Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[Se:20][C:21]([CH:24]=[CH:25][CH3:26])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1>C(OCC)(=O)C.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[Se:20][C:21]([CH2:24][CH2:25][CH3:26])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: CC=Cc1ccc(-c2ccc(-c3ccc(OCCC)c(F)c3F)cc2)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(-c3ccc(CCC)[se]3)cc2)c(F)c1F

Procedure:
0.7 g (1.7 mmol) of 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)-5-propenyl-selenophene is hydrogenated in 30 ml of ethyl acetate/toluene (2:1), in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness. Recrystallisation from n-heptane/toluene (4:1) gives 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)-5-propylselenophene as a solid having an m.p. of 114° C.
Reaction SMILES: [CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14]Cl)[C:8](=[O:16])[CH2:7][C:6]=3[CH:17]=2)[O:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH2:28][CH:27]([NH:34][CH3:35])[CH2:26][CH2:25]2>>[CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:34]([CH3:35])[CH:27]4[CH2:26][CH2:25][C:24]5[C:29](=[CH:30][C:31]([O:32][CH3:33])=[C:22]([O:21][CH3:20])[CH:23]=5)[CH2:28]4)[C:8](=[O:16])[CH2:7][C:6]=3[CH:17]=2)[O:2]1
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Reactant: O=C1Cc2cc3c(cc2CCN1CCCCl)OCO3
Product: COc1cc2c(cc1OC)CC(N(C)CCCN1CCc3cc4c(cc3CC1=O)OCO4)CC2

Procedure:
The title compound is prepared from 1-[7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 6,7-dimethoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene analogously to Example 1. Mp: 158° C. (decomp.).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[C:20]2[C:12]([N:13]3[C:18](=[CH:19]2)[C:17](=[O:22])[NH:16][CH2:15][CH2:14]3)=[N:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)=O>[OH:8][C:9]1[CH:21]=[C:20]2[C:12]([N:13]3[C:18](=[CH:19]2)[C:17](=[O:22])[NH:16][CH2:15][CH2:14]3)=[N:11][CH:10]=1
Reactant: O=C1NCCn2c1cc1cc(OCc3ccccc3)cnc12
Agent: [Pd]
Solvent: O=CO
Product: O=C1NCCn2c1cc1cc(O)cnc12

Procedure:
The suspension consistent of 0.20 g (0.68 mmol) 7-benzyloxy-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one and 30 μg palladium on activated charcoal (10% Pd; commercially available) in 2 mL formic acid was hydrogenated at room temperature at 1.5 bar for 3 hours. The reaction mixture was filtered over dicalite speed plus® (Aldrich), the filter cake was washed with formic acid and the volatile components were evaporated at a rotary evaporator. The residue was stirred in 3 mL ethyl acetate, filtered and the light brown product (65%) was dried under high vacuum.
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]([CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:7][C@@H:6]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][CH:32]=[N:33][C:34]=2[NH2:38])(=O)C.O.NN>N1C=CC=CC=1>[C:11]([O:10][C@@H:9]1[C@H:8]([CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:7][C@H:6]([N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][CH:32]=[N:33][C:34]=3[NH2:38])[C@H:5]1[OH:4])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O[C@H]1[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cnc2c(N)ncnc21
Agent: NN
Solvent: c1ccncc1
Solvent: O
Product: Nc1ncnc2c1ncn2[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 68 %

