Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH:9]=[CH2:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:12]([C:19]1[CH:20]=C([CH:24]=[CH:25][CH:26]=1)CO)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]CC.[Na+]>C1(C)C=CC=CC=1>[CH3:11][C:2]([CH3:1])([CH:9]=[CH2:10])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:24]=[CH:25][CH:26]=[C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=1)=[O:5]
Reactant: C=CC(C)(C)CC(=O)OCC
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(C)(C)CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 83.9 %

Procedure:
A mixture of 374 mg of ethyl 3,3-dimethyl-4-pentenoate, 400 mg of 3-phenoxybenzyl alcohol and 16 mg of sodium ethoxide in 10 ml of toluene was heated under reflux for 24 hours, with a Dean-Stark apparatus containing a molecular sieve to absorb the evolved ethanol. The mixture was neutralized by adding an anhydrous ether solution of hydrogen chloride. The neutral solution was poured into water. The ether layer was separated, dried over magnesium sulfate, and distilled to give 520 mg (70% yield) of 3-phenoxybenzyl 3,3-dimethyl-4-pentenoate, b.p. 155°-158°/0.3 mm.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:18](I)[CH3:19]>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH2:18][CH3:19])[CH:16]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=c1ccc(C2=CCC3(CC2)OCCO3)c[nH]1
Reactant: CCI
Product: CCn1cc(C2CCC3(CC2)OCCO3)ccc1=O

Procedure:
The title compound was prepared as a white solid from the ethylation of 5-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-1H-pyridin-2-one with EtI (Aldrich) using the procedure described in Step B of Example 38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][C@@H:8]([NH:15][S:16]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)(=[O:18])=[O:17])[C:7]1=[O:25].[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][C:10]([F:13])([F:14])[CH2:9][C@@H:8]([N:15]([CH2:40][C:37]2[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[S:16]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)(=[O:17])=[O:18])[C:7]1=[O:25]
Reactant: COc1ccc(CO)cn1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)s3)C2=O)c(OC)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC(F)(F)C[C@@H](N(Cc3ccc(OC)nc3)S(=O)(=O)c3ccc(Cl)s3)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-thiophene-2-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-amide (0.20 g, 0.40 mmol), (6-methoxy-pyridin-3-yl)-methanol (0.07 g, 0.48 mmol), triphenyl phosphine (0.22 g, 0.80 mmol) were dissolved in dry THF (15 ml) at 0-5° C. (ice-water bath) under an argon atmosphere followed by the dropwise addition of diisopropyl azodicarboxylate (0.16 ml, 0.80 mmol) in dry THF (1.5 ml). The reaction mixture was further stirred for 1 h at r.t. and then concentrated under reduced pressure. The crude oil was purified over silica gel (first: heptane-ethylacetate, 97:3-0:100; second: dichloromethane-methanol, 98:2-90:10): white solid 0.19 g (53%);
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[SH:16].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([S:16][C:12]2[NH:11][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: Sc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cncc1Sc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
A mixture of 3,5-dichloro-pyridine-4-carbaldehyde (600 mg, 3.41 mmol), 1H-imidazole-2-thiol (341 mg, 3.41 mmol) and Cs2CO3 (1.33 g, 4.09 mmol) in THF (10 mL) was stirred at RT for 8.5 h. The solvent was removed in vacuo and the residue was partitioned between EA (30 mL) and brine (30 mL). After extraction of the aqueous layer with EA (2×30 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 240.0 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][CH2:8][C:9]([O:11]C)=O)[CH2:2]1.[NH3:13]>CO>[NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][CH2:8][C:9]([NH2:13])=[O:11])[CH2:2]1
Reactant: COC(=O)CCC1CNCCO1
Reactant: N
Solvent: CO
Product: NC(=O)CCC1CNCCO1
Yield: 78 %

