Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NC1C=CC2C3SC(C(N(C4C=CC=CC=4Cl)C)=O)=CC=3CCOC=2C=1.C(N(CC)CC)C.C(OCC(Cl)=O)C1C=CC=CC=1.C([O:54][CH2:55][C:56]([NH:58][C:59]1[CH:60]=[CH:61][C:62]2[C:68]3[S:69][C:70]([C:72]([N:74]([C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=4[Cl:82])[CH3:75])=[O:73])=[CH:71][C:67]=3[CH2:66][CH2:65][O:64][C:63]=2[CH:83]=1)=[O:57])C1C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(S(O)(=O)=O)(F)(F)F>[Cl:82][C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][C:76]=1[N:74]([CH3:75])[C:72]([C:70]1[S:69][C:68]2[C:62]3[CH:61]=[CH:60][C:59]([NH:58][C:56](=[O:57])[CH2:55][OH:54])=[CH:83][C:63]=3[O:64][CH2:65][CH2:66][C:67]=2[CH:71]=1)=[O:73]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)COCc3ccccc3)cc1OCC2)c1ccccc1Cl
Agent: CN(C(=O)c1cc2c(s1)-c1ccc(N)cc1OCC2)c1ccccc1Cl
Agent: Cl
Agent: O=C(Cl)COCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CO)cc1OCC2)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
To a mixture of 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide HCl salt (1.0 g, 2.37 mmol) in 30 mL of DCM (dichloromethane, methylene chloride) was added triethylamine (1 mL, 7.12 mmol). The mixture was stirred at 0° C. for 10 min and BnOCH2COCl (0.53 g, 2.85 mmol) was added dropwise. After the addition was completed, the reaction mixture was raised to room temperature and stirred for another 2 hours. The mixture was quenched by water and extracted with EtOAc. The organic phases were combined, dried over Na2SO4 and evaporated to about 0.9 g of the crude product, which was used for the next step without further purification. A mixture of 8-(2-(benzyloxy)acetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.6 g, 1.13 mmol) in TFA (5 mL) and CF3SO3H (2 mL) was stirred at 60° C. overnight. After removal of the solvent, the crude product was purified by prep. TLC to give about 320 mg of 158 (isolated yield: 64%). 1H NMR (DMSO-d6, 400 MHz): δ 9.77 (s, 1H), 7.63-7.35 (m, 7H), 6.47 (s, 1H), 5.64 (s, 1H), 4.11 (s, 2H), 3.94 (d, J=5.2 Hz, 2H), 3.23 (s, 3H), 2.88 (d, J=5.2 Hz, 2H). MS: (ESI+) 443.0
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]=1[CH3:18])[C:3](=O)[CH3:4]>S(=O)(=O)(O)O>[CH3:1][C:2]1[O:6][C:7]2[C:8]([CH3:18])=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][C:17]=2[C:3]=1[CH3:4]
Reactant: CCOC(=O)c1ccc(OC(C)C(C)=O)c(C)c1
Agent: O=S(=O)(O)O
Product: Cc1oc2c(C)cc(C(=O)O)cc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
250.3 g (1.0 mol) of ethyl 4-(1-methyl-2-oxopropoxy)-3-methylbenzoate are stirred in 400 ml of 94% sulfuric acid, first at room temperature for 30 minutes and then at 60° for 30 minutes. The reaction mixture is cooled to room temperature, poured onto 2 kg of ice and extracted with ethyl acetate. The organic phase is washed twice with water and then extracted 3 times with 500 ml of 2 N sodium carbonate solution each time. The sodium carbonate solutions are rendered acid (pH about 2-3) with 5 N hydrochloric acid and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated completely under a waterpump vacuum. 2,3,7-Trimethyl-5-benzofurancarboxylic acid of melting point 235°-237° is obtained from the residue by recrystallising it once from hot ethanol.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH2:19][CH3:20])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:21])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH2:19][CH3:20])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:21]
Reactant: CCCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O

