Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:30][N:31]1CCOC[CH2:32]1.CNC>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([N:31]([CH3:32])[CH3:30])=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)O)cn1
Agent: CNC
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)N(C)C)cn1
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
To a cold solution of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylic acid (0.175 g, 0.37 mmol) in DMF (5 mL, −10° C.) was added IBCF (0.046 mL, 0.35 mmol) followed by NMM (0.041 mL 0.37 mmol). The reaction was activated for 20 minutes at −15° C. after which dimethylamine (0.375 mL, 0.74 mmol) was added. The reaction stirred at −10° C. to room temperature for 45 minutes. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC 10-90% CH3CN/water (30 minute gradient) at a flow rate of 70 mL/min. The appropriate fractions were combined and freeze dried to afford the desired product (0.140 g, 75%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.68 (s, 1H), 8.67 (s, 1H), 7.52 (m, 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 3.11 (s, 3H), 3.07 (s, 3H), 2.55 (s, 3H); ES-HRMS m/z 493.0680/495.0657 (M+H calculated for C21H20N4O3BrF2 requires 493.0680/495.0657).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.[C:12]([C:14]1[CH:29]=[CH:28][C:17]([CH:18]=[C:19]([C:25](=O)[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)#[N:13].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:12]([C:14]1[CH:29]=[CH:28][C:17]([CH:18]2[N:3]3[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]3[NH:1][C:25]([CH3:26])=[C:19]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)#[N:13]
Reactant: CCOC(=O)c1nc(N)n[nH]1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc(C(=O)OCC)nn2C1c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
Under an atmosphere of argon, ethyl 3-amino-1H-1,2,4-triazole-5-carboxylate (700 mg, 4.4 mmol) and ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (1.18 g, 4.9 mmol, 1.1 eq.) were dissolved in DMF (5 ml), and solid sodium bicarbonate (1.86 g, 22.1 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 6 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (1.3 g, 80% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[OH:13])/[C:8]([O:10][CH3:11])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:21]([NH:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[OH:13])/[C:8]([O:10][CH3:11])=[O:9])[N:6]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)/C(=N\O)c1csc(N)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
In 10 ml of N,N-dimethylformamide is dissolved 4.62 g of methyl 2-(2-amino-4-thiazolyl)-(Z)-2-hydroxyiminoacetate, followed by addition of 3 ml of triethylamine. Then, under stirring at -30° C., 6.42 g of trityl chloride is added over one hour. The mixture is further stirred at that temperature for one hour and, then at 15° C. for an additional 2 hours. To this reaction mixture is added 200 ml of water, followed by extraction with 200 ml of ethyl acetate. The ethyl acetate extract is washed twice with 200 ml portions of water and dried over anhydrous sodium sulfate. The solvent is then distilled off. The residue is purified by column chromatography [silica gel: 100 g; eluent: hexane-ethyl acetate (1:1)] and the resultant crystals are recrystallized from ethyl acetate to give methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-hydroxyiminoacetate as colorless granules, m.p. 204°-205° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[CH2:13][CH2:14][C:15]([OH:17])=[O:16]>[OH-].[K+]>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCl
Reactant: Oc1cccc2cccnc12
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCOc1cccc2cccnc12
Temperature: 0 °C
Yield: 24.7 %

Procedure:
A solution of 8-hydroxyquinoline (43.5 g, 0.30 mol) (Aldrich) in 150 ml 2 N potassium hydroxide was refluxed while an ice cold solution of 3-chloropropionic acid (36 g, 0.33 mol) (Aldrich) in 165 ml 2 N potassium hydroxide was added over 15 minutes. The pH of the reaction was maintained at pH 10 by addition of 5 N potassium hydroxide during the addition and the subsequent 1.5 hour reflux period. After cooling and filtration the mixture was brought to pH with 6 N hydrochloric acid and extracted with 6×100 ml chloroform. The aqueous layer was acidified to pH 3.8 with 6 N hydrochloric acid and the precipitate thus formed was filtered and washed thoroughly with water, to yield 3-[8-quinolinoxy]-propionic acid (16.12 g, 25% yield), m.p. 211°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:31](=[O:32])[CH2:30][OH:33])[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Reactant: O=C(O)CO
Product: O=C(CO)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1