Procedure:
Methyl 3-(morpholin-2-yl)propanoate (0.58 g, 3.35 mmol) was reacted with a solution of NH3 in methanol (7 mol/L, 10 mL) according to the procedure as described in Example 25, Step A to give the title compound as brownish oil (0.41 g, 78%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:26])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH3:18])[CH2:7][O:6]1)=[O:4].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:1][O:2][C:3]([C:5]1([CH3:26])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:23][CH:24]=2)[CH3:18])[CH2:7][O:6]1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccc(O)cc2)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccc(OS(C)(=O)=O)cc2)CO1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To an ice cold solution of Methyl-5-{4-[1-(4-hydroxy-phenyl)-ethylideneaminooxy]-butyl}-2-methyl-[1,3]dioxane-2-carboxylate (prepared as per example 40) (200 mg) in anhydrous dichloromethane were added triethyl amine (82 mg) and methane sulfonyl chloride (75 mg) and the reaction mixture was stirred at the same temperature for about an hour. Reaction mixture was diluted with dichloromethane, washed with water, dried over sodium sulphate and evaporated under, reduced pressure on a rotavapor. Crude product was flash chromatographed over silica gel using 20% ethyl acetate in petroleum ether as eluent to obtain 200 mg of pure product.
Reaction SMILES: CSC.B.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](O)=[O:15]>O1CCCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=C(O)CCc1ccccc1F
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of borane dimethylsulfide complex (2M in THF, 27.6 mL) was added dropwise to a solution of 3-(2-fluorophenyl)propanoic acid (3.09 g) in tetrahydrofuran (25 mL) and the resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with methanol and, when bubbling had ceased, evaporated. Purification was by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a clear oil. Yield 2.72 g.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:49])(=O)=O.[CH:52]1(B(O)O)[CH2:54][CH2:53]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH:52]1([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:36])[CH3:37])[CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:49])[CH2:54][CH2:53]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C3CC3)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 67.9 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (81.7 mg, 0.109 mmol) was dissolved in dimethoxyethane (4.1 mL), and the solution was treated with cyclopropylboronic acid (28.0 mg, 0.327 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (7.1 mg, 0.0087 mmol), potassium carbonate (75.0 mg, 0.545 mmol) and water (0.058 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 4-cyclopropyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (47.7 mg, yield 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]3[N:16](S(C4C=CC=CC=4)(=O)=O)[C:17]([I:19])=[CH:18][C:9]=23)[CH:7]=1.[OH-].[Li+].Cl>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]3[NH:16][C:17]([I:19])=[CH:18][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(C#N)cnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(C#N)cnc2[nH]c(I)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 236C (3 g, 5.63 mmol) in 20 mL tetrahydrofuran and 20 mL methanol was added 2N lithium hydroxide (8.44 mL, 16.88 mmol) and the mixture was stirred at room temperature for 4 hours. The mixture was neutralized with 2N aqueous hydrochloric acid, extracted with ethyl acetate and purified by flash chromatography eluting with 0-50% ethyl acetate in heptane to afford the title compound. MS (ESI(+)) m/e 394 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH3:15])[CH3:2].Cl[CH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH3:34].[Na+].[I-].[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:14])[CH2:18][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:34])=[CH:9][C:8]=1[CH3:15])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Yield: 113.6 %

Procedure:
To an ice-cooled and stirred solution of (2-methyl-4-methylamino-phenoxy)-acetic acid ethyl ester (0.357 g, 1.6 mmol), 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.513 g, 1.76 mmol, WO02/28433) and NaI (0.24 g, 1.6 mmol) in DMF (4.8 ml) was added NaH (55% in oil, 0.105 g, 2.4 mmol). The reaction was stirred at RT for 2¾h, diluted with Et2O and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.87 g (quantitative) of crude (2-methyl-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester as a yellow solid, MS: 479 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[O:6].ClC1C=C(C=CC=1OCC)C=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]([OH:19])=[O:6]
Reactant: CCOc1ccc(C=O)cc1Cl
Reactant: CC(C)Oc1ccc(C=O)cc1Cl
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Yield: 98 %