Procedure:
0.38 g of 5'-azido-2',5'-dideoxy-5-n-propyluridine was dissolved in 100 ml of ethanol and the solution was hydrogenated in the presence of 0.1 g of 10% palladium-on-charcoal catalyst for 2 hours at room temperature and under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to give 5'-amino-2',5'-dideoxy-5-n-propyluridine in the form of a solid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1c(C)cccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(O)c1C(=O)O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
Step 1 A solution of ethyl 2-hydroxy-6-methylbenzoate (2.04 g, 11.32 mmol) in methanol (25 mL) was treated at rt with 1 M aqueous sodium hydroxide (45.3 mL, 45.3 mmol) and the mixture was heated at reflux for 6 h. The mixture was cooled to rt and the methanol was removed under vacuum. The aqueous residue was treated with 1 M hydrochloric acid to pH ca. 1. The precipitate was collected by filtration, washed with water and dried under vacuum to give 2-hydroxy-6-methylbenzoic acid as a white solid (1.62 g, 94%). 1H NMR (400 MHz, methanol-d4) δ 7.26 (1 H, t, J=7.92 Hz), 6.75 (2 H, t, J=7.92 Hz), 2.55 (3 H, s). Mass spectrum m/z 153.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[C:7]3[CH:8]=[C:9]([C:14]([NH2:16])=O)[CH:10]=[CH:11][C:12]=3[CH2:13][CH:2]12.O=P(Cl)(Cl)Cl.O>O1CCOCC1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[C:7]3[CH:8]=[C:9]([C:14]#[N:16])[CH:10]=[CH:11][C:12]=3[CH2:13][CH:2]12
Reactant: NC(=O)c1ccc2c(c1)C1CCCNC1C2
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc2c(c1)C1CCCNC1C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxamide (I), hydrogen chloride salt (7.5 Kg, 25.2 mol) and dioxane (15 L) is stirred for 30 minutes at 25° C. and treated with POCl3 (7.77 Kg, 50.4 mol). The mixture is heated to 80° C. over 1 hour and held at 80° C. for 2 hours. The mixture is cooled to 20-25° C., treated over about 30 minutes with a solution of water (1.376 L, 75.6 mol) in dioxane (30 L), stirred for 30 minutes, and treated with additional water (1.376 L, 75.6 mol). The resulting slurry is stirred at 25° C. for about 18 hours and filtered. The resulting filter cake is washed portion-wise with 3.0 L of 1% H2O in 1,4-dioxane and dried for about 18 hours at ˜50° C. to provide 2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (III) in the form of the hydrogen chloride salt. Yield: 4.73 Kg, 20.16 mol; 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:22]([F:25])=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH:26]1([C:29]([NH:1][C:2]2[CH:3]=[C:4]([C:22]([F:25])=[CH:23][N:24]=2)[C:5]([NH:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=2)[CH3:9])=[O:6])=[O:30])[CH2:28][CH2:27]1
Reactant: CC(NC(=O)c1cc(N)ncc1F)c1ccc(OCC(F)(F)F)nc1
Reactant: O=C(Cl)C1CC1
Product: CC(NC(=O)c1cc(NC(=O)C2CC2)ncc1F)c1ccc(OCC(F)(F)F)nc1
Yield: 11 %

Procedure:
The title compound is prepared in 11% yield (4.4 mg) from 2-amino-5-fluoro-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (34 mg, 0.095 mmol, Step-1, single enantiomer) and cyclopropanecarbonyl chloride (20 mg, 0.19 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNC1
Reactant: O=C(O)CCCCCOc1cc(-c2ccccc2)c2ccccc2n1
Solvent: C1CCOC1
Product: O=C(CCCCCOc1cc(-c2ccccc2)c2ccccc2n1)N1CCCC1
Reaction time: 2 h

