Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(NCC(O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 14, 1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester, according to the procedure of Example 1 as an off-white solid; mp 74-83° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.10-1.20 (m, 6H), 1.20-1.90 (m, 8H), 2.60-3.40 (m, 6H), 3.80-4.10 (m, 6H), 4.85-4.95 (m, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 6.84 (t, 2H), 7.00 (d, 2H), 7.57 (d, 2H), 10.57 (br s, 1H), 10.70 (br s, 1H); MS (ES) m/z: 602.1 (MH+); HRMS Calcd. for C29H40N5O7S (MH+): 602.2634. Found: 602.2642.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=1)=[O:5].[OH-].[K+].C(O)C>O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)c2ccccc2Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(NC(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
A mixture of 1.52 g of ethyl 2-(2-chlorobenzoyl)amino-1,3-thiazole-4-carboxylate, 0.68 g of potassium hydroxide, 1.8 mL of water and 9 mL of ethanol was stirred at room temperature for 4 hrs. After the reaction mixture was diluted with water, it was washed with ethyl acetate. The separated aqueous phase was acidified with an aqueous 2N-hydrochloric acid solution and the precipitated crude product was washed with water and dried to obtain 0.96 g of the aimed 2-(2-chlorobenzoyl)amino-1,3-thiazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: COCOc1ccc(Br)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Yield: 74.2 %

Procedure:
To a degassed solution of 1-bromo-4-(methoxymethoxy)benzene (360 mg, 1.66 mmol), pyridin-4-ylboronic acid (307 mg, 2.50 mmol), and Cs2CO3 (1.09 g, 3.35 mmol) in THF (5 mL) was added Pd(PPh3)4 (190 mg, 0.16 mmol). The reaction mixture was heated at 80° C. overnight and diluted with EtOAc (50 mL). It was washed with H2O (2×25 mL), dried over Na2SO4, and concentrated. Purification on a silica gel column gave the desired product as a white solid (265 mg). NMR (CDCl3): 8.63 (d, 2H), 7.67 (d, 2H), 7.47 (d, 2H), 7.16 (d, 2H), 5.24 (s, 2H), 3.52 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br.[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][P:16](=[O:20])([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14]
Reactant: BrCCCc1ccccc1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccccc1CCCBr)OCC
Yield: 83 %

Procedure:
In a round bottom flask equipped for distillation, 11.36 g (38.9 mmol) of 2-(3-bromopropyl)benzyl bromide and 6.46 (38.9 mmol) of freshly distilled triethylphosphite were heated with stirring at 100°-110° C. on an oil bath. When ethyl bromide ceased distilling off (about 2 h) the remaining volatile by-products and the triethylphosphite were removed from the mixture by distillation under vacuum. The remaining oil was chromatographed on a column of silica gel with hexame-ethyl acetate (1:1) as eluant. The combined fractions were concentrated under reduced pressure to yield 11.2 g (83%) of the product as a clear oil. IR(neat): 2985, 1496, 1450, 1391, 1252, 1162, 104, 967, 843, 802, 758 cm-1. 1H NMR(CDCl3) δ 1.2 (t, 6); 1.8-2.3 (m, 2H); 2.7-3.55 (m, 4H); 3.8-4.2 (m, 2H); 7.1-7.4 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O.CCOCC>[Si:8]([O:6][CH:4]([CH3:5])[CH2:3][CH:2]([OH:7])[CH3:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(O)CC(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(O)CC(C)O[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a solution of 1.00 g (9.60 mmol) 2,4-pentanediol in 9 mL dimethylformamide was added 1.52 g (10.1 mmol) t-butyldimethylsilyl chloride and 915 mg (13.4 mmol) imidazole. The solution was stirred for 12 hrs, diluted in 100 mL of ether, and washed 5×, each with 2 mL water. The organic phase was dried over MgSO4, filtered, and concentrated. Chromatography on a 2×18 cm column, packed with hexane and eluted with 100 mL each of 5%, 10%, and 25% ethyl acetate/hexane provided 1.192 g of a clear colorless oil in 10 mL fractions 6-14.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][OH:27])=[C:20]([F:28])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]>O.CO>[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:25][CH2:26][OH:27])=[O:2])=[C:20]([F:28])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SCCO)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(S(=O)CCO)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium periodate (0.014 g, 0.065 mmol) in water (0.5 mL) was added to 5-(S)-acetamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]-oxazo-lidine-2-one (0.020 g, 0.061 mmol) in methanol (1 mL), and the mixture was stirred at r.t. overnight. Solvent was removed under vacuum, and the residue dissolved in ethyl acetate (ca. 5 mL). Resulting solution was washed with water, brine, and dried (MgSO4). Solvent was removed under vacuum, and the crude product purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.018 g (86%). MS (m/z): 345 [M+H]+. 1H NMR.
Reaction SMILES: FCC1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])C=1.[F:38][CH2:39][CH2:40][CH2:41][C:42]#[CH:43].FCC#C>>[F:38][CH2:39][CH2:40][CH2:41][C:42]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])[CH:43]=1
Reactant: O=C1C(=O)N(Cn2cc(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Reactant: C#CCCCF
Agent: C#CCF
Product: O=C1C(=O)N(Cn2cc(CCCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
is prepared according for the procedure for compound 6, with the exception that 5-fluoropent-1-yne is used in place of the (3-fluoroprop-1-yne). For the preparation of [18F]8, 5-[18F]fluoropent-1-yne is used in place of 3-fluoroprop-1-yne.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[S:43][CH:42]=[N:41][CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[S:43][CH:42]=[N:41][CH:40]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cncs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[Si:5](Cl)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.2 %

