Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:35][CH2:36][CH2:37][CH3:38])[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49](O)=[O:50])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40].Cl.CN(C)CCCN=C=NCC.ClCCl>CN(C)C1C=CN=CC=1.CN(C=O)C.ClCCl>[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49]([O:32][CH2:31][CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[C:18]([C:33]#[N:34])=[C:17]([NH:35][CH2:36][CH2:37][CH3:38])[N:16]=[C:15]([S:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[S:9][CH:10]=3)[C:20]=2[C:21]#[N:22])=[CH:24][CH:25]=1)=[O:50])[CH3:48])=[O:45])([CH3:41])([CH3:42])[CH3:40]
Reactant: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
758 mg (1.348 mmol) of 2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)-6-(propylamino)pyridine-3,5-dicarbonitrile (Example 12), 765 mg (4.043 mmol) of N-(tert-butoxycarbonyl)-L-alanine and 82 mg (0.674 mmol) of 4-dimethylaminopyridine were initially charged in 10.3 ml of DMF/dichloromethane (1:1). 336 mg (1.752 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the reaction solution was then stirred at RT overnight. The reaction solution was freed from dichloromethane and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 929 mg (94% of theory) of the target compound.
Reaction SMILES: [C:1]([OH:7])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[S:15](Cl)([CH3:18])(=[O:17])=[O:16]>C(OCC)C.O>[CH3:18][S:15]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])(=[O:17])=[O:16]
Reactant: CCCCC#CO
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2.3 ml of hexynol 17a, in 15 ml of diethyl ether was added 3 ml of triethyl amine, followed by 1.6 ml of mesyl chloride at 0° C. The mixture was stirred for 1 hr at 0° C., then diluted with 20 ml of water and extracted with diethyl ether. The extract was washed with 1N NaOH, water, dried and concentrated, to give 3.5 g of mesylate 17b as a colorless oil. Rf 0.65 (heptane/acetone 1/1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][CH:15]1[CH2:20][C:19](=[O:21])[O:18][C:17](=[O:22])[CH2:16]1>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:19](=[O:21])[CH2:20][CH:15]([CH3:14])[CH2:16][C:17]([OH:22])=[O:18])=[CH:3][C:4]=1[C:10]([F:11])([F:12])[F:13])#[N:7]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Yield: 114.1 %

Procedure:
A solution of 4-amino-2-(trifluoromethyl)benzonitrile (500 mg, 2.69 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (344 mg, 2.69 mmol) in THF (15 mL) was stirred at 90° C. for 14 hr. The reaction solution was concentrated to give 5-(4-cyano-3-(trifluoromethyl)phenylamino)-3-methyl-5-oxopentanoic acid (964 mg, 3.07 mmol, 114%) as a crude product.
Reaction SMILES: [CH:1](=[CH:8]/[C:9](=[O:11])[CH3:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1>[C:2]1([CH:1]([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(C)c1ccccc1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
143 mg of CuBr is added to 1.46 g (10 mmol) of cis/trans-benzylideneacetone (3-phenyl-but-3-en-2-one) in 20 ml of absolute dioxane. 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 10 minutes at 22° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate filtered off with dioxane is washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.21 g of 4-phenyl-pentan-2-one (75% of theory) is obtained a colorless liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:12]1[N:13]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 112.5 %

Procedure:
A mixture of 50.0 g of p-fluoronitrobenzene, 85.93 g of 2-methylimidazole and 44.9 g of potassium carbonate in 860 ml of dimethylsulfoxide is heated at 120° C. for 24 hours. The mixture is poured into 2.5 liter of water and stored in a refrigerator for two days. The mixture is filtered and cake washed with copious volumes of water and vacuum dried. The cake is dissolved in 1500 ml of ethyl acetate, filtered through hydrous magnesium silicate and the filtrate reduced to about 500 ml, cooled and the resulting solid, filtered, and air dried to give 81.0 g of the desired product as brown crystals, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13](=[O:22])[CH:12]=[CH:11]2)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[C:13](=[O:22])[CH:12]=[CH:11]4)[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2c(=O)ccn(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(=O)ccn(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-4(1H)-one (Intermediate 8, 60 mg, 0.20 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxyborohydride (127 mg, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was then filtered through a 0.45 μm membrane, acidified with conc. HCl to pH 1 and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to pH10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (4:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of 1M HCl in ether (0.45 mL). The colorless precipitate was collected by filtration and gave 84 mg (81% yield) of the bis-hydrochloride salt of the product, mp 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][C:38]2([CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCCl>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][C:38]2([CH2:45][CH2:44][CH:43]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:42][CH2:41]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
