Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([C@H](NC(OCC1C=CC=CC=1)=O)C(O)=O)C.C([O:26][C:27]([C:29]1([OH:63])[CH2:34][CH:33]([OH:35])[CH:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:31]([CH:40]([OH:62])[CH:41]([OH:61])[CH2:42][O:43][C:44](=[O:60])[CH:45]([NH:49]C(OCC2C=CC=CC=2)=O)[CH:46]([CH3:48])[CH3:47])[O:30]1)=[O:28])C1C=CC=CC=1>C1COCC1.C(OCC)(=O)C.[Pd]>[C:37]([NH:36][CH:32]1[CH:31]([CH:40]([OH:62])[CH:41]([OH:61])[CH2:42][O:43][C:44](=[O:60])[CH:45]([NH2:49])[CH:46]([CH3:48])[CH3:47])[O:30][C:29]([OH:63])([C:27]([OH:28])=[O:26])[CH2:34][CH:33]1[OH:35])(=[O:39])[CH3:38]
Reactant: CC(=O)NC1C(O)CC(O)(C(=O)OCc2ccccc2)OC1C(O)C(O)COC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)NC1C(O)CC(O)(C(=O)O)OC1C(O)C(O)COC(=O)C(N)C(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
In a 500 mL Parr shaker is placed the Z-valine protected benzyl ester (1-5) (2.50 g, 3.96 mmol) and the solid is dissolved in a mixture of THF (22 mL) and ethyl acetate (10 mL). To this is then added 10% Palladium on Carbon (2.0 g) in a single lot and the resulting suspension is hydrogenated at 50 psi at room temperature for overnight. LC/MS at this time of a small filtered aliquot, shows complete absence of starting material and the presence of the desired material (M+1=409). The remaining suspension is filtered through a Celite pad and the pad washed with THF. Evaporation of solvent leaves a light yellow semi-solid which upon trituration with isopropanol produces an off-white solid. The solid is collected by filtration through a Buchner funnel to provide 1.28 g (80% yield) of essentially pure pro-drug ester 1. LC/MS: (+) ESI: m/z=409.0 [M+1]; retention time=0.40 min. Melting Point: Decomposes between 140 to 145° C. Appearance: Off-white solid. Analytical HPLC; Column=Phenomenex Luna HILIC (reverse phase): Mobile Phase: A=0.05% H3PO4 in Water, B=0.05% H3PO4 in CH3CN: Gradient: 5% A to 50% B over 20 minutes, λ=205 nM; Retention Time: 3.8 minutes (Single Peak). 1H NMR (400 MHz, d4-MeOD) δ 4.41-4.49 (m, 2H), 3.98-4.08 (m, 3H), 3.87-3.97 (m, 2H), 3.57 (dd, J=9.6, 0.8 Hz, 1H), 2.28-2.39 (m, 1H), 2.22 (dd, J=12.8, 4.8 Hz, 1H), 2.04 (s, 3H), 1.83 (dd, J=12.8, 11.6 Hz, 1H), 1.04-1.06 (m, 6H); 13C NMR (400 mHz, D2O) δ 176.6, 174.6, 169.9, 96.4, 69.9, 68.4, 67.8, 67.4, 67.2, 58.4, 52.3, 39.4, 29.4, 22.1, 17.3, 17.1. Final Purity Estimate: 96-97% (Based upon 1H NMR integration in Trifluoroacetic Acid-D).
Reaction SMILES: C[O:2][C:3]1[N:11]([C@@H:12]2[CH2:15][C@H:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:13]2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.Cl>>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:16][C@@H:14]1[CH2:13][C@H:12]([N:11]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[NH:4][C:3]2=[O:2])[CH2:15]1
Reactant: COc1nc2cccnc2n1[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: Cl
Product: O=c1[nH]c2cccnc2n1[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Yield: 41.8 %

