Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[NH2:25][C:26]([NH2:28])=[S:27]>CC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[S:27][C:26](=[NH:25])[NH2:28])(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](SC(=N)N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C

Procedure:
2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (37.5 g) dissolved in acetone (180 ml) with thiourea (10.9 g) at 25° C. Batch heated to reflux for a minimum of 2 hrs. Reaction followed by TLC (1:1 petrol/EtOAc. Starting material 0.69, plus multiple peaks below. Product is a salt and therefore seen on baseline (uv-active)). Batch cooled to R.T. and crystallised as a white crystalline solid (35 g, 79%) with the aid of petrol as anti-solvent. M.p=169-171° C. (Lit3 169° C.). [α]D22+17 (EtOH, C=2.0) (Lit3+16). (1H NMR (DMSO, 400 MHz). δ=1.96, 2.02, 2.09, 2.14 (sx4, 4×3H, —C(O)CH3), 4.08-4.11 (m, 2H, H-6, H-61), 4.4 (t, J6.2 Hz, 1H, H-5), 5.1 (t, J2,39.9 Hz, 1H, H-2), 5.2 (dd, J2,39.9 Hz, J3,43.4 Hz, 1H, H-3), 5.4 (d, J3.3 Hz, 1H, H-4), 5.6 (d, J1,210 Hz, 1H, H-1), 9.2 (Br, 4H, 2×NH2).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](C)[CH2:15]C(O)=O)=[CH:10][CH:9]=1>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(CC(=O)O)c1ccc(F)cc1
Solvent: ClCCl
Product: CC(CC(=O)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
Oxalyl chloride (71 g, 48.8 ml, 0.560 mol, Aldrich) was added to a mixture of 3-(4-fluorophenyl)butyric acid (34 g, 0.187 mol) in 200 ml of dichloromethane at -5° C. After stirring for 20 min at this temperature, the solution was allowed to warm to 25° C. and stirring was continued for 2 h. The volatiles were removed by spin evaporation in vacuo with the addition of dichloromethane (4×) during concentration to give 35.1 g (94%) of 3-(4-fluorophenyl)butyryl chloride as a light yellow oil:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.[CH2:19]([NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=1)=[O:23])[CH3:20].O>C(=O)([O-])[O-].[K+].[K+].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>[CH2:19]([NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:26][N:25]=1)=[O:23])[CH3:20]
Reactant: CCNC(=O)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
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: [K+]
Solvent: O
Product: CCNC(=O)c1ccc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 80 °C
Yield: 108.2 %

Procedure:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (37, 0.424 g, 1.74 mmol), 5-bromo-pyridine-2-carboxylic acid ethylamide (36, 0.159 g, 0.694 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol) were mixed in 1.00 M potassium carbonate in water (4.2 mL, 4.2 mmol). The reaction mixture was heated at 80° C. overnight. The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (38, 200 mg). MS (ESI) [M+H+]+=267.2.
Reaction SMILES: [K].[C:2]1([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2C=[CH:23][C:24](=[O:27])NN=2)C=CC=CC=1.[OH-].[K+].CO.BrCCO>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[OH:27][CH2:24][CH2:23][N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:13]1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OCCBr
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1ccc(-c2ccccc2)nn1CCO
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
A mixture of 6-phenyl-3(2H)-pyridazinone potassium salt (10 mmol) (prepared from 6-phenyl-3(2H)-pyridazinone (1.72 g; 10 mmol) and KOH in methanol (0.56 g; 10 mmol), 2-bromoethanol (12 mmol), TBAB (1.19 g; 4 mmol) and atomised KOH (11 mmol) in toluene (60 mL) was stirred at room temperature for 6 hours. The reaction mixture was filtered, the filtrate was washed successively with 5% NaOH solution, 10% HCl solution and lastly water. The organic extracts were dried over anhydrous Na2SO4 and concentrated to dryness, and the obtained residue was purified by flash chromatography (CH22Cl2MeOH 98:2), yielding the title product (1.9 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)#[CH:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[NH2:26][C:25]1[CH:27]=[CH:28][C:22]([C:20]#[C:21][C:2]2[N:3]=[C:4]([C:9]3[N:10]([CH2:18][CH3:19])[C:11]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:17]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCn1c(-c2nc(C#Cc3ccc(N)cc3)cnc2N)nc2cnccc21
Reaction time: 1 h