Procedure:
A solution of 9-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)adenine 2 [Ref.: Gosselin, G.; Bergogne, M.-C.; Imbach, J.-L., “Synthesis and Antiviral Evaluation of β-L-Xylofuranosyl Nucleosides of the Five Naturally Occuring Nucleic Acid Bases”, Journal of Heterocyclic Chemistry, 1993, 30 (Oct.-Nov.), 1229-1233] (8.30 g, 16.05 mmol) and hydrazine hydrate 98% (234 mL, 48.5 mmol) in a mixture of pyridine / glacial acetic acid (4/1, v/v, 170 mL) was stirred at room temperature for 22 h. The reaction was quenched by adding acetone (40 mL) and stirring was continued for one additional hour. The reaction mixture was reduced to one half of its volume, diluted with water (250 mL) and extracted with chloroform (2×150 mL). The organic layer was washed successively with an aqueous saturated solution of NaHCO3 (3×100 mL) and water (3×100 mL), dried, filtered, concentrated and co-evaporated with toluene and methanol. The residue was purified by silica gel column chromatography (0-3% MeOH in dichloromethane) to give 3 (5.2 g, 68%) precipitated from diisopropylic ether: 1H NMR (DMSO-d6):δ 5 4.5-4.9 (m, 4H, H-2′, H-4′, H-5′ and H-5″), 5.64 (t, 1H, H-3′, J2′,3′=J3′,4′=3.5 Hz), 6.3 (br s, 1H, OH-2′), 6.45 (d, 1H, H-1′, J1′,2′=4.6 Hz), 7.3 (br s, 2H, NH2-6), 7.4-7.9 (m, 10H, 2 benzoyls), 8.07 and 8.34 (2s, 2H, H-2 and H-8); ms : matrix G/T, (FAB+) m/z 476 [M+H]+, 136 [BH2]+, (FAB-) m/z 474 [M-H]-, 134 [B]-; UV (95% ethanol): λmax257 nm (ε 16400), 230 nm (ε 29300), λmin246 nm (ε 14800); [α]D20=−64 (c 1.07, CHCl3). Anal. Calcd for C24H21N5O4 (M=475.45): C, 60.43; H, 4.45; N, 14.73. Found: C, 60.41; H, 4.68; N, 14.27.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][CH2:7][C:8]12O[CH:12]1[CH2:11][CH2:10][C:9]2=[O:14])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][CH:10]1[C:9](=[O:14])[C:8]([CH2:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH2:11]1)(=[O:3])[CH3:2]
Reactant: CCCCCC(CCC12OC1CCC2=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCC(CCC1=CCC(OC(C)=O)C1=O)OC(C)=O

Procedure:
A solution of 2-(3-acetoxyoctyl)-2,3-epoxycyclopentanone (26.8 g.)[prepared as described in (g) above] in glacial acetic acid (500 ml.) was heated at reflux for 12 hours. The excess acetic acid was then removed in vacuo and the residue distilled under reduced pressure to give 5-acetoxy-2-(3-acetoxyoctyl)cyclopent-2-enone (24.7 g.), b.p. 164°-175°C./0.2 mm.Hg.
Reaction SMILES: [CH3:1][C:2]1([OH:6])[CH2:5][CH2:4][CH2:3]1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:7]([O:6][C:2]1([CH3:1])[CH2:5][CH2:4][CH2:3]1)(=[O:9])[CH3:8]
Reactant: CC1(O)CCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(C)CCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of 1-methylcyclobutanol (6.2 g, 72.0 mmol) in DCM (50 mL) was added DMAP (0.440 g, 3.60 mmol) and TEA (15.05 mL, 108 mmol). Then, the mixture was cooled to 0° C. and acetic anhydride (13.46 mL, 108 mmol) was added and stirred at room temp for 24 h. The mixture was then washed with sat.NaHCO3 (100 mL), 1N HCl (100 mL), 10% NaOH (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to afford 1-methylcyclobutyl acetate (8 g, 62.4 mmol, 87% yield) as light yellow oil which was used in the next step as is without further purification. 1H NMR (500 MHz, CDCl3) δ 2.36-2.26 (m, 2H), 2.18-2.11 (m, 2H), 2.01-1.98 (m, 3H), 1.87-1.76 (m, 1H), 1.72-1.63 (m, 1H), 1.55 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH:26]=[CH:27][C:28]([CH2:30][C:31](O)=[O:32])=[CH:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH:26]=[CH:27][C:28]([CH2:30][C:31]([N:55]5[CH2:60][CH2:59][O:58][CH2:57][CH2:56]5)=[O:32])=[CH:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(O)Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of (4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}[1]benzothieno[2,3-d]pyrimidin-7-yl)acetic acid (50 mg, 0.10 mmol, 1 eq, from example 94) in DCM (2 mL) were added HOBt (14 mg, 0.10 mmol, 1 equiv) and EDCI (24 mg, 0.13 mmol, 1.2 equiv) under nitrogen. After the mixture was stirred at rt for 5 min, morpholine was added. The resulting reaction mixture was stirred at rt for 15 h. The solvent was concentrated in vacuo. Methanol was added to the residue and a white solid was precipitated out from the solution. The solid was filtered, washed with methanol (2×3 mL) then dried in vacuo to obtain a white solid (27.8 mg, 0.05 mmol, 51%). 1H-NMR (DMSO-d6) δ 9.0 (broad s, 1H), 8.58 (d, J=4.6 Hz, 1H), 8.51 (s, 1H), 8.49 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.87 (t, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.53 (dd, J=2.6, 8.8 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.35 (m, 1H), 7.24 (d, J=8.7 Hz, 1H), 5.30 (s, 2H), 3.91 (s, 2H), 3.50 (m, 8H); LCMS RT=2.69 min, [M+H]+=546.20
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Li]C(C)(C)C.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1.O>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]1[CH2:5][CH2:4][CH:3]=[CH:2][O:1]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1=COCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)C1CCC=CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of 2,3-dihydropyran (2.0 g, 23.8 mmol) in dry THF (50 mL) was added tert-BuLi (26.2 mmol) at -78° C. and the resulting solution was stirred at 0° C. for 1 hour. The mixture was cooled to -78° C. and tributylstannyl chloride (5.53 g, 17.0 mmol) was added and stirring was continued for fifteen minutes at which time the reaction mixture was diluted with water and extracted 3× with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was filtered through a plug of silica gel to yield 5.23 g (59%) of the title compound as a clear liquid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([CH3:11])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)=[C:4]([CH3:11])[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Br)cc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2c1cnn2C1CCCCO1
Temperature: 70 °C
Yield: 57.7 %

