Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:18]([CH:22]1[CH2:23][CH:24]2[N:29]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]3[C:6]4[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][C:8]3=[O:11])[CH:27]([CH2:26][CH2:25]2)[CH2:28]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(F)cc21
Yield: 68.6 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.219 g, 0.6 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.6 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc (4:1-4) gave the title compound (111MF26) (0.16 g, 58%). 1H NMR (CDCl3) δ 7.16 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.0 Hz, J=9.0 Hz, 1H), 6.69-6.63 (m, 1H), 4.58 (q, J=14.8 Hz, J=38.0 Hz, 2H), 4.10-3.93 (m, 2H), 3.16-3.06 (m, 2H), 2.33 (dd, J=4.0 Hz, J=12.8 Hz, 1H), 2.05 (t, J=11.6 Hz, 1H), 1.94-1.82 (m, 2H), 1.58-1.43 (m, 6H), 1.39-1.32 (m, 2H), 1.31-1.15 (m, 6H), 0.90-0.87 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.7 Hz), 130.0 (d, J=10.4 Hz), 117.5 (d, J=9.3 Hz), 109.4 (d, J=23.5 Hz), 103.9 (d, J=28.9 Hz), 67.8, 61.9, 60.1, 58.2, 45.6, 38.6, 38.5, 36.9, 31.8, 29.4, 28.2, 27.4, 26.5, 23.1, 17.1, 14.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH3:18])[C:11]=1[NH2:23].[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:23]=[C:25]([CH3:27])[C:24](=[O:28])[N:16]([C@H:17]([CH:19]3[CH2:20][CH2:21][CH2:22]3)[CH3:18])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1ccc(-c2ncnc(N[C@@H](C)C3CCC3)c2N)c(Cl)c1
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: COc1ccc(-c2ncnc3c2nc(C)c(=O)n3[C@@H](C)C2CCC2)c(Cl)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(S)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-cyclobutyl-ethyl)-pyrimidine-4,5-diamine (0.23 g, 0.69 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.78 ml, 6.9 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (S)-4-(2-chloro-4-methoxy-phenyl)-8-(1-cyclobutyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 567a). 1H NMR (300 MHz, CDCl3) δ ppm 9.06 (s, 1 H), 7.46 (d, J=8.79 Hz, 1 H), 7.09 (d, J=2.56 Hz, 1 H), 6.97 (dd, J=8.79, 2.56 Hz, 1 H), 5.82 (m, 1 H), 3.91 (s, 3 H), 2.51 (s, 3 H), 2.22 (m, 2 H), 1.87 (m, 4 H), 1.74 (s, 3 H), 1.55 (m, 1 H). MS (AP) 385.3 [(M+H)+, 100].
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:19][O:20][C:21]1[NH:25][N:24]=[C:23]([NH2:26])[N:22]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]2[N:24]3[N:25]=[C:21]([O:20][CH3:19])[N:22]=[C:23]3[NH:26][C:14]([CH3:15])=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: COc1nc(N)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc(OC)nn2C1c1ccc(C#N)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (297 mg, 1.2 mmol) and 5-methoxy-1H-1,2,4-triazole-3-amine (153 mg, 1.3 mmol, 1.1 eq.) were dissolved in DMF (2.5 ml), and solid sodium bicarbonate (513 mg, 6.1 mmol, 5 eq.) was added. The mixture was stirred at 65° C. for 12 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 (191 mg, 42% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.S(=O)(=O)(O)O.[CH2:17]=[CH:18][C:19](=[CH2:21])[CH3:20]>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:8]([CH:17]=[CH:18][C:19]([CH3:21])([CH3:20])[O:11]2)=[CH:9][CH:10]=1
Reactant: COCOc1cccc(O)c1
Reactant: C=CC(=C)C
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COCOc1ccc2c(c1)OC(C)(C)C=C2
Reaction time: 3 h
Yield: 69 %

