Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CCC(=O)Cl
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)CC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A179) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:2]1.C(O[CH2:16][C:17]([CH2:19][Si](C)(C)C)=[CH2:18])(=O)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]=[C:17]1[CH2:19][C@@H:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:18]1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: COC(=O)C=Cc1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccsc2)C1
Yield: 86.2 %

Procedure:
A mixture of methyl 3-(3-thienyl)acrylate (10.0 g, 59.5 mmol), tetrakis(triphenylphosphine)palladium(0) (5.15 g, 5.6 mmol), 1,2-bis(diphenylphosphino)ethane (1.35 g, 3.4 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (20 g, 107 mmol) in THF (125 mL) under argon was heated to reflux for 24 h. The volatiles were then removed in vacuo and the residue was purified by FC (5% ethyl acetate in hexanes) to afford the title compound (11.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[C:17]#[N:18]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[F:13])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Oc1cnc(Cl)c2ccccc12
Product: N#Cc1ccc(Oc2cnc(Cl)c3ccccc23)c(F)c1

Procedure:
Using the procedure outlined in Preparation 17, 1-chloro-4-hydroxyisoquinoline and 3,4-difluorobenzonitrile were converted to the title compound: RT=3.90 min; m/z (ES+)=299.04 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]2[CH:10]=[CH:9][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Clc1cc(-c2ccc3ccccc3c2)ncn1
Yield: 48 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 5.0 g of 4,6-dichloropyrimidine, 11.7 g of 2-naphthaleneboronic acid, 7.2 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 2.9 g of 2-naphthaleneboronic acid, 1.8 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1, so that a pyrimidine derivative 4-chloro-6-(naphthalen-2-yl)pyrimidine, which was the objective substance, was obtained (yellow white powder, yield of 48%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (h-1) of Step 1 is shown below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10]CC)=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1cc(Br)c(C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)O)cc1Br
Temperature: 70 °C

Procedure:
Ethyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 19, 16.5 g, 71.09 mmol) was dissolved anhydrous THF (100 ml) and was added to a preheated solution of 2 N lithium hydroxide (500 ml) at 70° C. The mixture was heated at 70° C. for 4 h and the solvent was removed in vacuo and the crude aqueous solution was cooled in an ice-bath and slowly acidified with 3 N HCl. The precipitate was extracted with EtOAc (3×100 ml), the organic extracts were washed with water, brine and dried with Na2SO4, treated with decolorizing charcoal for 1 h, filtered over celite and concentrated in vacuo. The brown solid was filtered and washed well with n-hexanes and dried in vacuo. (13 g).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]1([F:34])[O:26][C:25]2[CH:27]=[CH:28][C:29]([C:31](Cl)=[O:32])=[CH:30][C:24]=2[O:23]1>N1C=CC=CC=1.CO>[F:34][C:22]1([F:21])[O:26][C:25]2[CH:27]=[CH:28][C:29]([C:31]([NH:20][C:18]3[O:19][C:15]([C:12]4[CH:11]=[CH:10][C:9]([O:8][C:4]5[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=5)=[CH:14][CH:13]=4)=[N:16][N:17]=3)=[O:32])=[CH:30][C:24]=2[O:23]1
Reactant: O=C(Cl)c1ccc2c(c1)OC(F)(F)O2
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccc2c(c1)OC(F)(F)O2
Reaction time: 3 h
Yield: 12.3 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 2,2-difluoro-1,3-benzodioxole-5-carbonyl chloride (165.4 mg, 0.75 mmol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (27.0 mg). Yield 12.3%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[C:13]([CH3:21])[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>CC(N(C)C)=O.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].O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:23]5[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]6[CH2:31][CH2:32][CH2:33][CH2:34]6)=[CH:35][CH:36]=5)[N:19]=[C:15]4[CH:14]=[C:13]([CH3:21])[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(-c2ccc3c(c2)OCCO3)n2nc(N)nc2c1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3c(c2)OCCO3)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Temperature: 130 °C