3,4-Dichloroaniline (364 mg, 2.2 mmol), sodium triacetoxyborohydride (889 mg, 4.20 mmol) and acetic acid (0.24 mL, 4.20 mmol) were added to a solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (561 mg, 2.10 mmol) in 1,2-dichloroethane (30 mL) with crunched 4A mol sieves (10 g). The mixture was stirred a room temperature over night. Additional 4A mol sieves (12 g) and sodium triacetoxyborohydride (445 mg) was added and the mixture was stirred over night. The reaction was quenched with water and 5% citric acid was added. The mixture was filtered through kieselguhr and the filtrated was evaporated until only the aqueous layer remained. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with brine, dried with sodium sulphate, filtered and evaporated to give the crude product. Flash chromatography (ethyl acetale/heptane) gave 9-(3,4-dichloro-phenylamino)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (258 mg, 0.624 mmol, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C(CC1CCC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(CC1CCC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (0.25 g, 0.49 mmol) and lithium hydroxide monohydrate (0.206 g, 4.9 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid (0.106 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H); 7.18 (s, 1H); 3.98 (q, 2H); 3.51 (t, 1H); 2.15-2.28 (m, 2H); 1.55-2.15 (m, 7H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH:9]2[C:18](=O)[C:17]3[C:16]([C:20]([O:22]CC)=O)=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[CH:5]1)([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>CO>[CH:1]([N:4]1[C:8]([CH:9]2[C:18]3=[N:32][NH:33][C:20](=[O:22])[C:16]4[CH:15]=[CH:14][CH:13]=[C:12]([C:17]=43)[NH:11][CH:10]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[CH:5]1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1cncn1C(C)C)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)n1cncc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A suspension of ethyl 3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (770 mg, 1.9 mmol) and hydrazine monohydrate (6 ml, 85%) were added in methanol (10 mL) and stirred at 50° C. overnight. The mixture was filtered, and the white solid was washed with methanol and dried to give 9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (90 mg, yield 13%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.82-0.84 (d, J=6.8 Hz, 3H), 1.27-1.29 (d, J=6.4 Hz, 3H), 3.30-3.33 (t, J=6.6 Hz, 1H), 4.67-4.70 (d, J=11.2 Hz, 1H), 4.92-4.95 (d, J=11.2 Hz, 1H), 6.80 (s, 1H), 7.01 (s, 1H), 7.16-7.18 (s, 1H), 7.24-7.28 (m, 3H), 7.31 (s, 1H), 7.36-7.39 (m, 3H), 7.55-7.59 (m, 1H); LC-MS (ESI) m/z: 372 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][C:22]=1[O:36][CH3:37].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]([CH2:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:36][CH3:37])[CH:23]=3)[CH2:32][CH2:31]2)=[O:35])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: CC(C)c1n[nH]c(C(F)(F)F)c1Cl
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(C)C)c(Cl)c3C(F)(F)F)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-isopropyl-5-trifluoromethyl-1-H-pyrazol, K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.45) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.19–7.22 (d, 2H), 6.38–6.48 (m, 2H), 5 (s, 2H), 3.86 (s, 3H), 3.62–3.78 (m, 4H), 3.08–3.18 (m, 4H), 2.98–3.04 (m, 1H), 1.35–1.41 (d, 6H). 13C NMR (400 MHz, CDCl3): 163.8, 154.8, 150.5, 130, 109.8, 102, 56.4, 52.8, 50, 49.8, 45.2, 42.6, 26.8, 20.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C@H:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:4]=1[C:28]([O:30]CC)=O.[CH3:33][CH:34]([CH3:39])[CH2:35][CH2:36][NH:37][NH2:38]>O1CCOCC1>[CH3:33][CH:34]([CH3:39])[CH2:35][CH2:36][N:37]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7](=[O:19])[NH:6][C@H:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:4]=2[C:28](=[O:30])[NH:38]1
Reactant: CC(C)CCNN
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Solvent: C1COCCO1
Product: CC(C)CCN1CC2=C(C(=O)N1)[C@@H](c1ccc(C#N)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
150 mg (0.295 mmol) of the compound from Example 6A were dissolved in 3 ml of dioxane, and 91 mg (0.885 mmol) of (3-methylbutyl)hydrazine were added. The mixture was stirred at 120° C. for 3 h and then concentrated. The residue was taken up in DMSO and purified by preparative HPLC (Method 10). This gave 43 mg (29% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:20]>O1CCOCC1>[NH2:20][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: COc1ccccc1NC(=O)c1c(Cl)ncnc1Cl
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)c1c(N)ncnc1Cl
Temperature: 0 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
