Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:57]([NH:59][CH2:60][C:61](O)=[O:62])=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[C:44]([NH:54][C@H:55]([C:57]([NH:59][CH2:60][C:61]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:62])=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-alanyl-glycine.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:14][CH2:13]3)[C:7]=1[C:8]#[N:9].O.[NH2:33][NH2:34]>C(O)C>[F:28][C:27]([F:29])([F:30])[C:23]1[CH:22]=[C:21]([CH2:20][C:19]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]5[NH:33][N:34]=[C:8]([NH2:9])[C:7]=45)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[O:31])[CH:26]=[CH:25][CH:24]=1
Reactant: NN
Reactant: N#Cc1c(Cl)cncc1-c1ccc2c(c1)CCN2C(=O)Cc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2cncc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (80 mg, 0.181 mmol) was added hydrazine monohydrate (0.266 mL, 5.43 mmol) to a 5 mL sealable vial with Ethanol (3 mL). The reaction was then capped and heated at 100° C. overnight. Observed 80% product and 20% SM. Additional hydrazine monohydrate (0.266 mL, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated then dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 17% ACN/H2O, 0.1% TFA to 42% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and it was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The residue was then transferred into a 40 mL vial with MeCN, water was added and the solution was freeze-dried to afford 4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amine (20 mg, 25.3% yield) as a white solid. LC/MS (ES) m/z=438.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.74 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.56-7.67 (m, 3H), 7.44 (s, 1H), 7.33 (d, J=8.34 Hz, 1H), 4.61 (br. s., 2H), 4.30 (t, J=8.46 Hz, 2H), 4.05 (s, 2H), 3.26-3.30 (m, 2H).
Reaction SMILES: CS(O[C@@H:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)=O.[C:13]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[F-].[Cs+].O>CN(C=O)C>[CH:14]([C:13]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:12]
Reactant: CCOC(=O)[C@H](C)OS(C)(=O)=O
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 60 %

Procedure:
To a solution of (S)-ethyl 2-(methylsulfonyloxy)propanoate (28.4 g, 0.1 mol) in N,N′-dimethylformamide (400 mL) was added dibenzyl malonate (23.5 g, 0.12 mol) and cesium fluoride (15.2 g, 0.1 mol). The mixture was heated at 50° C. for 2 days. After cooled to room temperature, the mixture was poured into water and then extracted with ethyl acetate. The organic phases were combined, washed with brine, water and dried over anhydrous sodium sulfate, and then concentrated to afford the crude product (S)-1,1-dibenzyl 2-ethyl propane-1,1,2-tricarboxylate, which was purified by silica gel chromatography (23 g, yield 60%).
Reaction SMILES: C(S([C:10]1[N:15]2[N:16]=[CH:17][C:18]([CH:19]=[C:20]3[NH:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[C:14]2[N:13]=[C:12]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH:11]=1)=O)C1C=CC=CC=1.[NH2:35][CH2:36][CH2:37][OH:38].O>CN1C(=O)CCC1>[Cl:34][C:30]1[CH:29]=[C:28]([NH:27][C:12]2[CH:11]=[C:10]([NH:35][CH2:36][CH2:37][OH:38])[N:15]3[N:16]=[CH:17][C:18]([CH:19]=[C:20]4[NH:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])=[C:14]3[N:13]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(S(=O)Cc4ccccc4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: NCCO
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1NC(=O)C(=Cc2cnn3c(NCCO)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 120 °C

