Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.P(O)(O)O.[C:15]([O:19][C:20](=[O:23])[CH2:21][NH2:22])([CH3:18])([CH3:17])[CH3:16].C([BH3-])#N.[Na+].P(=O)(O)(O)O>CO.O>[C:15]([O:19][C:20](=[O:23])[CH2:21][NH:22][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)CN
Agent: O=P(O)(O)O
Agent: OP(O)O
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Yield: 62.8 %

Procedure:
2-Indanone (40 g) is dissolved in 300 ml of methanol, 78 g of glycine tert-butyl ester phosphite and 150 g of water are added, and then 23 g of sodium cyanoborohydride is added over 15 minutes with ice cooling and stirring. The resulting mixture is further stirred at room temperature for 4 hours. To the reaction mixture, 400 ml of 20% phosphoric acid is added portionwise over an hour, 200 ml of water is then added, the mixture is stirred for 30 minutes and then extracted with 800 ml of ethyl ether, and the aqueous layer is adjusted to pH 10 with 20% sodium hydroxide and extracted with 4 portions (500 ml in total) of chloroform. The extract is dried over anhydrous sodium sulfate and then distilled under reduced pressure. 50 ml of ethanol and then 150 ml of water are added to the oil obtained, and the mixture is cooled. The crystalline precipitate is collected by filtration and recrystallized twice from aqueous ethanol to give 47 g of (indan-2-yl)glycine tert-butyl ester as colorless prisms melting at 54°-55° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19].Cl.[NH:35]1[CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[N:35]1([C:14]([C:13]2[CH:17]=[CH:18][C:10]([O:9][C:8]3[CH:20]=[C:21]([C:23]4[NH:24][C:25]([C:28]5[S:29][CH:30]=[CH:31][N:32]=5)=[CH:26][CH:27]=4)[CH:22]=[C:6]([O:5][C@@H:4]([CH3:33])[CH2:3][O:2][CH3:1])[CH:7]=3)=[C:11]([CH3:19])[CH:12]=2)=[O:16])[CH2:38][CH2:37][CH2:36]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reactant: C1CNC1
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: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzoic acid (58 mg, 0.125 mmol) synthesized in Example (53a) and azetidine hydrochloride (29 mg, 0.310 mmol) were dissolved in dichloromethane (10.0 mL), and HATU (95 mg, 0.250 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.861 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=75%-90%) to afford the desired compound (58 mg, yield 92%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([C:16](N(OC)C)=[O:17])[N:6]=1)([CH3:4])[CH3:3].[CH3:22][Si:23]([CH3:32])([CH3:31])[C:24]#[C:25][CH2:26][CH2:27][CH2:28][Mg]Br>O1CCCC1>[CH3:15][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[N:6]=[C:7]([C:16](=[O:17])[CH2:28][CH2:27][CH2:26][C:25]#[C:24][Si:23]([CH3:32])([CH3:31])[CH3:22])[N:8]=1)([CH3:13])[CH3:14]
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: C[Si](C)(C)C#CCCC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)CCCC#C[Si](C)(C)C)nc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide (1,00 g, 3.38 mmols) in tetrahydrofuran (50 mL) under nitrogen atmosphere is added a freshly prepared 0.105M solution of 5-trimethylsilylpent-4-ynyl magnesium bromide (81 mL, 8.5 mmols) [from 5-bromo-1-trimethylsilyl-1pentyne (3.86 g, 17.5 mmol) and magnesium (1.50 g, 61.7 mg-atom) in tetrahydrofuran (140 mL)] dropwise. After stirring 16 hours, the resulting mixture is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl ether. The combined extracts are washed with brine and the organic phase is dried over magnesium sulfate. Concentration under vacuum is followed by purification of the organic residue by flash chromatography (SiO2, 20% ethyl acetate/hexane) to give 0.97 g (77%) of the title compound which is used without further purification to make the compound of Example 7.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:15][C:12]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:3]2=[N:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: Cc1cnc2c(Cl)nc3ccccc3n12
Reactant: C1CCNCC1
Product: Cc1cnc2c(N3CCCCC3)nc3ccccc3n12

Procedure:
By reaction of 4-chloro-1-methylimidazo[1,2-a]quinoxaline (example 2) with piperidine, according to a procedure that is similar to that followed in example 3, there is obtained 1-methyl-4-piperidinylimidazo[1,2-a]quinoxaline. m.p. (DSC)=78.9° C. (onset); IR (KBr): 3018, 2927, 1502 cm-1 ; 1H-NMR (CDCl3): δ8.05 (1H,dd), 7.65 (1H,dd), 7.5÷7.0 (3H,m), 4.25 (4H,t), 2.85 (3H,s), 1.9÷1.6 (6H,m); UV (EtOH): λmax =249, 281, 297, 310, 329 nm. Elementary analysis for C14H18N4 (m.w.266.35): calcd. C 72.15, H 6.81, N 21.03%; found C 71.84, H 7.09, N 20.70%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][N:23]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:15]([C:36]3[C:37]4[CH:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][CH2:42][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:31]1([N:23]([CH2:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[N:15]([C:36]4[C:37]5[CH:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][CH2:42][C:38]=5[N:39]=[CH:40][N:41]=4)[CH2:14][C:11]4([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:21]=23)[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN(C(=O)OC(C)(C)C)C5CCCC5)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)C1CCc2ncnc(N3CC4(CCNCC4)c4c(CN(C(=O)OC(C)(C)C)C5CCCC5)cccc43)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A solution of tert-butyl (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl(cyclopentyl)carbamate (0.095 g, 0.15 mmol) in MeOH (1 mL) was treated with Pd/C (0.0079 g, 0.0075 mmol) and ammonium formate (0.028 g, 0.45 mmol) and heated to reflux for 7 hours then stirred at room temperature overnight. The reaction was filtered through glass filter paper, and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (5% MeOH/DCM then 5% 7N NH4 in MeOH/DCM) to yield tert-butyl cyclopentyl((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)carbamate (0.066 g, 81%). LCMS (APCI+) m/z 546.1 [M+H]+; Rt=4.25 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([OH:36])[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([OH:36])[CH:35]=[C:30]([F:29])[CH:31]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 24 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (24 mg, 0.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.46 mol) according to the method described in Example 3 to give 17 mg (35% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Si:15]([O:22][CH2:23][CH2:24]O)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[C:18]([Si:15]([CH3:17])([CH3:16])[O:22][CH2:23][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CO[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCCO
Product: CO[C@@H](Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via the Mitsunobu coupling procedure with 2-(tert-butyldimethylsilanyloxy)ethanol (Standard Procedure B).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].C(NC(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1.C(OCC)(=O)C>[OH:17][C:15]([CH3:18])([CH3:16])[CH2:14][NH:13][C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: CC(C)(O)CN
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc([N+](=O)[O-])c(C(=O)NCC(C)(C)O)n1
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a suspension of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (0.9 g, 5.26 mmol) and 1-amino-2-methylpropan-2-ol (469 mg, 5.26 mmol) in THF (20 mL) cooled to 0-5° C. were added N,N-diisopropylamine (3.67 mL, 21.0 mmol) and 1-propanephosphonic acid cyclic anhydride (8.37 mL, 13.1 mmol, 50% solution in ethyl acetate). The mixture was stirred at 70° C. for 16 hours, cooled to ambient temperature, poured into ethyl acetate (50 mL) and extracted with HCl (1 M, 20 mL). The organic phase was washed with water and brine. The aqueous layers were back-extracted separately with ethyl acetate and dichloromethane. The combined organic layers were dried and concentrated in vacuo to give 1.4 g crude product. The crude material was purified by silica gel chromatography using a methanol/ethyl acetate gradient to give the title compound as colorless foam (391 mg, 31% yield).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([NH2:29])[CH2:6][C:7]1[CH:8]=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)C.[OH-].[Na+]>O1CCCC1>[NH2:29][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(N)Cc1cc(CP(=O)(OCC)OCC)cc(-c2ccc(Cl)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cc(CC(N)C(=O)O)cc(-c2ccc(Cl)cc2)c1)OCC

Procedure:
4.6 g (±)-α-amino-3-(4'-chloro-5-(diethoxyphosphinyl)methyl-[1.1'-bi-phenyl] -3-yl)propanoic acid ethyl ester, 1 equivalent of 1N sodium hydroxide and 4 parts by volume of tetrahydrofuran are stirred at room temperature for about 15 hours. The tetrahydrofuran is evaporated in vacuo. The residue is extracted with toluene/diethyl ether (1:1). The pH of the aqueous layer is adjusted to 5, whereby the heading compound crystallizes, m.p. 195°-205° (decomp.).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[CH:18]3[CH:21]([CH2:22][C:23]=2[S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]([CH:31]([OH:33])[CH3:32])[C:19]3=[O:34])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:25]1([S:24][C:23]2[CH2:22][CH:21]3[CH:18]([C:19](=[O:34])[CH:20]3[CH:31]([OH:33])[CH3:32])[C:17]=2[C:15]([OH:16])=[O:14])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3ccccc3)CC21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(O)C1C(=O)C2C(C(=O)O)=C(Sc3ccccc3)CC21
