Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[OH:12][CH:13]1[CH2:16][NH:15][CH2:14]1.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:15]2[CH2:16][CH:13]([OH:12])[CH2:14]2)=[N:6][CH:7]=1
Reactant: OC1CNC1
Reactant: COc1nc(Cl)ncc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1nc(N2CC(O)C2)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3.3 g, 14.8 mmol), 3-hydroxyazetidine hydrochloride (3.2 g, 29.5 mmol), and Et3N (4.3 mL, 31.0 mmol) in THF (50 mL) was stirred for 18 h at rt. 3-Hydroxyazetidine hydrochloride (1 g) was added. The reaction mixture was stirred for 24 h at rt and concentrated. The residue was diluted in CH2Cl2/water and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography (hexane/EtOAc, 1:1) to afford 3 g of the title compound. tR: 0.73 min (LC-MS 2); ESI-MS: 260.1/262.1 [M+H]+ (LC-MS 2); Rf=0.18 (hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][C:2]12[O:11][CH:8]([CH2:9][CH2:10]1)[CH:7]1[CH:3]2[C:4](=[O:13])[CH2:5][C:6]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[Cl:15][C:6]1[CH:7]2[CH:3]([C:2]3([CH3:1])[O:11][CH:8]2[CH2:9][CH2:10]3)[C:4](=[O:13])[CH:5]=1
Reactant: CC12CCC(O1)C1C(=O)CC(=O)C12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC12CCC(O1)C1C(Cl)=CC(=O)C12

Procedure:
To a solution of 1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (3 g, 16.6 mmol) in chloroform (8 ml) is added PCl5 portionwise. The reaction mixture is stirred and heated at reflux for 5 hours. The reaction mixture is evaporated to dryness The crude product is purified by flash chromatography on silica gel to give 5-chloro-1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (1.39 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15].[OH-].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:3][CH:4]=1
Reactant: O=C(CCCCCl)N1CCOCC1
Reactant: Oc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCCCSc1ccc(O)cc1)N1CCOCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 47.9 g (0.250 mole) of p-mercaptophenol, 51.4 g (0.250 mole) of 4-(5-chlorovaleryl)morpholine, 52 ml of 5N sodium hydroxide and 600 ml of water was heated to boiling and then stirred at 50° C. for one hour; and, thereafter, stirred at room temperature for 15 hours. The white, crystalline intermediate precipitated during this period. The dried, crude intermediate was recrystallized from benzene to give the intermediate, 4-[5-(4-hydroxyphenylthio)valeryl]morpholine, as white crystals, mp 112°-113° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])([OH:3])=[O:2].[C:16](OC(=O)C)(=O)C>>[CH3:16][O:2][C:1]([CH2:4][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC(=Cc1ccccc1)C(=O)O
Product: COC(=O)CC(=Cc1ccccc1)C(=O)O

Procedure:
2-Carboxymethyl-3-phenylpropenoic acid (4.1 g.) and acetic anhydride (9 ml.) are heated in the steam bath for 70 minutes. The mixture is concentrated to dryness and the residue triturated with ether, yield 3.6 g. This anhydride is dissolved in 7 ml. of methanol and heated in the steam bath for 1 hour.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[N:23]=[C:24]([N:29]([CH3:31])[CH3:30])[S:25][C:26]=1[CH:27]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[S:25][C:24]([N:29]([CH3:31])[CH3:30])=[N:23][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN(C)c1nc(Cl)c(C=O)s1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)c1nc(Cl)c(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)s1
Yield: 24.5 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 4-Chloro-2-dimethylamino-thiazole-5-carbaldehyde (53.5 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 29.03 mg (24%) of the title compound. (300 MHz, DMSO-d6) 7.93 (s, 1H), 7.76 (s, 1H), 7.23 (m, 2H), 6.38-6.31 (m, 2H), 4.99 (t, J=17 Hz, 8.5 Hz, 1H), 3.11 (s, 6H), 2.87 (s, 4H), 2.75 (s, 1H), 2.58 (d, J=8 Hz, 1H), 2.19 (d, J=8 Hz, 1H), 1.36 (d, J=8 Hz, 1H). MS=464 (M+H), HPLC: 2.37 min. (G Method)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1>[Pd].C(O)C>[NH2:17][C:16]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CN2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CN2CCC(O)CC2)ccc1N
Reaction time: 3 h

