Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1([CH2:23][CH3:24])[O:22][CH2:21][CH2:20][O:19]1)([C:10]([O-:12])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Li+].[OH-]>C1COCC1.O>[C:6]([O:5][C:3]([CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1([CH2:23][CH3:24])[O:19][CH2:20][CH2:21][O:22]1)[C:10]([OH:12])=[O:11])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCC1(CCCCCC(C)(C(=O)[O-])C(=O)OC(C)(C)C)OCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CCCCCC(C(=O)O)C(=O)OC(C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of A1 (1 eq.) in THF/H2O (2:1, 0.09 M solution) was treated with LiOH (1.1 eq) and the solution was stirred for 3 hr at RT. The reaction was quenched with 6N HCl and the product was extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure to yield a white solid which was used without any further purification. 1H NMR (400 MHz, CDCl3) δ: 3.86 (4H, s), 3.16 (1H, t, J=7.3 Hz), 1.90-1.68 (2H, m), 1.63-1.46 (4H, m), 1.39 (9H, s), 1.33-1.15 (6H, m), 0.84 (3H, t, J=7.5 Hz). MS (ES) C17H30O6 requires: 330, found: 331 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:15][CH2:14][CH2:13][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=1>CN1C(=O)CCC1.O>[CH:8]1([C:6]2[N:7]=[C:2]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=3)[C:3]3[CH2:15][CH2:14][CH2:13][C:4]=3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1nc(C2CCCC2)nc2c1CCC2
Reactant: Nc1ccc(CCO)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCc1ccc(Nc2nc(C3CCCC3)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 51.4 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.132 g, 0.59 mmol) and 4-aminophenethyl alcohol (0.162 g, 1.18 mmol) in NMP (4 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 2 h. The reaction mixture was cooled, diluted with water (40 mL) to afford a solid. The solid was isolated by filtration then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.098 g, 51%) as a light brown solid. MW=323.43. M.p. 178-180° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.47 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 4.59 (t, J=5.0 Hz, 1H), 3.61-3.55 (m, 2H), 3.09 (quin, J=8.0 Hz, 1H), 2.77 (q, J=7.5 Hz, 4H), 2.67 (t, J=7.0 Hz, 2H), 2.01 (quin; J=7.5 Hz, 2H), 1.97-1.90 (m, 2H), 1.87-1.78 (m, 2H), 1.78-1.68 (m, 2H), 1.65-1.55 (m, 2H); APCI MS m/z 324 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([F:17])[CH:9]=2)[CH2:5]1)#[N:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:73][C:74]([F:79])([F:78])[C@@H:75]([NH2:77])[CH3:76].FC(F)(F)C(O)=O>ClCCCl>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:77][C@@H:75]([CH3:76])[C:74]([F:79])([F:78])[F:73])=[O:13])=[C:10]([F:17])[CH:9]=2)[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)c(F)c5)C4)c3)ncnc21
Reactant: C[C@H](N)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluorobenzoic acid (25 mg, 0.046 mmol) (Example 15, Step 2) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) in 1,2-dichloroethane (0.5 mL) was added sequentially N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (26 mg, 0.068 mmol) and (2S)-1,1,1-trifluoropropan-2-amine (12 mg, 0.11 mmol). After stirring at ambient temperature for 1.5 h, trifluoroacetic acid (0.5 mL) was added to the reaction mixture and stirring was continued for 1 h. The volatiles were removed in-vacuo and the residue was azeotropically washed with acetonitrile (3×3 mL). The resulting residue was dissolved in methanol (1 mL) and to this was added ammonium hydroxide (0.1 mL) and ethylenediamine (0.020 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. The crude reaction mixture was subjected to RP-HPLC to afford the desired product. LCMS (M+H)+: m/z=513.1. 1H NMR (500 MHz, DMSO-d6): δ 12.64 (s, 1H), 9.06 (s, 1H), 8.85 (s, 1H), 8.56 (s, 1H), 8.33 (dd, J=8.9, 1.8 Hz, 1H), 7.79 (s, 1H), 7.52 (t, J=8.5 Hz, 1H), 7.23 (s, 1H), 6.47 (s, 1H), 6.45-6.42 (m, 1H), 4.83-4.75 (m, 1H), 4.59 (dd, J=8.9, 1.7 Hz, 2H), 4.34 (d, J=8.9 Hz, 2H), 3.77 (s, 2H), 1.31 (d, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][CH:11]=1>C(OC(=O)C)(=O)C>[N+:1]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[O:12][CH3:13])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(F)c1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A mixture of 32 ml of nitric acid and 95 ml of acetic acid anhydride was added dropwise with stirring at 0° to -5° C. to a solution of 12.6 g of 3-fluoro-anisole in 100 ml of acetic acid anhydride and the mixture was stirred at 0° to 5° C. for one hour. The reaction was poured over ice and was vacuum filtered. The recovered precipitate was dried to obtain 6.77 g of 2-nitro-5-fluoro-anisole with a melting point <50° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(C(=O)O)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl 4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(hexanoyl)amino]methyl}benzoate and NaOH 1M as a brown oil (95%). 1HNMR (CDCl3, 300 MHz) δ 8.14-8.01 (m, 2H), 7.56-7.40 (m, 4H), 7.34-7.22 (m, 2H), 7.21-7.07 (m, 4H), 4.69-4.58 (m, 2H), 4.54-4.43 (m, 2H), 2.62 (m, 2H), 2.48-2.33 (m, 2H), 1.80-1.53 (m, 4H), 1.43-1.15 (m, 6H), 0.97-0.78 (m, 6H). M− (ESI): 494.4; M+ (ESI): 496.4. HPLC, Rt: 5.54 min (Purity: 98%).
Reaction SMILES: [CH3:1][C:2]1=[CH:3][C:4]([O:6][C:7]1=[O:8])=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>C(O)(=O)C>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:16]2[C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[C:7]2=[O:8])=[CH:13][CH:12]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: COc1ccc(CN)cc1
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C=C(C)C2=O)cc1

