Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:26](O)[CH3:27]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([O:19][CH2:26][CH3:27])=[O:18])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)OCc1oc(-c2ccc(Cl)cc2)nc1C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
4.44 g (14.5 mmol) of 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid were dissolved in 40 ml of dry dichloromethane and 1 drop of dimethylformamide was added. 1.9 g (16 mmol) of thionyl chloride were added and the mixture was heated to reflux for 4 hours. 70 ml of ethanol were added slowly to a stirred solution of the thus-obtained acid chloride at 0° C. and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel using 17% by volume ethyl acetate in hexane for the elution. After evaporation of the eluate there were obtained 2.8 g (57.2%) of ethyl 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionate of melting point 75°-76° C.
Reaction SMILES: [F-:1].[Cs+].[CH2:3]([Sn:7](C1SC=CC=1)([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].ClCCl>C1(C)C=CC=CC=1.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>[Sn:7]([F:1])([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: [F-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC[Sn](F)(CCCC)CCCC
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Step a) Under inert atmosphere, to a mixture of chromophore 1, 1 mol % catalysator Pd(PPh3)4, 1 equivalent of CsF in toluene, 1.2 equivalent of tributylstannyl-thiophene were added. The reaction mixture was stirred at 120° C. for 12 h. After cooling to room temperature, dichloromethane was added. The white salt (Bu3SnF) formed during the reaction was filtered off and the solvent removed under reduced pressure. Purification of the crude product was performed by column chromatography on silica gel with (4/6) dichloromethane/ethylacetate to give the pure thiophene derived squarylium dye 3.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(OC(=O)C)=O.[CH3:14][NH:15][C@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.[OH-].[Na+]>C(O)=O>[C@H:16]1([N:15]([CH3:14])[CH:5]=[O:7])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)OC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C=O)[C@@H]1CCCc2ccccc21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
Acetic anhydride (54.1 g) was chilled to 0° C. and stirred as 98% formic acid (33.1 g) was added over 30 minutes, keeping the temperature below 5° C. The solution was warmed to 50° C., held at this temperature for 15 minutes, and chilled to 5° C. The resulting solution of acetic-formic anhydride was added over 5 minutes to a stirred, chilled solution of (R)(-)-N-methyl-1,2,3,4-tetrahydro-1-naphthylamine (19.08 g) in 98% formic acid (19.08 ml), keeping the temperature below 10° C. The reaction solution was warmed to room temperature, stirred for 1 hour, poured into an ice-water mixture (200 g) and stirred for 30 minutes. The mixture was basified to pH 9 with 10N aqueous sodium hydroxide solution (about 230 ml) and extracted with dichloromethane (3×200 ml). The combined extracts were back-washed with 1N aqueous hydrochloric acid (100 ml), then water (100 ml), and evaporated under vacuum to give the title compound (21.63 g, 96.6%) as a solid, m.p. 53°-55° C.; Rf 0.80 (silica; chloroform, methanol; 95:5).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([CH2:27][CH2:28][CH2:29][CH3:30])[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:23]1[CH2:24][CH2:25][C:20]2[C:19](=[O:26])[O:18][C:17]([CH2:27][CH2:28][CH2:29][CH3:30])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]=2[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCCC1(c2ccccc2)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Product: CCCCC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Benzyl isocyanate (0.02 g, 0.14 mmol) was added to a solution of 3-phenyl-3-butyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.025 g, 0.09 mmol prepared in a manner analogous to compound 2) in dichloromethane (5 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.018 g, 50%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.79 (t, J=7.16 Hz, 3H), 1.06-1.33 (m, 4H), 1.83-1.97 (m, 1H), 2.14-2.43 (m, 3H), 3.18-3.31 (m, 1H), 3.36-3.51 (m, 1H), 3.85 (dt, J=18.84, 2.64 Hz, 1H), 4.26-4.39 (m, 3H), 4.90 (t, J=5.27 Hz, 1H), 7.11-7.36 (m, 10H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][C:29]=2[NH2:30])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([NH:30][C:29]2[CH:28]=[CH:27][S:26][C:25]=2[C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccsc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