Procedure:
6-Bromo-4-methyl-1H-indazole (1.0 g, 4.7 mmol, J&W PharmLab) and p-TSA (0.082 g, 0.47 mmol) were dissolved in THF (20 mL). 3,4-Dihydro-2H-pyran (1.99 g, 23.7 mmol) was added and the mixture was heated at about 70° C. for about 6 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (5:1 hexanes:EtOAc) to give 6-bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.80 g, 41%): LC/MS (Table 2, Method g) Rt=2.28 min; MS m/z: 295, 297 (M+H)1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([NH:13][C:14](=[O:16])C)=[N:9]2)[CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([NH:13][CH:14]=[O:16])=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC1=NN(c2cccc(Cl)n2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNC1=NN(c2cccc(Cl)n2)CC1

Procedure:
A mixture of 5.0 g. of 2-(3-amino-2-pyrazolin-1-yl)-6-chloropyridine (prepared as described in Example 3) and 25 ml. of a mixture of formic acid and acetic anhydride (Feiser and Feiser, Reagents for Organic Synthesis, Vol. 1, page 4) at room temperature gives an immediate yellow precipitate. The precipitate is collected by filtration then is recrystallized from acetone-hexane to give 3.05 g. of the product of the Example as off-white crystals, m.p. 190°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][N:34]2[CH:35]=[C:31]([C:9]3[C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=4[NH:11][N:10]=3)[CH:32]=[N:33]2)[CH2:38][CH2:37]1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCC1CC1
Product: COc1nccc2[nH]nc(-c3cnn(CC4CC4)c3)c12
Yield: 45 %

Procedure:
Prepared according to the general procedure described in Example 86, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with cyclopropylmethyl bromide to give the title compound (21.3 mg, 45% over two steps). LC-MS (Method G): m/z=270.0 [M+H]+; 3.41 min. 1H-NMR (400 MHz, DMSO): δ 13.25 (s, 1H), 8.33 (s, 1H), 7.99 (s, 1H), 7.85 (d, J=5.7, 1H), 7.08 (d, J=5.9, 1H), 4.09-4.03 (m, 5H), 1.37-1.24 (m, 1H), 0.63-0.54 (m, 2H), 0.46-0.39 (m, 2H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10]CC1C=CC=CN=1>>[CH:1]1[N:7]=[C:8]([SH:9])[N:10]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: S=C=Nc1ccccc1
Reactant: NCc1ccccn1
Product: Sc1ncc2ccccn12
Temperature: 25 °C