Procedure:
3-Methylmaleic anhydride (10 g, 89.2 mmol) and 4-methoxybenzylamine (11.6 mL, 89.2 mmol) were heated to 100° C. in 35 mL glacial acetic acid for 5 h. Solvent was evaporated. The residue was taken up in EtOAc and washed with sat'd aq NaHCO3, water, and brine. The organic phase was dried (MgSO4), filtered, and evaporated. The title compound was obtained as a solid and used without further purification (18.75 g, quant).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]([C:12]([O:14][Si](C)(C)C)=[CH2:13])=[C:10]([CH2:19][CH3:20])[N:9]=[C:8]2[CH2:21][CH2:22][CH3:23])=[C:4]([F:26])[CH:3]=1.C1C(=O)N([Br:34])C(=O)C1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]([C:12](=[O:13])[CH2:14][Br:34])=[C:10]([CH2:19][CH3:20])[N:9]=[C:8]2[CH2:21][CH2:22][CH3:23])=[C:4]([F:26])[CH:3]=1
Reactant: C=C(O[Si](C)(C)C)c1c(CC)nc(CCC)n1Cc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1nc(CC)c(C(=O)CBr)n1Cc1ccc(Br)cc1F
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To 2.69 g (6.13 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(1-(trimethylsilyloxy)ethenyl)-1H-imidazole in 100 mL THF at 0° C. was added 1.09 g (6.13 mmol) of NBS. After stirring for 30 min, the solution was poured into saturated NaHCO3 solution. The mixture was extracted with anhydrous ethyl ether, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to give 2.32 g (85%) of the title compound as a brown oil, which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 0.96 (t, 3H); 1.42 (t, 3H); 1.76 (m, 2H); 2.46 (t, 2H); 3.02 (q, 2H); 5.30 (s, 2H); 5.50 (s, 2H); 6.59 (t, 1H); 7.14 (m H). ##STR104##
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:46][CH:45]([NH:47][CH3:48])[CH2:44][CH:43]1[CH2:49][OH:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH:45]([N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:30])[F:31])=[CH:28][C:3]=3[C:2]([F:33])([F:34])[F:1])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH3:48])[CH2:44][CH:43]1[CH2:49][OH:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNC1CC(CO)N(C(=O)OC(C)(C)C)C1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CC(CO)N(C(=O)OC(C)(C)C)C1