Procedure:
To a solution of 2-bromoethanol (5.0 g, 40.3 mmol) in DCM (20 mL) was added tert-butyldimethylsilyl chloride (9.1 g, 60.5 mmol) followed by the additions of triethylamine (8.14 g, 80.6 mmol) and 4-dimethylaminopyridine (49.2 mg, 0.4 mmol). The mixture was stirred at room temperature for 15 h and concentrated in vacuo. The residue was partitioned between 1N HCl and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford yellow oil, which was purified by column chromatography eluting with PE:EA (50:1) to afford 123a as colorless oil (6.0 g, 62.4%). LCMS: (M+H)+ 241.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH3:8])[N:3]=1.[C:9]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:33](O)=[O:34])[CH3:32])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:8][O:7][C:4]1[N:3]=[C:2]([NH:1][C:33](=[O:34])[C@H:31]([CH3:32])[NH:30][C:28](=[O:29])[C@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[S:6][N:5]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1nsc(N)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nsc(NC(=O)[C@H](C)NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-3-methoxy-[1,2,4]thiadiazole (0.37 g, 2.8 mmol) and N-carbobenzyloxy-L-phenylalanyl-L-alanine, N-Cbz-Phe-Ala-OH, (1.0 g, 2.7 mmol) in DMF (25 mL) was added 1,3-dicyclohexylcarbodiimide, DCC, (0.56 g, 2.7 mmol). After stirring for 30 min, 1-hydroxybenzotriazole hydrate, HOBT, (0.36 g, 2.7 mmol) was added and the resulting mixture was stirred at room temperature for 20 h. Volatile materials were removed in vacuo and the residue was purified by column chromatography on silica gel using a solvent mixture of dichloromethane and methanol (96/4) thereby affording the title compound as a white solid (1.2 g). Further purification by cristallization and chromatography on silica gel gave 3-methoxy-5-(N-carbobenzyloxy-L-phenylalanyl-L-alaninamido]-[1,2,4]thiadiazole (0.87 g, 67% yield). M.p. 161-162° C.; 1H-NMR (CDCl3) 7.14-7.38 (m, 12H, 10Ar—H and 2 NH), 5.92 (br. s, 1H, NH), 5.06 (s, 2H, OCH2), 4.38 (m, 1H, CHCH2Ar), 4.00 (m, 1H, CHCH3), 3.97 (s, 3H, OMe), 3.00-3.08 (m, 2H, CHCH2Ar), 1.34 (d, J=8.9 Hz, 3H, Me); MS (m/z) 484 (M++1), 416, 361, 316, 285, 185, 132, 75. The latter compound was also prepared by using diphenylphosphoryl azide and triethylamine instead of DCC/HOBT in 27.7% yield.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.CO[C:10]([CH:12]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)[CH2:13][CH:14]=[CH2:15])=[O:11]>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:13]([CH:12]1[N:16]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:21][CH2:22]2)[C:6](=[O:7])[NH:5][C:10]1=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCC(NC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OC
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C=CCC1C(=O)NC(=O)N1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Yield: 80.5 %