Procedure:
{5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine prepared in Example 160 and glycolic acid were reacted according to the same procedure as Step B of Preparation 101 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([C:12]([OH:15])([CH3:14])[CH3:13])[CH2:9][N:8]3[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=[C:7]3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>>[OH:34][C@:30]([C:27]1[CH:26]=[C:25]([CH3:24])[O:29][N:28]=1)([CH3:31])[C:32]#[C:33][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([C:12]([OH:15])([CH3:14])[CH3:13])[CH2:9][N:8]3[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=[C:7]3[C:6]=2[CH:23]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(C(C)(C)O)C2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: COC(=O)c1cn2c(n1)-c1cc(C#C[C@@](C)(O)c3cc(C)on3)ccc1OC(C(C)(C)O)C2

Procedure:
Similar to as described in General Procedure G, racemic methyl 10-bromo-6-(2-hydroxypropan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give methyl 10-((R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-6-(2-hydroxypropan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate. M+1=452. A solution of the above compound (100 mg, 0.22 mmol, 1.00 equiv) in methanol (Saturated with ammonia, 20 mL) was stirred for 3 days at 60° C. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (19:1) to give a mixture of diastereoisomers. The two diasteromers were separated by Chiral-Prep-HPLC with the following conditions (Prep-HPLC-004): Column, Chiralpak IC, 2*25 cm, 5 um; mobile phase, Hex and ethanol (hold 40.0% ethanol in 25 min); Detector, UV 254/220 nm to give 12.2 mg (13%) Compound 1 as a off-white solid, Chiralpak IC-3, 25° C., 254 nm, 60:40 Hex (0.1% TEA):EtOH, 1 mL/min, tR=2,7 min; and 11.5 mg (12%) of Compound 2 as an off-white solid, Chiralpak IC-3, 25° C., 254 nm, 60:40 Hex (0.1% TEA):EtOH, 1 mL/min, tR=5.0 min.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:5](=O)[O:6]C1C=CC=CC=1.[NH2:19][NH2:20].O>C(O)C>[NH2:19][N:20]1[CH2:2][CH2:3][N:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]1=[O:6]
Reactant: O=C(Oc1ccccc1)N(CCCl)CC(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN1CCN(CC(F)(F)F)C1=O

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of phenyl N-(2-chloroethyl)-N-(2,2,2-trifluoroethyl)carbamate (5.6 g, 19.88 mmol, 1.00 equiv) in ethanol (100 mL), NH2NH2.H2O (10 mL, 80%). The resulting solution was heated to reflux overnight in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate (1:1). This resulted in 0.8 g (22%) of 1-amino-3-(2,2,2-trifluoroethyl)imidazolidin-2-one as colorless oil. (ES, m/z): 184 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(OCC)C>ClCCl>[CH3:1][N:2]([C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To an ice bath cooled solution of N-methylaniline (536 mg) in dichloromethane (30 ml) were added triethylamine (0.837 ml) and p-nitrobenzoyl chloride (982 mg) and the mixture was stirred at ambient temperature for 3 hours. The solution was washed successively in 1N hydrogen chloride, saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the oil was solidified with diethyl ether to give N-methyl-N-(4-nitrobenzoyl)aniline (1.11 g) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][OH:11])[CH:5]=[N:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC#Cc1cncc(Br)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(5-Bromo-pyridin-3-yl)-prop-2-yn-1-ol (Intermediate 218) (1 eq, 2.41 mmol, 510 mg) is dissolved in DCM (5 ml), then TEA (1.5 eq, 3.61 mmol, 0.5 ml) and methanesulfonyl chloride (1.5 eq, 3.61 mmol, 0.28 ml) are added. The resulting mixture is stirred for 30 min at r.t. After addition of water the layers are separated, and the organic layer is dried with MgSO4, filtered, and concentrated under reduced pressure giving the title compound.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][N:6]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[O:4][C:5]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][N:6]=2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=1
Reactant: FC(F)(F)c1ccnc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3nccc(C(F)(F)F)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)-4-(trifluoromethyl)pyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H13F4N5O, 427.11; m/z found, 428.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J=4.9, 1H), 8.41 (d, J=1.4, 2H), 7.69 (d, J=4.9, 1H), 7.60-7.57 (m, 1H), 7.55-7.50 (m, 2H), 7.46-7.38 (m, 2H), 7.35-7.29 (m, 2H), 6.88 (s, 2H).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:21][C:22]1[CH:23]=[N:24][N:25]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 85 °C
Yield: 35.6 %

