Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:16][C:15]=4[CH3:30])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:34][O-:35].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[N:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][C:11]3[C:12]([O:35][CH3:34])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:16][C:15]=4[CH3:30])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3-(4-(1H-pyrazol-1-yl)benzyl)-2,4-dichloro-8-methylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1.05 g, 2.20 mmol, Intermediate 14: step a) and dry sodium methoxide (0.59 g, 11.02 mmol) in toluene (10 mL) was heated in a sealed tube at 110° C. for 12 hours. The mixture was cooled to room temperature, diluted with DCM, stirred for 30 minutes at room temperature and the resulting suspension filtered through Celite®, rinsing several times with DCM. The solvents were removed under reduced pressure and the residue chromatographed (DCM/10% MeOH in DCM, gradient) to provide the crude product. Recrystallization from MeOH, filtering and drying under reduced pressure overnight provided the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:49])[O:13][C:12]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[N:25]=[C:26]([C:34]5[CH:35]=[C:36]([CH:46]=[CH:47][CH:48]=5)[CH2:37][NH:38]C(=O)OC(C)(C)C)[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:11]=2[O:10]1>C(Cl)Cl.[OH-].[Na+]>[NH2:38][CH2:37][C:36]1[CH:35]=[C:34]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:33]=[C:24]([NH:23][C:21]([C:18]3([C:16]4[CH:15]=[CH:14][C:12]5[O:13][C:9]([F:49])([F:8])[O:10][C:11]=5[CH:17]=4)[CH2:19][CH2:20]3)=[O:22])[N:25]=2)[CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
TFA (500 μL) was added to a solution of tert-butyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzylcarbamate (115 mg, 0.200 mmol) in CH2Cl2 (1.5 mL). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with CH2Cl2 and 1N NaOH was added until the mixture become basic. The organic layer was dried over MgSO4, filtered and concentrated to yield N-(1-(3-(Aminomethyl)phenyl)isoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a white solid (95 mg, 99%). ESI-MS m/z calc. 473.2. found 474.2 (M+1)+. Retention time 1.62 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH2:20])[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:20][O:30]1)=[O:21])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCC1CCCCCCCCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCC2CCCCCCCCCC2)CO1

Procedure:
2.2 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate; thin layer chromatography on silica gel with petroleum ether/ethyl acetate 9:1:Rf =0.5), are obtained by the procedure described in Example (1a) from 4.4 g of 5-cycloundecyl-2-methylenevaleric acid ethyl ester and 5.15 g of m-chloroperbenzoic acid in 40 ml of methylene chloride.
Reaction SMILES: C1(C[N:8]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[NH:11][C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)C=CC=CC=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[H-].[Na+].C1(O)C=CC=CC=1>CN(C)C=O>[N:32]1([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:11]2[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[NH:8][C:9]3[CH:23]=[CH:22][CH:21]=[N:20][C:10]2=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C1c2ccccc2Nc2ncccc2N1Cc1ccccc1
Reactant: BrCCCCCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: O=C1Nc2cccnc2N(CCCCCCCN2CCCCC2)c2ccccc21
Yield: 17 %

Procedure:
Prepared analogously to Example 18 by reacting 5,11-dihydro-5-(phenylmethyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one with 1-bromo-7-(1-piperidinyl)-heptane in the presence of sodium hydride and dimethylformamide and subsequent acidolytic cleaving of the phenylmethyl group by heating with 80% polyphosphoric acid in the presence of phenol. Yield: 17% of theory. Colourless crystals m.p. 118°-120° C. (after recrystallisation from diisopropyl ether and cyclohexane).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:8]([NH2:10])[CH3:9])=[CH:3][CH:2]=1.[CH3:28][CH:29]1[CH2:35][C:34](=[O:36])[O:33][C:31](=[O:32])[CH2:30]1>>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:8]([NH:10][C:34]([CH2:35][CH:29]([CH3:28])[CH2:30][C:31]([OH:33])=[O:32])=[O:36])[CH3:9])=[CH:3][CH:2]=1
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CC(N)C(Cc1ccc2ccccc2c1)c1ccc(-c2ccccc2)cc1
Product: CC(CC(=O)O)CC(=O)NC(C)C(Cc1ccc2ccccc2c1)c1ccc(-c2ccccc2)cc1

