Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]1[NH:28][C:29](=[O:37])[C:30]2[CH2:36][O:35][CH2:34][CH2:33][C:31]=2[N:32]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([N:25]([CH2:24][CH2:23][O:22][CH3:21])[CH2:26][C:27]3[NH:28][C:29](=[O:37])[C:30]4[CH2:36][O:35][CH2:34][CH2:33][C:31]=4[N:32]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:19][CH:20]=1
Reactant: COCCNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Solvent: CC#N
Product: COCCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(OC)cc2)CC1
Yield: 23.4 %

Procedure:
The title compound (22 mg, 0.044 mmol) was prepared following the general procedure of Example 1 from [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (65 mg, 0.188 mmol, 1.0 eq) and 2-[(2-methoxy-ethylamino)-methyl]-3,5,7,8tetrahydro-pyrano[4,3-d]pyrimidin-4-one (51.7 mg, 0.188 mmol, 1.0 eq). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88-8.02 (m, 2H) 6.98-7.10 (m, 2H) 4.52 (br s, 1H) 4.36 (d, J=16.67 Hz, 3H) 3.75-3.92 (m, 5H) 3.52-3.58 (m, 3H) 3.42-3.45 (m, 3H) 3.27 (d, J=5.05 Hz, 15H) 3.17 (br s, 2H). HR-MS (m/z, MH+): 499.2580, 500.2607, 501.2628. HPLC retention time: 2.62 min (Ascentis column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23]C)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2CCCCC=2C=1C(OC)=O.[Cl:39]C1C=CC(S(Cl)(=O)=O)=CC=1>>[Cl:39][C:4]1[CH:5]=[CH:6][C:1]([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:9])=[O:8])=[CH:2][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: COC(=O)c1c(N)sc2c1CCCC2
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(Cl)cc2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 4-chlorobenzene-sulphonyl chloride
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C@H:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.C(#N)C>[OH:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C@H:14]([OH:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@@H](O)c1cccc(-c2ccc(O)cc2)n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](O)c1cccc(-c2ccc(OCCO)cc2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
A dry 250 mL three-necked flask was charged with (R)-1-[6-(4-hydroxyphenyl)pyridin-2-yl]-2,2-dimethylpropanol (4b) (2.54 g, 9.9 mmol), cesium carbonate (6.43 g, 19.8 mmol) and 100 mL of acetonitrile. Next, 2-bromoethyl-tert-butyldimethylsilyl ether was added through a dropping funnel. The mixture was heated under reflux for 2 hours and stirred for additional 14 hours at room temperature. After standard work-up with ethyl acetate the crude product was dissolved in 25 mL of THF and 11 mL of TBAF (1 M in THF) were added. After stirring for 1 hour at room temperature, the solution was quenched with 50 mL of water and standard work-up with dichloromethane followed by column chromatography (SiO2, eluent: ethyl acetate/hexanes=1:1) yielded 2.46 g (83%) of (5) as a white powder. Mp: 104° C. [a]D,=−14.4 ©=2.28, acetone). 1H NMR (300 MHZ, CDCl3): δ0.96 (s, 9H); 2.36-2.40 (m, 1H); 3.95-4.01 (m, 2H); 4.11-4.15 (m, 2H); 4.39 (d, J=7.4 Hz, 1H); 4.66 (d, J=7.4 Hz, 1H); 7.01 (d, J=8.8 Hz, 2H); 7.06 (dd, J=7.97 Hz, 0.8 Hz, 1H); 7.57 (dd, J=7.97 Hz, 0.8 Hz, 1H); 7.66 (m, 1H); 7.95 (d, J=8.8 Hz, 2H). 13C NMR (75 MHZ, CDCl3): δ26.0; 36.3; 61.4; 69.4; 80.2; 114.7; 118.2; 120.7; 128.2; 131.9; 136.4; 155.0; 159.3; 159.7. M S 70 eV):m/z(%)301(M, 7),244 (100).IR(KBr): 1608, 1576, 1516, 1453, 1255, 1174, 1046, 812 cm−1. Anal. Calcd. for C18H23NO3: C, 71.73; H, 7.69; N, 4.65. Found: C, 71.59; H, 7.68; N, 4.56.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1)([CH3:3])[CH3:2].[F:12][CH2:13][N:14]([CH2:18][F:19])[C:15](F)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[F:12][CH2:13][N:14]([CH2:18][F:19])[C:15](=[O:16])[O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: Cc1cc(O)cc(C(C)C)c1
Reactant: O=C(F)N(CF)CF
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OC(=O)N(CF)CF)cc(C(C)C)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
16 parts of 80 percent strength by weight 3-isopropyl-5-methyl-phenol in 30 parts of methylene chloride are added to 12.7 parts of N,N-bis-fluoromethyl-carbamic acid fluoride (from Example 2) in 50 parts of methylene chloride. 10.1 parts of triethylamine in 20 parts of methylene chloride are then added. The reaction mixture is stirred for one hour at 40° C. and when it has cooled it is extracted by shaking with 10 percent strength by weight sodium hydroxide solution and water, dried and distilled to dryness under reduced pressure. 24.1 parts (95% of theory) of O-3-isopropyl-5-methyl-phenyl N,N-bis-fluoromethyl-carbamate of boiling point 120° C./0.05 mm Hg are obtained.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>ClCCl.CO>[NH2:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]2=[O:26])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: NCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 33 %

