Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:20][CH2:19][C:18]3[N:17]4[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][C:10]=3[C:9]2=[O:21])[C:3]=1[CH2:22][OH:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][C:3]1[C:4]([N:8]2[CH2:20][CH2:19][C:18]3[N:17]4[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][C:10]=3[C:9]2=[O:21])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: O=C1c2cc3n(c2CCN1c1nccc(Cl)c1CO)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a mixture of 244a (900 mg, 2.7 mmol) and triethylamine (810 mg, 8.1 mmol) in dichloromethane (30 mL) was added acetyl chloride (630 mg, 8.1 mmol) dropwise. The reaction mixture was stirred at 30° C. for 1 h. It was then concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with dichloromethane to afford 244b as white solid (900 mg, 90%). MS-ESI: [M+H]+ 374.2
Reaction SMILES: OC1C=C(C=CC=1OC)C(OC)=O.ClC1C=C(CCO)C=CC=1.[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[CH:28]=1.C([O-])(=O)C.[Na+].[Br:51]Br>C(O)(=O)C>[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:28]=[C:29]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[C:30]([O:33][CH3:34])=[CH:31][C:32]=1[Br:51]
Reactant: BrBr
Reactant: COC(=O)c1ccc(OC)c(OCCc2cccc(Cl)c2)c1
Agent: CC(=O)[O-]
Agent: COC(=O)c1ccc(OC)c(O)c1
Agent: OCCc1cccc(Cl)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(OCCc2cccc(Cl)c2)c(OC)cc1Br
Temperature: 95 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
Methyl 3-hydroxy-4-methoxybenzoate and 2-(3-chlorophenyl)-ethanol were reacted in analogy to step 1 of example 1. The obtained 3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester (300 mg, 0.935 mmol) and sodium acetate (230 mg, 2.81 mmol) were dissolved in acetic acid (10 ml), bromine (224 mg, 1.40 mmol) was added, and the mixture was stirred at 95° C. with reaction control every hour. When the reaction did no more proceed, further bromine was added. After 5 h the reaction was completed. The volatiles were evaporated in vacuo, the residue was partitioned between EA and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous phase extracted with EA. The combined organic extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. This residue was purified by silica chromatography (HEP/EA gradient) to give 180 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC>O1CCOCC1.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:42]([O:41][C:39]([C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14])=[CH2:40])[CH3:43]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C=C(OCC)c1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 12 h
Yield: 34.2 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (500 mg, 0.964 mmol) in 1,4-dioxane (5 mL), tributyl(1-ethoxyvinyl)stannane (697 mg, 1.929 mmol), tris(dibenzylideneacetone)dipalladium (0) (88 mg, 0.096 mmol) and DPPF (53.5 mg, 0.096 mmol) were added. The reaction mixture was allowed to stir at 100° C. for 12 h. The reaction mixture was diluted with water and extracted in ethyl acetate. The organic layer was dried over sodium sulfate and concentrated which afforded (S)-tert-butyl (1-((9-(1-ethoxyvinyl)-4,6 dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.3 g, 0.33 mmol, 34% crude yield) as brown solid which was carried on without further purification. LC/MS (ESI) m/e 510.2 [(M+H)+, calcd for C29H40N3O5, 510.3]; LC/MS retention time (Method=C): tR=2.60 min.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([NH2:38])[CH3:37]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:38][CH2:36][CH3:37])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CCN
Product: CCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (750 mg, 1.48 mmol) and ethylamine (2M in THF, 2.22 ml, 4.4 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([C:38](=[O:49])[NH:39][C:40]3([C:43]4[N:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:42][CH2:41]3)[CH:31]=2)=[CH:28][C:5]2[C:6]([C:16]3[N:17](C(OC(C)(C)C)=O)[CH:18]=[CH:19][N:20]=3)=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N[C:51]1C(C2C=CC(OC)=C(C=2)C(NC2(C3N=CC=CN=3)CC2)=O)=CC2C(C3NC=CN=3)=C(C3C=CC(F)=CC=3)OC=2[CH:52]=1.C(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:51]([NH:1][C:2]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([CH:31]=2)[C:38]([NH:39][C:40]2([C:43]3[N:44]=[CH:45][CH:46]=[CH:47][N:48]=3)[CH2:42][CH2:41]2)=[O:49])=[CH:28][C:5]2[C:6]([C:16]3[NH:17][CH:18]=[CH:19][N:20]=3)=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1)[CH3:52]