Procedure:
Trityl chloride (9.02 g) was added to a stirred solution of 4-bromopyrazole (4.24 g) and 4-dimethylaminopyridine (0.711 g) in pyridine (90 ml). The reaction mixture was heated to 85° C. for 20 hrs, cooled to room temperature and partitioned between diethyl ether and water. The organic layer was separated, dried (MgSO4) and evaporated under reduced pressure. The crude product was recrystallized from hexane/toluene (5/1, 180 ml) to afford the title compound (4.0 g). The remaining solids and the mother liquors were combined and purified by column chromatography on silica gel eluting with pentane/ether (30/1, v/v) to afford a second batch of title compound (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23]CC)=[O:22].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(-n2ncc(C(=O)O)c2Cl)cc1C#N
Temperature: 60 °C
Yield: 49.4 %

Procedure:
To a solution (10 ml) of ethyl 5-chloro-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylate (1.01 g) in ethanol was added 1 N aqueous sodium hydroxide solution (3.4 ml) with stirring, and the mixture was heated at 60° C. for 1 hour. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.46 g of 5-chloro-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid, melting point 212° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 91 %

Procedure:
From 4-nitro-bromobenzene and 4-methoxyphenyl boronic acid, yield 91%; mp 104-105° C. (lit.,3 106-107° C.); IR: 1597, 1509, 1342 and 125I; 1H NMR (600 MHz; CDCl3): 8.27 (2H, d, J 9), 7.69 (2H, d, J 8.4), 7.58 (2H, d, J 9), 7.02 (2H, d, J 8.4) and 3.87 (3 H, s); 13C NMR (CDCl3): 160.4, 147.1, 146.5, 131, 128.5, 127, 124.1, 114.6 and 55.4; m/z (EI) 229 (25%, M+), 169. (30), 131 (30) and 69 (100)(Found: M+, 229.073. C13H11NO3 requires M, 184.074).
Reaction SMILES: Cl.N[C:3]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[I-:24].[K+]>O.C(O)(=O)C>[I:24][C:3]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: [I-]
Reactant: Nc1cc(CCc2ccccc2)ccc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(CCc2ccccc2)cc1I
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
To a suspension of acetic acid 17 mL, water 17 mL and hydrochloric acid 2.1 mL of 2-amino-4-phenethylbenzoic acid 1.7 g, was added water 3.0 mL solution of sodium nitrite 0.58 g at 4° C., and it was stirred at same temperature for 15 minutes. The reaction mixture was added to water 20 mL solution of potassium iodide 2.3 g at 4° C., and it was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and ethyl acetate was added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 5% sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate:acetic acid=66:33:1] to give 2-iodo-4-phenethylbenzoic acid 1.5 g of yellow solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[CH2:9][CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1Oc1ccc(C)c(C)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@@H]1CNCC[C@H]1Oc1ccc(C)c(C)c1

