Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[CH:18][C:19]([CH:23]=O)=[CH:20][CH:21]=4)[NH:16][N:15]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2.N1CCCCC1>CO>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:23]/[C:19]1[CH:18]=[C:17]2[C:22]([C:14]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:9][CH:10]=3)=[N:15][NH:16]2)=[CH:21][CH:20]=1
Reactant: CN1CCN(c2ncc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Reactant: COc1ccc2c(c1)CC(=O)N2
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(-c4cnc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Temperature: 60 °C
Yield: 2.6 %

Procedure:
A round bottom flask was charged with 3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-indazole-6-carbaldehyde (26 mg, 0.80 mmol), 5-methoxyoxindole (13 mg, 0.80 mmol), piperidine (0.8 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 4 hrs. An orange precipitate formed which was further precipitated by cooling to room temperature. The orange solid was then filtered and washed with MeOH (5 mL) giving 9.8 mg, 26% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 13.46 (s, 1H), 10.44 (s, 1H), 8.97 (s, 2H), 8.18 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 6.85 (d, J=10.6 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 3.82 (br t, 4H), 3.59 (s, 3H), 2.39 (br t, 4H), 2.23 (s, 3H); MS ESI 468.3 [M+H]+, calcd for [C26H25N7O2+H]+ 468.2.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:10]([CH3:13])=[CH:11][CH3:12])[CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]([OH:9])=O.ClC(OCC)=O.C(N(CC)CC)C.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.[Cl-].[Na+]>>[CH:28]1([NH:31][C:7](=[O:9])/[CH:6]=[CH:5]/[CH2:4][CH2:3][C:2]([CH3:1])([CH3:14])[C:10]([CH3:13])=[CH:11][CH3:12])[CH2:30][CH2:29]1
Reactant: CC=C(C)C(C)(C)CC/C=C/C(=O)O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC=C(C)C(C)(C)CC/C=C/C(=O)NC1CC1
Yield: 40 %

Procedure:
4-(2,2,3-Trimethyl-3-penten-1-yl)-2E-butenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, cyclopropylamine 1.5 eq, quench with 10% sodium chloride solution, yield=40%.
Reaction SMILES: C([CH2:3][O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=1)#N.C(N(CC)CC)C>CO>[C:25]1([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[CH:10]=[CH:11][C:6]([C:5]([O:4][CH3:3])=[O:31])=[N:7][CH:8]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#CCOC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Heat at reflux 4 gm. (0.01 mole) of cyanomethyl-5-(triphenylmethyl)picolinate and 2 ml. triethylamine in 50 ml. methanol for 4hr. Remove methanol under reduced pressure. Triturate solid residue with water and recrystallize from ethylacetate - isopropyl ether, to obtain the product of this example, m.p. 160°-164°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:12].O1CCOCC1.[C:19](=O)([O-:21])[O-:20].[Na+].[Na+]>O>[CH3:12][C:5]1[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([C:19]([OH:21])=[O:20])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c[nH]c2c(C)cc(Br)cc12
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(C)cc(C(=O)O)cc12
Temperature: 165 °C
Reaction time: 0.01 h
Yield: 93 %

Procedure:
A microwave tube was charged with 5-bromo-3,7-dimethyl-1H-indole (317 mg, 1.42 mmol), dioxane (3 mL), Hermann's catalyst (42.1 mg, 0.07 mmol) and a solution of sodium carbonate (450 mg, 4.24 mmol) in water (6 mL). The mixture was stirred for 20 sec, heated at 165° C. for 15 minutes in a microwave reactor at very high absorption setting. The reaction was vented before handling. The mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated and the residue was dissolved in water. The solution was acidified to pH 3 and the solid was collected to afford the title compound (250 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])(=[O:13])=[O:12])=[C:4]([N+:24]([O-])=O)[CH:3]=1.C(O)(=O)C.Cl.N>O1CCCC1.[Zn]>[NH2:24][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[O:22][CH3:23])(=[O:13])=[O:12]
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: N
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a stirred solution of 5.9 g of N-[2-(4-bromo-2-nitrophenyl)ethyl]-5-cyano-2-methoxybenzenesulfonamide and 46 mL of acetic acid in 67 mL of tetrahydrofuran were added successively 2.23 mL of concentrated hydrochloric acid and 8.76 g of zinc under ice-cooling. After the mixture was stirred at room temperature for an hour, and to the reaction mixture was added 25% aqueous ammonia solution to alkalify. After the mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 5.58 g of N-[2-(2-amino-4-bromophenyl)ethyl]-5-cyano-2-methoxybenzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][C:20](=[O:22])[NH:21][C:14]=23)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20](=[O:22])[NH:21][C:14]=34)=[CH:4][CH:3]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)c2ccccc12
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)c2ccccc12
Yield: 15.2 %

