Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15](Br)[CH:16]=[C:11]2[N:10]=[N:9]1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)CCC>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccccc1)nnn2-c1ccccc1F
Temperature: 100 °C
Yield: 51.8 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.15 g, 0.37 mmol), tributylphenyltin (0.14 ml, 0.44 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.02 g, 5 mol %) in dry DMF (2 ml) was purged with nitrogen and heated in a sealed tube at 100° C. for 24 h. The mixture was cooled, diluted with water (50 ml) and extracted with 10% methanol-dichloromethane (2×25 ml). The extracts were washed with brine (20 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 2% methanol-dichloromethane, gave a yellow oil that solidified on trituration and washing with diethyl ether (2 ml). The material was recrystallised from ethyl acetate-hexane to give 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[4,5-b]pyridine (0.077 g, 52%) as a cream-coloured solid, m.p. 144-146° C. (EtOAc-hexane). Found: C, 62.00; H, 4.00; N, 24.01. C21H16N7OF.0.33(H2O) requires C, 61.91; H, 4.12; N, 24.07%. δH (360 MHz; CDCl3) 3.64 (3H, s), 5.56 (2H, s), 7.38-7.47 (5H, m), 7.53 (2H, dd, J=8 and 1), 7.56-7.62 (1H, m), 7.71 (1H, dd, J=8 and 8), 7.82 (1H, s) and 8.32 (1H, s); m/z (ES+) 402 (M+H+).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:44])[C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([C@H:32]([NH:35]C(OC(C)(C)C)=O)[CH2:33][CH3:34])[C:25]=2[F:43])=[CH:19][N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C@@H:32]([C:26]1[C:25]([F:43])=[C:24]([C:23]([C:20]2[CH:19]=[N:18][C:17]([NH2:7])=[CH:22][CH:21]=2)=[O:44])[C:29]([O:30][CH3:31])=[CH:28][CH:27]=1)[CH2:33][CH3:34]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC)c(C(=O)c2ccc(N(Cc3ccc(OC)cc3)C(=O)OC(C)(C)C)nc2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(OC)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 70 °C
Yield: 59.3 %

Procedure:
Step 3 {5-[3-((R)-1-tert-Butoxycarbonylamino-propyl)-2-fluoro-6-methoxy-benzoyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (0.063 g, 0.1 mmol) treated with TFA (2 ml) in DCM (3 ml) over 48 hours, still PMB group present heated at 70° C. for 3 hours. Reaction evaporated to dryness then triturated with diethyl ether to give [3-((R)-1-Amino-propyl)-2-fluoro-6-methoxy-phenyl]-(6-amino-pyridin-3-yl)-methanone (0.018 g). [M-NH2]+287
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[CH:13]([NH:16][OH:17])([CH3:15])[CH3:14]>>[CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[N+:16]([CH:13]([CH3:15])[CH3:14])[O-:17])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)NO
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: CC(C)[N+]([O-])=Cc1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3,4-ethylenedioxybenzaldehyde and N-isopropylhydroxylamine. The crude produce was purified by column chromatography over silica gel using ethyl acetate as the eluant. The title compound was isolated in 53% yield as a solid, m.p. 108.8° C. (Rf=0.31 on a silica gel plate using EtOAc as the eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:22].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[O:22])[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Clc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(C(=O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
A mixture of 3-(4-chlorophenyl)-5-(piperazin-1-yl)-1,2,4-thiadiazole (539 mg, 1.92 mmol), 2-bromo-4′-methoxyacetophenone (440 mg, 1.92 mmol) and DIPEA (744 mg, 1.01 ml, 5.76 mmol) in 10 mL EtOH was stirred for 2 h at RT. Another portion 2-bromo-4′-methoxyacetophenone (220 mg, 960 μmol) was added and stirring continued for 2 h. The reaction was filtered off and washed with MeOH (4×5 mL) and Et2O (2×5 mL). The filter cake was dried in vacuo at 50° C. to yield 526 mg (64%) of the title compound as white solid. MS (m/e): 429.2 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 5-bromo-2,2-dimethyl-1-pentanol (78 g, 0.35 mol) and p-toluenesulfonic acid (0.42 g) in dichloromethane (0.5 L) was added 3,4-dihydro-2H-pyran (45 mL) slowly at 0° C. The reaction mixture was stirred at rt overnight, or until no more starting material was evidenced by TLC. The mixture was filtered through aluminum oxide and was washed with dichloromethane (300 mL). The filtrate was evaporated under vacuum to produce 5-bromo-1-(tetrahydropyranyloxy)-2,2-dimethylpentane (101 g, 94.7% yield) as a pale-yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 4.48-4.52 (m, 1H), 3.90-3.75 (m, 1H ), 3.50-3.35 (m, 4H), 2.95 (d, J=12 Hz, 1H), 1.90-1.20 (m, 10H), 0.90 (s, 6H). 13C NMR (75 MHz, CDCl3=77.0 ppm/TMS): δ (ppm) 99.2, 76.3, 62.0, 38.0, 34.9, 34.2, 30.7, 28.0, 25.7, 24.8, 24.7, 19.3.
Reaction SMILES: [CH:1]1([C@H:4]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:18]I>C1COCC1>[CH:1]1([C@H:4]([NH:7][C@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:5][O:6][CH3:18])[CH2:3][CH2:2]1
Reactant: C[C@H](N[C@H](CO)C1CC1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H](N[C@@H](C)c1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]ethanol (29.2 g, 0.143 mol) in THF (700 mL) at 0° C. was added NaH (6.29 g, 0.157 mol, 60% dispersion in mineral oil). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. Methyl iodide (20.30 g, 0.143 mol) was then added dropwise via syringe. Some warming occurred soon after the addition was complete. The temperature of the reaction mixture was controlled at ˜25° C. with a water bath containing a small amount of ice. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then slowly quenched with saturated aqueous NaHCO3 solution and was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (400 mL). The aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (5% MeOH in 1:1 ethyl acetate/hexanes) to afford (S)-1-cyclopropyl-2-methoxy-N-[(S)-1-phenylethyl]-ethanamine (26.52 g, 85% yield) as a light brown oil: [α]25D−61.5 (c 0.72, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30-7.25 (m, 4H), 7.20-7.16 (m, 1H), 3.98-3.93 (q, J=6.8 Hz, 1H), 3.50 (dd, JAB=9.5, JAX=3.5 Hz, 1H), 3.35 (s, 3H), 3.34 (dd, JBA=9.5, JBX=5.8 Hz, 1H), 1.79-1.74 (m, 2H), 1.33 (d, J=6.5 Hz, 3H), 0.73-0.67 (m, 1H), 0.36-0.34 (m, 2W), 0.03-0.06 (m, 2H); GC/MS (ESI) m/e 220.2 [(M+H)+, calcd for C14H22NO 220.2].
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)Oc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(NC2CCNCC2)cc1
Yield: 93.5 %