Procedure:
7.7 g (50 millimoles) of 3-methoxymethoxy-phenol and 110 g of 50% sulfuric acid are dissolved in 150 g of chloroform, whereupon 6.8 g of isoprene are added at 60° C. within 20 minutes. The reaction mixture is allowed to stated at 60° C. for 3 hours, separated, the organic phase is evaporated and the residue is heated to boiling in the presence of 2.5 g of dichloro-dicyano-benzoquinone in 100 ml of dioxane for 10 hours. Then one proceeds as described in Example 8. Thus 7.6 g of the desired compound are obtained in the form of a light yellow oil, yield 69%.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.Cl>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccncc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: Cl
Solvent: CC(C)O
Product: Clc1nc(Nc2ccncc2)c2ccccc2n1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a stirred suspension of 2,4-dichloroquinazoline (42 mg, 0.21 mmol) and 4-aminopyridine (21 mg, 0.22 mmol) in 3 mL of anhydrous isopropanol was added a drop of concentrated HCl and the mixture was stirred overnight. Solid precipitates were observed and the mixture was filtered. The solid was washed with cold isopropanol and dried to give the title compound as white solid (38 mg, 0.13 mmol, 61%). 1H NMR (DMSO-d6): 8.60 (d, J=7.5 Hz, 2H), 8.18-8.20 (m, 2H), 8.07-8.10 (m, 1H), 7.90-7.96 (m, 1H), 7.18 (d, J=7.8 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:16][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C#CCCCCO
Reactant: O=Cc1ccccc1Br
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1C#CCCCCO
Temperature: 25 °C

Procedure:
To a solution of 2-bromobenzaldehyde (5.0 g, 27.0 mmol) and 5-hexyn-1-ol (3.18 g, 32.0 mmol) in triethyl amine (100 mL) was added bis(triphenylphosphine)palladium (II) dichloride (0.28 g, 0.4 mmol) and cuprous iodide (51 mg, 0.27 mmol). After heating the resulting mixture to reflux under an argon atmosphere for 1 hour, the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with 2:1 diethyl ether/hexanes to afford a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[N:20]([CH2:33][CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Agent: Cl
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CCCC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-5-({1-[4-Methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 1-(2-chloroethyl)pyrrolidine hydrochloride following General Procedure H.
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7]CC)=[O:6].C(O)C.[OH-].[Na+]>O>[Cl:1][C:2](=[CH2:13])[CH2:3][CH:4]([CH:10]([CH3:11])[CH3:12])[C:5]([OH:7])=[O:6]
Reactant: C=C(Cl)CC(C(=O)OCC)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(Cl)CC(C(=O)O)C(C)C
Yield: 70.1 %

Procedure:
The ethyl 4-chloro-2-isopropyl-4-pentenoate (8.0 g, 0.039 mol) was refluxed for 20 hrs. in 15 ml of water and 15 ml of ethanol containing 4.8 g (0.12 mol) of sodium hydroxide. Most of the ethanol was removed on the rotary evaporator and the residue taken up in 100 ml of water. The aqueous solution was extracted with two 50 ml portions of ether, then acidified with conc. HCl. The acidified mixture was extracted twice with 100 ml of ether. The ether was washed with water, dried (MgSO4), and removed to leave 4.83 g (70% yield) of a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])[C:23](=[O:26])[CH2:24]Cl>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:24]=1[C:23](=[O:26])[C:22]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][O:32][CH3:33])=[C:20]([O:19][CH2:18][O:17][CH3:16])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: COCOc1ccc(C(=O)CCl)cc1OCOC
Product: CCOC(=O)n1c(C(=O)c2ccc(OCOC)c(OCOC)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and [3,4-bis(methoxymethyloxy)]phenacyl chloride (step 1). 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 7.61 (1H, d, J=2.2 Hz), 7.52 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=8.4, 1.8 Hz), 7.29 (1H, dd, J=8.4, 1.8 Hz), 7.18 (1H, d, J=8.4 Hz), 5.72 (2H, br s), 5.29 (2H, s), 5.25 (2H, s), 3.86 (2H, q, J=7.3 Hz), 3.52 (6H, s), 0.91 (3H, t, J=7.3 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:18](=O)[CH2:17][CH:16]([C:20](OC)=[O:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: -5 °C
Yield: 95.2 %