Procedure:
Compounds of Examples 57 to 65 were prepared in the same manner as in Example 56 except that (1RS, 2RS)-2-(4-biphenylyl)-1-methyl-3-(2-naphthyl)propylamine and/or 3-methylglutaric anhydride used as the starting materials in the above reaction were changed to the corresponding amine compounds and/or acid anhydrides.
Reaction SMILES: [C:1]([O:7]C(=O)C(C)(C)C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C-]#N.[Na+].[CH3:17][Si:18](C#N)([CH3:20])[CH3:19]>>[CH3:17][Si:18]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: [C-]#N
Agent: [Na+]
Product: CC(C)(C)C(=O)O[Si](C)(C)C

Procedure:
93 g (0.5 mol) of pivalic acid anhydride and 1 g of sodium cyanide are initially introduced and 49.5 g (0.5 mol) of trimethylsilyl cyanide are added dropwise. The reaction mixture is worked up by distillation. Yield: 56 g of pivaloyl cyanide (=98.9% of theory). Boiling point: 121°-125° C. In addition, pivalic acid-trimethylsilyl ester is obtained in a corresponding amount (98% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=2[O:25]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:29]4[CH:28]=[CH:27][C:26]5[O:25][CH2:24][O:32][C:31]=5[CH:30]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol) and 3,4-methylenedioxyphenylboronic acid (264 mg, 1.59 mmol) the subtitle compound was obtained (337 mg, 51%). The product was used directly in the next step without purification.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][NH2:13]>O1CCOCC1>[F:11][C:8]1[C:9]([F:10])=[C:2]2[C:3]([CH:4]=[N:12][NH:13]2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=Cc1ccc(F)c(F)c1F
Solvent: C1COCCO1
Product: Fc1ccc2cn[nH]c2c1F
Temperature: 150 °C
Yield: 45.8 %

Procedure:
In a microwave vial 2,3,4-trifluorobenzaldehyde (1.5 g, 9.4 mmol) was dissolved in 1,4-dioxane (6 mL) and hydrazine (6 mL, 191 mmol) was added. The vial was sealed and heated under microwave irradiation at 150° C. for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 664 mg (46%) of 6,7-difluoro-1H-indazole as a light brown powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.10 (d, J=3.4 Hz, 1H), 7.47 (dd, J=8.9, 4.0 Hz, 1H), 7.05 (ddd, J=10.6, 8.9, 6.6 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25]1.CO>CCO>[CH:24]1([CH2:28][NH:29][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:14][C:15]([F:16])([F:18])[F:17])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCC1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CO
Solvent: CCO
Product: O=C(c1ccc(NCC2CCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (237 mg, 0.680 mmol) and cyclobutylmethyl amine (0.205 mL of a 4M/MeOH solution, 0.816 mmol) in 3 mL of EtOH containing TEA (0.140 mL, 1.02 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 262 mg (93%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.83 (m, 2H), 1.97 (m, 1H), 2.02 (m, 1H), 2.20 (m, 2H), 2.73 (m, 1H), 3.37 (m, 2H), 4.27 (m, 4H), 6.93 (d, J=8.98 Hz, 1H), 7.53 (d, J=8.79 Hz, 1H), 8.24 (m, 1H), 8.30 (m, 1H); MS (ESI) 413.95 (MH+).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])[CH2:9][CH2:8]1
Reactant: COCCN1CCNCC1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN1CCN(S(=O)(=O)c2cccs2)CC1
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
To a suspension of 1-(2-methoxyethyl)piperazine dihydrochloride (2.61 g, 12.0 mmol) in THF (100 mL) was added triethylamine (10 mL) and the resulting mixture was stirred for 10 min. Then a solution of 2-thiophenesulfonyl chloride (1.98 g, 10.84 mmol) was added in THF (3 mL) over 5 min. The reaction mixture was allowed to stir at room temperature for 1 h, the volatiles were evaporated and the residue was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with a saturated sodium bicarbonate solution (50 mL), brine and dried over molecular sieves. Evaporation to dryness gave a viscous oil (2.09 g, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[CH:2].[CH3:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1)=[O:31].C(N(CC)CC)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([C:13]3[N:14]=[C:15]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]4)[S:16][CH:17]=3)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=2)=[CH:34][CH:33]=1)(=[O:31])[CH3:29]
Reactant: C#Cc1cc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(C#Cc4ccc(C(C)=O)cc4)cc(C(F)(F)F)c3)cs2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
In the same manner as in Example 98c, to a solution (3 mL) of the compound (200 mg, 0.49 mmol) obtained in Example 98b, 4-bromoacetophenone (150 mg, 0.74 mmol), triethylamine (0.14 mL, 0.98 mmol) and copper iodide(I) (19 mg, 0.10 mmol) in N,N-dimethylformamide was added tetrakistriphenylphosphinepalladium (58 mg, 0.050 mmol), and the mixture was stirred at 90° C. overnight. The palladium catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (97 mg, 38%) as a pale-yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.CS(O)(=O)=O.[CH2:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[OH:1][C:2]1[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: C=CCCCCCCCCCC
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCCCCc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 160 °C
Reaction time: 96 h