Procedure:
A mixture of (1-benzylpiperidin-4-yl)-(4-trifluoromethoxyphenyl)amine (3.0 g, 8.3 mmol) prepared in Reference Example 129 and a catalytic amount of 10% palladium/carbon in ethanol (30 ml) was refluxed under an atmospheric pressure of hydrogen for 20 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) to afford piperidin-4-yl-(4-trifluoromethoxyphenyl)amine (2.02 g, yield 94%) as a colorless crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:29]([O:42][C:43]([NH:45][C:46]1[N:54]=[CH:53][N:52]=[C:51]2[C:47]=1[N:48]=[CH:49][N:50]2[CH2:55][C:56](O)=[O:57])=[O:44])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:56](=[O:57])[CH2:55][N:50]1[CH:49]=[N:48][C:47]2[C:51]1=[N:52][CH:53]=[N:54][C:46]=2[NH:45][C:43]([O:42][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:44])[CH3:2]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [6-N-(benzhydryloxycarbonyl)-adenin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 10.90 (s, 0.45H), 10.89 (s, 0.55H), 9.30 (brs, 0.55H), 9.12 (brs, 0.45H), 8.59 (s, 0.45H), 8.58 (s, 0.55H), 8.39 (d, 0.55H), 8.38 (d, 0.45H), 8.34 (s, 0.55H), 8.33 (s, 0.45H), 8.02–7.97 (m, 1H), 7.92 (d, 0.55H), 7.89 (d, 0.45H), 7.53 (d, 4H), 7.38 (t, 4H), 7.29 (t, 2H), 6.83 (s, 1H), 5.39 (s, 1.1H), 5.18 (s, 0.9H), 4.48 (s, 0.9H), 4.23 (q, 0.9H), 4.09 (s, 1.1H), 4.03 (q, 1.1H), 3.73 (t, 1.1H), 3.54 (t, 1.1H), 3.45 (t, 0.9H), 3.29 (t, 0.9H), 1.27 (t, 1.35H), 1.15 (t, 1.65H).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][CH:15]([N:17]1[C:21]([NH2:22])=[CH:20][CH:19]=[N:18]1)[CH3:16]>C1C=CC=CC=1>[CH3:14][CH:15]([N:17]1[C:21]2[N:22]=[C:9]([CH2:10][CH2:11][CH3:12])[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:20]=2[CH:19]=[N:18]1)[CH3:16]
Reactant: CC(C)n1nccc1N
Reactant: CCCC(=O)CC(=O)C(=O)OCC
Solvent: c1ccccc1
Product: CCCc1cc(C(=O)OCC)c2cnn(C(C)C)c2n1
Temperature: 62 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
To a solution of ethyl 2,4-dioxoheptanoate (446 mg, 2.397 mmol) in benzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and the mixture was stirred at 62° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (Silica gel, gradient of 0 to 100% EtOAc/hexanes) to give 370 mg (56%) of product. LCMS E-S (M+H)=276.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.12 (m, 3 H), 1.46-1.54 (m, 3 H), 1.58-1.70 (m, 6 H), 1.82-1.96 (m, 2 H), 2.91-3.02 (m, 2 H), 4.51 (q, J=7.2 Hz, 2 H), 5.28-5.44 (m, 1 H), 7.58-7.68 (s, 1 H), 8.27-8.40 (s, 1 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:24]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccco4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
Route 2: 2-(4-aminophenyl)-6-methyl benzothiazole (2.0 gm, 8.3 mmole) and 2-Furoyl chloride (1.086 gm., 8.32 mmole) were suspended in methylene chloride (30 ml, anhydrous). triethylamine (1.24 gm., 12.25 mmole) was added to the reaction mixture with stirring at room temperature for 2 days. (pH 7.0-7.2). Methylene chloride (50 ml) was added to the reaction mixture, and the reaction mixture extracted with 1 N HCl (50 ml) to separate a solid. The solid was filtered and washed with water to yield 1.3 gm. (46%) of the desired compound. The product was crystallized from MeOH to obtain 0.99 gm. mp. 238-240° C. 1H and 13C NMR were consistent with the expected product. TLC showed one spot (5% MeOH—CH2Cl2 as developing solvent on silica gel plate).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[N:8]1([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][NH:20][C:18]=3[N:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(O)=O>[CH:1]([N:11]1[CH2:10][CH2:9][N:8]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][NH:20][C:18]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1c[nH]c2nc(N3CCNCC3)ncc2c1=O
Solvent: O=CO
Product: O=CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Temperature: 50 °C