Procedure:
Phenyl Isothiocyanate (22 mL, 0.184 mol) is added slowly to a solution of 2-(aminomethyl)-pyridine (19 mL, 0.184 mol) in xylenes (180 mL) with cooling on ice. The resulting solution is heated at reflux for 3 h, and then allowed to cool to RT overnight. The resulting suspension is cooled to 0° C. and the solid is collected by filtration. The solid is washed with toluene and ether, and dried under vacuum to yield imidazo[1,5-a]pyridine-3-thiol as a green solid: 1H-NMR (CDCl3) δ 12.9 (br s, 1H), 8.25 (dd, J=7.5, 0.9, 1H), 7.21 (d, J=9.3, 1H), 7.06 (s, 1H), 6.75 (dd, J=9.3, 6.3, 1H), 6.59 (dt, J=7.5, 0.9); MS (M+1)+ 151.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[C:33]([NH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of the compound of Example 20 (100 mg 0.29 mmol) in CHCl3 (8 mL) was added pyridine (0.1 mL) and acetic anhydride (0.1 mL). The reaction was stirred at ambient temperature for 6 h. The reaction was then washed with 2M HCl and saturated NaHCO3, dried (MgSO4), and concentrated under reduced pressure to give the title compound (103 mg) as a yellow solid, m.p. 212-216°. δH 8.69 (1H, s), 8.06 (2H, d, J 8.4 Hz), 7.63-7.60 (2H, m), 7.56 (2H, d, J 8.4 Hz), 7.12-7.08 (2H, m), 5.82 (1H, s), 2.03 (3H, s) and 1.74 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:8]2[CH2:11][N:10]([C:12]3[N:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=3[C:14](O)=[O:15])[CH2:9]2)[CH:3]=1.Cl.[NH2:26][C:27]1([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:8]2[CH2:11][N:10]([C:12]3[N:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:13]=3[C:14]([NH:26][C:27]3([C:30]4[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=4)[CH2:29][CH2:28]3)=[O:15])[CH2:9]2)[CH:3]=1
Reactant: Cc1cc(OC2CN(c3ncc(C(F)(F)F)cc3C(=O)O)C2)no1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4cc(C)on4)C3)CC2)cc1
Yield: 70.4 %

Procedure:
The title compound (D180) (20 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-((5-methylisoxazol-3-yl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D129) (19 mg, 0.055 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (12.6 mg, 0.055 mmol).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH:4]([CH3:5])CO1.[NH:8](CCO)[CH2:9][CH2:10][OH:11].[OH-].[Na+]>>[OH:11][CH2:10][CH2:9][N:8]1[CH2:5][CH2:4][O:6][C:1]1=[O:7]
Reactant: CC1COC(=O)O1
Reactant: OCCNCCO
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCCN1CCO
Temperature: 100 °C

