirring. A solution of 30 mg (0.12 mmol) of TEMPO derivative C in 3.5 ml of methylene chloride was dosed in within 30 minutes. The temperature was held at 0°-3° C. by constant cooling. The reaction had finished after 1 hour. The white precipitate was filtered off. The filtrate was worked up aqueous. 5.9 g (98%) of decanal were obtained as the crude product as a colourless liquid. GC content: 97% (area percent).
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>[NH2:8][C:7]1[N:9]=[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[NH:5][N:6]=1
Reactant: N=C(N)NN
Reactant: CCCCCCCCCCCC(=O)O
Agent: O=C(O)O
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCc1nc(N)n[nH]1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A slurry of aminoguanidine bicarbonate (8.0 g, 59 mmol), dodecanoic acid (11.8 g, 59 mmol), and N,N-dimethylaniline (0.1 mL, 0.8 mmol) in toluene (100 mL) was heated under reflux with the azeotropic removal of water (72 hours). The resulting slurry was cooled (25° C.) and concentrated in vacuo. The residue was partitioned between ethyl acetate (300 mL) and saturated sodium bicarbonate (300 mL). The aqueous layer was back extracted with ethyl acetate, and the combined organics were washed with brine (1×250 mL), then dried (MgSO4), and concentrated in vacuo. The resulting solid was dissolved in hot chloroform and chromatographed on silica (first ethyl acetate, then 90:10 chloroform:methanol). The product containing fractions were combined and concentrated in vacuo to yield 6.9 g (49.1%) of 3-amino 5-undecyl-1H-1,2,4-triazole as an off-white powder, m.p. 128.5°-132.0° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=[CH:19][N+:20]([O-])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[NH2:20][CH2:19][CH2:18][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:10]=2)[NH:14][CH:13]=1
Reactant: O=[N+]([O-])C=Cc1c[nH]c2ccc(CCc3ccccc3)cc12
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc(CCc3ccccc3)cc12
Yield: 56 %

Procedure:
A solution of the 5-phenethyl-3-(2-nitroethenyl)indole (0.1 g, 0.4 mmol)in dry THF was added dropwise to a cooled (ice bath) suspension of LiAIH4 (0.1 g, 2.4 mmol) in 5 ml of dry THF under nitrogen. The mixture was heated at reflux for 45 min. Excess LiAIH4 was destroyed by successive addition of H2O (0.15 ml), 15% NaOH (0.15 ml) and H2O (0.4 ml). The precipitate was removed by filtration and washed with THF (10 ml). After drying (MgSO4), the filtrate was evaporated under reduced pressure to give (56% yield) 3-(2-aminoethyl)-5-(2-phenylethyl)indole, a beige solid; mp 234°-236° C.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:29])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([Cl:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:32])=O>>[CH2:22]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([Cl:21])=[CH:15][CH:14]=2)[C:19]([Cl:32])=[C:10]([C:8]#[N:7])[C:11]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(NC1CCCCC1)c1c(O)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Yield: 51 %