Procedure:
To a 50-mL round-bottomed flask with N-(cis-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)benzo[d]thiazol-2-amine (example 9, 100 mg, 0.285 mmol) was added hydrogen chloride (1 M in diethyl ether, 1.0 mL, 1.0 mmol). The solution was stirred for minutes then concentrated under reduced pressure. The crude was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane (10 mL). The organic extract was dried over sodium sulfate then concentrated in vacuo to give the crude material as a off-white oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g, hexane to ethyl acetate gradient) to provide 3-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (40 mg, 0.119 mmol, 83% yield) as light-yellow solid. M+1: 338. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.67-2.80 (m, 2 H) 3.02-3.16 (m, 2 H) 4.12-4.26 (m, 1 H) 4.62-4.77 (m, 1 H) 6.93-7.10 (m, 2 H) 7.22 (td, J=7.20, 1.30 Hz, 1 H) 7.30 (dd, J=7.75, 1.32 Hz, 1 H) 7.37-7.43 (m, 1 H) 7.67 (dd, J=7.75, 0.73 Hz, 1 H) 7.98 (dd, J=5.19, 1.39 Hz, 1 H) 8.50 (d, J=6.72 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[N:4]([CH2:15][CH3:16])[CH:3]=1.Cl>CCO.[OH-].[Na+]>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: CCn1cc(Br)c2cnc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(Br)c2cnc(C(=O)O)cc21
Temperature: 80 °C
Reaction time: 120 h
Yield: 90.9 %

Procedure:
A mixture of methyl 3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (3A, 3.0 g, 11 mmol) in EtOH (10 ml) and 1N NaOH (10 ml) was stirred at 80° C. for 5 days. The reaction mixture was acidified with 1N HCl, concentrated in vacuo and dried to give 3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (3B, 2.8 g, 10 mmol, 98% yield) as a pale brown powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (t, J=7.20 Hz, 3 H) 4.49 (q, J=7.33 Hz, 2 H) 8.35 (s, 1 H) 8.65 (s, 1 H) 8.91 (s, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH:25][P:26](=[O:29])([OH:28])[OH:27])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.CO.O.[OH-].[Li+:36]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH:25][P:26]([O-:28])([O-:29])=[O:27])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[Li+:36].[Li+:36]
Reactant: O=P(O)(O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=P([O-])([O-])Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Yield: 71.3 %

Procedure:
To a mixture of (3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)phosphoramidic acid (8.5 mg, 0.019 mmol) described in Example 2 and methanol (1 mL) was added a mixture of lithium hydroxide monohydrate (1.9 mg, 0.045 mmol) and water (4 mL) at room temperature, and the solvent was evaporated from the reaction mixture under a reduced pressure. The resulting residue was washed with methanol to obtain the title compound (6.1 mg, 70%).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[C:1]1([CH2:11][C:12]([O:14][CH2:19][CH3:20])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)Cc1cccc2ccccc12
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cccc2ccccc12