Procedure:
5.1 mol of propylene carbonate were provided as an initial charge at 23° C. under a nitrogen atmosphere. 5 mol of diethanolamine were added over 30 to 120 minutes with stirring, and the temperature of the reaction mixture rose. On completion of the addition the mixture was heated to 100° C. in the course of 10 to 120 minutes. At 100° C., 2.5 mol % of NaOH in solid form were added, and the batch was left to stir at 100° C. for 2 hours. Then a 10 to 20 mbar vacuum was applied, the temperature was raised from 100° C. to 160° C. and propylene glycol was distilled off. The N-(2-hydroxyethyl)-oxazolidin-2-one obtained almost quantitatively as undistilled bottom product comprised 96-98% by weight of product of value and had a Hazen color number in the range from 0 to 25.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3[N+](=O)[O-])cc12
Temperature: 101 °C
Yield: 67 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-chloro-3-nitropyridine were used. Triethylamine was used as base, p-dioxane was used as solvent, and the reaction was heated at reflux (101° C.) for 3 hours. Chromatography afforded the title compound (67%) as a dark red foam: mp, 59.0°-61.0° C.; 1H NMR (CDCl3) δ 8.66 (br s, 1H), 8.51 (dd, J=8.3 and 1.8 Hz, 1H), 8.41 (dd, J=4.4 and 1.8 Hz, 1H), 7.76 (br s, 1H), 7.30-7.24 (m, 2H), 6.97 (d, J=2.1 Hz, 1H), 6.73 (dd, J=8.3 and 4.4 Hz, 1H), 2.97-2.91 (m, 2H), 2.70-2.63 (m, 2H), 2.36 (s, 6H); 13C NMR (CDCl3) δ 155.7, 151.5, 135.5, 134.5, 129.4, 128.2, 127.9, 122.8, 119.3, 114.4, 114.3, 113.0, 111.5, 60.3, 45.4, 23.7. Anal. calcd for C17H19N5O2.1/3 H2O: C, 61.62; H, 5.98; N, 21.13. Found: C, 61.58; H, 5.65; N, 20.80.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH3:12].C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>O1CCCC1.CCCCCC>[CH3:12][C:3]1[CH:4]=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[B:18]([OH:23])[OH:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(C(C)(C)C)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(C)(C)C)ccc1B(O)O
Temperature: -5 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
The obtained 1-bromo-2-methyl-4-(t-butyl)benzene (10.70 g, 47.1 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling at −5° C., solution of n-butyllithium in n-hexane (1.65 M, 31.40 mL) was dropped, and reaction solution was stirred for 1 hour, then, triisopropyl borate (14.10 mL, 61.3 mmol) was dropped, and stirred for 1 hour. Temperature was elevated up to room temperature, then, reaction solution was stirred for 1 hour, then, hydrochloric acid (0.5 M, 30 mL) was added, and reaction solution was stirred for 3 hours. Resulting solid was filtered, and dried under reduced pressure to obtain the desired 2-methyl-4-(t-butyl)phenylboronic acid (7.00 g, 36.4 mmol).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:28][CH2:27]3)=[O:25])[CH:19]=1)[C:14](=[O:38])[NH:13][C:12]2=[O:39].CO.[NH4+].[Cl-]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([N:26]3[CH2:27][CH2:28][N:29]([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:37]=4)[CH2:30][CH2:31]3)=[O:25])[CH:19]=1)[C:14](=[O:38])[NH:13][C:12]2=[O:39]
Reactant: COc1cccc2c(=O)[nH]c(=O)n(Cc3cccc(C(=O)N4CCN(c5ncccn5)CC4)c3)c12
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cccc(Cn2c(=O)[nH]c(=O)c3cccc(O)c32)c1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
A solution of BBr3 (4N in DCM, 10 mL, 40 mmol) was added dropwise to a mixture of 8-methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione (60 mg, 0.13 mmol) in DCM (25 mL) at −70° C. The mixture was warmed to room temperature and stirred at r.t overnight. After cooled at ice-bath, 10 mL MeOH was added dropwise and then NH4Cl (a.q.) was added. The mixture was extracted by DCM (50 mL×2), the combined organic layer was dried to give crude product which was purified by TLC (DCM/MeOH=20:1) to give the target product (7.64 mg, 13.1% yield). 1H NMR (DMSO-d6): 11.64 (s, 1H), 10.34 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 7.51 (dd, J=6.8 and 2.6 Hz, 1H), 7.39-7.34 (m, 1H), 7.27-7.23 (m, 3H), 7.10-7.03 (m, 2H), 6.65 (t, J=4.7 Hz, 1H), 5.63 (s, 2H), 3.85-3.53 (m, 8H). MS: m/z 459.4 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][CH2:9][CH:10]([OH:22])[CH2:11][C:12](=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[BH4-].[Na+].C(O)(=O)C>C1COCC1.O>[C:29]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:8][CH2:9][CH:10]([OH:22])[CH2:11][CH:12]([OH:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To the crude tert-butyl 6-triphenylmethyloxy-5-hydroxy-3-oxohexanoate was added 150 mL of THF followed by 15 mL of MeOH and was chilled to −60° C. 26 mL of MDEB (50% solution in THF) was added over a period of 20 minutes and stirring was continued for a further 30 minutes. The reaction mixture was cooled to −80° C. and 5 g of sodium borohydride was added in portions and the after completion of addition the reaction mixture was stirred for 5 hours at −78° C. Acetic acid was added to adjust the pH to 7 and water was added. The aqueous layer was extracted using EtOAC, washed with brine, dried and concentrated to give the title compound which was used as such for the next step.
Reaction SMILES: [OH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH-].[NH4+:16]>>[OH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([NH2:16])=[CH:4][N:3]=1
Reactant: Oc1ncc(Br)nc1N1CCOCC1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1cnc(O)c(N2CCOCC2)n1

Procedure:
A mixture of 2-hydroxy-3-morpholino-5-bromopyrazine (1 g.) in 100 ml. of concentrated ammonium hydroxide is heated overnight at 100°-140° C. in a sealed tube to give 2-hydroxy-3-morpholino-5-aminopyrazine.