Procedure:
4-({5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Hydroxymethyl-4-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([C:33]2([F:40])[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=CC=1>CCOC(C)=O.O>[F:40][C:33]1([C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1
Reactant: CN1CCC(F)(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCC(F)(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenyl)-4-fluoro-1-methylpiperidine (133 mg, 0.49 mmol). The reaction was then allowed to cool to room temperature and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give the title compound as a brown solid (281 mg, used without further purification). 1H NMR (400 MHz, MeOD) δ 7.76 (d, J=7.7 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 2.94-2.91 (m, 2H), 2.59 (t, J=12.0 Hz, 2H), 2.45 (s, 3H), 2.30-2.22 (m, 1H), 2.20-2.12 (m, 1H), 2.01-1.95 (m, 2H); 19F NMR (400 MHz, MeOD) δ—162.38; MS ESI 320.1 [M+H]+, calcd for [C18H27BFNO2+H]+ 320.21.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Li+]>C1COCC1.CO.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.3 %

Procedure:
Ethyl 3-bromo-1H-indole-2-carboxylate (0.070 g, 0.30 mmol) and powdered lithium hydroxide (0.073 g, 3.0 mmol) were dissolved in 1:1:1 mixture of THF/MeOH/water (3.0 mL) and the solution was stirred at RT for 4.5 h. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford (0.042 g, 67%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.09 (br. s., 1H), 7.50 (d, 1H), 7.43 (d, 1H), 7.30 (t, 1H), 7.15 (t, 1H). MS: m/z 240.1 (M+1).
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11].[S:14]1C=CC=C1CSCCC(OC)=O>>[S:14]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11]
Reactant: COC(=O)CCSCc1cccs1
Reactant: NNC(=O)CCSCc1ccco1
Product: NNC(=O)CCSCc1cccs1

Procedure:
3-[(2-thienylmethyl)thio]propanoic acid, hydrazide (56) was prepared in the manner that 3-[(2-furanylmethyl)thio]propanoic acid, hydrazide (12) was prepared (Example 12) on a 23 mmol scale from methyl 3-[(2-thienylmethyl)thio]propanoate (55). After the solvent was removed under vacuum, 2.77 g (69%) of the product, which was a water white viscous liquid, was recovered and was used immediately in the manner described in Example 57, below.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])(O)=O>O1CCCC1>[C:20]1(=[O:21])[N:16]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]12
Reactant: O=C(O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1NCCc1c[nH]c2ccccc12

Procedure:
As shown in reaction Scheme A, treatment of tryptamine (1) with N-carboxyphthalimide in an inert organic solvent such as tetrahydrofuran at a temperature of 20-65° C., preferably 65° C., for a period of 12-48 hours gives the corresponding N-phthalimidotryptamine derivative (2). The N-phthalimidotryptamine (2) could be further modified by treatment with a brominating agent such as pyridinium hydrobromide perbromide, pyrrolidone hydrotribromide, or the like in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform, or mixtures thereof at 0-25° C. for a period of 30 minutes to 4 hours to provide the 2-bromotryptamine (3). Bromide (3) may be reacted with an arylboronic acid (prepared essentially as described in: Gronowitz, S.; Hornfeldt, A. -B.; Yang, Y. -H. Chem. Scr. 1986,26, 311-314.) with palladium (0) catalysis, a weak base such as aqueous sodium carbonate or the like, and a chloride source such as lithium chloride in an inert solvent like toluene, benzene, ethanol, propanol or mixtures thereof at a temperature of 25°-100° C., preferably 80° C., for a period of 1-6 hours to give the 2-aryltryptamine derivative (4). Finally, the phthalimido group may be removed by treatment of (4) with aqueous hydrazine in an inert solvent such as methanol or ethanol at a temperature of 0°-25° C. for a period of 4-24 hours to give tryptamine (5). ##STR10##
Reaction SMILES: Cl.[CH:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CC.[CH3:13][CH2:14][O:15][C:16]([CH2:18]Br)=[O:17].S(=O)(=O)(O)O>[Zn].C1C=CC=CC=1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:13]
Reactant: CCCCCCCCCC=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: CCCCCCCC(O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
7.8 g of zinc activated by a hydrochloric acid and 25 ml of benzene were placed in a circulation device incorporating the Dean and Stark device. The solution was circulated while heated. To the resultant solution, a mixed solution of 15.6 g (100 mmol) of decanal and 18.4 g (110 mmol) of bromoacetic acid ethyl was dropped. After six hours, the solution was cooled to room temperature. A 50% (w/w) sulfuric acid was added to divide the solvent, and the organic layer was separated. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate=2/8). As a result, a 3-hydroxydecanoic acid ethyl ester was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[C:5]([CH:7]=O)[N:6]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[NH:11][NH2:12]>>[CH2:15]([O:14][C:10](=[O:13])[NH:11][N:12]=[CH:7][C:5]1[N:6]=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:9])[CH3:16]
Reactant: CCOC(=O)NN
Reactant: Cc1nc(C=O)c(C)[nH]1
Product: CCOC(=O)NN=Cc1nc(C)[nH]c1C