Procedure:
5-Bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.051 g, 0.16 mmol) (made in example 2), 4-ethynylaniline (0.060 g, 0.51 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.006 g, 0.009 mmol), copper iodide (0.004 g, 0.02 mmol) and triethyl amine (3 mL) were combined and subjected to 180° C. for 1 hr in a SmithSynthesizer microwave. The resulting mixture is treated with silica gel, and the volatiles removed in vacuo. The title compound is obtained by silica gel chromatography (0.004 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=4)[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]4[CH:18]=[C:19]([C:28]5[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=5)[CH:20]=[CH:21][CH:22]=4)[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc3c(c2)OCO3)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc3c(c2)OCO3)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 4-benzo[1,3]dioxol-5-yl-2-(3-bromo-phenyl)-6-methyl-pyridine (example E.91) (0.150 g, 0.407 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.099 g, 0.448 mmol) according to the general procedure VI. Obtained as a white solid (0.100 g, 64%). MS (ISP) 382.2 [(M+H)+]; mp 203° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[C:9]([CH3:20])=[C:10]([CH3:19])[C:11]2[O:15][CH2:14][C:13](=[O:16])[C:12]=2[C:17]=1[CH3:18].Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br.[Cl-].[NH4+]>C1COCC1>[Br:7][C:8]1[C:9]([CH3:20])=[C:10]([CH3:19])[C:11]2[O:15][C:14]3([CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:13](=[O:16])[C:12]=2[C:17]=1[CH3:18]
Reactant: BrCCOCCBr
Reactant: Cc1c(C)c2c(c(C)c1Br)C(=O)CO2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1Br)C(=O)C1(CCOCC1)O2
Temperature: 25 °C
Yield: 7.9 %

Procedure:
Potassium tert-butoxide (2.63 g, 23.5 mmol) was added to a solution of THF (60 mL) containing 5-bromo-4,6,7-trimethyl-1-benzofuran-3(2H)-one (2.00 g, 7.83 mmol) synthesized in Reference Example 45 and bis(2-bromoethyl)ether (2.72 g, 11.7 mmol), and the mixture was stirred at room temperature. After stirring for 15 hours, the reaction solution was poured into a saturated ammonium chloride aqueous solution and extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 98:2 to 92:8) to give 200 mg of the title compound (yield: 8%).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[NH4+].[CH2:6]([O:8][C:9]1[N:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:6]([O:8][C:9]1[N:19]=[CH:18][C:17]([N+:1]([O-:4])=[O:2])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cccnc1OCC
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1cc([N+](=O)[O-])cnc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
Ammonium nitrate (1.11 g) was added portionwise to an ice-cooled solution of the compound prepared in Example 285 (0.900 g) in trifluoroacetic anhydride (11.5 mL). The mixture was stirred at room temperature overnight and then carefully poured into ice-water and the resulting suspension stirred for an hour. The precipitate was collected by filtration and washed with water. The solids were dried under vacuo to obtain the title compound (0.624 g) having the following physical data.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([NH:24][C:25]([C:27]2[C:32]([OH:33])=[C:31]([O:34][CH3:35])[CH:30]=[CH:29][N:28]=2)=[O:26])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Rh]>[CH:2]1([CH2:1][C@@H:8]2[C@@H:16]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([NH:24][C:25](=[O:26])[C:27]3[C:32]([OH:33])=[C:31]([O:34][CH3:35])[CH:30]=[CH:29][N:28]=3)[CH2:11][O:10][CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccccc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Agent: [Rh]
Solvent: C1CCOC1
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](CC3CCCCC3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Yield: 85261 %

