Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[Br:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([Cl:29])[CH:19]=1>N1C=CC=CC=1.Cl.C(OCC)(=O)C>[Br:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([S:25]([NH:14][CH:3]([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[C:2]([F:1])([F:15])[F:16])(=[O:26])=[O:27])=[C:20]([Cl:29])[CH:19]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1c(Cl)cc(Br)cc1Cl
Temperature: 65 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 170 mg (0.75 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 243 mg (0.75 mmol) of 4-bromo-2,6-dichlorobenzensulfonyl chloride in 4 mL of pyridine was warmed at 65° C. The reaction was monitored by TLC indicating a new less polar product compared to amine. After 16 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with 1 N aqueous hydrochloric acid until acidic and extracted with ethyl acetate. The combined organic layers were washed with 1 N aqueous HCl, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by preparative TLC using EtOAc-hexanes (15:85). Material from the preparative TLC was isolated by suspending the silica gel in ethyl acetate followed by filtration. The filtrate was concentrated in vacuo to afford 112 mg (30%) of the title compounds as an off-white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([CH3:22])=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:33]1C[C@@H](N)C[C@H]1C1OC=CN=1)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:33])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([CH3:22])=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc([C@@H]2C[C@@H](O)CN2C(=O)OCc2ccccc2)o1
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Product: Cc1cnc([C@@H]2C[C@H](N)CN2C(=O)OCc2ccccc2)o1

Procedure:
(2S,4S)-4-Amino-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-4-hydroxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester. MS calcd. for C16H20N3O3 [(M+H)+] 302, obsd. 302.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[O:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=2)=[N:11][N:10]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[C:23]([O:22][C:21](=[O:27])[NH:20][C:16]1[CH:15]=[C:14]([C:12]2[O:13][C:9]([S:8][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=3)=[N:10][N:11]=2)[CH:19]=[CH:18][N:17]=1)([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2nnc(S)o2)ccn1
Reactant: Fc1cccc(CBr)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Yield: 93 %

Procedure:
In the same manner as in Example 1 and using tert-butyl [4-(5-mercapto-1,3,4-oxadiazol-2-yl)-2-pyridyl]carbamate triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 93%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[N+:21]([O-])=O)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C>[Fe].O1CCOCC1>[C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[NH2:21])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(C=Cc1ccccc1)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: C1COCCO1
Product: Nc1ccc(OC(=O)C=Cc2ccccc2)c(N)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
62.8 g (200 milimole) of 2,4-dinitrophenyl cinnamate, 15 g of activated charcoal with 5% Pt and 2% iron (product with water content of about 50%), and 500 ml of 1,4-dioxane were placed in a reaction vessel (hydrogenating apparatus), and then the reaction mixtures were heated at 60° C. with stirring under a hydrogen atmosphere. In approximately 2 hours, 29 L of hydrogen was absorbed, and the reaction was completed when the absorption of hydrogen stopped. Then the reacted solution was separated by filtration to remove the catalyst. The filtrate was concentrated, and 50.8 g of 2,4-diaminophenyl cinnamate was yielded. The exothermic peak temperature was 230° C.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[N:40]1([C:48](=O)[CH2:49]Cl)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:48][CH2:49][O:10][C:8]2[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:35][CH:34]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1cc(NCCCc2ccc(OCCN3CCCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 11.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 1-azocan-1-yl-2-chloroethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.2 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][CH2:6][OH:7])[CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH2:5][CH:3]2[CH2:4][O:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1COC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2COC2)cc1
Temperature: 0 °C
Yield: 56.2 %

Procedure:
Using the same reaction conditions and procedure as described for the preparation of Intermediate (I-16a), 2-(oxetan-3-yl)ethanol (1 g, 6.944 mmol) was reacted with p-Toluene sulfonyl chloride (1.9 g, 10.416 mmol) in dry pyridine (10 mL) to afford the crude product. The reaction mass was poured into ice-water and extracted using ethyl acetate. The organic layer was washed with 1N HCl, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 1 g of the product (40% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-ethylamine, (0.055 g, 0.21 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.046 g, 0.30 mmol) and DIPEA (0.07 mL, 0.38 mmol) in IPA (1.5 mL) was stirred at 80° C. in a sealed tube for 16 h. After cooling, the reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) to give 418 as a white solid (0.060 g, 75%). LCMS (Method K): RT 2.94 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.12 (1H, s), 7.96 (1H, s), 7.70-7.60 (3H, m), 7.25 (2H, s), 7.09 (1H, m), 6.96 (1H, m), 5.46 (1H, m), 3.88 (3H, s), 1.51 (3H, d, J=6.85 Hz)
Reaction SMILES: [N:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]1[OH:13])=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]1[OH:13]
Reactant: [N-]=[N+]=NC1Cc2ccccc2[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: NC1Cc2ccccc2[C@@H]1O
Reaction time: 8 h