Procedure:
A suspension of lithium aluminum hydride (7.50 g) in 150 ml THF was cooled to -5° C. A solution of methyl 1-benzyl-5-oxo-3-pyrrolidine carboxylate (0.064 moles, 15.0 g) in THF was added dropwise. The mixture was heated to 40° C. for 16 hours. Water (25 ml) was added. The mixture was filtered and extracted with ether. The organic phase was washed with water, dried over sodium sulfate and concentrated to yield 11.65 g of N-benzyl-3-hydroxymethylpyrrolidine. (MS) The alcohol (0.06 moles, 11.5 g) in 75 ml 2 N sulfuric acid was added dropwise to a stirred solution of chromium dioxide (0.15 moles, 15.0 g) in 100 ml 2 N sulfuric acid. The solution was stirred at room temperature for 16 hours. The solution was treated with barium hydroxide hydrate (0.317 mmoles, 100 g) in 250 ml hot water. The solid was filtered and washed with water. The aqueous solution was extracted with ether. Carbon dioxide was bubbled through the solution until the pH was 7.0. The solution was filtered and concentrated to yield 4.5 g of N-benzyl-3-pyrrolidinecarboxylic acid. (MS) The oil was dissolved in 50 ml methanol. Dry HCl gas was bubbled through the solution. The solution was heated to near reflux for 4 hours and concentrated. The residue was neutralized with aqueous sodium bicarbonate. The product was extracted with ether, dried and concentrated to yield 3.0 g of methyl N-benzyl-3-pyrrolidinecarboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30]([O:32]C)=O)=[CH:27][C:26]=3[CH:34]=2)[CH2:18][CH2:17]1)#[N:2].[NH3:35]>>[CH:11]1[C:3]([C:1]#[N:2])=[CH:4][C:5]2[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]5[O:29][C:28]([C:30]([NH2:35])=[O:32])=[CH:27][C:26]=5[CH:34]=4)[CH2:18][CH2:17]3)=[CH:7][NH:8][C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc2cc(N3CCN(CCCCc4c[nH]c5ccc(C#N)cc45)CC3)ccc2o1
Reactant: N
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1
Temperature: 27.5 °C

Procedure:
Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate (41 g) was added to saturated methanolic ammonia solution (8200 ml) under stirring at 25-30° C., the resulting mixture was stirred for 3 to 4 hours at the same temperature to form a clear solution. The reaction mass was stirred for 24 hours at 25-30° C., followed by filtration of the separated solid and then dried to produce 28 g of vilazodone. The mother liquors were taken and the solvent was distilled off under vacuum until the solvent quantity reaches around 1200 ml of the initial volume. The resulting mass was cooled to 25-30° C., followed by filtration and then drying to produce 11 g of Vilazodone (Purity by HPLC: 99.5%; Yield: 98.5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][C:9]([CH2:10][C@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:12]([OH:31])[CH2:13][N:14]([S:19]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.Cl[C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][N:48]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([S:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][C@@H:12]([OH:31])[C@@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:10][C:9]3[CH:44]=[CH:45][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47]4[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][N:48]=4)=[CH:7][CH:8]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCNc2ccc(C#N)cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 35 mg (0.054 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(3-aminopropoxy)benzyl]3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 22 mg (0.16 mmol) of 2-chloro-5-cyanopyridine, and 38 μL (0.22 mmol) of N,N-diisopropylethylamine in 0.5 mL of anhydrous DMF was heated to 80° C. with stirring. After 6 hours the solution was cooled to RT and concentrated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 33 mg (80%) of the desired compound as a white foam. 1H NMR (CDCl3): 8.30 (s, 1H), 7.50 (d, 1H), 7.29 (d, 1H), 7.13 (s, 1H), 7.09 (d, 2H), 6.84 (d, 1H), 6.78 (d, 2H), 6.37 (d, 1H), 6.04 (s, 2H), 5.62 (d, 1H), 5.44 (br s, 1H), 4.96 (m, 2H), 4.00 (t, 2H), 3.91 (m, 1H), 3.80 (m, 3H), 3.71-3.49 (m, 5H), 3.18-2.65 (m, 7H), 2.08 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.50 (m, 1H), 0.90 (d, 3H), 0.81 (d, 3H). MS(ESI): 752(M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:18][CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: BrCc1ccccc1
Product: CC(C)(Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1)NCc1ccccc1

