Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]#[N:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[N:42]([Sn](C)(C)C)=[N+:43]=[N-:44]>C1(C)C=CC=CC=1>[NH:9]1[CH:10]=[C:6]([C:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40]4[NH:41][N:44]=[N:43][N:42]=4)[CH:36]=3)[CH:31]=2)([OH:1])[CH:3]([CH3:5])[CH3:4])[N:7]=[CH:8]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC(C)C(O)(c1ccc2cc(C#N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: Cc1ccccc1
Product: CC(C)C(O)(c1ccc2cc(-c3nnn[nH]3)ccc2c1)c1c[nH]cn1
Yield: 74.9 %

Procedure:
A solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthonitrile (1.0 g) and azidotrimethyltin (770 mg) in toluene (10 mL) was refluxed for 48 h. The precipitate was collected by filtration, dissolved in THF-methanol (1:1) and concentrated. The residue was diluted with water and extracted with a mixed solution of ethyl acetate-THF (1:1). The extract was dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=1:3) and crystallized from ethyl acetate to give the titled compound (469 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:23][N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:28](=[O:29])/[CH:27]=[CH:26]/[CH2:25][N:24]([CH:31]([CH3:33])[CH3:32])[CH3:23])[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3,4-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 25A (65 mg, 0.19 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (52 mg, 0.27 mmol) to yield 34 mg (37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:43])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)([CH3:34])[CH3:33])[CH3:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:28]([O:30][C:31](=[O:43])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:38][CH:37]=1)([CH3:34])[CH3:33])[CH3:29]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 200 mg (0.512 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 5 ml tetrahydrofuran were added 126 mg (0.563 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (CAS RN 42806-90-6) and 124 mg (0.614 mmol) tri-n-butylphosphin. The reaction mixture was cooled down to 0° C. 106 mg (0.614 mmol) N,N,N′,N′-tetramethylazodicarboxamide were added and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the title compound as colorless solid (74%). MS (Turbo Spray): m/z=597.2 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26]([OH:31])([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][C:44](OC(C)=O)=[O:45]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26]([O:31][C:44](=[O:45])[CH3:43])([CH2:27][CH3:28])[CH2:29][CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2ccc(OCc3ccccc3)c(C)c2)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(CC)(COc1ccc(C(CC)(CC)c2ccc(OCc3ccccc3)c(C)c2)cc1C)OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
A reaction mixture containing 3-{4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxymethyl}-pentan-3-ol (3.92 g, 8.27 mmol), Et3N (11.5 mL, 82.7 mmol) and Ac2O (3.9 mL, 41.3 mmol), is stirred at rt for 3 h. It is diluted with EtOAc (100 mL), washed with 0.1 M HCl (2×60 mL) and brine (60 mL); MgSO4 dried and concentrated to give the title compound (2.82 g, 5.47 mmol, 66%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[C:12]([NH:16][C:17]([CH:19]1[CH2:21][C:20]1([CH3:23])[CH3:22])=[O:18])[C:13]([OH:15])=[O:14]>O>[CH3:22][C:20]1([CH3:23])[CH2:21][CH:19]1[C:17]([NH:16]/[C:12](=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:3][C:2]([NH2:4])=[NH:1])/[C:13]([OH:15])=[O:14])=[O:18]
Reactant: N=C(N)N
Reactant: CC1(C)CC1C(=O)NC(=CCCCCCBr)C(=O)O
Solvent: O
Product: CC1(C)CC1C(=O)N/C(=C\CCCCCNC(=N)N)C(=O)O
Temperature: 70 °C
Yield: 34.5 %