The title compound was prepared from 2-(1-trityl-1H-imidazol-4-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B (561 mg, 59%) as a brown solid. Method [7] Retention time 9.46 min by HPLC (MH+ 556).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH:12]1[O:16][CH2:15][CH2:14][O:13]1>CO.O=[Pt]=O>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C1OCCO1
Agent: O=[Pt]=O
Solvent: CO
Product: COc1ccc(N)cc1C1OCCO1
Yield: 104.2 %

Procedure:
To a solution of 2-(2-methoxy-5-nitrophenyl)-1,3-dioxolane (1.00 g, 4.4 mmol) in methanol (45 ml) was added PtO2 (20 mg) as a catalyst. The resulted mixture was reacted with Parr Shaker (2.2 kg/cm2) for 1.5 hr. After removal of catalyst by filtration, the reaction mixture was evaporated in vacuo to give crude 2-(5-amino-2-methoxyphenyl)-1,3-dioxolane (894.6 mg, 100%) as a brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C@H:21]1[CH2:23][O:22]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH3:35])=[O:33])=[C:27]([Cl:36])[CH:26]=1)#[N:8]>O1CCCC1>[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C@H:21]([OH:22])[CH2:23][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH3:35])=[O:33])=[C:27]([Cl:36])[CH:26]=1)#[N:8]
Reactant: C1CCNCC1
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H](O)CN4CCCCC4)c(C#N)cc23)cc1Cl
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (2.0 ml) and piperidine (0.20 ml) to N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea (110 mg), the mixture was heated at 60° C. for 3 hours. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (80 mg) as light yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[N+:10]([C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].C(N(CC)CC)C.O>O1CCOCC1>[N+:10]([C:13]1[CH:14]=[C:15]([S:19]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: NCCc1ccncc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.8 %

Procedure:
To a stirred solution of 4-(2-aminoethyl)-pyridine (1.21 g, 9.93 mmol) in dioxane (25 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol) and triethylamine (1.38 ml, 9.93 mmol). The light yellow suspension was stirred at room temperature for 6 h, poured into water (100 ml) and extracted with dichloromethane (6×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization from methanol/hexane to yield 3-nitro-N-(2-pyridine-4-yl-ethyl)-benzenesulfonamide (1.63 g, 59%) as an orange solid. MS (ISP) 306.1 [(M−H)−]; mp 153° C.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[CH3:19]I>C(Cl)Cl>[CH3:19][O:18][CH2:17][C:15]1[O:16][C:12]([CH2:11][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cnn(Cc2ccc(CO)o2)n1
Reactant: CI
Agent: N#N
Solvent: ClCCl
Product: COCc1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)furan-2-yl)methanol (WO 2009077990A1) (186 mg, 0.83 mmol) in CH2Cl2 (3.0 mL) was added to a suspension of Ag2O (288 mg, 1.24 mmol) and MeI (0.06 mL, 0.99 mmol). The resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.27. LC-MS-conditions 07: tR=0.74 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:3]=1.[C:17]([C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21])([OH:19])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:25]2[CH:24]=[C:23]([C:20]([CH3:22])([CH3:21])[C:17]([OH:19])=[O:18])[CH:28]=[CH:27][CH:26]=2)[CH:3]=[C:4]([NH:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[N:5]=1
Reactant: COc1nc(Cl)cc(NCc2ccsc2)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCc2ccsc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 4.7 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-thiophen-3-ylmethyl-amine (216 mg, 0.84 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [312 mg, 1.5 mmol, see Example 49(b) step 2], Cs2CO3 (821 mg, 2.52 mmol), and tetrakis(triphenylphosphine)palladium (0) (92 mg, 0.08 mmol) in ethylene glycol dimethyl ether (2.5 mL) and water (0.5 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (40 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{2-methoxy-6-[(thiophen-3-ylmethyl)-amino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [15 mg, 4.6%, Example 71] as a solid. LCMS RT=1.94 minutes, MS: 384 (M+H). IC50=393 nM
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4](=[O:12])[C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:8]([C:5]1[C:4](=[O:12])[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[C:2]([CH3:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CN
Reactant: COC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Product: CNC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.11 g, 0.35 mmol) was dissolved in a solution of methylamine (33% in ethanol, 5 ml) a vial. The vial was sealed and heated with stirring at 50° C. for 30 minutes. The volatiles were removed in vacuo giving a crude product which was purified for analytical purposes on preparative HPLC to give 0.079 g (73%) of N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide as a solid.
