Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[C:15]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:16])[CH3:11]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cc(F)ccc1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C=C(C)Oc1cc(F)ccc1F
Temperature: 130 °C
Yield: 62.6 %

Procedure:
A mixture of 2,5-difluoro-phenol (1.15 g, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130° C. for 2 h. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 0.5N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 5% ethyl acetate/hexanes) afforded 3-(2,5-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.35 g, 63%) as a clear oil: HR-ES-MS m/z calculated for C12H12O3F2 [M+H]+ 243.0828, observed 243.0827; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13 (t, J=7.0 Hz, 3H), 2.43 (s, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.78 (s, 1H), 7.16-7.30 (m, 1H), 7.37 (ddd, J=8.9, 6.2, 3.0 Hz, 1H), 7.51 (td, J=9.7, 5.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.Cl.[NH2:16][NH2:17].O.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:17][N:16]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)COC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(COC)n[nH]1

Procedure:
Ethyl 5-methoxy-2,4-dioxopentanoate (2.168 g, 11.52 mmol) was dissolved in ethanol (100 ml) and hydrazine dihydrochloride (4.84 g, 46.1 mmol) was added. The resulting mixture was refluxed for 2 h. 200 ml of water was added and the pH of the mixture was neutralized with NaHCO3. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried with Na2SO4, filtered and evaporated. The product was used in the next step without further purification. 1H-NMR (400 MHz; DMSO-d6): δ 1.29 (t, 3H), 3.26 (s, 3H), 4.27 (q, 2H), 4.42 (s, 2H), 6.72 (s, 1H), 13.62 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][S:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>CN(C=O)C.O>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:12]1[C:11](=[O:13])[CH2:10][S:9][C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a stirred suspension of 7-nitro-2H-benzo[b][1,4]thiazin-3(4H)-one (1.02 g, 4.85 mmol) and potassium carbonate (4.69 g, 34.0 mmol) in a pressure flask in DMF (30 mL) under argon was added 2-chloro-N,N-dimethylethanamine hydrochloride (3.49 g, 24.26 mmol). The flask was immediately sealed and heated with stirring to 90° C. overnight. The mixture was then cooled to room temperature, diluted with water and extracted (2× ethyl acetate). The combined organics were then washed with a 1:1 mixture of brine and water (3×) then brine (1×). The organic phase was dried, filtered, concentrated, and then chromatographed in 5% (2M NH3 in MeOH) in dichloromethane, giving the desired product (755 mg, 55.3%). 1H NMR (DMSO-d6) δ 8.30 (d, J=2.7 Hz, 1H), 8.13 (dd, J=9.3, 2.7 Hz, 1H), 7.59 (d, J=9.3 Hz, 1H), 4.11 (t, J=6.9 Hz, 2H), 3.62 (s, 2H), 2.41 (t, J=6.9 Hz, 2H), 2.17 (s, 6H); MS-EI: (m/z, %) 281 (M+, 55), 251 (65), 58 (100).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([O:19]C)=O)=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.Cl.[CH3:31][NH2:32]>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([NH:32][CH3:31])=[O:19])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with methylamine hydrochloride gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.71 (d, 1H, J=4.8 Hz), 8.00-7.92 (m, 2H), 7.56-7.52 (m, 1H), 7.44-7.39 (m, 2H), 7.12 (m, 2H), 6.69 (bdd, 1H), 2.96 and 2.94 (2s, 3H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:27]1(O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Reactant: Oc1ccccc1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccccc2)CC1