Procedure:
Method H2 was used with 7-(4-aminonaphthalen-1-yl-oxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (94 mg, 0.32 mmol) and 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (77 mg, 0.35 mmol) to afford the title compound as a brown solid (25 mg, 15%). 1H-NMR (6, ppm, DMSO-d6): 6.21 (d, 1H, HPy,5, J=5.9 Hz), 7.20 (m, 1H, Harom,Naph), 7.56-7.67 (m, 4H, Harom,naph+Py,6), 7.79-7.87 (m, 2H, Harom,Ph′), 7.94-7.97 (m, 1H, Harom,naph), 8.23-8.31 (m, 2H, Harom,naph), 10.52 (s, NH, NHPy), 11.26 (s, NH, NHPy). LC-MS (m/z): 514 (M+H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4cc(C)cc(C)c4)CC3)nc2c1
Yield: 65 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 65%). 1H NMR (300 MHz, CDCl3): δ 2.28 (s, 6H), 3.26 (s, 4H), 3.76-3.87 (m, 6H), 4.11 (s, 4H), 6.59 (s, 2H), 6.90 (m, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.32 (s, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[C:11]([O:22][CH2:23][CH3:24])(=[O:21])[C:12]1[CH:20]=[CH:19][C:17]([OH:18])=[C:14]([O:15][CH3:16])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH:20]=[CH:19][C:17]=1[O:18][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:11]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: ClCCCN1CCOCC1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCN2CCOCC2)c(OC)c1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
N-(3-Chloropropyl)morpholine (90 g, 0.55 mol) was added dropwise, over 30 minutes, to a solution of ethyl vanillate (98 g, 0.50 mol) and powdered potassium carbonate (104 g, 0.75 mol) in dimethylformamide (300 ml) at 80° C. The reaction was heated at 80° C. for 90 minutes, cooled to ambient temperature, filtered and the filtrate concentrated in vacuo. The crude product was taken up in diethyl ether (1000 ml), filtered and washed with water (2×200 ml) and brine (200 ml). Solvent evaporation in vacuo yielded ethyl 3-methoxy-4-(3-morpholinopropoxy)benzoate (161.5 g, 100% yield) as a pale yellow oil which crystallised on standing to afford a pale yellow solid:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:32])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:32][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCCCc1cc(O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-butyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ8.04 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.69 (br s, 2H), 6.64 (dd, J=8.8, 2.9 Hz, 1H), 4.25-4.19 (m, 4H), 2.97 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.46 (quintet, J=7.6 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.88 (t, J=7 Hz, 3H); Rf=0.16 (25% ethyl acetate/hexanes).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[C:1]1([CH2:11][C:12]([O:14][CH2:19][CH3:20])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cccc2ccccc12

Procedure:
100 g (537 mmol) of naphthalene-1-acetic acid in 200 ml of absolute ethanol are heated to 60° C., while stirring, and 80 ml of thionyl chloride are added slowly in such a way that reflux occurs. Reflux is maintained for 6 h, and the solvent is then evaporated under reduced pressure. The residue is taken up with 200 ml of dichloromethane, the solution is washed with a saturated solution of sodium hydrogen carbonate and then with water, dried over magnesium sulphate and filtered, and the solvent is evaporated under reduced pressure. 104 g (485 mmol) of product are obtained in the form of an oil. n25D =1.5800.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:18][O:17][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]2([CH3:10])[CH3:3]
Reactant: COc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dichloro-2,5-dimethyl-hexane (Intermediate 1, 25.3 g, 0.14 mol) in anisole (60 mL, 0.55 mol) at 0° C. was added AlCl3 (18.4 g, 0.14 mmol) portionwise. After stirring for 2 h at 0° C., the mixture was poured onto ice and extracted with hexane. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The excess anisole was removed by vacuum distillation and the title compound was obtained as a white solid upon cooling (30.5 g, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:24]O>>[CH3:24][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:22][CH:23]=1)=[O:3]
Reactant: Cc1cc(CCCCCCCOc2ccc(C(=O)O)cc2)on1
Reactant: CO
Product: COC(=O)c1ccc(OCCCCCCCc2cc(C)no2)cc1
Yield: 95 %