Procedure:
Formic acid (140 ml) was added dropwise to acetic anhydride (200 ml) cooled on an ice bath. The solution was heated at 50° C. for 15 minutes and then cooled to 5° C. To the solution, 5,8-dihydro-2-(1-piperazinyl)-5-oxopyrido[2,3-d] pyrimidine-6-carboxylic acid (70 g) was added. The mixture was heated at 80° C. for 3 hours and then cooled. The crystals precipitated were collected by filtration and washed with ethyl ether to give 5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (72.5 g). m.p. above 300° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:15]([CH2:19][C:20](=O)[CH3:21])[C:16]([CH3:18])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:21][C:20]1[CH:19]=[CH:15][C:16]([CH3:18])=[C:2]2[C:3]=1[C:4]1[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=1[NH:1]2
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)c1cccc2[nH]ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc2[nH]c3c(C)ccc(C)c3c12
Yield: 39.8 %

Procedure:
A mixture of 13.24 g of ethyl indole-4-carboxylate, 15.98 g of acetonylacetone and 13.31 g of p-toluenesulfonic acid monohydrate in 50 ml of ethanol was refluxed for 10 hours. The ethanol was evaporated under reduced pressure, the residue was chromatographed on silica gel column with hexane - ethyl acetate (9 : 1) to give 7.45 g of ethyl 5,8-dimethylcarbazole-4-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][CH2:11][CH2:12]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:10][CH2:11][CH2:12][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: FCCI
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCF)c1
Temperature: 70 °C

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 1-fluoro-2-iodoethane (3.849 g; 22.10 mmol), and K2CO3 (4.527 g; 32.80 mmol) in anh. DMF (30 ml) was heated to 70° C., under nitrogen, for 3 h. After cooling to rt, the reaction mixture was filtered over a pad of celite. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-(2-fluoroethoxy)benzaldehyde as a green oil. LC-MS (conditions A): tR=0.62 min.; no ionisation.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:14]([O:13][C:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of isonipecotic acid (5.0 g, 38.72 mmol) in 10% aqueous sodium carbonate (100 mL) was cooled to 0° C. and treated with benzyl chloroformate (7.93 g, 46.75 mmol). The resulting biphasic mixture was allowed to warm to room temperature over 2 h, at which time it became homogeneous. The mixture was washed with ether (2×50 mL), then was acidified to pH~2 by addition of concentrated hydrochloric acid. The aqueous solution was extracted with ether (2×100 mL). The organic extracts were washed with brine (50 mL), combined, dried (Na2 SO4), filtered and evaporated to afford the product as a clear oil which slowly crystallized on standing (9.64 g, 36.6 mmol, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH:35]=[CH2:36]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH:36]=[CH:35][C:34](=[O:37])[N:33]([CH3:38])[CH3:32])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CC(=O)N(C)C
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cc(C=CC(=O)N(C)C)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 80 %

