Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH3:12])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>O.CO>[OH:1][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:5])=[O:4]
Reactant: CCCC=CCC(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC=CCC(O)C(=O)O
Temperature: 25 °C

Procedure:
Methyl 2-hydroxy-4-octenoate (23)(7.04 g, 0.041 mol, 1.0 eq) is heated under reflux with a large excess of sodium hydroxide (13.5 g, 0.34 mol, 8.3 eq) in water (30 ml) and methanol (30 ml) for 1 hour. After cooling down to room temperature, the mixture is washed with hexane (50 ml) and the organic phase separated. The clear aqueous layer is acidified to pH 1 with concentrated hydrochloric acid and the resultant mixture is extracted with diethylether (3×50 ml), the combined organic layers being washed with brine (50 ml) thence dried over anhydrous magnesium sulphate and evaporated to give a colourless oil which slowly crystallised to furnish the product acid (21) as a white waxy solid, 5.72 g (88%), m p 37-38° C.
Reaction SMILES: [Sn](Cl)Cl.[N+:4]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:24]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:27]4[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=4[N:25]=3)=[N:12][N:13]2[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=1)([O-])=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[NH2:4][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:24]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[C:27]4[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=4[N:25]=3)=[N:12][N:13]2[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc(N)cc21
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
Tin(II) chloride (12.0 g, 63.3 mmol) was added to a solution of 6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl)-1-H-indazole (7.18 g, 13.3 mmol) in DMF/H2O (160 mL/10 mL), and the reaction stirred at 50° C. for 2.5 h. The reaction was cooled to 0° C., and saturated sodium bicarbonate was added slowly, with mixing, until all frothing from quenching had subsided. The material was concentrated in vacuo and taken up in ether (100 mL). Insoluble material was removed by filtration and rinsed with ether (50 mL). The filtrate was washed with brine (50 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (25% ethyl acetate/hexane) gave 6.05 g (89%) of 6-amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole as a faintly yellow waxy solid. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, 1H, J=9.0 Hz), 7.89-7.86 (m, 1H), 7.63-7.60 (m, 1H), 7.35-7.31 (m, 2H), 6.78 (dd, 1H, J=8.7, 1.8 Hz), 6.75 (s, 1H), 6.25 (s, 2H), 5.69 (s, 2H), 3.93 (br s, 2H), 3.65-3.55 (m, 4H), 0.93 (t, 2H, J=8.1 Hz), 0.85 (t, 2H, J=8.1 Hz), −0.04 (s, 9H), −0.15 (s, 9H). Anal. (C26H39N5O2Si2) C, H, N. Calculated: C, 61.26; H, 7.71; N, 13.74. Found: C, 61.18; H, 7.65; N, 13.82.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:48])[N:19]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[O:37][C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[N:43]([CH3:47])[N:42]=[CH:41]3)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:51]I>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([N:17]([CH3:51])[C:18]([N:19]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[O:37][C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[N:43]([CH3:47])[N:42]=[CH:41]3)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[O:48])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(Cc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)C(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)C(=O)N(C)c2cc(C(C)(C)C)nn2-c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Intermediate (30t) (150 mg, 0.23 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. Sodium hydride (60% in oil, 14 mg, 0.36 mmol) and methyl iodide (73.8 μL, 168 mg, 1.19 mmol) were added to the solution at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched by addition of 5 mL of water at 0° C., and then extracted three times with 50 mL of Et2O. The combined organic layer was washed with 5 mL of water twice and with brine once, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel with EtOAc/hexane (1:2) to obtain compound (31t) as a pale yellow amorphous (134 mg, 87% yield). 1HNMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.28 (d, J=9.4 Hz, 1H), 7.15-7.02 (m, 2H), 7.00-6.81 (m, 6H), 6.80-6.60 (m, 3H), 5.85 (s, 1H), 4.21 (s, 2H), 4.20 (s, 2H), 4.05 (s, 3H), 3.76 (s, 3H), 2.98 (s, 3H), 2.29 (s, 3H), 1.23 (s, 9H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.BrC[CH:29]1[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH2:18][CH:29]3[CH2:31][CH2:30]3)[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CC2CC2)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with (bromomethyl)cyclopropane in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=450.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].I.[CH3:9][N:10]1[C:15](=[O:16])[N:14]2[CH:17]=[N:18][C:19]([C:20](SC)=[NH:21])=[C:13]2[N:12]=[N:11]1>C(#N)C>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:20]([C:19]1[N:18]=[CH:17][N:14]2[C:15](=[O:16])[N:10]([CH3:9])[N:11]=[N:12][C:13]=12)=[NH:21]
Reactant: COC(CN)OC
Reactant: CSC(=N)c1ncn2c(=O)n(C)nnc12
Agent: I
Solvent: CC#N
Product: COC(CNC(=N)c1ncn2c(=O)n(C)nnc12)OC
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Aminoacetaldehyde dimethyl acetal (68 μL, 0.624 mmol) was added to a suspension of methyl 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide (200 mg, 0.568 mmol) in acetonitrile (8 mL) and the mixture was stirred overnight. The precipitate, which formed during the reaction, was filtered and washed successively with water, acetonitrile, ethyl acetate and diethyl ether to give the title product as a bright yellow solid (92 mg, 58%). δH (DMSO-d6): 9.50 (3H, bs), 9.17 (1H, s), 4.69-4.71 (1H, t, J=5.3), 3.95 (3H, s), 3.70-3.72 (2H, d, J=5.3), 3.37 (6H, s).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:18]([OH:20])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(=O)=O>O1CCOCC1>[CH2:2]([N:9]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH:14]1[C:15](=[O:17])[N:28]([C:27]1[CH:29]=[CH:30][C:24]([O:23][C:22]([F:21])([F:31])[F:32])=[CH:25][CH:26]=1)[C:18]2=[O:20])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@H]1CCC[C@@H](C(=O)O)N1Cc1ccccc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C=O
Solvent: C1COCCO1
Product: O=C1C2CCCC(C(=O)N1c1ccc(OC(F)(F)F)cc1)N2Cc1ccccc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione 1,1-Carbonyl diimidazole (CDI; 1.2 g, 7.4 mmol) was added to a mixture of cis-1-benzyl-piperidine-2,6-dicarboxylic acid hydrochloride (1.0 g, 3.34 mmol) and dioxane (10 mL) at rt under N2. The mixture was heated at 100° C. After 15 min, a solution of 4-trifluoromethoxyaniline (600 mg, 3.39 mmol) and dioxane (2 mL) was added. After an additional 2 h, CDI (500 mg, 3.08 mmol) was added (Caution: CO2 evolution). After an additional 1 h, the reaction was allowed to cool to rt, concentrated, diluted with ethyl acetate (120 mL) and washed with 0.5N HCl (100 mL×2). The organic extract was dried, filtered, concentrated, and purified by silica gel chromatography (1:0→4:1; hexanes:ethyl acetate) to give 9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione: MS (ESI): 405.4 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CCOCC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
In a 2-(5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 113 μmol), 4-(3-chloropropyl)morpholine (55.5 mg, 339 μmol, Eq: 3.0) and Cs2CO3 (147 mg, 452 μmol) in DMF (2 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. Then, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 94.2 μmol, 83.4%) as an off-white solid. MS (M+Na)+=680; 1H NMR (CDCl3) δ: 9.23 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.35 (dd, J=8.9, 2.1 Hz, 1H), 6.55 (t, J=74.4 Hz, 1H), 5.75 (s, 2H), 4.61 (t, J=6.4 Hz, 2H), 3.75 (br. s., 4H), 3.55-3.66 (m, 2H), 2.45 (br. s., 6H), 2.25 (br. s., 2H), 1.65 (s, 9H), 0.90-1.06 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc(C#N)cc2)c1