Procedure:
The title compound was prepared in analogy to example 162 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155) and phenol. White solid (71%). MS (EI): 477.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([CH3:35])=[CH:14][C:15]=3[N:17](COCC[Si](C)(C)C)[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[S:10][C:9]=2[C:36]2[CH:37]=[N:38][N:39](COCC[Si](C)(C)C)[CH:40]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[NH:101]1[CH2:105][CH2:104][CH2:103][CH2:102]1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:35][C:13]1[N:12]=[C:11]2[S:10][C:9]([C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:101]4[CH2:105][CH2:104][CH2:103][CH2:102]4)[CH:3]=3)[C:16]2=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:14]=1
Reactant: C1CCNC1
Reactant: Cc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccccc2)c2c(-c3cccc(Br)c3)c(-c3cnn(COCC[Si](C)(C)C)c3)sc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(-c3cccc(N4CCCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 35.5 %

Procedure:
To a mixture of N-{3-(3-bromophenyl)-6-methyl-2-[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyridin-4-yl}-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)benzenesulfonamide (Description 51) (485 mg, 0.617 mmol), BINAP (23.05 mg, 0.037 mmol), Pd2(dba)3 (11.30 mg, 0.012 mmol) and sodium tert-butoxide (178 mg, 1.851 mmol) in toluene (5 mL) was added pyrrolidine (0.102 mL, 1.234 mmol) and the mixture was heated at 120° C. for ca. 2 h. After cooling to RT, the mixture was passed through celite, washed with DCM (ca. 20 mL×5) and the filtrate concentrated. The residue was purified by normal phase chromatography, eluting with 0-50% ethyl acetate in cyclohexane to give a residue which was subsequently taken-up in DCM (5 mL) and TFA (0.475 mL, 6.17 mmol) added. The mixture was stirred at RT overnight (ca. 24 h). Extra TFA (0.475 mL, 6.17 mmol) was added and stirring continued at RT for ca. 4 h. Extra TFA (0.475 mL, 6.17 mmol) was added and stirring continued at RT overnight (ca. 20 h). The reaction mixture was then passed through SCX cartridge, eluting with MeOH (150 mL), then with 2M NH3 in MeOH (200 mL). The basic methanolic solution was concentrated and the residue purified by normal phase chromatography, eluting with 0-100% ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions) and then by MDAP (basic conditions), to afford the title compound (113 mg). LCMS (A) m/z: 516 [M+1]+, Rt 1.28 min (acidic).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36](=[O:37])[CH2:35][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C(Cl)COc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)COc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and phenoxyacetyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:31][N:32]([CH:38]1[CH2:40][CH2:39]1)[CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([NH:20][C@:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:46](Cl)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:31][N:32]([CH:38]1[CH2:40][CH2:39]1)[CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:14][C@H:13]1[C:18]([NH:20][C@:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:19])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a mixture of ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate (1.55 g, 2.75 mmoL) in 10 mL of DMF was added imidazole (0.47 g, 6.88 mmoL) and tert-butyldimethylsilyl chloride (826 mg, 5.50 mmoL). The mixture was stirred at rt for 18 h, concentrated in vacuo, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. Flash chromatography (eluting with methylene chloride and then ethyl acetate) gave ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-(tert-butyldimethylsilyloxy)pyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate as a white solid (1.75 g, 94%): LC-MS (Phenomenex 10 μm C18HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.51 min), MS m/z 677 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: Clc1cccc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cccc(Oc2ccccc2)n1
Temperature: 140 °C

Procedure:
A reaction mixture consisting of 1.48 g (10 mmol) of 2,6-dichloropyridine, 6 g (63.75 mmol) of phenol and 2.4 g (60 mmol) of sodium hydroxide in 10 ml of water is heated to 140° C. for 24 hours in a bomb. After cooling the reaction mixture is made strongly alkaline with sodium hydroxide solution and extracted with dichloromethane. The organic phase is separated off and dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=3:1).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH3:37])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([OH:15])=[C:7]([C:16]3[NH:21][C:20]4[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=4[S:18](=[O:35])(=[O:34])[N:17]=3)[C:6]2=[O:36])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CC3CC3)C1=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 164D (0.100 g, 0.1912 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (4 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and aqueous NaHCO3, the organic layer was removed and the bicarb layer extracted 3× with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo to yield a solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[N+:33]([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CO.O>[NH2:33][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)c([N+](=O)[O-])c4)cc3)c2cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)c(N)c4)cc3)c2cc1OC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 41.5 %