Procedure:
A solution of N-[(3S,7S,8R,9S)-7-benzyl-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-3-hydroxy-4-methoxy-pyridine-2-carboxamide (25 mg, 0.05 mmol) in THF (1.2 mL) was passed through an H-cube bench top hydrogenator (5% Rh/C catalyst, 100° C., 100 bar H2, 1 mL/min). The reaction mixture was concentrated to furnish N-((3S,7 S,8R,9S)-7-(cyclohexylmethyl)-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide as a white solid (21 g, 83%): mp 89-92° C.; 1H NMR (400 MHz, CDCl3) δ 11.97 (s, 1H), 8.60 (d, J=8.2 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 6.86 (d, J=5.2 Hz, 1H), 5.07-4.85 (m, 2H), 4.07 (dd, J=11.7, 7.1 Hz, 1H), 3.93 (s, 3H), 3.60 (dd, J=10.3, 3.3 Hz, 2H), 3.57-3.45 (m, 1H), 3.35 (dd, J=8.3, 6.3 Hz, 1H), 3.23 (dd, J=8.3, 6.6 Hz, 1H), 2.96 (t, J=9.0 Hz, 1H), 1.91-1.53 (m, 9H), 1.45 (d, J=6.4 Hz, 3H), 1.37-1.08 (m, 6H), 0.92 (dd, J=6.7, 3.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.0, 169.9, 155.3, 148.7, 140.6, 130.3, 125.5, 109.6, 85.0, 79.0, 76.1, 72.6, 56.1, 51.8, 42.7, 36.4, 34.9, 32.5, 30.3, 29.2, 26.6, 26.5, 26.2, 19.6, 19.5, 18.9. ESIMS m/z 493.0 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.[ClH:27]>CCOCC.O>[ClH:27].[OH:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:24])[N:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]32)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(O)cc3C(F)(F)F)[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C1c2c(cc(O)cc2C(F)(F)F)[C@@H]2CNCCN12
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (14 mg, 0.04 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 10 mg of a white solid. MS (ESI) 273 (M−Cl).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C([Li])CCC.[Cl:21][Si:22](Cl)([Cl:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C.CCCCCC>[Cl:21][Si:22]([Cl:29])([C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: Cl[Si](Cl)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (106 mL) of 1-bromo-3,5-di-tert-butylbenzene (10.60 g, 39.37 mmol), a 1.65 M hexane solution of n-butyllithium (23.86 mL, 39.37 mmol) was added dropwise at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 3 hours. The resultant mixture was added dropwise to a diethyl ether solution (106 mL) of trichlorophenylsilane (24.99 g, 118.12 mmol) at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane wad added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure. Trichlorophenylsilane was removed by heating to 100° C. under reduced pressure to obtain dichloro(3,5-di-tert-butylphenyl)(phenyl)silane (11.77 g, yield 81.8%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH2:38][CH3:39])[S:36][CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:32][C:33]1[N:34]=[C:35]([CH2:38][CH3:39])[S:36][CH:37]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc(CCl)cs1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CCc1nc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cs1
Yield: 82.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.20 g) and 4-chloromethyl-2-ethylthiazole (0.49 g) as starting materials, 5-benzyloxy-N-[(2-ethylthiazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.30 g) was obtained.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>O1CCCC1.[Cu]I>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Br
Reactant: CCOC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OCC
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC(c1ccc(OC)cc1OC)C(C(=O)OCC)C(=O)OCC
Reaction time: 0.25 h

Procedure:
686 mg (3.60 mmol) of copper (I) iodide were added to 24.2 ml (36.3 mmol) of a 1.5M butylmagnesium bromide solution in tetrahydrofuran, whilst cooling in an ice-salt bath, and the resulting mixture was stirred for 15 minutes to form a suspension. A solution of 7.47 g (24.3 mmol) of ethyl 3-(2,4-dimethoxyphenyl)-2-ethoxycarbonyl-2-propenoate (prepared as described in Preparation 1) in 25 ml of tetrahydrofuran was then added dropwise to this suspension at the same temperature over a period of 20 minutes, and the resulting mixture was stirred for 30 minutes. The reaction mixture was then neutralized with concentrated aqueous hydrochloric acid and the resulting mixture was filtered using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in ethyl acetate. The resulting solution was washed three times with a saturated aqueous solution of ammonium chloride and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 10:1 to 5:1 by volume as the eluent, to give 9.15 g (a quantitative yield) of diethyl 2-[1-(2,4-dimethoxyphenyl)pentyl]malonate as an oily substance.
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([N+:16]([O-])=O)=[C:11]([CH3:19])[CH:10]=3)=[N:5][NH:4][C:3]1=[O:20].[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[CH3:19])[O:8][CH2:7][C:6]1[N:15]2[CH:2]([CH3:1])[C:3](=[O:20])[NH:4][N:5]=1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])N1C(=NNC(=O)C1C)CO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(cc1N)N1C(=NNC(=O)C1C)CO2
Temperature: 70 °C
Yield: 77.4 %