Procedure:
To a solution of 5 g of 6-[(4-phenyl-2-quinolyl)oxy]hexanoic acid in 120 cc of tetrahydrofuran is added 2.9 g of 1,1'-carbonyldiimldazole. The mixture is stirred for 2 hours to 50 C. After cooling, 1.3 g of pyrrolidine is added and the mixture is stirred at room temperature overnight. The tetrahydrofuran is removed in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate solution is washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue is then purified by flash chromatography on silica gel (30-60mm; eluent: 3:7 cyclohexane/ethyl acetate) to give 1-[6-(4-phenyl-2-quinolyloxy)hexanoyl]pyrrolidine as a white solid (m.p.=52°-54° C.)
Reaction SMILES: [CH3:1][CH2:2][C@:3]1([C@H:31]2[O:35][C@H:34]([C@H:36]3[O:41][C@@:40]([OH:44])([CH2:42][OH:43])[C@H:39]([CH3:45])[CH2:38][C@@H:37]3[CH3:46])[CH2:33][C@H:32]2[CH3:47])[O:7][C@@H:6]([C@:8]2([CH3:30])[O:12][C@:11]3([O:17][C@H:16]([C@@H:18]([C@H:20]([O:26][CH3:27])[C@H:21]([C:23]([O-:25])=[O:24])[CH3:22])[CH3:19])[C@H:15]([CH3:28])[C@@H:14]([OH:29])[CH2:13]3)[CH2:10][CH2:9]2)[CH2:5][CH2:4]1.[Na+].O>C(O)C>[CH3:1][CH2:2][C@:3]1([C@@H:31]2[O:35][C@@H:34]([C@H:36]3[O:41][C@@:40]([OH:44])([CH2:42][OH:43])[C@H:39]([CH3:45])[CH2:38][C@@H:37]3[CH3:46])[CH2:33][C@@H:32]2[CH3:47])[O:7][C@@H:6]([C@@:8]2([CH3:30])[O:12][C@:11]3([O:17][C@H:16]([C@H:18]([C@@H:20]([O:26][CH3:27])[C@@H:21]([C:23]([OH:25])=[O:24])[CH3:22])[CH3:19])[C@H:15]([CH3:28])[C@@H:14]([OH:29])[CH2:13]3)[CH2:10][CH2:9]2)[CH2:5][CH2:4]1
Reactant: CC[C@@]1([C@H]2O[C@H]([C@H]3O[C@@](O)(CO)[C@H](C)C[C@@H]3C)C[C@H]2C)CC[C@H]([C@@]2(C)CC[C@]3(C[C@H](O)[C@@H](C)[C@@H]([C@H](C)[C@H](OC)[C@@H](C)C(=O)[O-])O3)O2)O1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC[C@@]1([C@@H]2O[C@@H]([C@H]3O[C@@](O)(CO)[C@H](C)C[C@@H]3C)C[C@@H]2C)CC[C@H]([C@]2(C)CC[C@]3(C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(=O)O)O3)O2)O1
Yield: 48 %

Procedure:
Treatments were: 1) C; 2) HS; 3) HS plus 10 ppm AQ; 4) HS plus 5 ppm RUMENSIN® (Elanco, Greenfield, Ind.) and 5) HS plus 10 ppm AQ. Fermentations supplemented with RUMENSIN® were prepared by first dissolving the RUMENSIN® in 96% ethanol and then adding the same volume of deionized water, yielding a concentration of monensin (in 48% ethanol) that would result in 5 ppm in the rumen fluid-buffer mix when 0.25 ml of the solution was added to 29.5 ml of the rumen fluid-buffer solution; finally, 0.25 ml of deionized water was added to yield a final volume of 30 ml. Each of the other treatment conditions (including the control fermentations) were modified by adding the same amount of ethanol to each as was present in the RUMENSIN® fermentation. This was done by doubling the concentration of the stock solutions, adding 0.25 ml of the stock solution (or deionized water for the controls) and 0.25 ml of 46% ethanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:29])=[C:8]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH:9]=1)=[O:4].FC(F)(F)C(O)=O>O1CCCC1>[F:28][CH:26]([F:27])[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([N:11]([CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=3[CH3:29])[CH3:12])=[CH:18][CH:17]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1CN(C)c1ccc(-c2ccc(OC(F)F)cc2)cc1
Reaction time: 30 h
Yield: 17.7 %

