Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][CH:8]([CH:17]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][NH:19][CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(O[N:49]1N=N[C:51]2[CH:52]=[CH:53][CH:54]=[N:55][C:50]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN([CH:68]=[O:69])C>C(OCC)(=O)C>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][CH:8]([CH:17]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][N:19]([C:68]([C:53]2[CH:54]=[N:55][C:50]([CH3:51])=[N:49][CH:52]=2)=[O:69])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)C2)cn1
Yield: 40 %

Procedure:
To a solution of 2-{(RS)-2-(tert-Butyl-dimethyl-silanyloxy)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine (8A-1) (220 mg) in DMF (12 mL) at −20° C. were added Hunig base (0.132 mL, 0.78 mmol) and then HATU (202 mg). The mixture was diluted with ethyl acetate and washed with aq.ammonium chloride solution three times and aq. sodium bicarbonate solution. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:20) yielded 24 mg (40%) of the title compound as a light yellow oil. ES-MS m/e: 623.1 M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O>C1(C)C=CC=CC=1.CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])=[O:21])[C:15]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a solution of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.537 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (1.9 g) in toluene (4 mL) and dimethyl sulfoxide (4 mL) was added dichloroacetic acid (0.33 mL) and the resulting solution was allowed to stir for 0.5 h. The reaction mixture was diluted with ethyl acetate, washed (saturated ammonium chloride, water), dried and evaporated to provide a white solid which was collected and washed with ether:hexane (1:1) to give 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.330 g). Chromatography of the mother liquor with ethyl acetate:dichloromethane (5:95, 10:90) as the eluent gave additional 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid (0.190 g); NMR (DMSO/D2O): 8.46 (s,1), 7.44 (m,10), 5.20 (s,2), 4.54 (m,2 ), 4.05 (d,1), 2.23 (m,1), 0.85 (d,3), 0.75 (d,3); MS: m/z=531(M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(OC([N:33]1[CH2:37][CH2:36][C@H:35]([C:38](O)=[O:39])[CH2:34]1)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:52].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:52].[ClH:52].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:38]([C@H:35]4[CH2:36][CH2:37][NH:33][CH2:34]4)=[O:39])[CH2:20][CH2:19]3)=[O:17])=[CH:24][CH:25]=2)=[N:2]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(C(=O)[C@H]2CCNC2)CC1
Temperature: 60 °C
Yield: 104.4 %

Procedure:
The product obtained using Compound 18 (300 mg, 0.90 mmol), (S)-pyrrolidin-1,3-dicarboxylic acid 1-tert-butyl ester (162 mg, 0.76 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg, 1.06 mmol) and N-methylmorpholine (0.17 mL, 1.52 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 124 (278 mg, 61%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][N:3]1[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][N:3]1[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:17][CH:16]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCCN2COc3ccccc3C2=O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(OCCN3COc4ccccc4C3=O)cc2)S1
Yield: 87 %

Procedure:
5.0 g (17 mM) of 4-[2-(4-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)ethoxy]benzaldehyde (Compound 4A) and 2.1 (18 mM) of 2,4-thiazolidinedione were dissolved in 150 ml of toluene. After the addition of a catalytic amount of acetic acid and piperidine, the mixture was reacted for two hours with heating while refluxing in a Dean Stark apparatus. After confirming completion of the reaction by TLC, the reaction mixture was gradually returned to room temperature. The resulting crystals were collected by filtration and washed with a small amount of toluene and then with hexane, and dried under vacuum at 50° C, to obtain 5.8 g (yield 87%) of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](N(OC)C)=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[C:3]([C:9]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1nc(Cl)ccc1Br
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1nc(Cl)ccc1Br
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 3-bromo-6-chloro-N-methoxy-N-methylpicolinamide (5.34 g, 19.1 mmol) in anhydrous THF (38 mL) at 0° C. was slowly added a solution of (4-chlorophenyl)magnesium bromide (1M in Et2O) (76 mL, 76 mmol). After 3 h at 0° C., a saturated aqueous solution of ammonium chloride was added and the product was extracted with MTBE (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (hexane/EtOAc 10:0 to 8:2) to give the title compound as a white solid (5.98 g). LC/MS m/z 332 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:27]=[C:26]([Cl:28])[C:10]2[O:11][C:12]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][C:13]=3[S:14](=[O:17])(=[O:16])[CH2:15][C:9]=2[CH:8]=1.N1C=CC=C[CH:30]=1>C(Cl)Cl>[CH3:30][O:24][C:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:12]2[O:11][C:10]3[C:26]([Cl:28])=[CH:27][C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])=[CH:8][C:9]=3[CH2:15][S:14](=[O:16])(=[O:17])[C:13]=2[CH:18]=1)=[O:25]
Reactant: c1ccncc1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reaction time: 2 h