Procedure:
Using the general procedure of Example 1, 112 grams of 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole, 33 ml of methanesulfonic acid and 444 ml (2 moles) of a mixture of tetracosenes (prepared by the dimerization of n-dodecene) are heated at 160° C.; for 96 hours. The reaction mixture is cooled and the product isolated by the general procedure described in Example 1. The excess hydrocarbons are removed by distillation at 190° C./0.04 mm. The above-named product is obtained in a yield of 103.6 grams as a yellow liquid. The liquid still contained inert hydrocarbon diluents which are removed by flash chromatography using silica gel and heptane/toluene 75/25 to give a pure product in a yield of 15 grams as a yellow liquid.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([CH:16]([C:33]([CH3:35])=[CH2:34])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=[O:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C(N(CC)CC)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:34])[CH3:35])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C:13]1=[O:36])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Yield: 100 %

Procedure:
To a solution of 50 mg of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-3-butenoate in 10 ml of methylene chloride was added 3 drops of triethylamine. After 2 hours at room temperature the reaction mixture was washed thoroughly with brine and dilute acid. After drying, the solution was evaporated in vacuo to dryness to provide 50 mg of the title product: nmr (CDCl3) δ 2.05 (s, 3, CH3), 2.25 (s, 3, CH3), 3.60 (2, m, azetidinone C4 --H), 5.02 (m, 1, C3 --H), 4.55 (s, 2, --OCH2CO--), and 7.2 (b, 15, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: Brc1ccc(N2CCOCC2)nc1
Temperature: 130 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-chloropyridine (5.0 g) was mixed with N,N-dimethylacetamide (25 ml), and morpholine (23 ml) was added thereto, followed by stirring at 130° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with EtOAc, and the organic layer was washed with saturated brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 4-(5-bromopyridin-2-yl)morpholine (6.07 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[N:4][O:5][C:6]=1[C:7]1([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8]1.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:15])=[N:4][O:5][C:6]=1[C:7]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: CCOC(=O)C1(c2onc(C)c2Br)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1noc(C2(C(=O)O)CC2)c1Br
Temperature: 45 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of ethyl 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylate (11.8 g, 43.0 mmol) in THF (60 mL) was added aqueous NaOH (86 mL, 86 mmol, 1 M). The dark brown bi-phasic reaction mixture was vigorously stirred and heated to 45° C. until consumption of SM (3-4 h) was detected by LC-MS and TLC analysis. After 4 h, the homogeneous mixture was cooled to room temperature and diluted with hexanes. The organic phase was separated and the aqueous phase (pH ˜14) was acidified with aqueous 1 N HCl (pH 1) (˜100 mL). The product crystallizes upon acidification of the aqueous layer. After vigorously stirring for 30 min, the solids were filtered, washed with cold (0° C.) water (3×50 mL), and dried to give white crystals. The product 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylic acid (10.0 g, 40.6 mmol, 94% yield) was isolated as white crystals. LC/MS m/z 246 [M+H]+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([CH:13]([NH:30][C:31]([CH:33]2[CH2:36][CH2:35][CH2:34]2)=O)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][N:12]=1.N.CC(O)C>>[Cl:6][C:7]1[C:8]2[N:9]([CH:31]([CH:33]3[CH2:36][CH2:35][CH2:34]3)[NH:30][C:13]=2[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCC1
Agent: N
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1=NC=CN2C1=C(c1ccc3ccc(-c4ccccc4)nc3c1)NC2C1CCC1
Temperature: 70 °C

