Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]=[C:14]([CH3:26])[CH2:15][P:16]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=[CH:29][CH:28]=1>ClCCl.C(O)C>[CH2:28]([O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]=[C:14]([CH3:26])[CH2:15][P:16]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:20])[CH3:21])=[O:17])[CH3:29]
Reactant: c1ccncc1
Reactant: CC(=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)CP(=O)(OC(C)C)OC(C)C
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)[C@@H](C=C(C)CP(=O)(OC(C)C)OC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
0.09 g of 1-amino-1-chloro-N,N,2-trimethylpropene is added at 0°-5° to a solution of 0.2 g of acid 3 according to c) in 15ml of dry dichloromethane. After stirring for 30 minutes at 0°, 0.4 g of pyridine in 5 ml of ethanol is added. The mixture is stirred further at 0° for 90 minutes and at room temperature for 15 hours, and is then diluted with 20 ml of dichloromethane and washed twice with 20 ml of water each time. The organic phase is dried using sodium sulphate, concentrated by evaporation and chromatographed on 25 g of silica gel. Elution with ethyl acetate/ methanol 10:1 yields 0.12 g of 4. 1H-NMR(300 MHz, CDCl3): 1.2-1.4 (m, 2 (CH3)2CHO, CH3CH2O); 1.45 (s, (CH3)3CO); 1.98 (d, J=3, CH3 --C(4)); 2.55 (d, J=23, 2H--C(5)); 4.2 (m, CH3CH2O); 4.69 (m, 2 (CH3)2CHO); 5.0 (m, H--C(2)); 5.16 (m, H--C(3), NH).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:16][CH2:17][N:18]([C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: Clc1ccc2c(c1)OCc1cccnc1C2=C1CCNCC1
Reactant: O=C(O)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccncc1)N1CCC(=C2c3ccc(Cl)cc3OCc3cccnc32)CC1

Procedure:
The title compound was prepared according to the method of Example 4 from 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-piperidine, 4-pyridine-acetic acid hydrochloride, HOBT, EDCl and NMM in DMF. 4-(8-Chloro-5,11-dihydro[1]benz-oxepino[4,3-b]pyridin-11-ylidene)-1-(4-pyridine-acetyl)piperidine was obtained as a white foam; MS (CI, M+H)=432; anal.: found: C, 68.71; H, 5.44; N, 9.44; C25H22ClN3O2 requires: C, 69.52; H, 5.13; N, 9.73.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29](O)=[O:30].[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:32]1([C:29](=[O:30])[CH2:28][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=4)[CH2:16][CH2:15]3)=[CH:7][C:2]=2[F:1])[CH2:35][CH2:34][CH2:33]1
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)n1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-fluoro-4-{2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (80.0 mg, 0.185 mmol) in 1 ml anhydrous DMF at RT was added azetidine (12.6.2 mg, 0.221 mmol) and N,N-diisopropylethylamine (0.097 ml, 0.554 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.369 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-95% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 473.2 (M+H)+. GPR119 Human EC50: 5.8 nM
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][O:28][CH3:29])=[C:21]4[O:30][CH2:31][O:32][C:20]=34)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34].[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36]>>[ClH:1].[ClH:1].[C:35]([N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][O:28][CH3:29])=[C:21]5[O:30][CH2:31][O:32][C:20]=45)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]3)=[CH:8][C:7]=2[O:33][CH3:34])[CH2:40][CH2:39]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCNCC1
Reactant: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCN4CCN(C(C)=O)CC4)c(OC)cc23)c2c1OCO2
Product: Cl
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 10, 7-(3-chloropropoxy)-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline was reacted with 1-acetylpiperazine to give the title compound in 58% yield; NMR Spectrum: (DMSOd6 and CF3CO2D at 100° C.) 2.04 (s, 3H), 2.3–2.37 (m, 2H), 3.27–3.37 (m, 9H), 3.74–3.84 (m, 4H), 3.96 (s, 3H), 4.3–4.36 (m, 4H), 6.04 (s, 2H), 6.89 (d, 1H), 6.96 (d, 1H), 7.51 (s, 1H), 7.96 (s, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 572.