Procedure:
To (S)-2-azido-indan-1-ol (9.39 mmol) in EtOH (45 mL) was added 10% palladium on carbon (0.20 g), and the mixture was stilled under H2 using a Parr apparatus for 4 hours. Analytical LCMS indicated that some starting material was still present, so additional 10% palladium on carbon (0.20 g) was added, and the reaction was stirred overnight under H2 using a Parr apparatus. The mixture was filtered over a pad of Celite and rinsed well with EtOH. The filtrate was concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:7](=[O:12])[O:6][CH2:5]2.[CH:14]([B-](F)(F)F)=[CH2:15].[K+]>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:11][C:9]1[CH:10]=[C:2]([CH:14]=[CH2:15])[C:3]([CH3:13])=[C:4]2[C:8]=1[C:7](=[O:12])[O:6][CH2:5]2
Reactant: C=C[B-](F)(F)F
Reactant: Cc1c(Br)cc(F)c2c1COC2=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1cc(F)c2c(c1C)COC2=O

Procedure:
A mixture of 5-bromo-7-fluoro-4-methyl-3H-isobenzofuran-1-one (0.6 g, 2.45 mmol), potassium vinyltrifluoroborate (492 mg, 3.67 mmol) and Pd(dppf)Cl2 (100 mg) in 20 mL of TEA and 20 mL of EtOH was heated to reflux under N2 for 4 hrs and then concentrated. The resulting oil was purified by prep-TLC to give 7-fluoro-4-methyl-5-vinyl-3H-isobenzofuran-1-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[OH:21].[C:22](O)(=O)C.C=O.C([BH3-])#N.[Na+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:22])[C:9]2[CH:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[OH:21]
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2ccn(-c3ccccc3)n2)cc(C)c1O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(N(C)c2ccn(-c3ccccc3)n2)cc(C)c1O

Procedure:
To 2,6-dimethyl-4-(1-phenyl-1H-pyrazol-3-yl)amino phenol (8 g), acetic acid (2.8 ml), and aqueous 40% formaldehyde (3.1 ml) in acetonitrile (40 ml) was added sodium cyanoborohydride (5.4 g). After 2 hours the mixure was quenched with water and extracted with dichloromethane. The organic phase was washed with aqueous sodium bicarbonate solution, then water, dried, evaporated and chromatographed (silica, dichloromethane) to give the title product (3 g), mp 139°-140° (from ethanol).
Reaction SMILES: [CH2:1]([C:3]1([OH:18])[C:13]2[C:8](=[C:9]([O:15]C)[N:10]=[C:11]([I:14])[CH:12]=2)[CH2:7][O:6][C:5](=[O:17])[CH2:4]1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C.O.[O-]S([O-])=O.[Na+].[Na+].[Cl-].[Na+].O>C(#N)C>[CH2:1]([C:3]1([OH:18])[C:13]2[CH:12]=[C:11]([I:14])[NH:10][C:9](=[O:15])[C:8]=2[CH2:7][O:6][C:5](=[O:17])[CH2:4]1)[CH3:2]
Reactant: CCC1(O)CC(=O)OCc2c1cc(I)nc2OC
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: CCC1(O)CC(=O)OCc2c1cc(I)[nH]c2=O
Temperature: 60 °C
Yield: 60.5 %

Procedure:
To a flame dried flask was added iodolactone (8) (0.33 g, 0.90 mmol) followed by dry acetonitrile (12 mL). Sodium iodide (0.22 g, 1.44 mmol) was added followed by chlorotrimethylsilane (0.18 mL, 1.44 mmol). The resulting mixture was stirred at 22° C. for 15 minutes at which point H2O (7.6 μL, 0.42 mmol) was added and the mixture was heated at 60° C. After 5 hours at 60° C. the mixture was poured into a 1:1 solution of 5% Na2SO3/Brine (75 mL) and then quickly extracted with EtOAc (6×75 mL). The organic layer was dried (MgSO4) and chromatographed (CH2Cl2:MeOH 95:5) to yield iodopyridone (9) as a white solid 0.19 g (61%): 1H NMR (300 MHz, CDCl3/CD3OD) δ 0.62 (t, J=7 Hz, 3H), 1.45-1.54 (m, J=7 Hz, 2H), 2.80 (d, J=14 Hz, 1H), 2.97 (d, J=14 Hz, 1H), 4.93 (d, J=15 Hz, 1H), 5.06 (d, J=15 Hz, 1H), 6.66 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 7.5, 35.6, 41.9, 61.6, 72.5, 94.4, 118.3, 121.1, 156.5, 162.6, 172.7; HRMS (EI) m/z calcd for C11H12INO4 (M+) 348.9811, found 348.9815 LRMS (EI) m/z 349 (M+), 331, 320, 303, 289, 278, 264, 250, 162, 150, 122, 94, 57.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]3)O1.C(OCC)(=O)C.Cl>O.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:11][CH2:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]3)=[CH:3][CH:4]=1
Reactant: OCC#Cc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc3cc(O)ccc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCC#Cc1ccc(-c2ccc3cc(O)ccc3c2)cc1