Procedure:
100 g (537 mmol) of naphthalene-1-acetic acid in 200 ml of absolute ethanol are heated to 60° C., while stirring, and 80 ml of thionyl chloride are added slowly in such a way that reflux occurs. Reflux is maintained for 6 h, and the solvent is then evaporated under reduced pressure. The residue is taken up with 200 ml of dichloromethane, the solution is washed with a saturated solution of sodium hydrogen carbonate and then with water, dried over magnesium sulphate and filtered, and the solvent is evaporated under reduced pressure. 104 g (485 mmol) of product are obtained in the form of an oil. n25D =1.5800.
Reaction SMILES: [NH2:1][C:2]1[C:7]([SH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:11])=[O:10].[N:22]#[C:23]Br>C1COCC1>[NH2:22][C:23]1[S:8][C:7]2[C:2](=[C:3]([S:9]([NH:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: N#CBr
Reactant: Nc1c(S)cccc1S(=O)(=O)Nc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: Nc1nc2c(S(=O)(=O)Nc3ccc(C(=O)O)cc3)cccc2s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 4-(2-amino-3-mercaptophenylsulfonamido)benzoic acid (671 mg, 2.07 mmol) in THF (15 mL) was added cyanic bromide (439.1 mg, 4.14 mmol) at r.t. The reaction mixture was stirred at 80° C. for 8 h. The resulting mixture was then cooled, and partitioned between water and EtOAc. The organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo to afford the title compound (730 mg). LC-MS: m/z 348.7 (M+H)+
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH3:37])[C:26](O)=[O:27]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[CH:36]=[CH:35][N:34]=[C:33]3[CH3:37])=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1F
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.71 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][CH:4]=[C:5]1[CH2:27][CH2:26][C:8]2([S:12][CH2:11][C:10](=[O:13])[N:9]2[CH2:14][CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:7][CH2:6]1.[OH-].[Na+].C(Cl)(Cl)Cl.O>O1CCOCC1>[CH3:1][CH:2]([CH3:28])[CH2:3][CH:4]=[C:5]1[CH2:27][CH2:26][C:8]2([S:12][CH2:11][C:10](=[O:13])[N:9]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC2(CC1)SCC(=O)N2CCC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)CC=C1CCC2(CC1)SCC(=O)N2CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
In 40 ml of dioxane was dissolved 4.11 g of benzyl 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate. Then, 20.5 ml of 1 mol/L aqueous solution of sodium hydroxide was added at 0-5° C., and the resulting mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into a mixture of chloroform and water, the aqueous layer was separated, ethyl acetate was added to the aqueous layer, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography (eluent: chloroform:ethanol=50:1) gave 2.72 g of 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid as a light yellow oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:43]=[CH:42][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=O)[C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClCCCl.C([SiH](CC)CC)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)=[CH:42][CH:43]=1)([O-:3])=[O:2]
Reactant: CCCCCCC(Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1)Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O
Product: CCCCCCC(Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 106.1 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 40.5 g of 1,3-bis(4-(4-nitrobenzoyl)phenyl)-2-n-hexyl propane, 100 milliliters of 1,2-dichloroethane and 49.7 g of boron trifluoride diethyl ether complex were introduced and heated at reflux. 36.2 g of triethylsilane was added dropwise for 20 minutes with maintaining the temperature. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured in water and extracted with chloroform. After washing with an aqueous solution of sodium hydrogencarbonate and water, the solution was dried with anhydrous sodium sulfate. After removing off the solvent by a rotary evaporator, the residue was dissolved in toluene, and a separating operation was carried out by a column chromatography with silica gel. After removing off the solvent again, 40.9 g of 1,3-bis(4-(4-nitrobenzyl)phenyl)-2-n-hexyl propane was obtained as yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:6]([NH:8][NH2:9])=O.Cl.Cl.[CH3:25][O:26][C:27]1[CH:28]=[C:29](/[CH:39]=[CH:40]/[C:41](=[NH:45])OCC)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>C(O)CC>[CH3:25][O:26][C:27]1[CH:28]=[C:29](/[CH:39]=[CH:40]/[C:41]2[N:45]=[C:6]3[CH:5]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)[CH2:4][CH2:3][CH2:2][N:8]3[N:9]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CCCCl)C(=O)NN)CC1
Agent: Cl
Solvent: CCCO
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(C(=O)OC(C)(C)C)CC2)ccc1-n1cnc(C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution of tert-butyl 4-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]piperidine-1-carboxylate (663 mg) in 1-propanol (4 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride obtained in Example 1 (792 mg) and TEA (1.7 mL) in 1-propanol (16 mL), and the reaction solution was stirred at 90° C. overnight. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate, water and a saturated sodium bicarbonate solution were added to the concentration residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system) to obtain 361 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:50][N:51]1[CH:56]2[CH2:57][CH2:58][CH:52]1[C:53]([NH2:65])([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:54][CH2:55]2>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([NH:65][C:53]2([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH2:54][CH2:55][CH:56]3[N:51]([CH3:50])[CH:52]2[CH2:58][CH2:57]3)=[O:8])[CH2:2][CH2:3]1
Reactant: CN1C2CCC1C(N)(c1ccccc1)CC2
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCC1C(NC(=O)c1ccc(C(F)(F)F)cc1C1CC1)(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23.4 mg (0.102 mmol) 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate B2), 53.1 mg (0.139 mmol) HATU and 64 ul (0.370 mmol) N-ethyldiisopropylamine in 0.8 ml N,N-dimethylformamide, was added a solution of 20 mg (0.0925 mmol) (1RS,2RS,5SR)-8-methyl-2-phenyl-8-aza-bicyclo[3.2.1]oct-2-ylamine (intermediate A1) in 0.2 ml N,N-dimethylformamide. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed once with water and twice with a saturated sodium bicarbonate solution. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica (5 g) eluting with a gradient formed from n-heptane and ethyl acetate (0 to 50%) to provide 10 mg (y: 25.2%) of the title compound as a colorless viscous oil. MS (m/e): 429.2 (M+H+)
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:15]=O>>[C:9]1([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:1]=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(c1ccccc1)c1ccccc1
Reactant: O=O
Product: O=CN(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 43.3 %