Reactant: COc1ccc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2N)cc1C(=O)NC1(c2ncccn2)CC1
Reactant: COc1ccc(-c2cc3c(-c4nccn4C(=O)OC(C)(C)C)c(-c4ccc(F)cc4)oc3cc2N)cc1C(=O)NC1(c2ncccn2)CC1
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)CC2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The above obtained mixture of tert-butyl 2-(6-amino-2-(4-fluorophenyl)-5-(4-methoxy-3-((1-(pyrimidin-2-yl)cyclopropyl)carbamoyl)phenyl)benzofuran-3-yl)-1H-imidazole-1-carboxylate and 5-(6-amino-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-5-yl)-2-methoxy-N-(1-(pyrimidin-2-yl)cyclopropyl)benzamide (170 mg, 0.257 mmol) in MeOH (25 mL) was cooled to 0° C. and then added with acetaldehyde (45.3 mg, 1.029 mmol). The reaction mixture was allowed to warm to rt and stirred for 45 min. The reaction mixture was again cooled to 0° C. and then added with sodium cyanoborohydride (32.3 mg, 0.515 mmol). The reaction mixture was allowed to warm to rt and stirring continued at rt for 2 hr. The reaction mixture was concentrated completely at reduced pressure at 35° C. The residue was diluted with water and 10% NaHCO3 solution, filtered, and the solid obtained dried under suction. The crude product was purified by preparative HPLC to separate the two compounds. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.32 (br s, 1H) 8.92 (s, 1H) 8.69 (d, J=4.8 Hz, 2H) 7.94-8.03 (m, 2H) 7.86 (d, J=2.51 Hz, 1H) 7.55 (dd, J=8.53, 2.51 Hz, 1H) 7.22-7.33 (m, 5H) 7.21 (s, 1H) 7.13 (s, 1H) 6.91 (s, 1H) 4.58 (t, J=5.65 Hz, 1H) 3.99 (s, 3H) 3.13-3.22 (m, 2H) 1.59-1.66 (m, 2H) 1.38-1.46 (m, 2H) 1.10-1.21 (m, 3H). 19F NMR (376.6 MHz, DMSO-d6) δ ppm: 112.76. LCMS: (ES−) m/z=587.2 (M−H); Column—Acentis Express C8 (50×2.1 mm; 2.7 u); M phase A: 2% MeCN-98% H2O-10 mM NH4COOH; M phase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C1(B(O)O)C=CC=CC=1.C=O.[C:29](O)(=[O:32])CC>C1C=CC=CC=1.O>[OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[CH2:29][OH:32]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCC(=O)O
Agent: C=O
Agent: OB(O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)c(CO)c1
Yield: 287.2 %

Procedure:
A solution of 27.4 g (0.12 mole) of benzyl 4-hydroxybenzoate, 14.7 g (0.12 mole) of benzeneboronic acid, 6 g (0.135 mole) of paraformaldehyde and 0.9 ml (12 mmoles) of propionic acid in 600 ml of anhydrous benzene is heated at reflux for 12 hours using a Dean-Stark reactor to separate the water formed. The reaction medium is poured into bicarbonated water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column eluted with dichloromethane. After evaporation of the solvent, 8.9 g (30% yield) of the expected product having a melting point of 109°-110° C. are obtained.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[C:30]([CH2:31][CH2:32][CH3:33])=[C:29]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:28][N:27]=3)[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:3][N:4]1[CH2:7][CH:6]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH:2]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[C:24]([C:26]3[C:30]([CH2:31][CH2:32][CH3:33])=[C:29]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[O:28][N:27]=3)[O:23][N:22]=2)=[CH:19][CH:20]=1)[CH2:3][N:4]1[CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Reaction time: 2 h
Yield: 112.4 %

Procedure:
To tert-butyl 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidine-3-carboxylate (8 mg, 0.015 mmol) was added DCM (2 mL) and TFA (2.000 mL). The reaction mixture was stirred 2 hours. Next, the solvent was removed and the remaining contents were freeze dried from MeCN to yield 8 mg of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (2H, d, J=8.35 Hz), 7.83 (2H, dd, J=8.02, 1.65 Hz), 7.58-7.73 (5H, m), 4.32-4.83 (3H, m), 3.43-4.20 (6H, m), 2.95-3.05 (2H, m), 1.65-1.75 (2H, m), 0.97 (3H, t, J=7.36 Hz). MS (m+1)=475. HPLC Peak RT=3.38 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:13](N(C)C)N(C)C>C1(C)C=CC=CC=1>[N:1]12[P:13]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][CH2:10]1)[CH2:3][CH2:2]2