Procedure:
13.0 g (0.047 mol) of sodium metaborate octahydrate are initially introduced in 100 ml of water, and a solution of 7.00 g (33.1 mmol) of 3-(4-bromophenyl)prop-2-yn-1-ol (CAS No. 37614-58-7) and 9.00 g (33.3 mmol) of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (CAS No. 269410-21-1) in 200 ml of THF is added. After addition of 1.00 g (1.40 mmol) of bis(triphenylphosphine)palladium(II) chloride, the batch is heated under reflux for 5 h, 100 ml of ethyl acetate are subsequently added, and the mixture is acidified using 2 M hydrochloric acid. The org. phase is separated off, dried over sodium sulfate and evaporated. The residue is filtered through silica gel with toluene/ethyl acetate (3:2), and the crude product is recrystallised from toluene/ethyl acetate, giving 6-[4-(3-hydroxyprop-1-ynyl)phenyl]naphthalen-2-ol as a colourless solid.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1.[NH4+].[OH-]>CS(C)=O>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:2]#[N:3])=[N:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc(C(F)(F)F)cn1
Temperature: 180 °C

Procedure:
Copper (I) cyanide (14.1 g) and 2-bromo-5-trifluoromethylpyridine (3.00 g, 13.3 mmol) in dry DMSO (70 mL) were combined and heated at 180° C. for 2 hours, cooled, and poured into NH4OH (3M). The mixture was then extracted with ethyl acetate (3×500 mL), washed with water (1×200 mL), dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO, 300 MHz) δ 8.22 (m, 1H), 8.42 (m, 1H), 9.01 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[H-].[Na+].[Cl:30][CH2:31][C:32](Cl)=[O:33]>CCOCC>[Cl:30][CH2:31][C:32]([N:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[N:14]=[N:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])=[O:33]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N#Cc1ccc(C(F)(F)F)cc1N=NN(C(=O)CCl)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 1 h

Procedure:
A solution of 10.0 g. (0.026 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene and 1.8 g. (0.037 mol.) of 50% sodium hydride in ether is added to a solution of 3.2 g. (0.028 mol.) of α-chloroacetyl chloride in 25 ml. of ether. The reaction mixture is stirred at 25° for one hour then filtered. The filtrate is concentrated under reduced pressure to give 3-(2-chloroacetyl)-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene as an oil which crystallizes upon trituration with isopropyl ether, m.p. 98°-100°.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2([CH3:21])SC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]2[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC1(C)C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: CC1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Reaction time: 2 h
Yield: 89 %

Procedure:
A stirred solution of 8 g. (0.027 mole) of 7-benzoyl-3-methyl-3-methylthioindolin-2-one in 80 ml. of tetrahydrofuran was treated under N2 with 40 g. of a commercial Raney nickelwater mixture over a 2 hr. period. At the end of this period the mixture was filtered and the residue washed thoroughly with tetrahydrofuran. One drop of concentrated hydrochloric acid was added to the filtrate and the dark orange solution turned pale yellow. The solution was stripped under vacuum to a yellow oil which crystallized on seeding. The material was recrystallized from toluene petroleum ether to give a white crystalline material. The solid (6.0 g., 89% yield) melted at 125°-127° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([C:16]([OH:18])=O)=[CH:3]1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][NH:38][C:37]1=[O:42].C(N(CC)CC)C.C(NC1CCCCC1)(NC1CCCCC1)=O>CN(C)C=O.ON1C2C=CC=CC=2N=N1>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][NH:5][C:4]([C:16]([NH:35][N:36]2[CH2:41][CH2:40][CH2:39][NH:38][C:37]2=[O:42])=[O:18])=[CH:3]1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: NN1CCCNC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NN1CCCNC1=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reaction time: 1 h
Yield: 128.9 %