Procedure:
A microwave tube was charged with 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50 mg, 0.177 mmol), 1-[2-(4-bromophenoxyl)ethyl]pyrrolidine (0.05 ml, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (8 mg. 0.009 mmol), Xantphos (10 mg, 0.018 mmol), sodium tert butoxide (35 mg, 0.354 mmol) and dioxane (1 ml). Dimethylacetamide (2 drops) was added to assist with microwave absorption. The mixture was heated at 130° C. for 15 min. Upon cooling the reaction mixture was filtered through a plug of silica and washed with methanol. The volatiles were removed in vacuo and the product was purified by preparatory HPLC. LCMS RT: 2.67 min, MI: 472, Method: 2. 1H NMR (DMSO, 300 MHz): 1.79 (m, 4H), 2.42 (s, 3H), 2.85 (m, 4H), 3.08 (t, 2H), 4.09 (t, 2H), 4.33 (brs, 4H), 6.89 (d, 2H), 7.00 (d, 1H), 7.04 (d, 2H), 7.29 (s, 1H), 7.60 (m, 3H), 7.65 (d, 2H), 9.36 (s, 1H).
Reaction SMILES: C([O:8][C:9](=[O:28])[C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH:17]=[CH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:12]([CH2:26][CH3:27])[CH:11]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[C:22]([O:21][C:19]([CH2:18][CH2:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]([C:9]([OH:28])=[O:8])=[CH:11][C:12]=1[CH2:26][CH3:27])=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: CCc1cc(C(=O)OCc2ccccc2)cc(C)c1C=CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.5 %

Procedure:
To a solution of 4-(2-tert-butoxycarbonyl-vinyl)-3-ethyl-5-methyl-benzoic acid benzyl ester (10.0 g, 26 mmol) in THF 100 mL), Pd/C (0.5 g, 20% Pd) is added under nitrogen. The mixture is stirred at rt for 48 h under 1 bar of H2. The catalyst is filtered off over a celite pad and the filtrate is concentrated to dryness to give 4-(2-tert-butoxycarbonyl-ethyl)-3-ethyl-5-methyl-benzoic acid (7.64 g) as a white solid; 1H NMR δ 1.29 (t, J=7.5 Hz, 3 H), 1.49 (s, 9 H), 2.36-2.41 (m, 2 H), 2.74 (q, J=7.5 Hz, 2 H), 2.99-3.05 (m, 2 H), 7.77 (s, 1 H), 7.80 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[N+:28]([O-])=O)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].[NH4+].[Cl-].C1COCC1.O>CCO.[Fe]>[NH2:28][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:18]=1[S:17][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])=[C:2]([F:1])[CH:3]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)c(F)c2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)c(F)c2)c(N)c1
Yield: 49.6 %

Procedure:
The product of Example 96C (2.8 g, 5.6 mmol), Fe powder (1.6 g, 28 mmol) and NH4Cl (1.5 g, 28 mmol) in a mixture of EtOH (28 mL), THF (14 mL) and water (28 mL) was gently refluxed for 1 hour. The reaction mixture was cooled and filtered through celite pad. The filtrate was concentrated. The aqueous residue was partitioned between ethyl acetate and water, and adjusted to pH 8-9 with NaHCO3. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated. The oily residue was separated by column chromatography (SiO2, n-hexane/ethyl acetate=3/1) to give the title compound as pale yellow crystal (1.3 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1

Procedure:
A mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, step 1) (12.1 g, 39.2 mmol), sodium bicarbonate (6.58 g, 78.3 mmol), and 90% ethyl bromopyruvate (16.9 g) in 480 ml of 2-propanol was stirred at reflux overnight. After cooling, the mixture was concentrated. The residue was partitioned between dichloromethane and water and the aqueous layer further extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Trituration of the residue with ethyl acetate gave the title compound as a pale beige, crystalline solid (6.61 g): mp (DSC) 218° C. Anal. Calc'd. for C19H17ClN2O4S (MW 404.87): C, 56.37; H, 4.23; N, 6.92. Found: C, 56.28; H, 4.13; N, 6.80.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][CH2:11][C@H:12]([NH:14][CH2:15][C@H:16]([O:24][Si](C(C)(C)C)(C)C)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH3:13])=[CH:8][CH:7]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][CH2:11][C@H:12]([NH:14][CH2:15][C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[OH:24])[CH3:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O)c2cccc(Cl)c2)cc1
Yield: 73.3 %