Procedure:
A solution of 370 mg (0.6 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.3 ml (6 mmol) of hydrazine hydrate in 5 ml of dichloromethane/methanol was stirred at room temperature under an atmosphere of nitrogen overnight. The reaction mixture was evaporated and the residue purified by flash chromatography on silica gel, eluting with dichloromethane/methanol/acetic acid/water (120:14:3:2). Product containing fractions were combined and evaporated and the residue re-evaporated with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated to give 100 mg (33%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 131-135° C. [Mass spectrum (ESI) MH+ =505].
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH2:6].P(=O)(O)(O)O.[C:15](O)(=[O:18])[CH:16]=[CH2:17]>C1(NC2C=CC3C(=CC=CC=3)C=2)C=CC=CC=1>[CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH:6][C:15](=[O:18])[CH:16]=[CH2:17]
Reactant: C=CC(=O)O
Reactant: CN(C)CC(C)(C)CN
Agent: O=P(O)(O)O
Agent: c1ccc(Nc2ccc3ccccc3c2)cc1
Product: C=CC(=O)NCC(C)(C)CN(C)C
Temperature: 200 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A 500-ml three-neck flask fitted with a magnetic agitator, a thermometer, and a short column with a distillation set was charged with 260 g (2 mol) 3-dimethylamino-2,2-dimethylpropylamine; 4 g N-phenyl-β-naphthylamine; and 4 ml 85% phosphoric acid. 144 g (2 mol) acrylic acid was added drop by drop for 0.5 hours, whereupon the temperature of the mixture rose to 150° C. Finally, the mixture was heated to 200° C. in a nitrogen atmosphere for 2 hours, and then stirred at this temperature for 1 hour. During this time, 35.5 g of the distillate was obtained. Distillation was carried out in a vacuum after cooling and 247 g (67%) N-(3-dimethylamino-2,2-dimethylpropyl)acrylamide, boiling point 110°-115° C. at 66.5 Pa, was obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.BrC1C=C(C#N)[CH:31]=[N:32]C=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:31]#[N:32])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Product: Cc1ccc(Nc2cncc(C#N)c2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) in accordance with the general method of example 20 using 5-Bromo-3-cyanopyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=405.4 (M+H+).
Reaction SMILES: [Cl-].[C:2]1(C)[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=O)=[CH:4][CH:3]=1.[NH+:13]1C=CC=C[CH:14]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[S:8]1(=[O:10])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[CH:14]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: c1cc[nH+]cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=S1(=O)N=Cc2ccccc21