Procedure:
To a solution of 4.7 g. (19.2 mmol) 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid in 50 ml N,N-dimethylformamide was added 4.74 g (23 mmol) dicyclohexylcarbodiimide and 0.29 g (1.92 mmol) N-hydroxybenzotriazole. The mixture was stirred for 1 hour. To this was added a solution of 2.85 g (19.2 mmol) 3-aminotetrahydro-2(1H)-pyrimidinone, monohydrochloride and 1.94 g (19.2 mmol) triethylamine in 30 ml N,N-dimethylformamide. After stirring overnight the dicyclohexylurea was filtered off and the N,N-dimethylformamide evaporated in vacuo. The residue was triturated with ether to yield 8.47 g of the desired product (contained dicyclohexylurea). This crude material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C1COCC1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[N:4]=[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:2]([C:34]([C:33]2[CH:37]=[C:38]([S:41][CH3:42])[CH:39]=[CH:40][C:32]=2[Cl:31])=[O:35])=[CH:7][N:6]=1
Reactant: CSc1ccc(Cl)c(C(=O)Cl)c1
Reactant: Fc1ccc(Oc2ncc(Br)c(Oc3ccc(F)cc3F)n2)c(F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1ccc(Cl)c(C(=O)c2cnc(Oc3ccc(F)cc3F)nc2Oc2ccc(F)cc2F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
To 5-bromo-2,4-bis-(2,4-difluoro-phenoxy)-pyrimidine (3.83 g, 9.23 mmol) in dry THF at 0° C. was added isopropyl magnesium chloride (6.93 mL of 2.0 M solution in THF, 13.85 mmol). The resulting mixture was stirred at 0° C. for 20 minutes. A solution of 2-chloro-5-methylsulfanyl-benzoyl chloride (4.27 g, 19.33 mmol) in 20 mL dry THF was added dropwise, with stirring at 0° C. continued for one hour. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 5-25%) to give 3.015 g of [2,4-bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-(2-chloro-5-methylsulfanyl-phenyl)-methanone, MS (M+H)=521.
Reaction SMILES: C1COCC1.O.[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:16][C:8]1=2.[OH-].[Na+].C(O)(=O)C>O>[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:16][C:8]1=2
Reactant: CCOC(=O)C(C)c1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the flask was added THF/H2O (1:1, 4 mL) followed by Ethyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)propanoate (133 mg, 0.563 mmol) and NaOH (30 mg, 0.750 mmol) at room temperature. The reaction mixture was stirred for 16 hrs at room temperature. The mixture was diluted with H2O (20 mL) and acidified with acetic acid (4 mL, pH=4) then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Colorless oil, yield: quantitative.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:35])[C:14]([C:18]3[N:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([C:33]#[N:34])[CH:24]=4)[O:20][N:19]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])CCC.[OH-].[Na+]>C(O)C>[C:33]([C:25]1[CH:24]=[C:23]([C:21]2[O:20][N:19]=[C:18]([C:14]3[C:13]([CH3:35])=[C:12]4[C:17](=[CH:16][CH:15]=3)[CH:8]([CH2:7][C:6]([OH:43])=[O:5])[N:9]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:10][CH2:11]4)[N:22]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:31])[CH3:32])#[N:34]
Reactant: CCCCOC(=O)CC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CC(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 101.9 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1h)-isoquinolinecarboxylate (Preparation 21; 41 mg, 0.070 mmol) in ethanol (2 ml) was added 2N aqueous sodium hydroxide (0.070 ml, 0.139 mmol) and the resulting mixture was stirred at room temperature for ca. 3.5 h. Most of the solvent was removed and the residue was partitioned between ether and water (with dropwise addition of 2N sodium hydroxide to keep the mixture basic). The layers were separated, and the aqueous layer acidified 2N aqueous hydrochloric acid giving a white precipitate which was extracted twice with ethyl acetate. The combined ethyl acetate fractions were dried over MgSO4 and concentrated in vacuo to give the title compound (38 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C@H:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:21][OH:22]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (1.5 g, 7.73 mmol) in EtOH (25 ml) at 0° C. was added triethylamine (1.6 ml, 11.6 mmol) and a solution of (2R)-2amino-2-(4-fluorophenyl)ethanol (prepared according to a procedure in J. Med. Chem. 1999, 42, 4981-5001, 1.2 g, 7.73 mmol). The reaction mixture was stirred at 0° C. for 3 hours. The solvent was removed and the residue was dissolved in EtOAc and was washed with water. The organic layer was concentrated. Flash chromatography on silica gel (20-50% EtOAc in hexanes) gave the title compound as a solid (703 mg, 29%). NMR (CDCl3) 4.00 (m, 2H), 5.50 (m, 1H), 7.07 (m, 2H), 7.38 (m, 2H), 9.04 (s, 1H), 9.10 (br s, 1H).