Yield: 80.4 %

Procedure:
A solution of 50 mg of 3-phenylthio-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid diphenylmethyl ester, and 50 mg of anisole in 1 mL of trifluoroacetic acid was stirred for 5 min at room temperature after which time the solvent was removed by evaporation. Trituration of the residue with ether-petroleum ether afforded 26 mg (80%) of 3-phenylthio-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid as colorless crystals. IR (Nujol mull): 1765, 1650, 1535 cm-1 ; NMR (220 MHz; CDCl3 /DMSO-D6): δ 1.18 (3H, d, J=6.5), 2.32 (1H, dd, J=19, 3.5), 2.67 (1H, m), 2.85 (1H, dd, J=19, 8), 3.07 (1H, m), 3.92 (1H, dq, J=6.5, 6.5), 4.41 (1H, m), and 7.3-7.6 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[C:9]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>CN(C)C=O>[CH2:14]([O:13][C:11]1[CH:12]=[C:2]([Cl:1])[C:3]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[C:9]([Cl:21])[CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCc3ccccc3)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A mixture of 0.5 g of 3-(2,6-dichloro-4-(benzyloxy)phenoxy)-1-propyl alcohol thus obtained, 0.1 g of an oily mixture containing 60% sodium hydride, and 3 ml of N,N-dimethylformamide was stirred at room temperature for 1 hour. Then, 0.3 g of 2-chloro-5-trifluoromethylpyridine was added to this mixture, followed by heating to 100° C. After stirring continued for 1 hour, the mixture was poured into 50 m of ice-water, and extracted with toluene at a total volume of 50 ml. The combined toluene layer was successively washed with diluted hydrochloric acid and aqueous sodium bicarbonate solution, dried with magnesium sulfate, and concentrated. The residue was silica gel chromatography, which afforded 0.5 g of 1-benzyloxy-3,5-dichloro-4-[3-(5-trifluoromethylpyridin-2-yloxy)propyloxy]benzene (67% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[NH2:22])[CH2:19]2.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[NH:22][C:8](=[O:10])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH2:19]2
Reactant: O=C(O)c1cccc(Br)n1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
After 6-bromopicolinic acid (500 mg, 2.48 mmol) was suspended in acetonitrile (25 ml), 2-adamantylamine hydrochloride (558 mg, 2.97 mmol), N,N-diisopropylethylamine (1.30 ml, 7.44 mmol), and HBTU (1.13 g, 2.97 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 602 mg of white solid (73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH2:36][CH:37]=[CH2:38])([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]=[CH2:17])=[CH:10][CH:9]=1>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([CH2:36][CH2:37][CH3:38])([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=1
Reactant: C=CCC(CC=C)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCC(CCC)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of 3-{4-[1-allyl-1-(4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoylamino}-propionic acid methyl ester (0.0731 g, 0.126 mmol) in EtOH (4.0 mL) is treated with 10% palladium on carbon (16 mg), flushed with hydrogen, and stirred under 1 atm pressure overnight. The mixture is then filtered through Celite® and concentrated to provide 0.0703 g (96%) of the title compound as a clear syrup. MS (ES): 84.4 [M+H]+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:10]=[CH:9][C:8]=1[C:23]([O:25]CC)=[O:24])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:20])([F:22])[F:21])[CH:13]=2)[N:10]=[CH:9][C:8]=1[C:23]([OH:25])=[O:24])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)c(C(F)(F)F)c2)c1C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1c(C(=O)O)cnn1-c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