Procedure:
To a solution of 2 mmoles of guanidine (prepared from 432 mg of guanidine sulfate and 630 mg of barium hydroxide octahydrate) in 7 ml of water was added 332 mg (1 mmole) of 8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)octenoic acid, and the solution was heated at 70° C. in a nitrogen atmosphere for 1 hr. The reaction mixture was applied to a 2×25 cm column of Dowex 50W-X8 (H +, 100-200 mesh). After elution with water the fractions containing the product were pooled and evaporated under reduced pressure. The residue was dissolved in several ml of warm ethanol and added dropwise to 100 ml of ether with rapid stirring. Filtration and washing with ether gave 107 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino-2-octenoic acid as an amorphous electrostatic powder. Homogeneous by TLC (n-BuOH, HOAc, H2O; 4:1:1). NMR (D2O, NaOD): ##STR9##
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH3:16])[C:14]=1[CH3:15])[CH3:7]>CO>[CH2:6]([O:8][C:9]1[N:10]=[N:11][C:12]([S:5][CH2:2][CH:3]=[CH2:4])=[C:13]([CH3:16])[C:14]=1[CH3:15])[CH3:7]
Reactant: C=CCS
Reactant: CCOc1nnc(Cl)c(C)c1C
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OCC)c(C)c1C

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 100 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.87 g(0.01 mol) of 3-ethoxy-4,5-dimethyl-6-chloropyridazine obtained from Preparation 8. The reaction solution was refluxed for 3 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing white crystal.
Reaction SMILES: Br[CH2:2][C@@H:3]1[O:7][C@@H:6]([P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4]1.[NH2:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][CH:22]=[N:23]2)=[C:19]([Cl:26])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[CH2:2][C@@H:3]2[O:7][C@@H:6]([P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4]2)=[C:19]([Cl:26])[N:18]=1
Reactant: CCOP(=O)(OCC)[C@H]1CC[C@H](CBr)O1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)[C@H]1CC[C@H](Cn2cnc3c(Cl)nc(N)nc32)O1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of (±)-trans-5-bromomethyl-2-diethoxyphosphinoyl-tetrahydrofuran (example 66) (529 mg, 1.76 mmol), 2-amino-6-chloropurine (358 mg, 2.11 mmol) and cesium carbonate (860 mg, 2.64 mmol) in dry DMF (2 mL) was stirred at 90° C. for 6 h. The mixture was then cooled and filtered. Concentration of the filtrate gave a residue which was purified by chromatography eluting with 2→5% MeOH in methylene chloride. The desired product was obtained a foam (384 mg, 56%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.Cl.[Cl:15][C:16]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][NH2:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:15][C:16]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][N:24]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)[CH3:10]
Reactant: NOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(=NOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a mixture of 0.15 g of 4′-(trifluoromethyl)acetophenone and 10 ml of pyridine was added 0.30 g of O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.30 g (yield, 75.5%) of 4′-(trifluoromethyl)acetophenone O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)oxime, nD21.5 1.5420.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1.[P:14]([O-:26])([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([O:16][CH3:17])=[O:15].[K+].CC(C)=O>CCOCC>[P:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([O:16][CH3:17])([O:26][CH2:10][C:9]([NH:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:13])=[CH:5][CH:6]=1)=[O:12])=[O:15]
Reactant: Cc1ccc(NC(=O)CCl)c(C)n1
Reactant: COP(=O)([O-])Oc1ccc(Cl)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COP(=O)(OCC(=O)Nc1ccc(C)nc1C)Oc1ccc(Cl)cc1

Procedure:
N-(2,6-Dimethyl-3-pyridyl)-α-chloroacetamide (32.2 grams), potassium O-methyl O-(4-chlorophenyl) phosphate (26 grams) and acetone (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 24 hours. After this time the mixture is stripped of solvent on a steam bath and the resulting residue is dissolved in ether. The ether solution is washed with water and is dried over magnesium sulfate. The dried solution is then evaporated under vacuum to yield the desired product O-[2-(2,6-dimethyl-3-pyridylamino)-2-ketoethyl] O-methyl O-(4-chlorophenyl) phosphate.
Reaction SMILES: [NH3:1].[CH:2]([NH:5][C:6]1[NH:11][C:10]2[CH:12]=[C:13]([CH2:16][C:17](OCC)=[O:18])[CH:14]=[CH:15][C:9]=2[S:8](=[O:23])(=[O:22])[N:7]=1)([CH3:4])[CH3:3].[C-]#N.[Na+]>CO>[CH:2]([NH:5][C:6]1[NH:11][C:10]2[CH:12]=[C:13]([CH2:16][C:17]([NH2:1])=[O:18])[CH:14]=[CH:15][C:9]=2[S:8](=[O:23])(=[O:22])[N:7]=1)([CH3:4])[CH3:3]
Reactant: N
Reactant: CCOC(=O)Cc1ccc2c(c1)NC(NC(C)C)=NS2(=O)=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NC1=NS(=O)(=O)c2ccc(CC(N)=O)cc2N1
Temperature: 57.5 °C