Procedure:
When the 3-chloro-4-isopropoxybenzaldehyde was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49, Step A the identical process afforded the title compound in 98% yield, as a colourless solid. 1H-NMR (CDCl3) 1.4 (d, 6H, J=5.1 Hz); 4.67 (m, 1H); 6.95 (m, 1H); 7.96 (m, 1H); 8.10 (m, 1H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Br)[CH:17]=2)[C@H:12]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:11][C@@H:10]1[CH3:43])=[O:8])[CH3:5].O>CN(C)C=O>[CH2:4]([O:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][S:2][CH3:1])[CH:17]=2)[C@H:12]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:11][C@@H:10]1[CH3:43])=[O:8])[CH3:5]
Reactant: C[S-]
Reactant: CCOC(=O)N1c2cc(CBr)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1c2cc(CSC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
To a suspension of sodium thiomethoxide (11 mg, 0.156 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-bromomethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 90) (100 mg, 0.156 mmol), and the reaction was stirred for 6 h. The reaction mixture was then poured into water and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The excess N,N-dimethylformamide was azeotroped off with heptanes. Purification by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent afforded the title product (0.040 g, 42%): 1H NMR (CDCl3) δ 1.1 (d, 3H), 2.1 (s, 3H), 3.8 (m, 6H), 6.4 (s, 1H), 7.3 (s, 1H), 7.7 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])(=[O:16])=[O:15])[CH:5]=1.Br[CH2:28][CH2:29]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]2[O:12][CH2:29][CH2:28][N:13]([S:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])[C:6]=2[CH:5]=1)=[O:26]
Reactant: BrCCBr
Reactant: COC(=O)c1cc(NS(=O)(=O)c2cc(Cl)ccc2OC)c(O)c(OC)c1
Product: COC(=O)c1cc(OC)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=531.1 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methoxy-benzoic acid methyl ester (example 42, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.ClN1C(=O)CCC1=O.[CH:17]1([CH2:20][N:21]2[C:29]3[N:28]=[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([NH:37][CH3:38])=[CH:33][CH:32]=4)[NH:26][C:25]=3[C:24](=[O:39])[N:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:22]2=[O:48])[CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[CH:17]1([CH2:20][N:21]2[C:29]3[N:28]=[C:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([N:37]([CH3:38])[C:6]([C:4]5[N:3]=[N:2][S:1][CH:5]=5)=[O:8])=[CH:35][CH:36]=4)[NH:26][C:25]=3[C:24](=[O:39])[N:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:22]2=[O:48])[CH2:19][CH2:18]1
Reactant: O=C(O)c1csnn1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1csnn1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A mixture of [1,2,3]thiadiazole-4-carboxylic acid (29 mg, 0.30 mmol) in dichloromethane (6 mL) at 25° C. was treated with triphenylphosphine-polystyrene 100–200 mesh (372 mg, 0.46 mmol). This mixture was cooled to 0° C. and then treated with N-chlorosuccinimide (49 mg, 0.37 mmol). This mixture was stirred at 0° C. for 15 min and at 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (55 mg, 0.12mmol) and triethylamine (96 μL, 0.69 mmol). The reaction was then stirred at 25° C. for 3 days. At this time, the reaction was filtered to remove solids and rinsed with dichloromethane. The filtrate was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:99 methanol/dichloromethane) afforded [1,2,3]thiadiazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (17 mg, 24.7%): LR-MS for C27H24FN7O3S (M+H)+ at m/z=546.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:22][OH:23])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:23][CH2:22][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:21])[F:20])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 92 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.46 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(4-trifluoromethoxy-phenyl)cyclopropane (Example 11) (0.25 g), benzene (12 ml) and pyridine (0.09 ml) to yield the title compound (0.27 g, 92%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Na].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[N:9][N:8]=1>>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:4][CH2:1][C:2]#[CH:3])=[N:8][N:9]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C#CCO
Agent: [Na]
Product: C#CCOc1nnc(Cl)c2ccccc12
Temperature: 127 °C
Reaction time: 0.03 h
Yield: 15 %