Procedure:
Using a method similar to example 2, using 6-[4-(2-amino-2-methyl-propyl) phenoxy]-nicotinamide and benzyl bromide gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.96 minutes, Purity: 100%; mass spectrum (ion spray): m/z=376.2 (M+1).
Reaction SMILES: C([C:8]1[N:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:12](=[O:19])[C:11]([NH:20][C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28]C=2)=[O:22])=[CH:10][CH:9]=1)C1C=CC=CC=1.[K+].[Br-]>>[CH2:24]([O:23][C:21]([NH:20][C:11]1[C:12](=[O:19])[N:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:9][CH:10]=1)=[O:22])[C:25]1[CH:26]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)Cn1c(Cc2ccccc2)ccc(NC(=O)OCCc2ccccc2)c1=O
Agent: [Br-]
Agent: [K+]
Product: COC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O

Procedure:
Methyl [6-benzyl-1,2-dihydro-2-oxo-3-(2-phenylethoxy)carbonylamino-1-pyridyl]acetate (49i), was isolated (88%) as a colorless solid: mp. 130-133° C.; IR (KBr) 3363, 1746, 1732, 1651, 1604, 1515, 1368, 1231, 1212, 1185; 1H NMR (CDCl3) δ8.00 (1H, d, J=7.0), 7.68 (1H, s), 7.36-7.10 (10H, m), 6.15 (1H, d, J=7.6), 4.7 (2H, s), 4.38 (2H, t, J=7.0), 3.88 (2H, s), 3.67 (3H, s), 2.98 (2H, t, J=7).
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]([NH:20][CH3:21])[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22]O>>[CH:3]1([CH:9]([OH:10])[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH2:11][N:20]([CH3:21])[CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CO
Reactant: CNC1C=C(c2ccccc2)C(c2ccccc2)O1
Agent: [BH4-]
Agent: [Na+]
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Sodium borohydride (10.3 g) is added over approximately 30 minutes at a temperature in the region of 5° C. to a solution of 2,3-diphenyl-5-methylamino-2,5-dihydrofuran (9.7 g) in methanol (90 cc) and distilled water (10 cc). The reaction mixture is then stirred for 18 hours at a temperature in the region of 20° C., and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is triturated with methylene chloride (100 cc); the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica gel (400 g) in a 4 cm diameter column [eluent: methanol/aqueous ammonia (98/2 by volume)]. Elution is first carried out with solvent (400 cc); the corresponding eluate is discarded; elution then continues with solvent (600 cc); the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is recrystallised from a mixture of hexane (70 cc) and isopropanol (10 cc). In this way 1,2-diphenyl-4-methylamino-2-buten-1-ol (Z) (3.8 g) is obtained in the form of white crystals melting at 90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][CH2:14][CH2:15][OH:16])=[N:10]2)=[CH:5][C:4]=1[N+:17]([O-])=O.[Cl-].[NH4+]>C(O)C.CN(C)C=O.[Fe]>[NH2:17][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[C:9]([NH:13][CH2:14][CH2:15][OH:16])[CH:8]=[CH:7]2
Reactant: COc1cc2nc(NCCO)ccc2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2nc(NCCO)ccc2cc1N
Yield: 95.9 %