Procedure:
To 5-((7-(benzylsulfinyl)-5-(3-chlorophenylamino) pyrazolo[1,5-a]pyrimidin-3-yl) methylene) imidazolidine-2,4-dione (15 mg, 0.0304 mmol) in NMP was added 2-aminoethanol (14.6 μL, 0.242 mmol). The mixture was heated in the microwave at 120° C. for 20 minutes. Water was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with methanol to yield 5-((5-(3-chlorophenylamino)-7-(2-hydroxyethylamino) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione LCMS (M+1=414). Similar products (shown below) were also obtained as precipitates by addition of water while other reactions were purified by prep HPLC to yield corresponding products.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH2:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([NH2:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Nc1c([N+](=O)[O-])cc(-c2ccccc2Cl)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
4-Bromo-2-nitro-6-trifluoromethyl-phenylamine (1.01 g, 3.55 mmol), 2-chlorophenylboronic acid (1.5 eq., 833 mg, 5.33 mmol), and (dppf)PdCl2.DCM (0.05 eq., 145 mg, 0.178 mmol) were placed in a 40 mL vial equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and DME (15 mL) and 2M aq Na2 CO3 (5 mL) were added via syringe. The vial was capped tightly and placed in a heating block where the reaction was stirred at 90° C. for 18 h. The mixture was cooled to rt, diluted with EtOAc, and washed with water. The aqueous layers were combined and extracted with EtOAc. The combined organic extracts were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0 to 1:4, v/v over 20 min, yielding 1.05 g (94%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 8.47 (d, J=2.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.47-7.53 (m, 1H), 7.30-7.37 (m, 3H), 6.76 (br. s., 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15]CC3C=CC=CC=3)[C:12]([O:23][CH3:24])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.Cl.[OH-].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[C:12]([O:23][CH3:24])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)c(OCc3ccccc3)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2cc(OC)c(O)cc2o1

Procedure:
6-Benzyloxy-5-methoxybenzofuran-2-carboxylic acid ethyl ester (7.3 g), acetic acid (45 ml) and conc. HCl (24 ml) were stirred at 50° C. for 0.5 hour. Water was added and pH adjusted to 3 with NaOH. The mixture was extracted with ethyl acetate. Ethyl acetate was dried with Na2SO4 and evaporated to dryness. The product was recrystallized from toluene.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C(#N)C>C(Cl)Cl>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Clc1ccccc1CNCCCOc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2-chlorobenzylamine and acetonitrile essentially as described above in example 48 except that the crude product is dissolve in DCM and purified by using a step gradient of 50% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=98%, [M+H]+=399.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)CCC>>[S:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cccs2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 4 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)thiophene. The solid obtained from flash chromatography was further purified by reverse phase HPLC on a C18 column using a gradient of 5-45% acetonitrile/water (each solvent containing 0.1% trifluoroacetic acid as a buffer) as the eluant. The product-containing fractions were evaporated. The residue was partitioned between saturated aqueous potassium carbonate and chloroform and the chloroform layer was dried (magnesium sulfate), filtered and evaporated to give the title compound as an off-white solid (100 mg), m/z 347 (MH+).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[K+].[Cl:8][C:9]1[C:17]([Cl:18])=[C:16]2[C:12]([CH2:13][C:14]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]2=[O:19])=[CH:11][C:10]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:8][C:9]1[C:17]([Cl:18])=[C:16]2[C:12]([CH2:13][C:14]([CH3:26])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:15]2=[O:19])=[CH:11][C:10]=1[O:27][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Reaction time: 18 h

Procedure:
A solution containing chloroacetone (11 g., 0.12 mole) and potassium iodide (0.5 g.) in acetone (30 ml) is stored in the dark for 18 hours then added in portions over a one hour period to a stirred refluxing mixture of 6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone (24.5 g., 0.08 mole) and potassium carbonate (11.0 g., 0.08 mole) in acetone. The acetone is distilled at reduced pressure and the residue slurried with ether and water to give 6,7-dichloro-2-methyl-5-(2-oxopropoxy)-2-phenyl-1-indanone which melts at 144° C. after recrystallization from ethanol.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])[CH2:3]1.N1C=CC(=[O:32])NC1=O>>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][N+:19]2([O-:32])[CH2:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])[CH2:3]1
Reactant: CN1C[C@H](CN2CC(=O)NC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=c1cc[nH]c(=O)[nH]1
Product: CN1C[C@H](C[N+]2([O-])CC(=O)NC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 63 %