Procedure:
Into a par bottle, 1-(3-Methoxy-4-nitro-benzyl)-piperidin-4-ol (0.74 g, 2.8 mmol), Ethanol (20 mL) and 10% Pd/C (10:90, Palladium:carbon black, 0.30 g, 0.28 mmol) were added. The reaction mixture was evacuated and charged with hydrogen at 35 psi. The mixture was shaken for 3 hours. The solid was filtered through Celite and washed with methanol. The solvent was removed under vacuum to give 1-(4-Amino-3-methoxy-benzyl)-piperidin-4-ol as a semi-solid.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[N+:8]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])([O-:10])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:12]=[C:13]([NH:14][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
36.24 g (362 mmol) Acetylacetone, 10.00 g (72 mmol) 3-nitroaniline, and 1.25 g (7.2 mmol) 4-toluenesulfonic acid are dissolved in 100 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH:12]1[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:19]([F:29])[CH:18]=3)(O)[CH2:13]1)=[O:11])[CH2:2]2.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH:5]12[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:10]([CH:12]1[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[C:19]([F:29])[CH:18]=3)=[CH:13]1)=[O:11])[CH2:4]2
Reactant: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CC2CCC(CC2)C1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1)N1CC2CCC(CC2)C1

Procedure:
A solution of example 26, 3-aza-bicyclo[3.2.2]nonan-3-yl(3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutyl)methanone (0.59 g, 1.48 mmol) in trifluoroaceticacid (2.5 mL) and 1,2-dichloroethane (16 mL) was refluxed for 20 h and concentrated to give crude 3-aza-bicyclo[3.2.2]nonan-3-yl(3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobut-2-enyl)methanone trifluoroacetate salt as a dark purplish-brown oil, with residual TFA. This material was dissolved in EtOH (40 mL) and added to a hydrogenation bottle containing 10% palladium on carbon (93 mg) slurried in EtOH (˜3 mL). The mixture was shaken at room temperature under 48 psi of hydrogen for 2 h, filtered through diatomaceous earth with an EtOH rinse and concentrated to yield an orange oil. This was dissolved in EtOAc and washed with aqueous K2CO3 and brine, dried over MgSO4 and concentrated to afford 0.38 g of light orange oil. Flash chromatography on a 2″×3.5″ silica gel column flushing with 2% MeOH/EtOAc (500 mL) and then eluting with 500 ml each 5% and 10% MeOH/EtOAc afforded 0.256 g (45%) of the title compound as a light orange oil: Rf=0.21 (20% MeOH/EtOAc).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH3:24])[C:20]=1[C:21]([NH2:23])=[O:22]>>[CH3:24][C:19]1[C:20]([C:21]([NH2:23])=[O:22])=[C:16]([NH:15][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[N:4]=[CH:3][CH:2]=[N:1]3)[S:17][CH:18]=1
Reactant: Cc1csc(N)c1C(N)=O
Reactant: O=C(O)Cc1cccc2nccnc12
Product: Cc1csc(NC(=O)Cc2cccc3nccnc23)c1C(N)=O

Procedure:
The title compound was prepared from 2-(quinoxalin-5-yl)acetic acid and 2-amino-4-methylthiophene-3-carboxamide using protocol B. Method[1], MS (ESI) 327.0 [M+H], Retention time=1.644 min.
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:57][C:58](=[O:70])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:17][S:18][CH2:19][C@H:20]([NH:39]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1>C(#N)C>[C:1]([O:14][CH2:15][C@@H:16]([O:57][C:58](=[O:70])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:17][S:18][CH2:19][C@H:20]([NH2:39])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCC(=O)OCc1ccccc1)OC(=O)CCCCCCCCCCC
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCC(=O)OCc1ccccc1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-(benzyloxy)-6-oxohexylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting mixture was stirred at 25° C. until the deprotection completed. To the mixture was concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc, then 0-10% MeOH/DCM to give the product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:12]Br.O>C(=S)=S>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][C:8]=1[Br:12]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: BrBr
Solvent: S=C=S
Solvent: O
Product: Oc1ccc(Br)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 59.2 %