4,6-Dichloro-N-(2-methoxyphenyl)pyrimidine-5-carboxamide (506 mg, 1.70 mmol) was dissolved in dioxane (8 ml) and cooled in an ice bath. Ammonia solution (1.25 ml, 8.75 mmol, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h. After evaporation of the solvent under reduced pressure, the residue was suspended in ethyl acetate and filtered, washing successively with ethyl acetate. The solvent of the filtrate is evaporated under reduced pressure to yield the final compound as a solid (454 mg, 93% purity, 89% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:23][CH:22]=4)=[O:19])=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:34][I:35]>CN(C=O)C>[I-:35].[CH3:34][N+:28]1([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:18]([C:14]3[CH2:13][CH2:12][C:11]4[C:16](=[CH:17][C:8]([C:5]5[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=5)=[CH:9][CH:10]=4)[CH:15]=3)=[O:19])=[CH:26][CH:25]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CI
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CC3)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In DMF (3 ml) was dissolved 7—(4-methylphenyl)-N-[4—(piperidinomethyl)phenyl]-3,4-dihydronaphthalene-2-carboxamide (400 mg), and to the mixture was added methyl iodide (171 μl). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1-methyl-1-[4-[7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamido]benzyl]piperidinium iodide (Compound 16) (490 mg) as colorless crystals.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[N:48][C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[CH:50][CH:51]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[N:48][C:49]([N:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[CH:50][CH:51]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCOCC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 3-amino-6-morpholinopyridine as the aniline component. (26%, MS=542.3 (M+H))
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>CCOC(C)=O.CCCCCC>[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH2:16]1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: CC1(C)CC=C(B(O)O)CC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c([N+](=O)[O-])c1
Yield: 99.2 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 11, step (e) using 1-(4-bromo-3-nitro-phenyl)-ethanone (347 mg, 1.42 mmol), and 4,4-dimethylcyclohexen-1-ylboronic acid (254 mg, 1.65 mmol). Silica gel chromatography (5-15% EtOAc/hexane) afforded the title compound (385 mg, 99%) as a faint green oil. Mass spectrum (APCI, m/z): Calcd. for C16H19NO3, 274.1 (M+H), found 274.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 12 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (18 mg, yield 12%). 1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.09-8.05 (m, 3H), 7.78 (s, 1H), 7.71-7.68 (t, J=7.8 Hz, 1H), 7.24-7.19 (m, 2H), 3.66 (s, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C23H16F4N4O3: 474.13. found: 475.1 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[N:3][C:4]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[N:5][CH:6]=1.[C:18](Cl)([Cl:20])=[S:19].C(N(CC)CC)C>ClCCl>[Cl-:20].[N:3]1[CH:2]=[CH:1][CH:6]=[N:5][C:4]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]=[S:19])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of sulfadiazine (192 mg, 0.77 mmol) in dichloromethane (20 mL) were slowly added thiophosgene (0.06 mL, 0.83 mmol) and triethylamine (0.05 mL, 0.32 mmol) under cooling with an ice bath. After the reaction mixture was stirred for five hours at room temperature, it was washed with water and brine, dried over anhydrous sodium sulfate, filtered, evaporated and dried under vacuum. The product was used immediately for the next reaction.
Reaction SMILES: [S-2].[Na+].[Na+].[Se].[CH3:5][N:6]([CH2:8][CH:9]([C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:10]1[CH:11]=[CH:12][C:13]([O:16]C)=[CH:14][CH:15]=1)[CH3:7].C(OC(=O)C)C>CN1CCCC1=O.O>[CH3:5][N:6]([CH2:8][CH:9]([C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[CH3:7]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: [Na+]
Agent: [S-2]
Agent: [Se]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 145 °C
Yield: 60.2 %

Procedure:
A mixture of 1.90 g of anhydrous sodium sulfide, 2.0 g of selenium and 6 mL of 1-methylpyrrolidone was heated to 145° C. under nitrogen, and then 3.5 g of venlafaxine dissolved in 10 mL of 1-methylpyrrolidone was added. The mixture was stirred and heated at 145° C. under nitrogen. Reaction mixture was heated at 145° C. for 16 hours, then it was cooled and mixed with 70 mL of ethylacetate and 50 mL of water. The mixture was placed into a refrigerator and crystals were filtered. After being recrystallized from 45 mL of ethanol, 2.0 g of desvenlafaxine was obtained with the yield 60%.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH:3]([NH:14]C(=O)O)[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:14][CH:3]([CH:2]([CH3:1])[CH2:18][CH3:19])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5]
Reactant: CCC(C)C(NC(=O)O)C(=O)NCc1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)C(N)C(=O)NCc1ccccn1

Procedure:
To 2.35 g of product from Example 1 in 10 ml of methylene chloride is added 2.8 ml of trifluoroacetic acid. The reaction is heated at 80°-90° C. for 41/2 hours and then concentrated in vacuo to give 3.6 g of the desired product as tris-trifluoroacetic acid salt.