Procedure:
A solution of 4-{[(4′-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid methyl ester (175) (30 mg, 0.07 mmoles) in dry tetrahydrofuran (20 ml) was treated with potassium trimethylsilanoate (19 mg, 0.15 mmoles) and the mixture stirred under an argon atmosphere for 30 hours. Trifluoroacetic acid was added until the pH=2. After evaporation of the solvent, the residue was purified by HPLC to afford compound 176 (4.8 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:14]1[C:13](=[O:16])[CH:12]=[C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:15]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1
Product: COc1ccc(-c2cc(=O)n(Cc3ccccc3)nc2-c2ccc(OC)c(F)c2)cc1
Yield: 95.8 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one and benzyl bromide as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 95.8%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16].[Cu](C#N)[C:25]#[N:26]>O1CCOCC1.[C-]#N.C([N+](CC)(CC)CC)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[C:25]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH3:13])[C:4](=[O:14])[C:3]([C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])=[C:2]2[OH:1])#[N:26]
Reactant: N#C[Cu]C#N
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(I)ccc2n(C)c1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(C#N)ccc2n(C)c1=O
Temperature: 145 °C
Yield: 89.1 %

Procedure:
Ethyl 2-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.200 g, 0.46 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.048 g, 0.087 mmol), Copper cyanide (0.194 g, 2.2 mmol) and Tris(dibenzylideneacetone)dipalladium (0.020 g, 0.022 mmol) in 1,4-dioxane (2 ml) were combined in a 10 ml tube. Tetraethylammonium cyanide (0.085 g, 0.54 mmol) and 1,4-dioxane (1 ml) were added and the tube was sealed and heated to 145° C. for 15 min under Argon in a microwave (Personal Chemistry 300 W). After cooling, the mixture was filtered and washed with methylene chloride (50 ml). The filtrate was washed with deionized water (3×50 ml), then with brine (50 ml), dried over magnesium sulfate then concentrated and dried in vacuo. Flash column chromatography (Silica gel, 0-100% methylene chloride in hexane) gave a solid which was washed with diethyl ether, filtered and dried in vacuo to give ethyl 2-(6-cyano-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.135 g, 90% yield).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CCO>[O:19]([C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=[C:16]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:17]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(NC(=S)Nc1ncc(Sc2ccccn2)cc1Oc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=S)Nc1ncc(Sc2ccccn2)cc1Oc1ccccc1
Temperature: 25 °C
Yield: 29.8 %

Procedure:
A mixture of 1-benzoyl-3-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)thiourea (2.10 g, 4.58 mmol) and K2CO3 (3.16 g, 22.9 mmol) was refluxed in EtOH (50 mL) for 18 hours. The reaction was cooled to ambient temperature, filtered and concentrated. The residue was purified by silica gel to provide 1-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)thiourea (0.484 g, 29.8% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C@H:7]([OH:12])[C:8]([O:10]C)=[O:9])[C:4]([OH:6])=[O:5].CCN(C(C)C)C(C)C.C(O)(=O)C.C(#N)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[OH:12][C@H:7]([C:8]([OH:10])=[O:9])[C@@H:3]([C:4]([OH:6])=[O:5])[NH2:2]
Reactant: COC(=O)[C@@H](O)[C@H](N)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CN(C)C=O
Product: N[C@H](C(=O)O)[C@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S)-3-Hydroxyaspartic acid is prepared by the method of G. Cardillo, L. Gentilucci, A. Tolomelli, C. Tomasini, Synlett 1999, 1727-1730, and converted in analogy to P. G. Mattingly, M. J. Miller, J. Org. Chem. 1983, 48, 3556-3559, using microwave radiation in a closed reactor into (2S,3S)-2-amino-3-hydroxy-4-methoxy-4-oxobutyric acid hydrochloride. (2S,3S)-2-Amino-3-hydroxy-4-methoxy-4-oxobutyric acid hydrochloride (447 mg, 2.24 mmol) is dissolved in DMF (9 ml). The solution is cooled to 0° C., Boc-glycin-N-hydroxysuccinimide ester (763 mg, 2.91 mmol, 1.3 equivalents), DMAP (14 mg, 0.11 mmol, 0.05 equivalents) and finally DIPEA (1170 μl, 6.72 mmol, 3 equivalents) are added. The mixture is allowed to warm slowly to room temperature and is then stirred for 2 h. The mixture is acidified with glacial acetic acid, mixed with acetonitrile and chromatographed on Sephadex LH 20 (method 45). Product-containing fractions are combined, concentrated and again chromatographed (method 46). The obtained product (761 mg, quant.) is reacted further without further purification. For analytical purposes, a pure sample is obtained by HPLC (method 44).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([S:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:52][CH2:53][CH3:54].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH:51]([S:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:52][CH2:53][CH3:54])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Reactant: CCCCSCCCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCSC(CCC)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of the compound of Example 1 (3.0 g, 4.2 mmol) and butyl sulfide (18 mL) in acetonitrile (24 mL) at 0° C. was added benzoyl peroxide (2.0 g) in three portions over 3 hours, and the reaction was stirred at 0° C. for 1 hour and then at room temperature for 1 hour. Additional benzoyl peroxide (4.0 g) was added in two portions over 2 hours at room temperature. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic phase was dried over MgSO4, filtered and evaporated. The concentrate was chromatographed on silica gel eluting with a gradient starting with 50% ethyl acetate in chloroform and ending with ethyl acetate to give the title compound (2.43 g, 68% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6]1)=[O:4].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:1][CH2:2][C:3]([N:5]3[CH2:9][CH2:8][CH:7]([N:10]4[CH2:11][CH2:12][CH:13]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:14][CH2:15]4)[CH2:6]3)=[O:4])=[N:24][CH:25]=[N:26]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1ncnc2cc(Cl)ccc12)N1CCC(N2CCC(c3ccccc3)CC2)C1
Yield: 58.9 %