Procedure:
For longer side chains, the rearrangement is performed with n-BuLi (ca 1.6 M in hexane) in THF at −78° C. as above, followed by addition of a cosolvens such as DMPU and reaction with O-protected 1-bromo-alcohols or α-chloro-ω-iodoalkane (e.g. 1-bromo-n-tetrahydro-pyaranyloxyalkane) to yield the O-protected compounds 9b or the chloro compound 9c (step i). O-protected compounds 9b can be deprotected to the corresponding alkynol 9a (in MeOH at 50-60° C., in the presence of catalytic amount of pyridinium toluene-4-sulfonate). Alcohol 9a can be reacted with Huenig's base/trifluoromethane sulfonic acid anhydride at −15° C. in CH2Cl2 (in situ generation of the corresponding triflate) followed by treatment with Huenig's base and the corresponding amine NHA1A2at −15° C. to RT to give amine 5. Alternatively, mesylation of alcohol 9a with methanesulfonylchloride, pyridine and DMAP in CH2Cl2 at 0° C. to RT gives mesylate 10. Conversion of the mesylate 10 or the chloride 9c (or the in situ generated iodide) to the amine 5 can be accomplished with an excess of the corresponding amine NHA1A2 in DMA at RT or as described above (step 1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22][CH2:21][CH2:20][C:19]([C:23](O)=[O:24])=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:49][N:50]([CH2:57][C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1)[CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>CN(C=O)C.C(N(CC)CC)C>[CH3:49][N:50]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([NH:62][C:23]([C:19]2[CH2:20][CH2:21][S:22][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[CH:26][C:17]=3[CH:18]=2)=[O:24])=[CH:63][CH:64]=1)[CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3SCC2)cc1)C1CCOCC1
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 7- (4-morpholinophenyl) -2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (0.11 g) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g), and the mixture was stirred for 1 hour. To the mixture was added a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (135 mg) and triethylamine (0.11 ml) in DMF (5 ml), and the mixture was stirred for 18 hours. Under reduced pressure, the mixture was concentrated, and to the mixture was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:2) to give yellow crystals of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 285) (113.9 mg).
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:19])[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([I:18])[CH:9]=1)([CH3:5])[CH3:4].S(Cl)(Cl)=O>>[I:18][C:10]1[CH:9]=[C:8]([C:7]2[O:19][CH2:2][C:3]([CH3:4])([CH3:5])[N:6]=2)[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=1
Reactant: CC(C)(CO)NC(=O)c1cc(I)cc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2cc(I)cc(C(F)(F)F)c2)=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To N-(2-hydroxy-1,1-dimethylethyl)-3-iodo-5-(trifluromethyl)benzamide (2.11 g) was added thionyl chloride (1.29 ml), and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, quenched with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (X2). The combined extracts were dried over magnesium sulfate, evaporated, and purified with column chromatography (silica gel, ethyl acetate:hexane=2.5:97.5) to give 2-[3-iodo-5-(trifluoromethyl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1.66 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14](/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1.C(N(CC)CC)C>O1CCCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][N:15]([CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[C@H:14](/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Yield: 56.7 %

Procedure:
A mixture of (2S, 4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (1.00 g), 3-picolylchloride hydrochloride (509 mg) and triethylamine (0.43 ml) in tetrahydrofuran (25 ml) was refluxed for 48 hours and the solution was diluted with chloroform (40 ml). The solution was washed successively with saturated aqueous sodium bicarbonate and brine, and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel (50 g) column with a mixture of chloroform and methanol (100:1) as an eluent to give (2S, 4R)-4-(4-chlorophenylsulfonylamino)-2[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(3-pyridylmethyl)pyrrolidine (700 mg) as a pale brown oil.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH:38]2[CH2:40][CH2:39]2)[C:6]2[CH:41]=[CH:42][CH:43]=[CH:44][C:5]1=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH:38]2[CH2:39][CH2:40]2)[C:6]2[CH:41]=[CH:42][CH:43]=[CH:44][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccccc2N(C(C)=O)[C@H]1C
Reaction time: 2.5 h