Reaction SMILES: O.[NH2:2][C:3]1[C:8]2[CH2:9][CH2:10][O:11][C:7]=2[C:6]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH3:24])[CH2:17][C@H:16]2[O:25][CH3:26])=[O:13])=[CH:5][C:4]=1[Cl:27].ClC(Cl)Cl.[N:32]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(N(CC)CC)C>[OH2:11].[NH2:2][C:3]1[C:8]2[CH2:9][CH2:10][O:11][C:7]=2[C:6]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[C:37]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:38])[CH2:17][C@H:16]2[O:25][CH3:26])=[O:13])=[CH:5][C:4]=1[Cl:27]
Reactant: O=C(Cl)N1CCCC1
Reactant: CNCCN1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OCC3)[C@H](OC)C1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(CCN(C)C(=O)N2CCCC2)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
To a cooled (ice-bath) mixture of 3.8 parts of cis-4amino-5-chloro-2,3-dihydro-N-[-3-methoxy-1-[2-(methylamino)ethyl]-4-piperidinyl]-7-benzofurancarboxamide monohydrate in 104.3 parts of trichloromethane were added 1.3 parts of 1-pyrrolidinecarbonyl chloride. After stirring for 15 min. at 0° C., there were added dropwise 1.3 1 parts of N,N-diethylethanamine, keeping the temperature below 10° C. Stirring was continued for 20 hours at room temperature. The reaction mixture was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile (to which some water was added). The product was filtered off at 0° C. and dried in vacuo at 40° C., yielding 3.3 parts (73.6%) of cis-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-[2-[methyl(1-pyrrolidinylcarbonyl)amino]ethyl]-4-piperidinyl]-7-benzofurancarboxamide monohydrate; mp. 112.0° C. (comp. 43).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-:19].[K+].[K+].OO>O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:19])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzonitrile (3.6 g, 16.1 mmol), dimethylsufoxide (25 mL), potassium carbonate (2.1 g, 15.2 mmol), and 3 mL of 30% hydrogen peroxide solution. Stir 18 h at ambient temperature. Dilute with 100 mL of water, extract with ethyl acetate (3×100 mL). Wash the organic phase with 100 mL of water, and 50 mL of brine. Dry the organic phase over sodium sulfate, filter, and concentrate under vacuum. Purify via aBiotage Flash 40L system using 75:25 hexanes/ethyl acetate as eluting solvent to give 3.0 g (77%) of the title compound: 1H NMR (chloroform-d): 9.95 (s, 1H), 7.88 (m, 4H), 7.12 (m, 4H), 5.29-5.14 (br m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:31])([CH3:30])[C@H:4]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:5](CC1C=CC(OC)=CC=1)CC1C=CC(OC)=CC=1>CO.[Pd]>[CH3:1][O:2][C:3]([CH3:31])([CH3:30])[C@H:4]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:5]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@@H](c2ccccc2)C(C)(C)OC)cc1
Agent: [Pd]
Solvent: CO
Product: COC(C)(C)[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (S)-2-methoxy-N,N-bis(4-methoxybenzyl)-2-methyl-1-phenylpropan-1-amine (0.7 g, 1.67 mmol) in anhydrous MeOH was added Pd on C (0.1 g) and the contents were stirred at ambient temperature in H2 atmosphere. After 14 h, the reaction mixture was filtered through a pad of celite and the volatiles were removed under reduced pressure. The residue thus obtained was further purified by preparative HPLC to afford the title compound. H1NMR (ppm, 400 MHz, CDCl3) δ 7.45-7.44 (m, 2H), 7.35-7.33 (m, 3H), 4.1 (s, 1H), 3.32 (s, 3H), 1.2 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([NH2:15])=[CH:7][CH:6]=1.[N:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=2)[CH:20]=1>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]1[C:10]([C:11]([F:13])([F:14])[F:12])=[CH:9][C:8]([NH:15][C:35](=[O:36])[CH2:34][C:31]2[CH:30]=[CH:29][C:28]([N:21]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:27]4[N:19]=[CH:20]3)=[CH:33][CH:32]=2)=[CH:7][CH:6]=1
Reactant: Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2cnc3cccnc32)cc1)Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 1 but using 3′-bromo-2-trifluoromethyl-biphen-4-ylamine and (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid. Title compound: ES-MS: 552.8 [M+H]+; tR=5.24 min (System 1); Rf=0.20 (CH2Cl2/MeOH, 96:4).