Reactant: C1CNCCNCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: C1CN2CCN3CCN(C1)P23
Yield: 88.9 %

Procedure:
A solution of 5.00 g of 1,4,7-triazacyclodecane and 5.70 g of hexamethylphosphorous triamide in 50 ml. of toluene is refluxed for 48 hours. The toluene is removed under reduced pressure, and the residue is distilled through a short-path column, to give 5.31 g (89%) of 1,4,7-triaza-11-phosphatricyclo[5.3.1.04,11 ] undecane as a clear, colorless liquid having a boiling point of 96°-98° C. at 0.70 mm. The product solidifies on standing at room temperature.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17]
Reactant: CC(C)(C)NO
Reactant: COc1ccc(O)c(C=O)c1
Product: COc1ccc(O)c(C=[N+]([O-])C(C)(C)C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-hydroxy-5-methoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 68.1 % yield as a crystalline solid, m.p. 70.4-71.6° C. (Rf=0.23 on a silica gel plate using 3:7 EtOAc/hexanes as an eluant).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH3:1][C:2]1[C:7]([O:8][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(I)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1nc(I)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A suspension of 810 mg (3.45 mmol) of 2-methyl-3-hydroxy-6-iodopyridine (from Step A), 533 μL (4.48 mmol) of benzyl bromide, 953 mg (6.89 mmol) of potassium carbonate and catalytic amount of tetrabutylammonium iodide in 10 mL of acetone was refluxed for 3 h and cooled to rt. Solid was filtered off through a cake of Celite and washed with EtOAc, and the filtrate was concentrated. Chromatography on a Biotage 40M cartridge using 1:19 v/v EtOAc/hexanes as the eluant afforded 1.03 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 2.48 (s, 3H), 5.04 (s, 2H), 6.79 (d, J=8.4, 1H), 7.32-7.42 (m, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([O:19][C:20](=[O:33])[NH:21][C:22]1[C:27]([C:28](=[O:31])[CH2:29][CH3:30])=[CH:26][CH:25]=[C:24](Cl)[N:23]=1)([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C>CS(C)=O.C(OCC)(=O)C>[C:15]([O:19][C:20]([NH:21][C:22]1[N:23]=[C:24]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:31])[CH2:29][CH3:30])=[O:33])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CCC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1NC(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
610 mg (3.0 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate, 700 mg (2.3 mmol) of tert-butyl(6-chloro-3-propanoylpyridin-2-yl)carbamate (Example 23A) and 610 μl (3.5 mmol) of diisopropylethylamine were suspended in 7 ml of DMSO and heated in a microwave reactor at 90° C. for 45 min. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous ammonium chloride solution (3×40 ml), then with saturated aqueous sodium bicarbonate solution (40 ml), and the organic phase was dried over magnesium sulfate, diluted and concentrated. The residue was chromatographed on silica gel (mobile phase: cyclohexane-ethyl acetate 5:1 to 1:1). This gave 380 mg (35% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][C:4]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)=[CH:42][C:41]=1[O:57][CH3:58]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:58][O:57][C:41]1[CH:42]=[C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)[CH:44]=[CH:45][C:40]=1[O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:26][C:4]1[CH:5]=[C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Reactant: COc1ccc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)on2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)on2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 78.5 %

Procedure:
2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenol (20a) (357.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (21d) (546 mg, 80% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[O:5].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][C:13]([F:18])=[C:12](Cl)[N:11]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN1C(=O)CCC1>[Cl:9][C:10]1[N:11]=[C:12]([NH:2][C@H:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[O:5])[C:13]([F:18])=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CC[C@@H](N)C(N)=O
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC[C@@H](Nc1nc(Cl)c(C#N)cc1F)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To the mixture of (R)-(−)-2-aminobutanamide hydrochloride (1.00 g, 7.2 mmol) and 2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (0.92 g, 4.8 mmol) in 40 mL NMP added DIEA (2.5 mL, 14.4 mmol). The mixture was then sent to 100° C. for stirring for 1 h. The mixture was cooled to RT, and to it was poured 300 mL EtOAc. The mixture was washed with brine four times. The organic phase was dried, concentrated and purified using silica flash column (70% EtOAc-30% DCM) to isolate (R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)butanamide (1.21 g, 98% yield).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:14]2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH2:14]2)=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(N1CCc2cc(S(=O)(=O)Cl)c(Br)cc2C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (35.6 mL) was added dropwise to a solution of 1-(7-bromo-3,4-dihydroisoquinolin-2(1 H)-yl)-2,2,2-trifluoroethanone obtained (25.4 g, 82.3 mmol) in chloroform (35 mL) while cooling in ice, and the mixture was stirred at room temperature for 1 hr and at 60° C. for 4 hr. After cooling, the reaction mixture was added dropwise to ice water and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The concentrate was powdered with hexane and ethyl acetate (5:1) and then collected by filtration to afford 7-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonyl chloride as a pale yellow powder (22.7 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([C:7]2[S:37][C:11]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[CH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Temperature: 145 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of ethyl 4-[2-(4-trifluoromethylbenzoylamino)-1-oxoethyl]benzoate (900 mg), Lawesson's reagent (960 mg) and xylene (5 ml) was stirred at 140 t 145° C. for 2 hours. The reaction mixture was cooled, and precipitated crystals of ethyl 4-[2-(4-trifluoromethylphenyl)-5-thiazolyl]benzoate (378 mg, yield: 43%) were collected by filtration. The product was recrystallized from xylene-isopropyl ether to obtain pale yellow prisms. Melting point: 174 to 176° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1>C(O)(=O)C>[NH2:8][C:6]1[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]3)=[CH:29][CH:30]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1N
Temperature: 70 °C
Yield: 94.7 %

Procedure:
A mixture of 2-chloro-5-methylpyrimidin-4-amine (540 mg, 3.7 mmol), tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (1.1 g, 3.7 mmol) was suspended in acetic acid (20 mL) and heated at 70° C. for 1 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH˜7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the title compound (1.4 g, 95%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH2:26])=[N:22]1>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH:26][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:4]([O:14][CH3:15])[CH:3]=2)=[N:22]1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Nc1ncn(Cc2cccc(Cl)c2)n1
Product: COc1cc(Nc2ncn(Cc3cccc(Cl)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 1b) starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352) and 1-(3-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine from example 7a). The title compound was obtained as a slightly yellow solid (Yield=13%). MS ISP (m/e): 395.2 (100) [(M+H)+].
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.[Cl:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[CH2:18][C:17]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:16]=1[Cl:15]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1Cc1ccc(F)cc1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.