Procedure:
Repeating Example 1 but using 1-[(6-methylergolin -8β- yl)methyl]-2,4-imidazolidinedione instead of 1-[(6-methyl -Δ- 9,10-ergolen -8β- methyl]-2,4-(1H,3H)-pyrimidinedione the title compound was obtained in 63% yield, m.p. 163-165° C.
Reaction SMILES: [CH3:1][C:2]([C@@H:13]1[C:22]2[C:17](=[N:18][C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)[O:16][C:15]2[N:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:14]1=2)([CH3:12])[C:3]([NH:5][C:6]1N=N[N:9](C)[N:10]=1)=[O:4].NN1NC=[C:45]([CH:48]2[CH2:50][CH2:49]2)[S:44]1>>[CH:48]1([C:45]2[S:44][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:1])([C@@H:13]3[C:22]4[C:17](=[N:18][C:19]([C:23]5[CH:24]=[CH:25][C:26]([C:29]([N:31]6[CH2:36][CH2:35][O:34][CH2:33][CH2:32]6)=[O:30])=[CH:27][CH:28]=5)=[CH:20][CH:21]=4)[O:16][C:15]4[N:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:14]3=4)[CH3:12])=[N:10][N:9]=2)[CH2:49][CH2:50]1
Reactant: NN1NC=C(C2CC2)S1
Reactant: Cc1ccc2c(n1)Oc1nc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc1[C@H]2C(C)(C)C(=O)Nc1nnn(C)n1
Product: Cc1ccc2c(n1)Oc1nc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc1[C@H]2C(C)(C)C(=O)Nc1nnc(C2CC2)s1

Procedure:
Following conditions described for Step 9 of Example 14, the acid from Step 1 of Example 92 was coupled with 2-amino-5-cyclopropylthiadiazole to give Example 93. 1H NMR (400 MHz, chloroform-d) δ ppm 1.16-1.41 (m, 10H) 2.27-2.38 (m, 1H) 2.57 (s, 3H) 3.43-3.93 (m, 8H) 4.59 (s, 1H) 7.01 (d, J=7.78 Hz, 1H) 7.51 (t, J=8.53 Hz, 3H) 7.56-7.67 (m, 2H) 8.12 (d, 2H); MS (ES+) m/z: 597 (M+H); LC retention time: 3.08 min (analytical HPLC Method B).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1cccc(OCCN2CCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(OCCN2CCCC2)c1

Procedure:
A mixture of 1-(2-(3-nitrophenoxy)ethyl)pyrrolidine (3.49 g, 14.8 mmol), 10% palladium on carbon (400 mg) and ethyl acetate (20 ml) was reduced under 50 psi hydrogen for 10 h. The reaction mixture was filtered through Celite 545 and the product extracted into 1M HCl (3×20 ml). The acidic layer was washed with ether (2×20 ml) and then the pH adjusted to >10 with 2M NaOH. The aqueous layer was extracted with ether (3×20 ml), dried over MgSO4 and concentrated in vacuo. The product was eluted through a silica gel pad (75% ethyl acetate/hexane/1% Et3N) to yield the product as a pale yellow oil.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[N:42]=[C:43]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:44][C:45]=2[CH3:46])=[CH:35][CH:34]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:46][C:45]1[O:44][C:43]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[N:42][C:41]=1[CH2:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:20]=2[CH2:19][OH:18])=[CH:34][CH:35]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2nc(-c3ccccc3)oc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2nc(-c3ccccc3)oc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a mixture of 5-(tert-butyldiphenylsilyloxymethyl)-4-[[4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy]methyl]-2-phenyl-1,3-oxazole (1.44 g) and tetrahydrofuran (30 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 5 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and 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 to give [4-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-5-yl]methanol as colorless crystals (0.55 g, yield 59%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]([C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:14])[F:15])=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1ccccc1C(F)(F)F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1C(F)(F)F
Yield: 83 %