Reaction SMILES: [CH2:1]([C:8]1([O:18][CH3:19])[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([C:8]1([O:18][CH3:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC1(Cc2ccccc2)CCC(=O)CC1
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of Example 11B (8.5 g, 32.5 mmol) in acetone (200 mL) was treated with water (100 mL) and p-toluenesulfonic acid monohydrate (1 g), heated to reflux, stirred overnight, and concentrated to remove the acetone. The remaining aqueous solution was extracted with ethyl acetate (3×100 mL) and the combined extracts were washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (6.95 g, 95%). MS (CI) m/e 236.2 (M+18)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:31]#[N:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCC#N)c(-c3ccccc3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (63.0 mg) and triethylamine (22.8 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (18.9 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was added to sodium cyanide (14.7 mg) in dimethylformamide (2 mL) and the mixture was stirred at 60° C. for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]hexanenitrile as an yellow oil (58.5 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][OH:14].[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10][CH3:9])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1ccccc1CO
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1COc1cncc(Cl)n1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (298 mg, 2.00 mmol), 2-methoxybenzyl alcohol (303 mg, 2.20 mmol) and NaH (55% in mineral oil, 96 mg, 2.2 mmol). The yield of the crude product was 0.49 g (98%) and was used directly as such in the next step. MS m/z 250 (M)+. HRMS m/z calcd for C12H11ClN2O2 (M)+ 250.0509, found 250.0522.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.C(=O)([O-])[O-:9].[K+].[K+].[CH3:14][O:15][CH2:16][CH2:17]Br>C(#N)C.ClCCl>[CH3:14][O:15][CH2:16][CH2:17][N:1]1[CH2:6][CH2:5][C:4](=[O:9])[CH2:3][CH2:2]1
Reactant: O=C1CCCCN1
Reactant: COCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COCCN1CCC(=O)CC1
Temperature: 25 °C

Procedure:
To a solution of piperidone (317 mg) and potassium carbonate (530 mg) in acetonitrile at room temperature (20 mL) was added 2-bromoethyl methyl ether (0.48 mL). The reaction mixture was heated at reflux for 16 h, allowed to cool to room temperature and then reduced in vacuo. The residue was then redissolved in dichloromethane (20 mL) and washed with water (20 mL) and brine (20 mL), dried (MgSO4) and reduced in vacuo to give 1-(2-methoxy-ethyl)-piperidin-4-one as colourless oil (171 mg).
Reaction SMILES: [Na].[OH:2][CH:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1)=[CH2:9])[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C>CO>[CH3:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1)[C:3](=[O:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(c1ccc(-c2ccccc2)c(F)c1)C(O)C(=O)OC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Yield: 73.8 %

Procedure:
To a solution of 1.1 g of metallic sodium in 100 ml of anhydrous methanol was added a solution of 12.2 g of methyl 2-hydroxy-3-(2-fluoro-4-biphenylyl)-3-butenoate in 40 ml of anhydrous methanol, and the resulting mixture was refluxed for 20 minutes and then cooled. The reaction liquid was charged with 10 ml of glacial acetic acid, and the methanol was removed therefrom by distillation at a low temperature and under reduced pressure. The residue was charged with ethyl acetate and water, thereby effecting ethyl acetate extraction. The ethyl acetate layer was successively washed with water, aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. Thereafter, the ethyl acetate was removed by distillation under reduced pressure to obtain 9.0 g of methyl 3-methyl-3-(2-fluoro-4-biphenylyl)-pyruvate. The yield was 73%.