Procedure:
A solution of Compound 65 (2 g, 4.86 mmol) in 20 mL neat phosphorus oxychloride was heated to 90° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 810 mg (51%) of yellow solids. M.P. 243° C. 1H NMR (DMSO-d6): δ 5.55 (s, 2H), 7.25 (m, 3H), 7.32 (m, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.85 (dd, J=2.1, 9.0 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H). EIMS m/z 352 (M+23).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.FC1C=CC=CC=1I>>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2F)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Fc1ccccc1I
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccccc2F)o1
Yield: 98 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(2-fluorophenyl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (75 mg, 0.113 mmol) and 1-fluoro-2-iodobenzene following General Procedure A. Flash chromatography (2% EtOAc/hexanes) yielded the title compound as a clear oil (52 mg, 98%): 1H NMR (CDCl3, 400 MHz) 7.77 (dt, 1H, J=9.6, 5.6 Hz), 7.42 (d, 1H, J=4.0 Hz), 7.31-7.21 (m, 4H), 7.18-7.13 (m, 4H), 4.85 (t, 1H, J=6.0 Hz), 2.59 (t, 2H, J=7.2 Hz), 1.90-1.93 (m, 2H), 1.62-1.60 (m, 2H), 1.33-1.36 (m, 6H), 0.90 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.7, 163.4 (d, J=250 Hz), 150.6, 157.9, 134.4 (d, J=8.3 Hz), 133.5, 133.3, 131.2 (d, J=12.6 Hz), 131.1, 131.1, 130.7, 129.6 (d, J=3.2 Hz), 121.7 (d, J=13.0 Hz), 120.1 (d, J=20.9 Hz), 73.8, 41.6, 41.0, 36.5, 34.3, 34.3, 30.9, 30.3, 23.3, 0.2, 0.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:8][C:9]([OH:11])=O)=[O:5])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C(#N)C.C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([CH2:7][CH2:8][C:9]([N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[O:11])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)C(CCC(=O)O)Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)C(CCC(=O)N1CCOCC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
600 mg (2.4 mmol) of (RS)-4-(ethoxycarbonyl)-5-phenylvaleric acid in 20 ml of acetonitrile were treated with 1.06 g (2.4 mmol) of BOP, 310 mg of Hunig base and 0.21 ml of morpholine and stirred at room temperature for 1 hour and thereafter at 50° for 2 hours. After the usual working-up and chromatography on silica gel using a 10:1 mixture of methanol and chloroform as the eluting agent, there were obtained 400 mg (52%) of (RS)-α-[2-(morpholinocarbonyl)ethyl]hydrocinnamic acid ethyl ester which was used directly in the next step. MS: 319 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:18]=[C:19](\[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)/[CH3:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC(=CBr)c1cccc(F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1cccc(F)c1
Temperature: 25 °C

Procedure:
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.45 (s, 1H), 7.25 (d, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 6.92 (t, 1H), 6.82 (s, 1H), 6.62 (m, 2H), 3.60 (m, 1H), 3.50 (m, 1H), 3.30-3.0 (m, 4H), 2.90 (s, 3H), 2.70 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[OH:15].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:27][C:28]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26].OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:27][C:28]1([C:34]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]2[OH:15])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
To the solution of tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate (20 g, 92 mmol) obtained in step 4 of Preparation Example 1 and 1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarboxylic acid (26 g, 92 mmol) obtained in step 2 of Preparation Example 2 in 150 ml of dimethylformamide, were added hydroxybenzotriazole(HOBt; 24 g, 180 mmol) and diisopropylethylamine (DIEA; 23 g, 180 mmol). The reaction mixture was cooled to 0° C. and was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl; 35 g, 180 mmol) thereto. The reaction mixture was stirred for 4 hours at room temperature, diluted with 300 ml of ethyl acetate, and washed with 10% citric acid solution, a saturated sodium bicarbonate solution and brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 30 g of the titled compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[CH3:10][NH:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1>>[CH3:10][N:11]([C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([OH:9])=[O:8])[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1
Reactant: O=C(O)CCCC(=O)O
Reactant: CNCCc1c[nH]c2ccccc12
Product: CN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)O
Temperature: 150 °C
Yield: 75 %

Procedure:
6.6 g of glutaric acid were added to 8.70 g of N-methyl-tryptamine (i.e., 3-(2-methylaminoethyl)-indole), and the mixture was heated at 150° C. under reduced pressure for 2 hours. After the reaction was completed, the product was recrystallized from a mixture of ethyl acetate and n-hexane. 10.8 g of N-methyl-N-(4-carboxybutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-carboxybutanamido)ethyl]-indole) were thereby obtained. M.p. 125°-126° C. Yield: 75.0%
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[S:4][N:3]=1>O1CCCC1>[Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[S:4][N:3]=1
Reactant: Cc1ccccc1-c1snc(Cl)c1C(=O)O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1snc(Cl)c1CO
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed 3-chloro-5-(2-methylphenyl)-1,2-thiazole-4-carboxylic acid (3 g, 11.82 mmol, 1.00 equiv), tetrahydrofuran (30 mL). This was followed by the addition of BH3(1M) (30 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 30° C. The reaction was then quenched by the addition of 30 mL of methanol. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (26/84). The collected fractions were combined and concentrated under vacuum. This resulted in 260 mg (9%) of [3-chloro-5-(2-methylphenyl)-1,2-thiazol-4-yl]methanol as yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([Cl:19])=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1)=[O:24])[CH3:21].ClCCl.O>C(#N)C.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:30]=[C:29]([C:2]2[C:3]([Cl:19])=[C:4]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]3=[N:6][CH:7]=2)[CH:28]=[N:27][CH:26]=1)[CH3:21]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(Br)cnc21
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)c1
Temperature: 110 °C
Yield: 56.4 %