Procedure:
To a solution of 4,7-dimethyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.085 g, 0.31 mmol) and ammonium chloride (0.164 g, 3.1 mmol) in MeOH (10 mL) and THF (10 mL) was added zinc powder (0.200 g, 3.1 mmol) and the resulting mixture was heated at 70° C. for 4 h. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was washed with MeOH (15 mL). The filtrate was concentrated in vacuo and the residue was dissolved in water (20 mL). The aqueous solution was extracted with EtOAc (3×15 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give 6-amino-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.060 g, 0.24 mmol, 79%) as a solid, which was used directly in the next step. TLC (eluting with 25% EtOAc in petroleum ether) Rf=0.2.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([F:49])=[C:44](B(O)O)[CH:45]=1>>[NH2:30][C:29]1[S:28][C:27]([C:42]2[CH:41]=[C:40]([Cl:39])[CH:45]=[CH:44][C:43]=2[F:49])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)c1cc(Cl)ccc1F
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Cl)ccc3F)sc2N)c1N1CCC(CN)CC1
Yield: 31 %

Procedure:
Following the procedure for Example 278 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-chloro-2-fluorophenylboronic acid gave 314 as a grey solid (29.2 mg, 31%). 1H NMR (400 MHz, d4-MeOD) δ 8.34 (dd, J=6.4, 2.7 Hz, 1H), 7.47 (s, 1H), 7.43-7.37 (m, 1H), 7.27 (dd, J=10.9, 8.8 Hz, 1H), 3.74 (s, 3H), 3.27-3.11 (m, 4H), 2.63 (d, J=6.6 Hz, 2H), 1.86 (d, J=12.6 Hz, 2H), 1.56-1.47 (m, 1H), 1.38 (qd, J=11.9, 4.4 Hz, 2H). LCMS (ES+) m/z 480 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>O=S(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
4-bromobenzoic acid (17-a, 10 g, 0.05 mol) was dissolved in SOCl2 (100 ml) and the resulting mixture was stirred at rt for 3 hours, then concentrated under vacuum. The residue was dissolved in 1-fluorobenzene (24 g, 0.25 mol) and AlCl3 (8.24 g, 0.06 mol) was added portion-wise with stirring under N2. The resulting reaction mixture was refluxed overnight. The reaction mixture was cooled to temperature and poured into 20% HCl (1500 ml), stirred for 1 h, and the layers were separated. The aqueous layer was further extracted with DCM (2×50 ml). The combined organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was washed with hexane to afford the product, 17-b, (12.2 g, 85%).
Reaction SMILES: [C:1](Br)(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)=O.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:8]=[C:7]1[NH:9][C:2]([C:1]([NH:12][CH:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19])=[O:10])=[CH:3][C:4](=[O:5])[NH:6]1
Reactant: O=C(Br)c1cc(=O)[nH]c(=O)[nH]1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)CC(NC(=O)c1cc(=O)[nH]c(=O)[nH]1)C(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the orotoyl bromide solution, 5.90 g (45 mmol) of Leucine is suspended, with stirring, in 50 mL of dry DCM. To this suspension a catalytic amount (˜0.1 mmol) of DMAP is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of about −15° C. When the target temperature is reached the drop wise addition of orotoyl bromide is commenced. Addition of orotoyl bromide continues, with constant cooling and stirring, until all of the orotoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant agitation. The solution is then filtered to remove any remaining Leucine and the volatile DCM is removed from the filtrate under reduced pressure, the remainder is then purified by flash chromatography (ethyl acetate/hexanes; 1/5), yielding 2-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-4-methylpentanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11]3=[C:27]([CH3:31])[N:28]=[C:29]([CH3:30])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:32](O)(=[O:35])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)CCl>CN(C=O)C>[CH3:31][C:27]1[N:28]=[C:29]([CH3:30])[N:10]2[C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[N:13][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[CH2:32][OH:35])=[CH:7][CH:6]=1)=[N:9]2
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(Nc2nc(-c3ccc(NC(=O)CO)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of are 50 mg (0.12 mmol) of N-[2-(4-aminophenyl)-5,7-dimethyl-imidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 in DMF is treated with 18 mg (0.24 mmol) of glycolic acid, 90 mg (0.24 mmol) of HATU and 46 mg (0.24 mmol) of EDC. It is stirred overnight at 20° C. The solvent is removed under reduced pressure and the residue is purified by HPLC.