Procedure:
2 g of 3-fluoro-4-nitroanisole and 15 ml of 4-aminobenzonitrile were stirred for 22 hours at 140° C. The batch was then diluted with ethyl acetate, washed three times with 2N aqueous hydrochloric acid, three times with water and once with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([O:13][CH3:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16]>N1C=CC=CC=1>[Cl:1][C:2]1[C:11]([NH:12][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26])=[C:10]2[C:5]([C:6]([O:13][CH3:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccnc2c(N)c(Cl)ccc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccnc2c(NS(=O)(=O)c3ccccc3[N+](=O)[O-])c(Cl)ccc12
Yield: 56.6 %

Procedure:
In a similar fashion using route 18 general procedure 26, 8-amino-7-chloro-4-methoxyquinoline 70 (550 mg, 2.6 mmol), 2-nitrobenzenesulphonylchloride (642 mg, 2.9 mmol) in pyridine (10 ml) gave the title compound (580 mg, 55%) which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:12]([C:14]1[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)=O.[OH-].[K+]>CCO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])/[CH:10]=[CH:12]/[C:14]2[CH:15]=[CH:16][C:17](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc(CO)c1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A mixture of 1-(3-hydroxymethyl-phenyl)-ethanone (810 mg), 4-formylcinnamic acid (950 mg, 5.4 mmol) and 1.7 M KOH (6.4 ml) in EtOH (40 ml) was stirred at room temperature for 18 h. The resulting precipitate was filtered and washed with EtOH to give 1.25 g of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid as its potassium salt.
Reaction SMILES: CS(O[CH2:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])(=O)=O.[C-:16]#[N:17].[Na+]>CS(C)=O.O>[CH3:8][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:15])[CH2:6][C:16]#[N:17]
Reactant: [C-]#N
Reactant: CC(C)(COS(C)(=O)=O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(CC#N)c1ccccc1
Temperature: 110 °C
Yield: 57.3 %

Procedure:
2-Methyl-2-phenylpropyl methanesulfonate (52) (12 g, 52.6 mmol) was stirred in dimethyl sulfoxide (106 ml), sodium cyanide (10.3 g, 210 mmol, Eq: 4) was added and the reaction mixture was heated to 110° C. for 20 hours. The reaction mixture was cooled, diluted with water, extracted three times with ether, washed with ether, water, and brine, and dried over magnesium sulfate. The solvent was removed on a rotary evaporator. Chromatography was conducted (2% to 15% over 20 min on a 40 g silica gel column) to give 3-methyl-3-phenylbutanenitrile (53) as a clear oil (4.8 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11][NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25]([N:27]([CH2:29][C:30](O)=[O:31])[CH3:28])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:26])[N:27]([CH2:29][C:30](=[O:31])[N:12]([CH2:11][C:10]1[CH:17]=[CH:18][CH:19]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:9]=1)[CH:13]([CH3:16])[CH2:14][OH:15])[CH3:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C[C@@H](CO)NCc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(CO)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(=O)CN(C)C(=O)OC(C)(C)C

Procedure:
Intermediate 73 was coupled with (tert-butoxycarbonyl-methyl-amino)-acetic acid following procedure K. LC-MS showed the product had the expected M+H+ of 449. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (m, 1H) 8.1 (m, 1H) 8.0 (m, 1H) 7.7 (m, 1H) 7.5 (m, 2H) 4.6 (m, 2H) 4.3 (m, 2H) 4.0 (m, 1H) 3.7 (s, 1H) 3.5 (s, 1H) 3.0 (m, 4H) 1.4 (m, 9H) 1.2 (m, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:39])([F:38])[F:40])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1C(F)(F)F
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 5.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thio-phene-2-carboxylate and 500 ml of a 7 N solution of ammonia in methanol is stirred in an autoclave at 125° C. for 4 hours. The mixture is allowed to cool down to room temperature and concentrated to dryness. During the reaction the TBDMS group of the title product is partially removed. The crude is purified by flash chromatography [silica gel, eluent: cyclohexane/ethyl acetate/methanol, elution gradient of 40/60/0 (v/v/v) to 0/100/0 (v/v/v) and then to 0/90/10 (v/v)] to give the title compound. Additionally, 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:20])#[N:2].[Si:21]([O:38][C:39]1[CH:40]=[C:41]([CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH:42]=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[Si:21]([O:38][C:39]1[CH:40]=[C:41]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:17]([C:14]2[N:13]3[CH:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:20])[CH:5]=4)[CH2:10][CH2:11][C:12]3=[N:16][CH:15]=2)=[O:19])[CH:42]=[CH:43][CH:44]=1)([C:34]([CH3:35])([CH3:36])[CH3:37])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](Oc1cccc(CCCCN)c1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C2CCc3ncc(C(=O)O)n32)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](Oc1cccc(CCCCNC(=O)c2cnc3n2C(c2ccc(C#N)c(F)c2)CC3)c1)(c1ccccc1)c1ccccc1