Procedure:
1.59 g (4.40 mmol) of 5-bromo-4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine, 1.482 g (5.35 mmol) of 3-(ethoxycarbonyl)pyridine-5-boronic acid pinacol ester and 181 mg (0.22 mmol) of (1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct were dissolved in a mixture of 7 mL of acetonitrile, 7 mL of toluene and 8 mL of a saturated aqueous solution of sodium bicarbonate. The resulting mixture was heated to 110° C. in a closed vial for 15 h. The resulting mixture was distributed between dichloromethane and water. The aqueous phase was separated and extracted three times with dichloromethane and the once with ethyl acetate. The ethyl acetate phase was washed with brine and combined with the other organic phases, dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 1.0703 g (2.48 mmol, 56%) of 5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester as a pale yellow oil. 1H-NMR [500 MHz, d6-DMSO] δ: 9.15 (d, 1H), 8.97 (d, 1H), 8.41 (m, 1H), 8.40 (m, 1H), 7.89 (d, 1H), 5.69 (s, 2H), 4.38 (q, 2H), 3.55 (t, 2H), 1.35 (t, 3H), 0.84 (t, 2H), −0.08 (s, 9H); MS [MH+] m/z: 432+434.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([NH:5][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(F)cc1F
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
A solution of t-butylamine (0.2962 g, 4.05 mmol) and triethylamine (0.70 ml, 5.02 mmol) in dichloromethane (2 ml) was cooled to 0° C. in an ice-bath. To the above solution was added a solution of 2,4-difluorobenzoyl chloride (0.3652 g, 2.07 mmol) in dichloromethane (3 ml) dropwise and stirred for 2.5 hours. The mixture was added to saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous NaHCO3 and dried over MgSO4. The solvent was evaporated to give the title compound (0.4086 g; 93%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.N1([C:18](N2C=CN=C2)=[S:19])C=CN=C1>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]=[C:18]=[S:19])=[CH:4][CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Br)c2ccccc12
Solvent: ClCCl
Product: S=C=Nc1ccc(Br)c2ccccc12
Reaction time: 16 h

Procedure:
To a solution of 1-bromo-4-aminonapthalene (2.6 g, 12 mmol) in dichloromethane (45 mL) was added di(1H-imidazol-1-yl)methanethione (2.1 g, 12 mmol). The reaction was allowed to stir for 16 h, at which point the reaction was concentrated to give a gray solid. The solid was slurried in 50% EtOAc/hexanes and filtered through a pad of silica gel, rinsing with 400 mL 50% EtOAc/hexanes. The solution was concentrated to give 1-bromo-4-isothiocyanatonaphthalene as a gray solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1>>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH2:3][O:2][CH3:1])[CH:15]=1
Reactant: COC[C@@H]1CCCN1
Reactant: ClCc1cncc(Br)c1
Product: COC[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], (S)-2-(methoxymethyl)pyrrolidine has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a yellow oil. MS: 285.0, 286.9 (M+H+).
Reaction SMILES: CC1C=CC2C(=CC=CC=2)C=1C.[CH3:13][C:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=2[CH:17]=[CH:16][CH:15]=1>>[CH3:24][CH:23]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[C:19]=2[CH2:20][CH2:21][CH2:22]1
Reactant: Cc1cccc2c(C)cccc12
Agent: Cc1ccc2ccccc2c1C
Product: Cc1cccc2c1CCCC2C

Procedure:
The dimethylnaphthalene isomer mixture as a raw material introduced to the distillation column (1) for purification of low boiling point materials are a mixture comprising isomers rich in 1,5-DMN, and high boiling point and low boiling point hydrocarbons, which are produced from dehydrogenation of 1,5-DMT. Further, the mixture further comprises 2,6-DMN, 1,6-DMN, 1,5-DMN and other materials, which are recycled to a distillation column after separation and purification for crystallization, in the amounts as depicted in the following Table 1, respectively.