Procedure:
16.0 g (0.04 mol) of trans-3-acetoxy-4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-piperidine are dissolved in 400 ml of methanol and hydrogenated in the presence of 1.5 g of a 5% strength palladium-on-charcoal catalyst under normal pressure. After the reaction has ended, the catalyst is filtered off by means of a layer of diatomaceous earth and the filtrate is evaporated under a water pump vacuum, whereupon trans-3-acetoxy-4-(3,4-dimethylphenoxy)-piperidine is obtained in the form of a yellow oil. Reaction of the base with fumaric acid in ethanol/ether gives the crystalline acid fumarate with a melting point of 170°-172°.
Reaction SMILES: [I-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18]OS(C)(=O)=O)[CH:7]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH:36][CH3:37])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@@H:33]([N:36]([CH3:37])[CH2:18][CH2:17][C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([N:6]4[CH:7]=[N:3][N:4]=[CH:5]4)[CH:9]=3)[NH:13][CH:12]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)OCCc1c[nH]c2ccc(-n3cnnc3)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CN(CCc1c[nH]c2ccc(-n3cnnc3)cc12)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 20 h

Procedure:
Sodium iodide (300 mg, 2.0 mmol) was added to a stirred solution/suspension of methanesulphonic acid 2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethyl ester (prepared from the corresponding alcohol, WO 95/32196) (600 mg, 2.0 mmol), (R)-3-methylaminopyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 3.0 mmol) and potassium carbonate (830 mg, 6.0 mmol) in dry isopropanol (50 ml) at room temperature under nitrogen. The mixture was stirred and heated at reflux, protected from light for 20 hours. Upon cooling, the volatiles were removed in vacuo. The residue was partitioned between dichloromethane/water. The aqueous was further extracted with dichloromethane (×2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 95:5:0.5→93:6:1→91:8:1 to give the title tryptamine (770 mg) as a thick gum. (1H nmr indicated contamination with the pyrrolidine-amine. Corrected yield of desired product≈60%≈500 mg). δ (360 MHz, CDCl3 +d4MeOH) 1.46 (9H, s, tBu), 1.70-1.85 (1H, m), 2.05-2.15 (1H, m), 2.42 (3H, s, NCH3), 2.75-3.60 (9H, m), 7.17 (1H, d, J=8.7 Hz, ArH), 7.22 (1H, s, ArH), 7.52 (1H, d, J=8.6 Hz, ArH), 7.60 (1H, s, ArH), 8.62 (2H, br s, triazole-H); MS (ES+) 411 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH:28]([OH:30])[CH3:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:30][CH:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[CH3:29])[N:3]=1
Reactant: CC(O)c1ccc2ccccc2c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(Oc1nc(N)nc(-c2ccco2)c1C#N)c1ccc2ccccc2c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (RS)-1-(2-naphthyl)ethanol and DBU in DME. ES-MS m/e (%): 357 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].[CH3:20][C:21](C)([O-:23])[CH3:22].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[CH2:22][O:23]1
Reactant: COc1ccccc1CCCCc1ccccc1O
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1CCCCc1ccccc1OCC1CO1
Yield: 92.8 %

Procedure:
Following a procedure similar to that described in Example 1(a), 230 mg of 2-[4-(2-methoxyphenyl)butyl]phenol (prepared as described in Preparation 4), 101 mg of potassium t-butoxide and 246 mg of epibromohydrin were reacted in 15 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 260 mg (yield 93%) of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19].[CH3:20][O:21][CH2:22][CH2:23][C:24](Cl)=O>N1C=CC=CC=1>[CH3:20][O:21][CH2:22][CH2:23][C:24]1[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1
Reactant: COCCC(=O)Cl
Reactant: CSCCCCCNc1c(N)cnc2ccccc12
Solvent: c1ccncc1
Product: COCCc1nc2cnc3ccccc3c2n1CCCCCSC
Temperature: 0 °C
Yield: 67.5 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (3.56 g, 12.93 mmol) and anhydrous pyridine (52 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to 0° C. in an ice-water bath. To the cooled solution was added neat 3-methoxypropionyl chloride (2.74 g, 22.36 mmol). After addition of the acid chloride, the reaction was heated to reflux for 14 hours at which time the acylated intermediate was completely consumed. The solution was cooled and then partitioned between chloroform and saturated aqueous ammonium chloride. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-(2-methoxyethyl)-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (3.0 g, 8.73 mmol) which was isolated as a brown oil and used without further purification.