Procedure:
Following a procedure similar to that described in Example 27, but using 3.02 g of N-[2-(4-methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethanamine (prepared as described in Preparation 50), 4.81 g of tetrabutylammonium fluoride and 100 ml of tetrahydrofuran, 1.7 g of the title compound were obtained having an Rf=0.39 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent). [α]D23 -13.2° (c=0.99, methanol).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:24])([F:23])[F:22])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:50](=[O:65])[C:51]1[CH:56]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:54]=[C:53]([S:61]([CH3:64])(=[O:63])=[O:62])[CH:52]=1>C(Cl)Cl>[CH3:64][S:61]([C:53]1[CH:52]=[C:51]([CH:56]=[C:55]([C:57]([F:58])([F:59])[F:60])[CH:54]=1)[C:50]([N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:23])([F:24])[F:22])=[O:65])(=[O:63])=[O:62]
Reactant: CS(=O)(=O)CCNc1cnccc1-c1ccccc1OC(F)(F)F
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OC(F)(F)F
Yield: 13 %

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2-methanesulfonyl-ethyl)-[4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-amine, DIPEA and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d) in CH2Cl2 after a reaction time of 12 hours at 25° C. The crude thus obtained was purified by preparative HPLC (ammonium acetate/acetonitrile) to furnish the title compound as an off-white solid (15 mg, 13%). MS (ESI): m/z=611.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[N:27]1([C:31]([C:33]2[S:37][C:36](Cl)=[N:35][CH:34]=2)=[O:32])[CH2:30][CH2:29][CH2:28]1>C(#N)C>[N:27]1([C:31]([C:33]2[S:37][C:36]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:35][CH:34]=2)=[O:32])[CH2:28][CH2:29][CH2:30]1
Reactant: O=C(c1cnc(Cl)s1)N1CCC1
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1cc(Oc2ncc(C(=O)N3CCC3)s2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
Cesium carbonate (488 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (187 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole (152 mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixture heated at 160° in a Biotage Initiator Microwave for 2 hours. The mixture was cooled to RT and pressure, poured onto water (75 mL) then extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica eluting with ethyl acetate, to give the desired compound (142 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 2.4 (m, 2H), 3.7 (s, 3H), 4.1-4.4 (m, 4H), 4.5 (m, 1H), 6.75 (s, 1H), 6.9 (s, 1H), 7.2 (s, 1H), 7.25 (d, 1H), 7.4 (s, 1H) and 8.95 (s, 1H). m/z 442 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)CC(=O)NC=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(=O)NCC2

Procedure:
A mixture of 2,3-dihydro-8-methoxy-2-oxo-1H-3-benzazepine (12 g, 0.063 m) and 10% palladium-on-carbon (1.2 g) in acetic acid (200 ml) was shaken in an atmosphere of hydrogen (60 psi), degassed, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride, washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue was triturated with ether and filtered to give 8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:2]1([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1CCCN1c1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Into a 150 mL sealed tube purged and maintained with an atmosphere of nitrogen, was placed 1-bromobenzene (4 g, 25.48 mmol). To this was added pyrrolidin-2-one (2.18 g, 25.65 mmol). Addition of Pd(OAc)2 (57 mg, 0.25 mmol) was next. This was followed by the addition of BINAP (240 mg, 0.39 mmol). This was followed by the addition of Cs2CO3 (12.5 g, 38.34=mol). To the mixture was added toluene (50 mL). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 1:10 ethyl acetate/petroleum ether solvent system. This resulted in 1 g (24%) of 1-phenylpyrrolidin-2-one as yellow oil.
Reaction SMILES: C1C2C(OC([NH:17][C@@H:18]([CH3:49])[C:19]([NH:21][C:22]3[CH:48]=[CH:47][C:25]([CH2:26][C@@H:27]4[CH2:31][CH2:30][C@H:29]([C@H:32]([OH:39])[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:24][CH:23]=3)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1>[NH2:17][C@@H:18]([CH3:49])[C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][C@@H:27]2[CH2:31][CH2:30][C@H:29]([C@H:32]([OH:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:28]2[C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[CH:47][CH:48]=1)=[O:20]
Reactant: C[C@H](NC(=O)OC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: C[C@H](N)C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 35 °C