Procedure:
N-(4-Chloro-3-nitrophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (100 mg) was dissolved in chloroform/methanol/water (5ml/15ml/3ml), sodium thiosulfate (358 mg) was added, and the admixture was stirred at 60° C. for 20 minutes. The reaction mixture was extracted 2 times with chloroform, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 39 mg of the title compound (yield: 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:14])[C:9](=[O:13])[CH:10](Br)[CH3:11].[C:15]1([CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1)[OH:16].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:14])[C:9](=[O:13])[CH:10]([O:16][C:15]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1)[CH3:11]
Reactant: Oc1ccc(O)cc1
Reactant: CC(Br)C(=O)N(C)c1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CC(Oc1ccc(O)cc1)C(=O)N(C)c1ccccc1F
Temperature: 25 °C
Yield: 86.4 %

Procedure:
N-(2-fluorophenyl)-N-methyl-2-bromo-propionamide(18.2 g, 0.07 mol), hydroquinone(7 g, 0.064 mol), potassium carbonate(10.54 g, 0.076 mol) and tetra-n-butylammonium bromide(1 g) were dissolved in 350 ml of acetonitrile and heated at reflux for 6 hours. The reaction mixture was cooled to room temperature and solid remained during the reaction was filtered out. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography(eluent: ethyl acetate/n-hexane=½) to afford 16 g of the target product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([NH2:12])[CH2:10][NH2:11].BrN1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)Cl>[NH:11]1[CH2:10][CH2:9][N:12]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: NCCN
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1ccc(C2=NCCN2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Pyridinecarboxaldehyde (0.95 ml, 10 mmol) is added into a reaction flask containing 20 ml of methylene chloride and ethylene diamine (0.78 ml, 10.5 mmol) is added. After the reaction is carried out at 0° C. for 20 minutes, N-bromosuccinimide (1.87 g, 10.5 mmol) is added. The reaction temperature is slowly raised from 0° C. to the room temperature and the reaction is further carried out for 24 hrs at the room temperature. 10% sodium hydroxide solution is added to have the solution become alkaline. After extraction with a small amount of methylene chloride is carried out for 2 times, the organic layer is collected and concentrated to obtain white solids. After purified by silicone chromatographic column, the product pyil is obtained. The yield is about 90%. 1H NMR (400 MHz, CDCl3): δ 8.55-8.54 (m, 1 H), 8.11 (d, 1 H, J=7.6 Hz), 7.76-7.71 (m, 1 H), 7.34-7.21 (m, 1 H), 3.82 (s, 4 H).
Reaction SMILES: [S-2].[Na+].[Na+].CN1CCCC1=O.[CH3:11][N:12]([CH2:14][CH:15]([C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:16]1[CH:17]=[CH:18][C:19]([O:22]C)=[CH:20][CH:21]=1)[CH3:13].C(OC(=O)C)C>O>[CH3:11][N:12]([CH2:14][CH:15]([C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[CH3:13]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: [Na+]
Agent: [S-2]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 145 °C
Yield: 77.4 %

Procedure:
A mixture of 78.5 g of anhydrous sodium sulfide, and 525 mL of 1-methylpyrrolidone was heated to 145° C. under nitrogen, and then 145 g of venlafaxine was added. The mixture was stirred and heated at 145° C. under nitrogen for 30 hours, then it was cooled and mixed with 2.9 L of ethylacetate and 2.0 L of water. The mixture was kept in the refrigerator overnight, crystals were filtered and dried to give 106.5 g of desvenlafaxine. Yield 77%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:56]1([C:62]([CH:64]2[CH2:67][NH:66][CH2:65]2)=[O:63])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>ClCCl.CN(C)C=O>[CH:56]1([C:62]([CH:64]2[CH2:67][N:66]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[O:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:65]2)=[O:63])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: O=C(C1CCCCC1)C1CNC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)N2CC(C(=O)C3CCCCC3)C2)cc1
Reaction time: 5 h
Yield: 3.1 %