Procedure:
Chloro-acetyl chloride (3.3 mL, 40.8 mmol) was added with stirring to a solution of the ester of Example 35j (5 g, 13.6 mmol) in CH2Cl2 (100 mL) at 15° C., followed by addition of pyridine (6.6 mL, 81.6 mmol). The reaction mixture was stirred for 2 h, concentrated, treated with water and the solid that precipitated was filtered and purified by refluxing it with stirring in ethyl acetate for 0.5 h. The solid was filtered and dried to obtain the title compound. Yield: 5.5 g, (90.9%); 1H NMR (DMSO-d6): δ 2.7 (s, 3H, CH3), 3.9 (s, 3H, OCH3), 4.31 (s, 2H, CH2), 5.4 (s, 2H, CH2), 7.71 (s, 1H, Ar), 7.98 (s, 1H, Ar), 8.12 (s, 1H, Ar), 8.2 (s, 1H, Ar), 10.77 (s, 1H, Ar); MS: m/e (ES−) 442(M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: NC1CCc2ccccc21
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3OC)CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)=[N:9][C:10]=2[C:11]2[CH:27]=[CH:26][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>>[C:34]([N:29]1[CH2:30][CH2:31][CH2:32][CH2:33][C@H:28]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:26][CH:27]=2)[N:9]=1)(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4)n4ccnc(N)c34)cc2)c1
Product: C=CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(C#N)ccn3)cc2)c2c(N)nccn12
Yield: 10.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-cyanopyridin-2-yl)benzamide (intermediate 24) and acryloylchloride, to afford the title compound (4.8 mg, 10.4%). Data: UPLC(C) Rt: 2.31 min.
Reaction SMILES: [OH:1][C:2]([C:10](=[O:28])[NH:11][C@@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]1=2)([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](O)=[O:4].[F:29][C:30]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:31]N.C([N:40](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C:2]([CH2:6][CH:7]([CH3:9])[CH3:8])([C:3]([NH2:40])=[O:4])[C:10]([N:11]([C@@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]1=2)[CH2:31][C:30]([F:37])([F:29])[C:33]([F:36])([F:35])[F:34])=[O:28]
Reactant: CC(C)CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)CC(O)(C(N)=O)C(=O)N(CC(F)(F)C(F)(F)F)[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A solution of 50.0 mg (0.13 mmol) 2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid and 39.0 mg (0.26 mmol) 2,2,3,3,3-pentafluoropropylamine in 1.5 ml dimethylformamid was cooled to 0° C. and 20 μl (0.14 mmol) triethylamine and 54.5 mg (0.14 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) were added. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 19:1 to 1:1) yielded 45.0 mg (67%) (R/S)-2-hydroxy-2-isobutyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide: MS (m/e): 514.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2oc(-c3ccc(C)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1