Procedure:
A mixture of POCl3 (5 mL, 8 g, 55 mmol) and cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)methyl]-amide [275 mg, 0.583 mmol] is heated to 70° C. for 21.5 h. POCl3 is evaporated, a cold solution of NH3 in iPrOH (2M, 11 mL, 22 mmol) is added, the suspension is sonicated, the solid is filtered off and washed with iPrOH. The solid is suspended in CHCl3 and filtered, and the filtrate is concentrated to obtain the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz) δ 2.04-2.15 (m, 1H), 2.15-2.28 (m, 1H), 2.50-2.60 (m, 2H), 2.64-2.76 (m, 2H), 3.89 (quint, J=8.4 Hz, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.44-7.50 (m, 1H), 7.51-7.57 (m, 3H), 7.89-7.93 (m, 3H), 8.17-8.22 (m, 2H), 8.27 (dd, J=0.8, 8.8 Hz, 1H), 8.53 (d, J=0.8 Hz, 1H). MS (ES+): m/z 410.9/412.9 (100/39) [MH+]. HPLC: tR=3.7 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [F:1][C:2]1[C:26]([F:27])=[C:25]([F:28])[C:24](F)=[C:23](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][C@@H:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15]O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+].[OH2:33]>C1COCC1>[F:1][C:2]1[C:3]2[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]3[C@@H:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:15][O:33][C:24]([C:23]=23)=[C:25]([F:28])[C:26]=1[F:27]
Reactant: CCOC(=O)C(=CN[C@H](CO)c1ccccc1)C(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)OC[C@@H]2c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of ethyl (S)-2-(2,3,4,5,6-pentafluorobenzoyl)-3-[(2-hydroxy-1-phenylethyl)amino]acrylate (2.15 g, 5.00 mmol) in THF (20 mL) was added NaH (440 mg, 11.0 mmol, 60% in oil) at 0° C. and the mixture was stirred at 0° C. for 0.5 h, at room temperature for 1 h, and then refluxed for 2 h. The mixture was treated portionwise at 0° C. with water. A precipitate formed and was collected by filtration, washed successively with EtOAc and then dried to give ethyl (S)-8,9,10-trifluoro-2,3-dihydro-7-oxo-3-phenyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (465 mg, 24%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:31]([CH3:30])[CH2:32][CH2:33][OH:34])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: CNCCO
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN(C)CCO)c34)cc2Cl)cn1
Yield: 34 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and N-methylethanolamine to give the title compound in 34% yield; NMR Spectrum: 2.31 (s, 3H), 2.45 (s, 3H), 2.54 (t, 2H), 2.88 (t, 2H), 3.49 (t, 2H), 4.41 (t, 2H), 7.19 (d, 1H), 7.26 (br s, 2H), 7.72 (d, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 470 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2=NCCO2)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: BrCCCCCCOc1ccc(C2=NCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 114 %

Procedure:
A stirring suspension of 163 g (1.0 mole) of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole and 276 g (2.0 mole) milled potassium carbonate in 750 ml acetonitrile was heated to reflux in a 5 liter round-bottomed flask. A total of 457.5 ml (3.0 mole) of 1,6-dibromohexane was added all at once and reflux continued for 1 hour. The reaction mixture was filtered and the cake of inorganic salts washed with 100 ml of acetonitrile. The filtrate was evaporated on a rotary evaporator (bath temperature <40° C.) and the resulting residue slurried in 1.6 liters of hexane and chilled to 0° C. The resulting white solid was filtered and washed with 500 ml cold hexane. The recovery was 263 g (80%) of white solid. A total of 535 g of crude product was slurried in 1.1 liter of refluxing tert-butyl methyl ether. The mixture was allowed to cool to 30° C. and filtered with suction. The filtrate was cooled to 0° C. and the product crystallized. The solid was filtered off and dried to yield 372 g (70% recovery) of 2-[4-(6-bromohexyloxy)phenyl]-4,5-dihydro-oxazole, m.p. 79°-81° C. The crude product can also be recrystallized from acetonitrile. This removes excess dibromohexane and most of an undesired byproduct formed by reaction of 1 mole of dibromohexane with 2 moles of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole, namely 1,6-bis[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexane, m.p. 174°-175° C. when isolated and purified.