Procedure:
Trimethylsilyl isocyanate (1.66 g, 14.4 mmol) was added to a solution of benzyl 4-{[1-(methoxycarbonyl)but-3-en-1-yl]amino}piperidine-1-carboxylate (2.00 g, 5.77 mmol) and DMAP (71 mg, 0.57 mmol) in THF (30 mL) at room temperature. The reaction was heated at 50° C. for 48 h. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with methylene chloride (3×), dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by chromatography (silica gel, 0 to 20% methanol in methylene chloride gradient elution), which gave the title compound (1.66 g). MS 358.2 (M+1).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.CCOC(/N=N/C(OCC)=O)=O.[CH2:37]([O:39][C:40](=[O:60])[C@@H:41]([OH:59])[CH2:42][CH2:43][C:44]1[C:45](O)=[N:46][C:47]([NH:51][CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:48][C:49]=1[OH:50])[CH3:38]>CN(C=O)C>[OH:50][C:49]1[C:44]2[CH2:43][CH2:42][C@H:41]([C:40]([O:39][CH2:37][CH3:38])=[O:60])[O:59][C:45]=2[N:46]=[C:47]([NH:51][CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[N:48]=1
Reactant: CCOC(=O)[C@@H](O)CCc1c(O)nc(NC2CCOCC2)nc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CCc2c(O)nc(NC3CCOCC3)nc2O1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A flask was charged with PPh3 (0.807 g, 3.08 mmol), anhydrous THF (20 mL) and DEAD (0.655 g, 3.08 mmol). The solution was stirred for 10 min under N2 then a solution of 400, THF (5 mL) and DMF (5 mL) was added and solution stirred 18 h. The solution was concentrated in vacuo to afford an orange oil. The crude product was purified by reverse phase chromatography (SP4 biotage 40M C18 using a C18 Biotage 40 samplet) and eluted with a MeCN/H2O gradient (0-60% MeCN) to afford a light yellow oil which solidified under high vacuum. The crude product was re-purified by SiO2 chromatography (SNAP 25) eluting with DCM/MeOH (95:5) to afford 0.42 g (60%) of Obtained (R)-ethyl 4-hydroxy-2-(tetrahydro-2H-pyran-4-ylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-7-carboxylate (402) as a clear oil: m/z (APCI-pos) M+1=324.0
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:9]1[CH:30]=[CH:29][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.C1(C)C=CC=CC=1>CC(N(C)C)=O>[O:7]([C:9]1[CH:30]=[CH:29][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccc(C#Cc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1
Temperature: 23 °C
Yield: 96.3 %