Procedure:
By essentially the procedure of Example 1, a tube was charged with 40 g of methyldiphenylamine and 2.0 g CuCl2. 2H2O. The reaction was run at 115°-125° C. for 2 hr at 290-400 psi. About 0.1 mole of oxygen was injected incrementally. GC/MS analysis showed a 98.6% conversion of methyldiphenylamine and a 43.3% yield of diphenylformamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: CNc1ncc(Br)cc1N
Temperature: 70 °C

Procedure:
A suspension of (5-bromo-3-nitro-pyridin-2-yl)-methyl-amine (Stage 67.1.5, 4.58 g, 19.75 mmol) and tin dichloride dihydrate (Acros, Basel, Switzerland, 13.38 g, 59.3 mmol) in 200 ml of THF was heated at 70° C. for 220 min. The solvent was removed by evaporation and the residue taken in CH2Cl2 (100 ml) and 5 M aqueous NaOH (50 ml) and stirred until all the solid was dissolved. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a brown solid. (HPLC: tR 1.69 min (Method A); M+H=202, 204 MS-ES).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:17][C:18](SC)=[N:19][N:20]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:17][C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:19][N:20]=1
Reactant: C1COCCN1
Reactant: CSc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Solvent: C1COCCO1
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnc(N2CCOCC2)o1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of (2-Fluoro-4-iodo-phenyl)-[4-(5-methylsulfanyl-[1,3,4]oxadiazol-2-yl)-pyridin-3-yl]-amine (100 mg, 0.23 mmol) in dioxane (5 mL) were added morphline (101 mg, 1.17 mmol). The reaction mixture was stirred at 120° C. for 8 h. The solvent was evaporated, residue was purified with prep plate (CH2Cl2:MeOH=20:1 5% TEA), collected product 24 mg. LC-MS (Method A) [5.20 min; 468(M+1)]
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH:36]3[CH2:38][CH2:37]3)=[N:19][C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:21][C:22]=2[CH2:23][O:24][CH3:25])=[CH:11][C:10]=1C)([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH:36]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[CH:10][CH:11]=3)=[C:22]([CH2:23][O:24][CH3:25])[N:21]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)[N:19]=2)[CH2:37][CH2:38]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1COc1ccc(OC(C)(C)C(=O)O)cc1
Yield: 85.5 %

Procedure:
A solution of 198 mg (0.385 mmol) 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.1 ml 1N LiOH-solution in 2.5 ml tetrahydrofurane was stirred for 2 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude residue was suspended in Ethylacetate/heptane 1:19. The resulting crystals were filtered off to provide 170 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[NH:26][C:25]([CH3:27])=[N:24][CH:23]=1>>[CH3:27][C:25]1[NH:24][C:23]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:22][N:26]=1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Cc1ncc(I)[nH]1
Product: Cc1ncc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)[nH]1
Yield: 51 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 5-iodo-2-methyl-1H-imidazole were reacted to give the title compound as an off-white foam (28 mg, 51%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[O:19]C(=O)[NH:17][CH:16]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:17][CH:16]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[CH:23]=1)[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[OH:19]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2cccc(OCc3ccccc3)c2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1

Procedure:
To a solution of (4RS,5SR)-5-[3-(benzyloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (6.5 g, 13.7 mmol) in ethanol (70 ml) was added 8N aqueous sodium hydroxide solution (5.13 ml, 41 mmol), and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (6.26 g, 100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cn(-c2nccc(N3CCCCC3CCNCc3ccc4c(c3)OCO4)n2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCC1CCCCN1c1ccnc(-n2ccnc2)n1)Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 48.2 %

Procedure:
Alternatively, to THF (3 mL) was added N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (8 mg, 0.03 mmol), Hünig's base (8 mg, 0.06 mmol), and methanesulfonyl chloride (4.5 mg, 0.04 mmol). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 7 mg (51%) of N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-N-(methylsulfonyl)piperidine-2-ethanamine (the compound of formula (Iff); 1H MNR (CDCl3) δ8.10 (s, 1), 7.78 (d, 1), 7.13 (s, 1), 6.82 (s, 1), 6.72 (s, 2), 6.30 (d, 1), 5.94 (s, 2), 4.23 (m, 3), 3.20 (m, 2), 2.80 (s, 3), 1.14 (m); MS: 485.7 (M+H)+.