Procedure:
[I; R is CH3, n is 7, X is O, Ar is 4--CH3OOCC6H4 ], m.p. 60° C. in 95% yield from 5-[7-(4-carboxyphenoxy)heptyl]-3-methylisoxazole (Example 16) and methanol; MIC vs. rhinovirus Type 2 in vitro=3 μg/ml.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[Cl:24][CH2:25][C:26](Cl)=O>ClC(Cl)C>[Cl:24][CH2:25][C:26]1[O:1][N:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[N:4]=1
Reactant: O=C(Cl)CCl
Reactant: N=C(NO)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: ClCc1nc(-c2ccc3ccccc3c2)no1
Temperature: 50 °C
Yield: 21.4 %

Procedure:
A solution of N-Hydroxy-naphthalene-2-carboxamidine (364 mg, 1.95 mmol) in dichloroethane (6 mL) and DIEA (683 μL, 3.91 mmol) was treated with a solution of chloroacetyl chloride (157 μL, 2.350 mmol) in dichloroethane (2 mL) which was added dropwise to the reaction vessel at room temperature. After the addition, the reaction mixture was heated at 50° C. for 4 hours. The reaction mixture was then concentrated to dryness and redissolved in dichloromethane. The organic layer was washed with saturated aqueous NaHCO3 and brine, respectively. The organic layer was dried over anhydrous Na2SO4, concentrated onto silica gel and purified by flash chromatography (0-50% ethyl acetate/hexanes gradient) to afford the required intermediate, 5-chloromethyl-3-naphthalen-2-yl-[1,2,4]oxadiazole (102 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.[H][H]>C(O)C>[CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]([CH3:9])[O:3]1
Reactant: [H][H]
Reactant: Cc1cc(=O)cc(C)o1
Solvent: CCO
Product: CC1CC(O)CC(C)O1
Yield: 70.8 %

Procedure:
2,6-Dimethyl-4H-pyran-4-one (5.0 g) in ethanol (40 ml) was hydrogenated under 10% Pd-C (0.5 g) at 10 bar of hydrogen for 2 days. The solution was then evaporated to an oil which was purified by silica-gel MPLC [using a 1:1 mixture of ethyl acetate and hexane as eluant] to give the title product (3.71 g, 74%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].N1C=CC=CC=1>C(OCC)C>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: O=C(Cl)Cl
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 70.1 %

Procedure:
In 150 ml of ethyl ether was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 18.2 g of pyridine in 50 ml of ethyl ether was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of pyridine hydrochloride was removed by filtration and the filtrate was distilled to recover ethyl ether, whereby 17.3 g of γ-triethoxysilylpropyl isocyanate was obtained as a fraction having a boiling point of 95° C. to 100° C. under 8 mmHg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl.[CH2:11]([O:18][C:19](=[O:23])[CH2:20][NH:21][CH3:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19](=[O:23])[CH2:20][N:21]([C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH3:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CNCC(=O)OCc1ccccc1
Agent: Cl
Product: Cc1cc(N(C)CC(=O)OCc2ccccc2)nc(Cl)n1
Yield: 62 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-6-methylpyrimidine and sarcosine-benzylester hydrochloride. The title compound was isolated as a slightly yellow oil in a yield of 62%. MS ISP (m/e): 306.1 & 308.2 (100 & 38) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.40-7.35 (m, 5H), 6.23 (s broad, 1H), 5.19 (s, 2H), 4.39 (s broad, 2H), 3.11 (s broad, 3H), 2.36 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][OH:14])[C:5]2=[N:4][C:3]=1[C:15]([O:17]CC)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:15]([C:3]2[N:4]=[C:5]3[N:11]([CH2:12][CH2:13][OH:14])[CH2:10][CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:17])=[CH:23][CH:22]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCN2CCO
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCN2CCO
Yield: 81.6 %