Procedure:
Ammonia gas was passed through a solution of ethyl (3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetate (0.20 g) and sodium cyanide (20 mg) in 10 ml of methanol at room temperature for 5 min. The solution was heated at 55-60° C. in a sealed flask overnight. The solvent was removed in vacuo and the residue was treated with 25 ml of water. On standing, a crystalline precipitate was formed. The crystals were filtered off and dried to give the title compound; m.p. 321-325° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:7]=1[CH:18]=[CH:19][CH2:20][C:21]([O:23]C)=[O:22])[CH3:5]>CO.O>[CH3:5][CH:4]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[CH:9]=[C:8]([CH:15]([CH3:16])[CH3:17])[C:7]=1[CH:18]=[CH:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:3]
Reactant: COC(=O)CC=Cc1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1cc(C(C)C)c(C=CCC(=O)O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
Sodium hydroxide (0.23 g, 5.7 mmol) was added to a solution of 3-[2,4,6-tris(1-methylethyl)phenyl]-2-propenyl carboxylic acid, methyl ester (1.5 g, 5.2 mmol) in 100 mL methanol and 10 mL water. Stirred at room temperature for 48 hours and concentrated to dryness. Partitioned theresidue between water and diethyl ether. The aqueous layer was acidified with concentrated HCl and extracted with dichloromethane. The organic extract was dried over MgSO4, filtered, and concentrated to give 1.33g of 3-[2,4,6-tris-(1-methylethyl)phenyl]-2-propenyl carboxylic acid as a white solid, mp 201°-203° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][OH:30]>O>[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][O:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3OCC(F)(F)C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of 2,2,3,3,3-pentafluoropropanol was heated to reflux while stirring for 5.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.33 g of 2-[3-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 75”).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH3:20].[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([CH2:19][CH3:20])=[CH:22][CH:23]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(C(=O)Nc2ncc3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 501 mg (2.0 mmol) was added at 0° C. to a solution of 4-ethylbenzoic acid chloride 296 μl (2.0 mmol) in pyridine (25 ml) and stirring was performed for 2 h at 0° C. and then overnight at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(4-ethyl-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 640 mg (1.67 mmol, 84% of theoretical) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=1>C(Cl)Cl>[O:15]=[C:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([NH:2][S:29]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3cccnc3)cc2)CC1
Reaction time: 18 h
Yield: 11.6 %

Procedure:
To a stirred solution of 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) (8.76 g, 0.32 mol) in methylene chloride (100 mL) at room temperature was added triethylamine (9 mL). To this mixture was added a mixture of 3-pyridinesulfonyl chloride (7.45 g, 0.035 mol) and triethylamine (9 mL). The reaction was stirred for 18 hours. The reaction mixture was concentrated. The product was flash silica gel chromatographed eluting with 7:3 ethyl acetate/hexanes and then flash silica gel chromatographed eluting with 3% methanol in methylene chloride to give the titled compound as a yellow solid (1.34 g, 13%); 1H NMR (300 MHz, CDCl3) δ 2.54 (t, J=6 Hz, 4H), 3.56 (t, J=6 Hz, 4H), 6.79 (s, 1H), 6.85 (d, J=12 Hz, 2H), 6.98 (d, J=12 Hz, 2H), 7.40 (m, 1H), 7.97 (dd, J=3 Hz, 1H), 8.75 (dd, J=6 Hz, 1H), 8.90 (d, J=3 Hz, 1H); MS (ES) m/z: 331.9 (MH+, 100%); HRMS Calcd. for C16H17N3O3S(MH+): 332.1063. Found: 332.1063.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1.FC(F)(F)C(O)=O>CS(C)=O>[CH:26]1([CH2:25][NH:24][C:2]2[N:23]=[CH:22][CH:21]=[CH:20][C:3]=2[C:4]([NH:6][CH2:7][C:8]2[S:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: O=C(NCc1ccc(Oc2ccccc2)s1)c1cccnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Oc2ccccc2)s1)c1cccnc1NCC1CC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 17 %