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28](O)=[O:29])=[CH:20]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:2][CH2:1][CH:3]([NH:6][C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2([CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]2)[CH:20]=1)=[O:29])[CH2:4][CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(C(=O)O)c3ccccc32)CC1
Reactant: CCC(N)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-ethylpropylamine (0.5 mL) was added to a stirred solution of compound (C4) (0.50 g, 1.52 mmol), EDAC.HCl (0.6 g, 3.00 mmol), HOBt (0.31 g, 2.32 mmol) in DMF (10 mL) and the solution was stirred at room temperature for 2 h. The solution was poured into water (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage SP1 on silica gel eluting with 5-70% EtOAc in hexanes to provide tert-butyl 3-(pentan-3-ylcarbamoyl)spiro[inden-1,4′-piperidine]-1′-carboxylate (F1) as a white solid (0.6 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 399 (M+1), Rt 3.66 minutes. 1HNMR (500 MHz, DMSO-d6) δ 7.78 (d, 1H), 7.55 (m, 1H), 7.43 (d, 1H), 7.23 (br m, 1H), 4.07 (m, 2H), 3.75 (m,1H), 3.15 (m, 2H), 1.98 (d, 2H), 1.55 (m, 2H), 1.45 (s, 9H), 1.25 (m,2H), 0.88 (m, 6H).
Reaction SMILES: CN1CCOCC1.O.[C:9]([NH:16][C@H:17]([C:22]([OH:24])=O)[CH2:18][CH:19]([CH3:21])[CH3:20])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=CC2N(O)N=NC=2C=1.[NH2:35][C@H:36]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39].Cl.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[NH:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@H:17]([C:22]([NH:35][C@H:36]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:24])[CH2:18][CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
4-Methylmorpholine (12.62 g, 124.8 mmol), Boc-Leucine monohydrate (29.92, 120.0 mmol) and HOBt (1.62 g, 12.0 mmol) were added to a solution of H-Leu-OMe.HCl (21.80 g, 120.0 mmol) in ethyl acetate (205 g). A solution of DCC (29.71 g, 144.0 mmol) in ethyl acetate (25.0 g) was added at 0 to 5° C. over 30 min and the resulting mixture was stirred over 2 h at a maximum temperature of 20° C. The resulting urea was removed by filtration and washed with ethyl acetate and the combined organic filtrate was extracted with successive portions of 5% aq. K2CO3 and 5% aq. KHSO4. The organic layer was dried (MgSO4), concentrated in vacuo, and the residual solid was recrystallized from petroleum ether (bp 100-125° C.) to give Boc-Leu-Leu-OMe (38.6 g, 89.8%).
Reaction SMILES: [OH:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Br:45][CH2:46][CH2:47][CH2:48]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Br:45][CH2:46][CH2:47][CH2:48][O:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:39])([CH3:40])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)nc1
Yield: 30.7 %

Procedure:
A suspenssion of tert-butyl (3-(6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (30 mg), 1,3-dibromopropane (14.7 mg) and K2CO3 (13.4 mg) in acetone (6 mL) was heated to reflux for 16 hours. The mixture was diluted with EtOAc (200 mL), washed with water (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give desired product tert-butyl 3-(6-(6-(4-(3-bromopropoxy)benzylamino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate (11 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([O:25]CC)=[O:24])=[CH:7]1.O.[OH-].[Li+].Cl>C1COCC1.O.[Cl-].[NH4+]>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([OH:25])=[O:24])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(-c3ccco3)c(F)cc2c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(-c4ccco4)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 30A (166 mg) in THF (8 mL) was treated with lithium hydroxide monohydrate (155 mg) in water (7.4 mL), stirred at ambient temperature for 3 hours, diluted with 10% ammonium chloride (20 mL), adjusted to pH 3 with 1M HCl, and extracted with dichloromethane. The extract was dried (Na2SO4), filtered, and concentrated.