Procedure:
A 100 mL flask equipped with nitrogen inlet, overhead stirring assembly, Dean-Stark trap, and reflux condenser was charged with phenol (0.35 g, 0.0038 mol), 4-fluoro-4'-phenylethynylbenzophenone (0.10 g, 0.0038 mol) potassium carbonate (0.39 g, 0.003 mol), 25 mL of toluene, and 50 mL of DMAc. The mixture was heated to reflux and water was removed by azeotropicdistillation, followed by the removal of toluene over a 20 hour period. Thereaction was cooled to 23° C., and the mixture was poured into 1 L of acidic (HCl) water. The precipitate was collected by filtration to afford 1.37 g (96%) of 4-phenoxy-4'-phenylethynylbenzophenone as a white powder: mp 165.5° C. IR (KBr): 2216 cm-1 (ethynyl), 1650 cm-1 (carbonyl): 1H-NMR (CDCl3): 7.8-6.8 pp, (m H aromatic). Anal Calcd. for C27H18O2: %C=86.61, %H=4.85. Found: %C=86.46, %H=4.68. The structure of this compound is given below: ##STR10##The DSC thermogram of this compound is presented in FIG. 3.
Reaction SMILES: [OH-:1].[K+].Br.[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][C@@H:17]([C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16]3)=[CH:12][C:7]=2[CH2:6][CH2:5]1.O>CC(O)(CC)C>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][C@@H:17]([C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]([NH2:22])=[O:1])[CH2:16]3)=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Agent: Br
Agent: [K+]
Solvent: O
Solvent: CCC(C)(C)O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A slurry of potassium hydroxide (48.7 g, 0.87 moles) in 2-methylbutan-2-ol (175 mL) is heated at 50-60° C. After 1 hour (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile hydrobromide (VI) (25.0 g, 0.051 moles) is added and the resulting mixture is heated at reflux for 20 hours. The reaction mixture is cooled to ambient temperature and water (125 mL) is added maintaining the temperature below 30° C. The mixture is stirred for 15 minutes, then allowed to settle and the organic phase is separated. The organic phase is washed with aqueous sodium chloride (125 mL of 5% w/w solution) to provide a solution of (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide as a solution in 2-methylbutan-2-ol (VII). The solution is heated at reflux in the presence of Amberlite® resin (37.5 g) for 22 hours then cooled to ambient temperature. The Amberlite® resin is removed by filtration and washed with 2-methylbutan-2-ol (25 mL). The combined 2-methylbutan-2-ol phases are concentrated and essentially replaced by toluene to a final volume of approximately 140 mL. The toluene solution is cooled to 0° C. during which time crystallisation occurs. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide toluene solvate (VIII) is collected by filtration, washed with chilled toluene (25 mL) and dried at 35° C. under vacuum. Yield (22.2 g, 84%).
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:11])[CH3:10])[C:4]([O:6]CC)=O)#[N:2].[CH2:12]([NH:14][C:15]([NH2:17])=[O:16])[CH3:13].[O-]CC.[Na+].Cl>C(O)C.O>[CH2:12]([N:14]1[C:1]([NH2:2])=[C:3]([CH:9]([CH3:10])[CH3:11])[C:4](=[O:6])[NH:17][C:15]1=[O:16])[CH3:13]
Reactant: CCOC(=O)C(C#N)C(C)C
Reactant: CCNC(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCn1c(N)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 12.25 h
Yield: 39.3 %

Procedure:
A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 10.0 g, 64.4 mmol), ethyl urea (3a, 5.96 g, 67.6 mmol) and EtOH (129 mL). To the slurry at room temperature was added sodium ethoxide in ethanol (21% w/w soln, 28.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4 to 12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×20 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10 white to off-with solids began forming and as the pH was further reduced to 9 (by pH paper) white slurry resulted. This slurry was aged for 0.5-24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40-50° C. giving 4.99 g (39%) of 1-ethyl-5-isopropyl-6-amino uracil 2:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C([O:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](O)=[O:18])(=O)C>CC(C)=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10])[NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[OH:14]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccccc1O
Yield: 100.1 %

Procedure:
2,6-Dichloro-4-aminophenol (0.37 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. While mixing, an acetone solution (10 ml.) of the acid chloride prepared from acetylsalicylic acid (0.38 g.) was added by drops. After the reaction was completed, the solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and then was washed with water then with 1N-hydrochloric acid. After evaporating off the ethyl acetate under reduced pressure the resulting residue was dissolved in a mixture of methanol and 2N-sodium hydroxide (10 ml. each). The solution was agitated for several hours then acidified with 2N-hydrochloric acid to precipitate the product. By recrystallization in acetone-water, white needle-like crystals of 3',5'-dichloro-2,4'-dihydroxybenzanilide (0.62 g.) were obtained. The yield was 78% and the melting point was 217°-219° C.
Reaction SMILES: [C:1]([C:5]1[CH:46]=[CH:45][C:8]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[CH:40][CH:39]=4)=[CH:36][N:37]=3)=[CH:28][CH:27]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[O:10])=[CH:45][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CCCCBr
Reactant: CC(C)(C)OC(=O)CCNC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Product: CC(C)CCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCCC(=O)OC(C)(C)C)cc3)nc2)cc1

Procedure:
Prepared using General Procedure 12 from tert-butyl (S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate and 1-bromo-5-methyl hexane. LCMS-ESI (m/z) calculated for C44H56N4O5: 720.9. found 721.4 [M+H]+, tR=5.39 min. (Method 16).