A solution of Sodium hydroxide (6.67 mL, 13.34 mmol) was added in one portion to a stirred solution of ethyl 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate #120) (1 g, 2.67 mmol) in methanol (20 mL). The resulting suspension was stirred at 80° C. for 6 hours. The resulting mixture was evaporated to remove the methanol, washed with ether (20 mL). The reaction mixture was acidified with 2M HCl, extracted with ethyl acetate (2×30 mL) The organic layers were combined and washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and evaporated to afford pure 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylic acid (0.766 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C(O)=O>C(O)C.O>[Br:15][C:12]1[CH:13]=[N:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cn1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cn1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2-[bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine 10 (216 kg crude, 460 mol, assuming quantitative yield in previous step) in anhydrous ethanol (1692 L) was slowly added a solution of sodium hydroxide (55.2 kg, 1380 mol) in water (344 L) while maintaining the temperature at 0-20° C. The mixture was stirred at that temperature until the content of 2-[bis(tert-butoxycarbonyl)-amino]-5-bromopyrimidine (10) was ≦0.5% by HPLC. The reaction mixture was cooled to 0-5° C. and the pH was adjusted to 7 by addition of oxalic acid (86.0 kg, 955 mol) while maintaining the temperature below 5° C. The mixture was then distilled under vacuum to a volume of 500-600 L while controlling the temperature below 50° C. Water (800 kg) was added and the mixture was stirred for 1 h. The solid was collected by filtration and stirred with water (2×500 L). The resulting solid was collected by filtration and dried under reduced pressure at 50° C. to afford tert-butyl 5-bromopyrimidin-2-ylcarbamate 11 (107 kg, 85% yield over two steps). 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 2H), 8.12 (s, 1H), 1.55 (s, 9H). LCMS (ESI) m/z [M+H-Boc] 176
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:18]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 2-benzyloxybenzyl alcohol (4.83 g) in diethyl ether (40 ml) was added dropwise, at 0° C., a solution of phosphorus tribromide (6.27 g) in diethyl ether (10 ml). The mixture was warmed to ambient temperature, diluted with diethyl ether (100 ml) and filtered through a pad of silica gel washing with 1 litre of diethyl ether. The combined organic solution was washed with saturated aqueous sodium hydrogen carbonate (100 ml) and brine (100 ml), dried (sodium sulphate), filtered and evaporated to give 2-benzyloxybenzyl bromide (5.88 g) as an oil.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[NH:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]([CH2:21][CH:22]([CH3:26])[C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18]>C(=S)=S>[C:17]([CH2:21][CH:22]([CH3:26])[C:23]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[NH:3][CH:2]2[CH3:1])=[O:24])([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: CC1NC(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)C(C)NC(=O)N2
Temperature: 25 °C

Procedure:
3,4-Dihydro-4-methyl-2(1H)-quinazolinone (3.9 g) is added to a stirred suspension of anhydrous aluminum chloride (16.5 g) in carbon disulfide (120 ml) under nitrogen. 3-Carbomethoxy-2-methyl-propionyl chloride (4 g) is added dropwise to the stirred suspension, which is refluxed for about 17 hours and cooled to RT. The liquid phase is decanted and the residue is treated with ice/H2O (150 ml) and extracted with methylene chloride. The organic extract is dried, filtered, and concentrated in vacuo, affording the desired crude product as an oil, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH2:21]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH2:21][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1n[nH]c(=O)n1Cc1cc(Br)ccc1F
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 24.1 %

Procedure:
To a solution of 5.75 g (50 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 30 ml of acetonitrile was added 6.21 g (45 mmol) of potassium carbonate. A solution of 13.54 g of crude 5-bromo-2-fluorobenzylbromide in 50 ml of acetonitrile was added dropwise at 55° C. thereto. After the mixture was stirred at 55° C. for 2.5 hours, 1.15 g of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one and 1.24 g of potassium carbonate were added thereto and then the mixture was stirred at 55° C. for 3 hours. Water was added to the reaction mixture and the mixture was extracted with a mixed solvent of ethyl acetate and tert-butyl methyl ether. The organic layer was washed with water, dried and concentrated. Then, to the semisolid residue (13.37 g) was added a mixture of equal amounts of tert-butyl methyl ether and hexane, then stirred for a while and cooled. The resultant solid was collected by filtration to obtain 3.64 g of 4-(5-bromo-2-fluorobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.