Reaction SMILES: C(OP([CH:9]([C:17]#[N:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=O)OCC)C.[F:19][C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:27]=1)[CH:25]=O>C1COCC1.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:25]=[C:9]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:17]#[N:18])[CH:27]=1
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCOP(=O)(OCC)C(C#N)CC1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
[1-Cyano-2-(tetrahydro-pyran-4-yl)-ethyl]-phosphonic acid diethyl ester (5.4 g, 19.6 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Lithium (bistrimethylsilyl)amide (20 mL, 20 mmol, [1M]) was the added dropwise. The resulting mixture was stirred 20 min, and then 5-fluoro-2-nitro-benzaldehyde (3.31 g, 19.6 mmol) was added. The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution. The organic phase was separated and dried with MgSO4 and filtered. The solvent was removed to yield an oil which was purified by silica column chromatography (120 g column, 20% EtOAc/heptane) to yield a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].C([Li])CCC.[CH:16]1([C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH2:18][CH2:17]1.Cl>C1COCC1>[CH:16]1([C:19]([CH:21]2[CH2:23][CH2:22]2)([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([SH:8])[CH:3]=2)[OH:20])[CH2:18][CH2:17]1
Reactant: O=C(C1CC1)C1CC1
Reactant: Sc1cccc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cccc(S)c1)(C1CC1)C1CC1
Temperature: -5 °C

Procedure:
3-Bromobenzenethiol (2.0 g, 10.6 mmol) was dissolved in THF (20 mL) and cooled to −5° C. under N2. Sodium hydride (60 wt %, 477 mg, 11.6 mmol) was added portionwise, and the reaction was then cooled to −78° C. n-Butyllithium (2.5M, 4.7 mL, 11.6 mmol) was added over 20 minutes, followed by dicyclopropylmethanone (1.2 mL, 10.6 mmol), and the reaction was slowly warmed to room temperature over 3 hours. The reaction was acidified with 1N aqueous HCl to pH 2, and the reaction mixture was extracted with EtOAc three times. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc in hexanes) to give the desired product, 10i.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][CH:16]=[C:15]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1.[NH2:35][C:36]1[CH:37]=[N:38][N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH:40]=1>CN(C=O)C>[CH3:44][O:43][CH2:42][CH2:41][N:39]1[CH:40]=[C:36]([NH:35][C:32](=[O:34])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:15]3[C:14]4[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=4)[N:18]=[CH:17][CH:16]=3)=[CH:26][CH:27]=2)[CH:37]=[N:38]1
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Reactant: COCCn1cc(N)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1cc(NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cn1
Yield: 38.9 %

Procedure:
Diisopropylethylamine (0.124 ml) and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.247 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetic acid (0.2 g), 4-amino-1-(2-methoxyethyl)pyrazole (0.092 g) and DMF (3 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The resultant mixture was evaporated and the residue was purified by column cliromatography on silica using a solvent gradient from 100:0 to 24:1 mixtures of methylene chloride and a 3.5M methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.106 g); 1H NMR: (DMSOd6) 3.21 (s, 3H), 3.62 (s, 2H), 3.63 (t, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 4.12 (t, 2H), 6.47 (d, 1H), 7.22 (d, 2H), 7.4 (s, 1H), 7.44 (s, 1H), 7.45 (d, 2H), 7.49 (s, 1H), 7.89 (s, 1H), 8.47 (d, 1H), 10.2 (s, 1H); Mass Spectrum: M+H+ 463.