Procedure:
A solution of ethyl 6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.110 g, 0.408 mmol) and 4-fluorobenzylamine (0.200 g, 1.6 mmol) in anhydrous ethanol (5 ml) was heated under reflux for 6 h. The reaction mixture was then diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethanol gave 0.116 g (82% yield) of the title amide as white cubes; mp 203° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.54 (2H, t, J=5.0 Hz, CH2), 3.80 (2H, t, J=8.5 Hz, CH2), 3.89 (2H, t, J=5.0 Hz, CH2), 4.15 (2H, t, J=8.5 Hz, CH2), 4.57 (2H, d, J=6.0 Hz, NCH2), 7.07 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.92 (1H, broad t, NH), 11.68 (1H, s, OH). Anal. Calcd for C16H17FN4O4: C, 55.17; H, 4.92; N, 16.08. Found: C, 55.22; H, 5.06; N, 15.89.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:27]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K45) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (176 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=[C:3]1[C:18]([O:20]CC)=O.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[C:18]([C:3]1[C:2](=[O:1])[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=1)=[O:20]
Reactant: CNC
Reactant: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Product: CCCOc1ccccc1-c1ncc(C(=O)N(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
Ethyl 1,6-dihydro-6-oxo-2-(2-propoxyphenyl)pyrimidine-5-carboxylate (1.5 g, U.S. Pat. No. 4,031,093) was treated with dimethylamine (33% in industrial methylated spirit, 50 ml) in a pressure vessel (414 kPa) at 120° C. for 15 hours. Solvent was removed under reduced pressure affording a yellow oily residue which was washed several times with ether. The volume of the combined ethereal washings was reduced by evaporation to afford on standing overnight a white precipitate (540 mg). This was recrystallised from ether to afford the title compound, 310 mg, m.p. 104°-105° C.
Reaction SMILES: O.[OH-].[Li+].[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][F:8]>O.C1COCC1>[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][F:8]
Reactant: COC(=O)c1cnc(Oc2cc(OC(CF)CF)cc(C(=O)Nc3ccn(C)n3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)cn3)cc(OC(CF)CF)c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
Lithium hydroxide monohydrate (77 mg, 1.82 mmol) in water (2 mL) was added to methyl 5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate (325 mg, 0.73 mmol) in THF (4 mL) and the mixture stirred at RT for 20 hours. The THP was removed in vacuo and the aqueous residue washed with ethyl acetate to remove impurities then acidified with 1M citric acid. Ethyl acetate was added and a white solid removed by filtration and dried in vacuo to give the desired compound as a white solid (0.28 g). 1H NMR δ (d6-DMSO): 3.79 (s, 3H), 4.77 (m, 4H), 5.12 (t, 1H), 6.59 (s, 1H), 7.22 (s, 1H), 7.50 (s, 1H), 7.62 (s, 2H), 8.69 (s, 1H), 8.80 (s, 1H), 10.90 (s, 1H), 13.50 (s, 1H), m/z 434 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@H:14]4[CH2:16][C@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.Cl.[F:21][CH2:22][C:23]([CH3:26])([NH2:25])[CH3:24]>>[F:21][CH2:22][C:23]([NH:25][C:17]([C:10]1[C:11]2[CH2:12][C@@H:13]3[CH2:16][C@@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])([CH3:26])[CH3:24]
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Reactant: CC(C)(N)CF
Agent: Cl
Product: CC(C)(CF)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method UU using (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 1-fluoro-2-methylpropan-2-amine hydrochloride. LCMS m/z=349.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.42-0.47 (m, 1H), 1.24 (td, J=7.9, 4.8 Hz, 1H), 1.48 (s, 3H), 1.49 (s, 3H), 2.22-2.29 (m, 1H), 2.76-2.82 (m, 1H), 2.90 (d, J=16.8 Hz, 1H), 2.99 (dd, J=16.6, 6.2 Hz, 1H), 4.56 (d, J=47 Hz, 2H), 6.80 (s, 1H), 7.20 (dd, J=−5.4, 1.9 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H).