Reaction SMILES: [Mg].II.[CH2:4]([CH:6]([CH2:9][CH3:10])[CH2:7]Br)[CH3:5].[CH2:11]([Si:17](Cl)([Cl:19])[Cl:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O1CCCC1.CCCCCC.C(OCC)C>[CH2:11]([Si:17]([CH2:7][CH:6]([CH2:9][CH3:10])[CH2:4][CH3:5])([Cl:19])[Cl:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCC(CC)CBr
Reactant: CCCCCC[Si](Cl)(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC[Si](Cl)(Cl)CC(CC)CC

Procedure:
Anhydrous diethyl ether (100 mL) was put into a reactor with magnesium (5.0 g, 0.21 mol) which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. 2-Ethylbutylbromide (29.5 g, 0.18 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing n-hexyltrichlorosilane (38 g, 0.17 mol) in anhydrous tetrahydrofuran (100 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 60° C.-70° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 2-amino-N-methylacetamide (9.19 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (70.4 mg, 0.696 mmol) were added to DMF (1 mL). This was stirred overnight before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.0 min) to provide (R/S)-2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.5 mg, 6.28 μmol, 9.03% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.55 (1 H, br. s.), 8.17 (2 H, d, J=8.14 Hz), 7.59-7.85 (7 H, m), 5.20 (1 H, s), 3.78-4.01 (2 H, m), 2.75 (3 H, s); HPLC peak RT=8.2 min (Method A).
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](SC)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[N:16]1)(=O)C1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[NH2:30].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[N:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1
Reactant: CSc1ncnc2cnn(CCOCCOC(=O)c3ccccc3)c12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: OCCOCCn1ncc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 16.5 h
Yield: 30.6 %

Procedure:
A mixture of 2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethyl benzoate (200 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (140 mg), pyridine hydrochloride (96 mg) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 140° C. for 16.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (30 mL), and extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→20:80). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). 1N Aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 11.5 hrs. After concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (45 mL×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) and recrystallized from ethanol-ethyl acetate to give the title compound (78 mg).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:19]I>CN(C)C=O>[CH3:18][C:12]([C:9]1[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CI
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A suspension of 924 mg (23 mmol) of sodium hydride (60% in oil) in 21 mL of dry N,N-dimethylformamide was stirred under nitrogen in an ice bath as a solution of 4.68 g (21 mmol) of ethyl (±)-2-(4-nitrophenyl)propionate in 20.5 mL of dry N,N-dimethylformamide was added gradually over about 10 minutes. An intense violet color developed during the addition. The mixture was then allowed to warm to room temperature. After about 1 hour, the mixture was again cooled in an ice bath as a solution of 1.44 mL (3.28 g; 23 mmol) of methyl iodide in 5 mL of dry N,N-dimethylformamide was added dropwise by syringe over about 10 minutes, while maintaining the internal temperature at 10°-15° C. The mixture was allowed to warm to room temperature, and the color changed to brown. After 1 hour, an additional 187 mL (426 mg, 3 mmol) of iodomethane was added. By the next day, the mixture consisted of a suspension of some grayish solid in a golden liquid. It was stirred vigorously and quenched by gradual addition of 10 mL of 5% aqueous potassium bisulfate solution. The mixture was partitioned between 400 mL of diethyl ether and 400 mL of water. The organic layer was washed with an additonal 3×400 mL of water and then with 50 mL of saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 19:1 hexane-ethyl acetete) yielded 4.31 g (87%) of an oil; homogeneous by TLC in 9:1 hexane-ethyl acetete. 400 MHz 1H NMR (CDCl3) was consistent with the assigned structure.