Procedure:
In the same manner as described in Example 203, 550.4 mg (1.0 mmol) of the product of Example 89 and 297.4 mg (3.0 mmol) of N,N-dimethylacrylamide provided 419 mg (80%) of the desired product as a white solid. Electrospray Mass Spec 524(M+H).
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[C:15]([CH2:20][OH:21])[NH:14]4)[CH2:7][C@H:6]([NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:5]1)[CH:2]=[CH2:3].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:21][CH2:20][C:15]1[NH:14][C:13]2[C:19]3[C:16]=1[CH2:17][C@@H:18]1[C@@H:8]([C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]([NH:22][C:23](=[O:29])[N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:5][N:4]1[CH2:1][CH:2]=[CH2:3])(=[O:32])[CH3:31]
Reactant: C=CCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]c(CO)c(c34)C[C@H]21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]c(COC(C)=O)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
213.6 mg (0.54 mmol) of 3-(6-allyl-2-hydroxymethyl-8α-ergolinyl)-1,1-diethylurea is dissolved in 5 ml of pyridine and mixed with 10 ml (0.11 mol) of acetic anhydride. After stirring for 2 hours at room temperature, the reaction mixture is added to ice, stirred for 1 hour and worked up in the way indicated above.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)(Cl)Cl>C(O)C.O=[Mn]=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCc1ccc(Oc2ccc3[nH]cnc3c2)cc1
Agent: O=[Mn]=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(Oc2ccc3[nH]cnc3c2)cc1
Yield: 100.8 %

Procedure:
[4-(1H-benzimidazol-5-yloxy)phenyl]methanol (1.26 g) was dissolved in 70 ml of ethanol and 70 ml of chloroform and heated with MnO2 (4.56 g, 52.5 mmol) in a 75 degrees Centigrade oil bath for 14 hrs. An additional 1 g of MNO2 was added and the reaction continued heating for 3 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to afford 1.26 g of 4-(1H-benzimidazol-5-yloxy)benzaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C[O:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][CH2:2][NH:1][C:12](=[O:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN1CCCC1CCN
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
Toluene (18 ml), dried using MS 4A, was mixed with 12.3 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 2.42 ml (16.7 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 5 minutes. The 2-(2-aminoethyl)-1-methylpyrrolidine was finally washed using 2 ml of toluene. After stirring for 20 minutes, the temperature was raised to room temperature, and 7 ml of a toluene solution of 5.0 g (16.9 mmols) of oleic acid methyl ester was added dropwise over 2 minutes. After stirring for 2.5 hours at 70° C., the mixture was cooled with ice, and 30 ml of 0.67N hydrochloric acid was added dropwise. An aqueous solution of 1N NaOH (about 100 ml) was added, and the mixture was extracted with about 100 ml of ethyl acetate. At this time, the pH of the aqueous layer was 9 to 10. The organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride. After this layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure on a 32° C. water bath to obtain the captioned compound. This compound was subjected to silica gel column chromatography (BW·80S 150 g, FUJISILYSIA, mobile phase: CHCl3:MeOH (9:1→4:1→3:1 (V/V))) for purification. The purified compound was concentrated under reduced pressure on a 35° C. water bath to obtain 4.09 g of a pale yellow liquid (10.4 mmols, yield 62%). NMR confirmed this product to have the following structure:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19]>C(OC(=O)C)(=O)C>[CH3:18][C:14]1[C:13]([CH:19]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:12][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccnc1C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccnc1C=Cc1ccc([N+](=O)[O-])cc1
Yield: 53.1 %

Procedure:
A mixture of 4-nitrobenzaldehyde (30.2 g) and 2,3-lutidine (42.8 g) in acetic anhydride (100 ml) was refluxed for 9.5 hours under stirring. After cooling the reaction mixture, the precipitate was collected by filtration. The residue was washed with diethyl ether to give 3-methyl-2-[2-(4-nitrophenyl)vinyl]pyridine (25.5 g).