Procedure:
A solution of 2-amino-1-[3-(4-phenylpiperidin-1-yl)pyrrolidin-1-yl]ethanone (preparation #9) (0.108 g, 0.377 mmol), 4,7-dichloroquinazoline (0.075 g, 0.377 mmol) and DIEA (0.1 mL, 0.565 mmol) in n-butanol was heated in a microwave (CEM Explorer, maximum power 300 W) at about 120° C. for about 20 min. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (20% to 50% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5, over 30 min at 81 mL/min; λ=254 nm; Microsorb C18, 100 Å, 5 μm, 250×46 mm column) to yield 2-(7-chloroquinazolin-4-ylamino)-1-[3-(4-phenylpiperidin-1-yl)pyrrolidin-1-yl]ethanone (0.100 g, 0.222 mmol) as a yellow solid. RP-HPLC (Table 1, Method a) Rt 1.77 min; m/z: (M+H)+ 450.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21]CC)=[O:20])[O:16]2)=[CH:11][CH:10]=1.I[CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:27]=[C:26]([O:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH2:37][CH3:38])([C:19]([OH:21])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCI
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(Oc4ccc(F)cc4)cc3Cl)cc2O1
Product: CCC1(C(=O)O)CCc2ccc(OCCCOc3ccc(Oc4ccc(F)cc4)cc3Cl)cc2O1

Procedure:
The title compound was synthesized following the procedure described in Example 2 employing ethyl 7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-chromane-2-carboxylate (Example 20) instead of ethyl 7-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate, and iodoethane instead of iodopropane.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.CC1(C)OC(=O)CC(=O)O1.[CH3:33][C@H:34]([CH2:40][CH3:41])[CH2:35][CH2:36][C:37]([OH:39])=O>ClCCl.O.C(O)(=O)C>[CH3:33][C@H:34]([CH2:40][CH3:41])[CH2:35][CH2:36][C:37](=[O:39])[CH3:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC[C@@H](C)CCC(=O)O
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC[C@@H](C)CCC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Dicyclohexyl carbodiimide (9.51 g, 46.1 mmol), N,N′-dimethyl-4-aminopyridine (1.13 g, 9.2 mmol) and triethylamine (6.4 ml, 46.1 mmol) were added to a solution of Meldrum's acid (6.64 g, 46.1 mmol) in dichloromethane (150 ml). (4R)-4-Methylhexanoic acid (6 g, 46.1 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was filtered and the solid was washed with dichloromethane (2×100 ml). The filtrate and washings were combined and evaporated under reduced pressure to give an orange oil. Acetic acid (50 ml) and water (50 ml) were added and the reaction was heated under reflux overnight. After the solution had cooled to room temperature it was extracted with pentane (100 ml). The organic extract was dried (MgSO4) and evaporated to give a residue that was purified by column chromatography on silica gel using an elution gradient of pentane to pentane:diethyl ether 19:1 to give the title compound (2.8 g) as a pale yellow oil.