Procedure:
A mixture of 2-(7-methoxy-6-nitro-quinolin-2-ylamino)-ethanol (0.5 g, 1.90 mmol), iron powder (0.32 g, 5.70 mmol) and ammonium chloride (0.32 g, 5.70 mmol) in a mixture of ethanol and water (3/1, 16 mL) was heated at reflux for 2 hours. The reaction mixture was then filtered through a CELITE™ pad, the filtrate was evaporated under reduced pressure and the residue was triturated ten times with a mixture of dichloromethane and methanol (9/1, 50 mL). The residue was concentrated under reduced pressure to afford 0.425 g of 2-(6-amino-7-methoxy-quinolin-2-ylamino)-ethanol as a brown solid.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:38]=[C:37]([CH3:39])[C:29]3[NH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:28]=3[CH:27]=2)[CH:20]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:39][C:37]1[C:29]2[NH:30][C:31]([C:33]([F:34])([F:36])[F:35])=[N:32][C:28]=2[CH:27]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:38]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C(F)(F)F)[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2nc(C(F)(F)F)[nH]c12

Procedure:
21 mg (0.08 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 22 mg (0.07 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(trifluoromethyl)-1H-benzo[d]-imidazole and 40 μL (0.24 mmol) DIPEA in 2.0 mL DMF were stirred at 50° C. over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:13])[CH3:12]>C1C=CC=CC=1>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 0.25 h

Procedure:
A solution of 20 g. of 4-hydroxybenzoic acid in 200 ml. of benzene and 40 ml. of acetyl chloride is refluxed for 3 hours. Solvent and excess acetyl chloride are evaporated. The mixture is dissolved in methanol (150 ml.) and water (20 ml.) added; after 15 minutes, addition of more water results in the precipitation of 4-acetoxy benzoic acid, m.p. 192°-193° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([NH:13][C:14]([CH3:19])([CH3:18])[CH2:15][S:16][CH3:17])=[O:12].[CH3:20][C:21]1[CH:27]=[C:26]([CH:28]([N:30]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[N:31]2)[CH3:29])[CH:25]=[CH:24][C:22]=1[NH2:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:18][C:14]([NH:13][C:11](=[O:12])[C:3]1[C:4](=[CH:8][CH:9]=[CH:10][C:2]=1[I:1])[C:5]([NH:23][C:22]1[CH:24]=[CH:25][C:26]([CH:28]([N:30]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[N:31]2)[CH3:29])=[CH:27][C:21]=1[CH3:20])=[O:7])([CH3:19])[CH2:15][S:16][CH3:17]
Reactant: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)O
Reactant: Cc1cc(C(C)n2ccc(C(F)(F)F)n2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(C(C)n2ccc(C(F)(F)F)n2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
3-Iodo-N-(1,1-dimethyl-2-methylsulfanyl-ethyl)-phthalamic acid (0.39 g) and N-(3-dimethylaminopropyl)-N1-ethylcarbonyl diimidazole hydrochloride (0.19 g) were stirred in dichloromethane (10 ml) at room temperature for 30 minutes. Then, 2-methyl-4-[1-(3-trifluoromethyl-1H-pyrazol-1-yl)-ethyl]-aniline (0.30 g) and p-toluenesulphonic acid monohydrate (0.02 g) were added thereto and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain N2-(1,1-dimethyl-2-methylsulfanyl-ethyl)-3-iodo-N1-{2-methyl-4-[1-(3-trifluoromethyl-1H-pyrazol-1-yl)-ethyl]-phenyl}-phthalamide (0.38 g) (compound No. 558). mp. 79-86° C.