Procedure:
3-Trifluoromethylphenol (compound I) (5.0 g) was dissolved in carbon disulfide (3.0 ml) and then to the solution was added a solution of bromine (5.0 g) in carbon disulfide (2.0 ml) over a period of about 15 minutes at 25° C. or less, followed by allowing the reaction to proceed for 2 hours at 25° C. The resulting reaction mixture was added to water (10 ml) and then subjected to repeated extraction with methylene chloride. The methylene chloride layer was washed with aqueous sodium hydrogen-carbonate solution and then with water and dehydration-dried by adding anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3-trifluoromethyl-4-bromophenol (compound II, 4.4 g).
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Br[C:62]1[CH:63]=[C:64]([CH2:69][CH:70]([CH:78]2[CH2:81][CH2:80][CH2:79]2)[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH:65]=[CH:66][C:67]=1[Cl:68]>C1(C)C=CC=CC=1>[CH2:53]([NH:60][C:66]1[CH:65]=[C:64]([CH2:69][CH:70]([CH:78]2[CH2:79][CH2:80][CH2:81]2)[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH:63]=[CH:62][C:67]=1[Cl:68])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(Br)c1)C1CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(NCc2ccccc2)c1)C1CCC1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
Under argon, 848.6 mg (8.83 mmol) of sodium tert-butoxide, 337 mg (0.39 mmol) of tris(dibenzylidenacetone)dipalladium and 183 mg (0.29 mmol) of rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were weighed out into a dry flask, kept under high vacuum for 10 min and then vented with argon. 5 ml of abs. toluene, 0.96 ml (8.83 mmol) of benzylamine and a solution of 2.75 g (7.36 mmol) of (+/−)-tert-butyl 3-(3-bromo-4-chlorophenyl)-2-cyclobutylpropanoate in 5 ml of abs. toluene were added in succession. Three more times, the reaction mixture was evacuated and in each case vented with argon, and the mixture was then stirred at 110° C. for 3 h. After cooling, the reaction mixture was added to saturated aqueous ammonium chloride solution. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1 to 2:1, then pure dichloromethane) This gave 1.95 g of the title compound (65.1% of theory).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH2:32]([C:34]1[S:35][C:36]([CH3:53])=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([OH:52])=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:32]([C:34]1[S:35][C:36]([CH3:53])=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([O:52][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)c(C)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(CC)sc4C)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 28.4 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.72 g), 4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (1.39 g), potassium carbonate (1.11 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, tetrahydrofuran-hexane (1:5, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.80 g, yield 28%) as crystals. Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][CH3:12])=O.[NH3:14]>>[CH2:11]([C:10]1[N:14]=[CH:1][C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=1)[CH3:12]
Reactant: CCC(=O)Nc1ccccc1C=O
Reactant: N
Product: CCc1ncc2ccccc2n1
Temperature: 100 °C
Yield: 100 %

Procedure:
N-(2-Formyl-phenyl)-propionamide (1.65 g, 9.3 mmol) was combined with ammonia (24 mL, 2M solution in methanol) in a flask fitted with a condenser and stopper with a needle to vent. The reaction was heated to 100° C. for 1 day. The reaction mixture was concentrated in vacuo to yield the crude product as an orange oil (1.47 g, 100%). This product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 7.99 (d, J=10.0 Hz, 1H), 7.89 (m, 2H), 7.60 (t, J=8.1 Hz, 1H), 3.16 (q, J=7.6 Hz, 2H), 1.47 (t, J=7.6 Hz, 3H); HPLC ret. time 0.61 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 159.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:13][C@H:10]([C:8]2[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]3[CH:21]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][CH3:12])[N:26]=[CH:25][N:24]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]propylamine (88 mg, 0.32 mmol), 4-amino-6-chloro-5-cyanopyrimidine (49 mg, 0.32 mmol) and DIPEA (0.11 mL, 0.64 mmol) in IPA (1 mL) was heated for 5.5 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in EtOAc) to afford 350 as a pale yellow solid (83 mg, 64%). LCMS (Method K): RT 3.67 min [M+H]+ 407.0. 1H NMR (CDCl3, 400 MHz): δ 8.68 (1H, d, J=2.7 Hz), 8.60 (1H, br s), 8.01 (1H, s), 7.70 (1H, dd, J=9.0, 4.9 Hz), 7.67 (1H, br s), 7.06 (1H, app. td, J=9.2, 2.4 Hz), 6.79 (1H, dd, J=8.3, 2.4 Hz), 6.00 (1H, d, J=8.0 Hz), 5.40 (2H, s), 5.31 (1H, dt, J=8.0, 7.3 Hz), 2.05 (1H, dqd, J=14.7, 7.4, 7.3 Hz), 1.97 (1H, dqd, J=14.7, 7.4, 7.3 Hz), 0.86 (3H, t, J=7.4 Hz)
Reaction SMILES: [CH2:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CCCS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCC)n1