Procedure:
To 189 mg (0.57 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy-phenyl)propanoic acid (cf. preparation 2-3) dissolved in 3.5 mL of dichloromethane and 1.0 mL of dimethylformamide are added 0.2 mL (1.14 mmol) of diisopropylethylamine, 202 mg (0.63 mmol) of TBTU and 95 mg (0.57 mmol) of 3-cyclohexanecarbonylazetidine. After 5 hours, the solution is washed with 1N sodium hydroxide solution and the organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product obtained is purified by preparative TLC (9/1 dichloromethane/methanol). 8.5 mg of 1-[2-(3-cyclohexanecarbonylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea are obtained in a yield of 3%.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8]CC2C=CC=CC=2)[CH:6]([O:16]CC2C=CC=CC=2)[CH:5]([CH2:24][O:25]CC2C=CC=CC=2)[CH2:4][CH:3]1[OH:33].[CH2:34]([N:36]=[C:37]=S)[CH3:35].CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:34]([NH:36][C:37]1[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][OH:25])[CH:6]([OH:16])[CH:7]([OH:8])[CH:2]2[N:1]=1)[CH3:35]
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: CCN=C=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCNC1=NC2C(CC(CO)C(O)C2O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 203.1 %

Procedure:
To a solution of Intermediate B (173 mg, 0.387 mmol) in dry THF (5 mL) was added a solution of ethyl isothiocyanate (42 mg, 0.48 mmol) in dry THF (3 mL). The mixture was stirred at room temperature for 24 h. Solvents were evaporated under reduced pressure. The residue was dissolved in acetone (3 mL). MeI (110 mg, 0.774 mmol) was added. The mixture was stirred at room temperature for 9 h. Satd. aqueous NaHCO3 (2 mL) was added and stirred at room temperature for 10 min. The mixture was further diluted with satd. aqueous NaHCO3 (20 mL), extracted with EtOAc (2×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 96:3:1 EtOAc-MeOH—NH4OH (28% aqueous) to give the aminooxazoline (181 mg, 94%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.36-7.25 (m, 15H), 4.88-4.85 (m, 1H), 4.78 (d, J=11.8 Hz, 1H), 4.76 (d, J=11.8 Hz, 1H), 4.66 (d, J=11.3 Hz, 1H), 4.46 (d, J=11.3 Hz, 1H), 4.45 (s, 2H), 4.07 (dd, J=8.0, 5.1 Hz, 1H), 3.67 (t, J=5.7 Hz, 1H), 3.55-3.51 (m, 2H), 3.46 (dd, J=9.0, 4.2 Hz, 1H), 3.29-3.15 (m, 2H), 2.20 (dt, J=14.9, 3.7 Hz, 1H), 2.07-2.00 (m, 1H), 1.89 (ddd, J=15.2, 11.9, 3.6 Hz, 1H); MS, m/z=500 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](N)[N:11]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][N:11]4[N:15]=[C:16]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=5)[N:17]=[C:10]4[CH:9]=3)=[CH:4][CH:3]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: Nc1cc(-c2ccc(Cl)nc2)cc2nc(-c3ccccn3)nn12
Product: c1ccc(-c2nc3cc(-c4ccc(N5CCOCC5)nc4)ccn3n2)nc1
Yield: 62 %

Procedure:
A solution of 0.10 g (0.0003 mol) 7-(6-chloro-pyridin-3-yl)-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 15 ml morpholine were stirred at 130° C. for 4 hours. Removal of the amine and chromatography on silicagel with dichloromethane/methanol 9/1 gave 0.07 g (62%) 7-(6-morpholin-4-yl-pyridin-3-yl)-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin beige solid, MS m/e (%):374 (M+H+,100).