Procedure:
A 6.2 gm. portion of 2,5-dimethyl-4-imidazolecarboxaldehyde and 6.24 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 207.5°-210° C. (resolidifies 248°-252° C.)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[CH2:12][OH:13])=[CH:6][C:5]=1[CH3:15].Br[CH2:17]Br>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11](=[O:14])[CH2:12][O:13][CH2:17]2)=[CH:6][C:5]=1[CH3:15]
Reactant: Cc1cc(NC(=O)CO)ccc1Br
Reactant: BrCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N2COCC2=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 21.5 %

Procedure:
Sodium hydride (81 mg, 1.80 mmol) was added to a solution of N-(4-bromo-3-methyl-phenyl)-2-hydroxy-acetamide (200 mg, 0.819 mmol) in DMF (4.0 ml), and the mixture was stirred at room temperature for 50 minutes. Further, dibromomethane (0.114 ml, 1.64 mmol) was added to the reaction solution, and the mixture was heated with stirring at 110° C. for two hours. Cooling to room temperature and subsequent purification by silica gel column chromatography (hexane-ethyl acetate) gave 3-(4-bromo-3-methyl-phenyl)-oxazolidin-4-one (45 mg, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(NC(C)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(NC(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-acetamidobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound: Rf=0.18 (silica gel, 1/1 ethyl acetate/methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][N:10]([CH3:23])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[S:16][C:15]=2[NH2:22])(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34].O>O1CCCC1>[C:19]([C:17]1[S:16][C:15]([NH:22][C:32](=[O:35])[CH2:33][CH3:34])=[C:14]([S:11](=[O:13])(=[O:12])[N:10]([CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:24])[CH3:23])[CH:18]=1)(=[O:21])[CH3:20]
Reactant: CCC(=O)Cl
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(N)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)Nc1sc(C(C)=O)cc1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-acetyl-2-amino-thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 99) (150 mg) and triethylamine (557 μL) in tetrahydrofuran was added propionic acid chloride (195 μL) in small amounts. After stirring at room temperature for 2 hours, triethylamine (557 μL) and propionic acid chloride (195 μL) were further added, and the solution was stirred for 30 minutes. Water was added to the reaction solution, the solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (75 mg) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:6]=2[N:7]=1.[CH3:21][NH2:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: Fc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1F
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(F)c(F)c1

Procedure:
2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation Y) was reacted as described in Preparation Xa with methanamine to give 2-chloro-8-(3,4-difluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Yc). LC-MS (M+H)+=312.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:12]=[N:13][N:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:23])=[CH:20][N:19]=3)[C:15]=2[O:16]C)[CH:6]=[CH:5][N:4]=1.[Cl-].[Li+]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:12]=[N:13][N:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:23])=[CH:20][N:19]=3)[C:15]=2[OH:16])[CH:6]=[CH:5][N:4]=1
Reactant: COc1nccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2OC)c1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: COc1nccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c1OC
Yield: 26 %

Procedure:
Combined 6-(4-(2,3-dimethoxypyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (0.029 g, 0.064 mmol) and lithium chloride (0.014 g, 0.320 mmol) in DMA (0.639 mL) and heated at 50° C. for 16 hours. The reaction mixture was purified by preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) eluting with ACN (with 0.1% ammonium hydroxide) in water (with 0.1% ammonium hydroxide) to give the title compound (7.3 mg, 26.0%). 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.23 (m, 2H) 1.49-1.58 (m, 2H) 1.74 (ttt, J=11.1, 11.1, 7.3, 7.3, 3.7, 3.7 Hz, 1H) 2.01 (s, 1H) 3.08-3.13 (m, 3H) 3.63 (s, 3H) 3.77 (d, J=2.8 Hz, 1H) 3.80 (s, 4H) 7.07 (br. s., 1H) 7.63 (d, J=5.3 Hz, 1H) 8.04-8.09 (m, 2H) 8.19 (dd, J=8.8, 2.3 Hz, 1H) 8.45 (d, J=8.8 Hz, 1H) 8.53 (t, J=5.8 Hz, 1H) 8.78 (d, J=2.0 Hz, 1H). MS m/z [M+H]+ 440.5.