Procedure:
A mixture of 5.25 g. 3-propylsulphonyl-1,2,4-triazole, 5.3 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to give a solid product which was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-diallylcarbamoyl-3-propylsulphonyl-1,2,4-triazole, m.p. 41° - 42° C. Elemental analysis satisfactory.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:5]2[N:6]([N:22]=[N:23][N:24]=2)[CH:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:8]=1[C:9](OCC)=[O:10].[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>CC(C)=O>[CH3:35][O:36][CH2:37][CH2:38][N:39]1[C:9](=[O:10])[C:8]2[CH:7]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)[N:6]3[N:22]=[N:23][N:24]=[C:5]3[N:4]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[C:3]=2[CH2:2]1
Reactant: COCCN
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Solvent: CC(C)=O
Product: COCCN1CC2=C(C1=O)C(c1ccc(C#N)cc1)n1nnnc1N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-(bromomethyl)-7-(4-cyanophenyl)-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo-[1,5-a]pyrimidine-6-carboxylate (35.3 mg, 66.1 μmol) was initially charged in acetone (1.0 ml). 2-Methoxyethylamine (12.4 mg, 4 μl, 165 μmol, 2.5 eq.) was added dropwise, and the mixture was then stirred at RT overnight. After addition of more 2-methoxyethylamine (9.9 mg, 132 μmol, 2 eq.), the mixture was stirred at RT for a further 5 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (13 mg, 41% of theory).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:11]([CH3:18])([CH3:17])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:16][O:15][CH2:14][CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C:11]1([CH3:18])[CH3:17]
Reactant: C1COCCN1
Reactant: COCCN1c2nc(Cl)cc(=O)n2CCC1(C)C
Product: COCCN1c2nc(N3CCOCC3)cc(=O)n2CCC1(C)C
Yield: 58 %

Procedure:
0.07 g of 2-chloro-9-(2-methoxyethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido-[1,2-a]pyrimidin-4-one in 2.5 mL of morpholine are heated with the microwave oven to 80° C. for 2 h. The crude is purified by flash chromatography on silica gel SiO2 (100% CH2Cl2 to 92/8 CH2Cl2/MeOH). 0.050 g (yield=58%) of 9-(2-methoxyethyl)-8,8-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are obtained as a white solid including the following characteristics:
Reaction SMILES: [Cl:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[CH:11][CH:10]=1>O1CCCC1>[Cl:1][C:2]1([C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[CH:20][CH:21]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: O=C(Cl)C1(Cl)CC1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)C2(Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.3 %

Procedure:
3.9 g (28.1 millimoles) of 1-chlorocyclopropanecarboxylic acid chloride are added, with stirring, to 4.5 g (23.3 millimoles) of 3-(p-aminobenzoyl)-propionic acid in 100 ml of absolute tetrahydrofuran. The reaction mixture is then stirred for 20 hours at room temperature, followed by 7 hours under reflux. A small amount of solid is filtered off and discarded, and the filtrate is concentrated. The residue obtained is recrystallized from ethyl acetate, giving 3.4 g (49% of theory) of 3-[p-(1-chlorocyclopropylcarbonylamino)-benzoyl]-propionic acid as colorless crystals, of melting point 178°-179° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[CH:17]=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.[C:41](O)([C:43]([F:46])(F)F)=O>C(Cl)Cl>[F:46][C:43]1[CH:41]=[CH:17][CH:16]=[CH:15][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]([C:32]4[N:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)[CH2:23][C:22](=[O:39])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)nn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (2′-fluoro-3-{3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example M13) (292 mg, 0.541 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (181 mg).