Procedure:
To a stirred solution of 3.15 g (4.65 mmol) of tert-butyl (2S,5R)-2-{4-[((2S)-2-{[(9H-fluoren-9-yloxy)carbonyl]amino}propanoyl)amino]benzyl}-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate from step A above in 3 mL of anhydrous THF was added 0.396 g (4.65 mmol) of piperidine. The resulting mixture was heated to 35° C. underan atmosphere of nitrogen for 2 h then all volatiles were removed in vacuo to afford the crude title compound which was used without further purification. LC-MS: m/z (ES) 454 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c(F)c1F
Product: CC(=O)Nc1ccc(F)c(F)c1F
Yield: 82.5 %

Procedure:
2,3,4-Trifluoroaniline (36.7 g, 0.25 mol) was acetylated using acetic anhydride (105 mL, 1.25 mol), using an analogous procedure to that described in preparation 1 (step 1) to yield N-(2,3,4-trifluorophenyl)acetamide (39.0 g, 83%) as a white solid. mp 87-88° C. ; IR (KBr) 3271, 1673, 1514 cm-1 ; 1H NMR (CDCl3) δ 2.16 (s, 3H, CH3), 6.90 (q, J=4.3 Hz, 1H), 7.60 (brs, 1H, NH), 7.90 (m, 1H); Mass (m/z) 189 (M+.).
Reaction SMILES: [ClH:1].C([O:9][CH:10]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[NH:29])[C:11](=[O:18])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[ClH:1].[NH:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20](=[O:31])[NH:19][CH:10]([OH:9])[C:11](=[O:18])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:28]([NH2:30])=[NH:29]
Reactant: N=C(N)NCCCCCCC(=O)NC(OCc1ccccc1)C(=O)NCCCCO
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCCO
Yield: 95.1 %

Procedure:
0.65 g (1.42 mmol) of 7-benzyloxy-15-guanidino-1-hydroxy-5,8-diazapentadecane-6,9-dione hydrochloride was dissolved in 20 ml of 1N acetic acid and catalytically reduced in the presence of 0.2 g of palladium black under a hydrogen pressure of 10 kg/cm2 at room temperature for 36 hours. After filtering off the catalyst, the filtrate was adsorbed on 100 ml of CM-Sephadex® C-25 (Na) and subjected to gradient elution between 500 ml of distilled water and 500 ml of 0.3M sodium chloride. Fractions containing the aimed product were combined and concentrated to dryness under reduced pressure. 90% ethanol was added to the residue and the insoluble sodium chloride was filtered off. The filtrate was then passed through a column packed with 100 ml of Sephadex® LH-20 and eluted with 90% ethanol. Fractions containing the aimed compound were combined and concentrated to dryness under reduced pressure. The residue was dissolved in a small amount of distilled water and the insoluble matters were filtered off. The obtained aqueous solution was lyophilized to thereby give 0.497 g of the aimed compound (yield: 95.1%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([CH3:16])=[CH:10][C:11]([CH:14]=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([CH3:16])=[CH:10][C:11](/[CH:14]=[N:25]/[S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(C=O)ncc1OCc1ccc(F)cc1
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCc1ccc(F)cc1
Yield: 67 %

Procedure:
The title compound is prepared in 67% yield (972 mg, pale yellow solid) from 5-((4-fluorobenzyl)oxy)-4-methylpicolinaldehyde (1.03 g, 4.19 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (762 mg, 6.29 mmol) in a similar manner to Step-6 of Amine-49.