Procedure:
To 2-propynol (3 mL) is slowly added sodium (70 mg, 3.04 mmol) followed by 1,4-dichlorophthalazine (400 mg, 2.01 mmol). The brown suspension obtained is stirred under argon for 2 min and then heated at 121-133° C. for 2 h. Excess 2-propynol is removed under vacuum, and the residue is diluted with cold water and then extracted with CHCl3 (120 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (25% to 50% ethyl acetate/hexane) to give 66 mg (15%) of 2 as a cream solid, mp 134-136° C. IR 2882, 1404, 1292 cm−1; 1H NMR (CDCl3) δ 2.61 (t, J=2.4 Hz, 1H, C≡CH), 5.33 (d, J=2.4 Hz, 2H, CH2C≡CH), 7.94-8.04 (m, 2H, 6,7-PhthH), 8.24 (m, 5-PhthH), 8.31 ppm (m, 8-PhthH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12

Procedure:
18 mg (0.28 mmol) of copper powder were added to 12.2 g (27.5 mmol) of the compound from Example 13A in 200 ml of pyridine and 55 ml of ethanol. The reaction mixture was heated under reflux for 4 h. It was concentrated, and the residue was taken up in dichloromethane, washed with water, 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient). 6.68 g (56% of theory) of the target compound were obtained.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:29]5[CH2:30][CH2:31][N:27]([CH3:26])[C:28]5=[O:32])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCN(C)C3=O)cn2)CC1
Yield: 54.7 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 243 and 1-methylimidazolidin-2-one (56 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (86 mg) was obtained.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:11][C:12](=O)[C@H:13]([OH:31])[CH2:14][C@H:15]([NH2:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:19][CH:18]=1)C.Cl.O1CCOCC1>>[CH2:1]([O:8][C:12](=[O:11])[C@H:13]([OH:31])[CH2:14][C@H:15]([NH2:30])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
Benzyl alcohol (13.0 mL, 126 mmol) was added to (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (1.9 g, 5.3 mmol) followed by 4.0 M HCl in 1,4-dioxane (5.3 mL, 21.3 mmol), and the mixture was stirred at 60° C. for 1 hour. The mixture was purified (Interchim reverse phase chromatography column; 30-90% MeCN in water with 0.05% TFA) to yield (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-pentanoic acid benzyl ester (2.2 g) as a white solid. (evaporated in vacuo with water (4×300 mL) to remove excess benzyl alcohol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][O:6][C:7](=[O:34])[C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:9]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][O:6][C:7](=[O:34])[C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:9]
Reactant: COc1ccc(COC(=O)[C@H](Cc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c(OC)c1
Solvent: ClCCl
Solvent: CCNCC
Product: COc1ccc(COC(=O)[C@@H](N)Cc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500-mL round-bottom flask was charged with Fmoc-L-phenylalanine-2,4-dimethoxybenzyl ester (26.00 g, 48.3 mmol), CH2Cl2 (150 mL) and diethylamine (75 mL, Acros). Mixture was stirred at room temperature and the completion monitored by HPLC. After 4 h, the mixture was concentrated (bath temp<30° C.). The residue was resuspended in CH2Cl2 (200 mL) and concentrated. This was repeated once. To the residue was added MeOH (20 mL), which caused the formation of a gel. This residue was diluted with CH2Cl2 (200 mL), concentrated and the cloudy oil left under vacuum overnight. The residue was suspended in CH2Cl2 (100 mL), then toluene (120 mL) was added. The mixture was concentrated and the residue left under vacuum overnight.