Procedure:
To a solution of 2-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Preparation Example A+-7 (64 mg, 0.186 mmol) in dimethylsulfoxide (1 mL) was added (aminomethyl)cyclopropane (48 μl, 0.56 mmol), and the solution was stirred for 14 hours at 120° C. The reaction mixture was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (15.6 mg, 0.0316 mmol, 17%) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:34][CH:33]5[N:35](C(OC(C)(C)C)=O)[CH:30]([CH2:31][CH2:32]5)[CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:30]12[NH:35][CH:33]([CH2:32][CH2:31]1)[CH2:34][CH:28]([C:25]1[N:24]=[C:23]([NH:22][C:10]3[C:9]([O:8][C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][C:13]([S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][N:11]=3)[S:27][N:26]=1)[CH2:29]2
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Reaction time: 0.75 h
Yield: 95.5 %

Procedure:
tert-Butyl 3-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (550 mg, 0.911 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (1 mL) was added and the reaction was stirred for 45 minutes. The reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford 3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (438 mg, 0.870 mmol, 95.5% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16]([O:18][C:19](=[O:45])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]OS(C)(=O)=O)[C:23]=1[CH2:42][CH2:43][CH3:44])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:16]([O:18][C:19](=[O:45])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:23]=1[CH2:42][CH2:43][CH3:44])[CH3:17]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCOCCOc1c(C(C)=O)ccc(OCC(=O)OCC)c1CCC
Yield: 30.8 %

Procedure:
A mixture of 0.512 g (0.00224 mol) of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)-ethanone, 1.000 g (0.00224 mol) of [4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester and 0.620 g (0.00448 mol) of anhydrous potassium carbonate in 20 ml of anhydrous acetone and 10 ml of anhydrous dimethylformamide was stirred at reflux for 24 hours. The reaction mixture was filtered and concentrated in vacuo to an oil which was treated with ethyl acetate and sodium chloride solution. The crude oil obtained on concentration of the ethyl acetate was purified by column chromatography, eluting with 20-30% ethyl acetate-hexane to yield 0.400 g (31% yield) of [4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]2-propylphenoxy]acetic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([CH3:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([CH3:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[O:27][CH:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: Cc1c2ccccc2c(-c2cc(Br)c(O)c(Br)c2)c2c1sc1ccccc12
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1c2ccccc2c(-c2cc(Br)c(OC(Cc3ccccc3)C(=O)O)c(Br)c2)c2c1sc1ccccc12

Procedure:
Prepared from 2,6-dibromo-4-(6-methyl-benzo[b]naphtho[2,3-d]thiophen- 11-yl)-phenol (Example 62) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: mp 117-122° C.: [a]D25=+34.13° (9.963 mg/mL CHCl3); NMR (DMSO-d6): δ8.17 (d, J=8 Hz, 1 H), 7.81 (d, J=8 Hz, 1 H), 7.63-7.58 (m, 1 H), 7.57 (dd, J=6, 2 Hz, 2 H), 7.52-7.46 (m, 2 H), 7.42-7.38 (m, 3 H), 7.37-7.28 (m, 3 H), 7.16-7.10 (dt, J=1, 6 Hz, 1 H), 6.76 (d, J=8 Hz, 1 H), 5.45 (t, J=7 Hz, 1 H, CH), 3.59 (d, J=7 Hz, 2 H), 2.98 (s, 3 H); MS (EI): [M+], 643.6 (20%), 644.4 (50%), 645.5 (100%) 647.7 (30%); Anal. Calc. for C32H22Br2O3S: C, 59.46, H, 3.43, N, 0.00. Found: C, 59.34, H, 3.24, N, 0.04.