Procedure:
A solution of 3-oxo-3-(2-trifluoromethyl-phenyl)-propionic acid ethyl ester, prepared following an analogous procedure to that outlined in Example 231, (3.14 g, 12.1 mmol, 1.0 equiv) and 1,1-dimethoxy-N,N-dimethylmethanamine (5.60 mL, 42.2 mmol, 3.5 equiv) in N,N-dimethylformamide was heated to reflux for 5 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed sequentially with water (4×) and saturated aqueous sodium chloride. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 3.20 g (83%) of 3-dimethylamino-2-(2-trifluoromethyl-benzoyl)-acrylic acid ethyl ester as an orange waxy solid. 1H NMR (400 MHz, CDCl3) δ: 7.86 (s, 1H), 7.67-7.64 (m, 1H), 7.51-7.41 (m, 2H), 7.35 (d, 1H), 3.81 (q, 2H), 3.42-3.17 (m, 3H), 3.11-2.93 (m, 3H), 0.78-0.69 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1cccc(O)c1
Product: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3cccc(O)c3)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 4 was coupled with 3-(2-amino-ethyl)-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 556. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 2H) 7.9 (d, 1H) 7.5 (m, 2H) 7.2 (m, 1H) 7.0 (d, 1H) 6.8 (m, 3H) 4.9 (s, br, 1H) 4.5 (s, 2H) 3.8 (m, 2H) 3.3 (m, 2H) 3.1 (m, 2H) 2.9 (m, 5H) 1.7 (m, 2H) 1.4 (s, 9H).
Reaction SMILES: [CH2:1]([C:3](O)([CH2:6][CH2:7][CH:8]=[C:9]([CH3:12])[CH2:10][CH3:11])[CH:4]=[CH2:5])[CH3:2].P(Br)(Br)[Br:15]>>[Br:15][CH2:2][CH:1]=[C:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:12])[CH2:10][CH3:11]
Reactant: BrP(Br)Br
Reactant: C=CC(O)(CC)CCC=C(C)CC
Product: CCC(C)=CCCC(=CCBr)CC

Procedure:
Following the procedure of Example 9, 3-ethyl-7-methyl-1,6-nonadien-3-ol and phosphorus tribromide are reacted to form 1-bromo-3-ethyl-7-methyl-2,6-nonadiene.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(=O)[nH]1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from 6-methyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (20 g, 79 mmol) and phosphoryl chloride (36.0 mL, 395 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (17.35 g, 81%). NMR (DMSO-d6) δ 7.71 (s, 1H), 7.73 (s, 1H), 7.88 (d, 2H, J=8.1 Hz), 8.05 (d, 2H, J=8.1 Hz) ppm.
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[N:10]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:11]([C@@H:13]([NH:15][C:16]4[N:24]=[CH:23][N:22]=[C:21]5[C:17]=4[N:18]=[CH:19][N:20]5C4CCCCO4)[CH3:14])=[N:12][C:8]=3[CH:7]=[CH:6][C:5]=2[F:37])[CH2:3][CH2:2]1>Cl.CO>[CH:1]1([C:4]2[C:9]3[N:10]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:11]([C@@H:13]([NH:15][C:16]4[N:24]=[CH:23][N:22]=[C:21]5[C:17]=4[N:18]=[CH:19][NH:20]5)[CH3:14])=[N:12][C:8]=3[CH:7]=[CH:6][C:5]=2[F:37])[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccn1
Agent: Cl
Solvent: CO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
[(S)-1-(7-Cyclopropyl-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine (59 mg, 0.12 mmol) was dissolved in HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resultant residue subjected to preparative HPLC (C18 Phenomenex column, 5-80% MeCN in water 0.1% formic acid, 20 min gradient) to yield 274 as a white solid (28 mg, 57%). 1H NMR 400 MHz (DMSO-d6): δ 12.83 (1H, br s), 8.50 (1H, br s), 8.22-7.58 (7H, m), 7.00 (1H, dd, J=11.3, 9.4 Hz), 5.66-5.20 (1H, m), 1.52 (3H, d, J=6.6 Hz), 1.32-1.21 (1H, m), 0.37-0.20 (2H, m), 1.89-0.07 (1H, m), 0.03-0.00 (1H, m), LCMS (Method K): RT=3.27 min, [M+H]+=415