Procedure:
Carboxylic acid from Step K, Example 5 (13.4 mg, 0.0496 mmol), amine from Step D (20.0 mg, 0.0496 mmol), EDC hydrochloride (19.0 mg, 0.0991 mmol), HOBT (13.4 mg, 0.0991 mmol), and N,N-diisopropylethylamine (0.0432 mL, 0.248 mmol) were stirred in dry, degassed DMF (1 mL) at 25° C. for 16 hours. The reaction was poured onto aq. NaHCO3 (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:6]
Reactant: NCC(c1ccccn1)N1CCOCC1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)NCC(c2ccccn2)N2CCOCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:28]=[C:27]([CH3:29])[C:18]([O:19][CH2:20][CH2:21]OS(C)(=O)=O)=[C:17]([CH2:30][CH3:31])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:32])[N:5]=1)[CH3:2].[CH3:35][NH2:36]>CO>[CH2:1]([N:3]([CH2:33][CH3:34])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:28]=[C:27]([CH3:29])[C:18]([O:19][CH2:20][CH2:21][NH:36][CH3:35])=[C:17]([CH2:30][CH3:31])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:32])[N:5]=1)[CH3:2]
Reactant: CN
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCNC

Procedure:
A solution of crude methanesulfonic acid 2-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethyl ester (110 mg, 0.225 mmol, Example 55 step a)) in 8 M methylamine in methanol (4 mL) is stirred in a sealed glass vial at 70° C. for 15 h. The solvent is evaporated and the crude product is purified on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (93 mg) as a pale yellow oil; LC-MS: tR=0.71 min; [M+1]+=424.19.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Br)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.S(=O)(=O)(O)[OH:18]>O>[Br:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:5][C:6](=[O:18])[C:7]=1[CH2:8][CH3:9]
Reactant: O=S(=O)(O)O
Reactant: CCc1c(Br)nc(-c2ccccc2)nc1Br
Solvent: O
Product: CCc1c(Br)nc(-c2ccccc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To 8.29 g (26.1 mmol) of crude 4,6-dibromo-5-ethyl-2-phenylpyrimidine was added a mixture of 4 mL of water and 15 mL of concentrated sulfuric acid. The mixture was stirred for 18 h and poured onto 200 g of crushed ice. After the ice had melted the precipitate was collected by filtration and dried under vacuum to afford 7.21 g (99%) of crude 6-bromo-5-ethyl-2-phenyl-4(3H)-pyrimidinone. 1H-NMR (d6 -DMSO)δ1.10(3H,t), 2.55(2H,q), 7.55(3H, m), 8.10(2H,m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][C:23]([CH2:25][CH3:26])=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:27]=[C:28]([O:31][Si](C(C)(C)C)(C)C)[CH:29]=[CH:30][C:15]3=4)[C:11](=[O:39])[NH:10][C:9]2=[O:40])[CH:5]=[CH:4][N:3]=1.[C:41]([CH:44]1[CH2:47][NH:46][CH2:45]1)([OH:43])=[O:42].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH2:25]([C:23]1[CH:24]=[CH:19][C:20]2[CH:14]([C:12]3[C:11](=[O:39])[NH:10][C:9](=[O:40])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:46]5[CH2:47][CH:44]([C:41]([OH:43])=[O:42])[CH2:45]5)[N:7]=4)[CH:13]=3)[C:15]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:16]=3[CH:17]=[CH:18][C:21]=2[CH:22]=1)[CH3:26]
Reactant: CCc1ccc2c(c1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Reactant: O=C(O)C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)C=Cc1cc(O)ccc1C2c1cn(-c2ccnc(N3CC(C(=O)O)C3)n2)c(=O)[nH]c1=O
Temperature: 90 °C

Procedure:
A mixture of the product from step (viii) (0.5 g), 3-carboxyazetidine (0.13 g) and N,N-diisopropylethylamine (0.52 ml) in 1-methyl-2-pyrrolidinone (10 ml) was heated at 90° C. for 6 hours and partitioned between ethyl acetate and 1M HCl. The organic phase was washed with water, dried (MgSO4) and concentrated in vacuo to 10 ml. Isohexane (5 ml) was added and the product was collected by filtration. Yield 0.25 g.