Procedure:
A solution contaning 16.0 g. (0.06 mole) of methyl 2-(4-methylphenyl)-5-benzoxazolecarboxylate (1a), 4.0 g. (0.1 mole) of sodium hydroxide, and 50 ml. of water in 275 ml. of ethanol was stirred at 25° for 16 hours. The reaction mixture was poured into 1 l. of water. Acidification gave a white precipitate which was filtered, washed with water, and when air-dried amounted to 14.44 g. (95%) of 2-(4-methylphenyl)-5-benzoxazolecarboxylic acid (1b). The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12]([CH2:28]S([O-])(=O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24]CCC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:28][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCC/C=C\CCCCCCCCCS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC/C=C\CCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
5.32 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 12.26 grams of powdered potassium hydroxide and 10 grams of cis-9-hexadecenyl-methanesulfonate were stirred in 250 ml benzene and refluxed for 10.5 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 50 ml. The reaction mixture was cooled to room temperature, 50 ml water was added, and the mixture was extracted thrice with 100 ml diethyl ether. The combined organic phase was washed with 100 ml water and the solvent was removed under reduced pressure. The residue (12.01 grams) was dissolved in 200 ml of a 90:10:3 (v/v) mixture of methanol:water:concentrated hydrochloric acid, and the resulting solution was stirred at room temperature overnight and then refluxed for 1 hour. After cooling to room temperature, 100 ml water was added. The product was extracted thrice with 75 ml diethyl ether, washed consecutively with 100 ml water, 100 ml saturated aqueous solution of sodium bicarbonate, and again with 100 ml water. After drying on Na2SO4, the solvent was removed under reduced pressure, yielding 9.104 grams of crude 1-(cis-9-hexadecenyl)-sn-glycerol. The crude product was purified by chromatography on a silica gel (30 grams) column. 9.07 grams of pure 1-(cis-9-hexadecenyl)-glycerol was eluted by chloroform followed by a mixture of chloroform and 5% methanol. The yield was 91.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH3:16].C(N(C(C)C)C(C)C)C.[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.C(OCC)(=O)C>C(Cl)Cl>[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39]([N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH3:16])=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1ccccc1-c1ccccc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccccc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A solution of 53 mg (0.25 mmol)(2′-methoxy-biphenyl-2-yl)-methyl-amine and 0.064 ml (0.375 mmol) N-ethyldiisopropylamine in 4 ml CH2Cl2 was cooled in an ice bath and a solution of 88 mg (0.275 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml CH2Cl2 was added dropwise. The reaction mixture was stirred overnight at room temperature. Ethyl acetate was added and the organic layer was washed with saturated Na2CO3 solution, 1 N HCl solution, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate 4:1) to give 107 mg (87%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2′-methoxy-biphenyl-2-yl)-N-methyl-isobutyramide as orange crystals, MS (ISP): 496.1(M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[C:81]([F:84])([F:83])[F:82])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27]([NH:68][C@H:69]([CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=2[C:81]([F:82])([F:83])[F:84])[CH2:70][C:71]([OH:73])=[O:72])=[O:28])[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2C(F)(F)F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)-phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (19.5 mg, 0.0514 mmol) and DIPEA (44.7 uL, 0.257 mmol) in DMF (1.59 mL, 20.5 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-trifluoromethylphenyl)butanoic acid.HCl (14.6 mg, 51.4 μmol)) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (21.1 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C31H29F3N8O3, 619.23; found 619.6.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCCC1>[CH3:1][CH:2]([CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][C:4]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:6]
Reactant: C1COCCN1
Reactant: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)N1CCOCC1
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
In anhydrous tetrahydrofuran was dissolved 6.9 g of the compound obtained in step (c) above, and 3 g of triethylamine and then 3.3 g of ethyl chlorocarbonate were added to the solution at 0° C. The mixture was stirred for 20 minutes. Into the liquid reaction mixture was dropped 3.1 g of morpholine at 0° C., and the mixture was stirred for 30 minutes. The liquid reaction mixture was extracted with n-hexane, and the extract was washed with water and dried. The solvent was removed by distillation and the residue was purified by column chromatography using silica gel to obtain 5.6 g of the intended compound in the form of an oil.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)#[CH:10].O>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:10][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:12][CH:13]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: Nc1ccccc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: O
Product: Cc1ccc(C#Cc2ccccc2N)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
To 2-iodoaniline (2.19 g, 10.0 mmol) in diethylamine (40 ml) were added 4-ethynyltoluene (1.16 g, 10.0 mmol), bis(triphenylphosphine) palladium(II) chloride (702 mg, 1.00 mmol) and copper iodide (190 mg, 1.00 mmol) successively, and the mixture was stirred for 6 hours at 50° C. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the subject compound (1.80 g, 87%).
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:11](O)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(#N)C.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:11]1[C:12]2[CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)C1CCc2ncnc(O)c21
Solvent: CC#N
Product: CC(C)C1CCc2ncnc(Cl)c21
Temperature: 80 °C
Yield: 26 %

Procedure:
A solution of 5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (4.29 g, 24.09 mmol) in acetonitrile (94.75 mL, 1814 mmol) was treated with POCl3 (6.62 mL, 72.28 mmol). The mixture was heated at 80° C. overnight. No reaction was observed by LC-MS or HPLC. An additional 3 equivalents of POCl3 were added, and the reaction was heated at 80° C. for 4 hours. The reaction was charged with an additional 10 equivalents of POCl3 and TEA (6.716 mL, 48.18 mmol) and heated at 80° C. overnight. The reaction was cooled to room temperature, and the solvent and POCl3 were removed under reduced pressure. The residue was taken up in DCM and was carefully added to stirring saturated NaHCO3. The mixture was stirred for 1 hour to confirm complete neutralization. The organics were combined and washed with brine, dried Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (25% EtOAc/Hexane) to yield 4-chloro-5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.23 g, 26%). LCMS (APCI+) m/z 196.9 [M+H]+; Rt=3.57 min.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[C:6]([C:13](Cl)=[O:14])[CH:5]=1>C(O)C.ClCCl>[CH3:1][N:2]([CH3:3])[C:13]([C:6]1[CH:5]=[N:4][N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=12)=[O:14]
Reactant: O=C(Cl)c1cnn2ccccc12
Reactant: CNC
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C(=O)c1cnn2ccccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of dimethylamine in ethanol (35% w/v; 300 ml) was added to dichloromethane (1100 ml) and the resulting solution was stirred at 0° C. and treated slowly with a solution of pyrazolo[1,5-a]pyridine-3-carbonyl chloride (61.0 g) in dry dichloromethane (1100 ml). When the addition was complete, the mixture was allowed to warm up to room temperature and stand at room temperature overnight. The mixture was then washed twice with water and the organic solution was then dried over sodium sulphate and evaporated under reduced pressure. The resulting brown oil was recrystallised from cyclohexane, to give 3-(N,N-dimethylcarbamoyl)pyrazolo[1,5-a]pyridine (42.0 g), m.p. 86°-87° C.