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-5-((3-cyclopropylquinolin-4-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (65 mg, 108 μmol) in CH2Cl2 (434 μl) was added TFA (108 μl). The reaction was stirred for 2.5 h, then concentrated and purified by reverse phase preparative HPLC to provide, after extraction from sat. aq. NaHCO3 and lyophilzation, (S)-N-((2S,3S)-1-acetyl-5-((3-cyclopropylquinolin-4-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide (27.2 mg, 50%) as a white solid. MS m/z 500 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=3)[C:20]([OH:22])=[O:21])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:34][CH2:35]O>O1CCOCC1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=3)[C:20]([O:22][CH2:34][CH3:35])=[O:21])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:11]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(F)C(c1cc(F)cc(C(=O)O)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C)(C)F)c1
Reaction time: 10 h

Procedure:
A mixture of 7.5 g (17.15 mmol) of 3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorobenzoic acid, 25 mL of 4N HCl in dioxane, and 200 mL of EtOH was refluxed. After 10 h, it was concentrated to remove solvents. To the residue was added 150 mL of CH2Cl2 and 30 mL of H2O and pH was adjusted to 7-8 with aq NaHCO3, then extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as an white solid; 1H-NMR(CDCl3) δ 1.25(d, 3H, J=22 Hz), 1.30(d, 3H, J=22 Hz), 1.42 (t, 3H, J=7.1 Hz), 2.35 (t, 1H, J=8 Hz), 2.89 (t, 1H, J=8 Hz), 2.97 (m, 1H), 3.12 (m, 1H), 3.24 (m, 1H), 3.68 (t, 1H, J=6 Hz), 4.27 (s, 1H), 4.38 (q, 2H, J1=14, J2=7 Hz), 7.103-7.66 (m, 13H); Mass Spectrum: m/e=464 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH2:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH:24][C:14]([C:3]1[N:4]=[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]2[C:7](=[O:8])[C:2]=1[OH:1])=[O:16]
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Product: CN1C(=O)Cn2c1nc(C(=O)NCc1ccc(F)c(Cl)c1)c(O)c2=O
Yield: 52.6 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.050 g, 0.197 mmol) with 3-chloro-4-fluorobenzylamine (0.10 g, 0.63 mmol) as described in the preparation of example 1 gave 0.038 g (52% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.15 (3H, s, NCH3), 4.48 (2H, s, CH2), 4.49 (2H, d, J=6.4 Hz, NCH2), 7.3–7.55 (3H, m, aromatics), 9.50 (1H, broad t, NH), 12.16 (1H, s, OH). MS (ESI+) m/z 367 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:17]2[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([Cl:12])[N:18]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Product: Cc1cc(Oc2ccc(C(C)(C)C)cc2)nc(Cl)n1
Yield: 51 %

Procedure:
Prepared in analogy to example 81a) from 4-t-butylphenol and 2,4-dichloro-6-methylpyrimidine in a yield of 51%. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.44 (d, 2H), 7.07 (d, 2H), 6.54 (s, 1H), 2.45 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12]C(C#N)=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>>[N:1]1([C:6]2[CH:13]=[CH:12][C:20]([C:19]([OH:22])=[O:21])=[CH:8][C:7]=2[C:14]([F:15])([F:16])[F:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(-n2ccnc2)c(C(F)(F)F)c1
Agent: Cl
Product: O=C(O)c1ccc(-n2ccnc2)c(C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(1H-imidazol-1-yl)-3-(trifluoromethyl)-benzonitrile (1.99 g, 8.4 mmol), 12 mL of acetic acid and 6 mL of 12M hydrochloric acid (37%) is shaken for 16 hours at 95° C. After cooling down the reaction mixture is evaporated under reduced pressure. The resulting residue is dissolved in water and the pH is adjusted to ˜5-6 by dropwise addition of 1M sodium hydroxide solution. The precipitate is filtered off, washed with water and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][OH:22])[CH3:17])=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:24]1[CH:56]=[CH:55][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]2=[O:54])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][O:22][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][CH:29]4[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]4=[O:54])=[CH:26][CH:25]=3)[CH3:17])=[CH:12][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(S(=O)(=O)c2ccccc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(S(=O)(=O)c2ccccc2)nc1
Yield: 33.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 640 mg of 2-[1-(2-phenylsulfonyl-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 33), 907 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 550 mg of triphenylphosphine and 365 mg of diethyl azodicarboxylate, 500 mg of the title compound were obtained as a foam-like solid.