Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:27]2[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccc(-c2cc(CNC(C)(C)C)c(O)c(-c3ccccc3)c2)cn1
Temperature: 64 °C
Yield: 80.2 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.659 g, 1.91 mmol), (6-methoxypyridin-3-yl)boronic acid (0.438 g, 1.5 equiv), and potassium carbonate (1.056 g, 4 equiv) in 2-methoxyethyl ether (10 mL) and water (2 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (110 mg, 5 mol %) was added and the resulting mixture was heated at 61-67° C. for 2.5 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-5-(6-methoxypyridine-3-yl)-[1,1′-biphenyl]-2-ol (0.555 g) as yellow oil. 0.28 g of the oil was dissolved in ethanol and a solution of tartaric acid (0.108 g) in ethanol was added. The resulting precipitate was filtered and rinsed with ethanol to give 3-((tert-butylamino)methyl)-5-(6-methoxypyridine-3-yl)-[1,1′-biphenyl]-2-ol tartarate (100 mg).
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[C:6](\[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:11][CH:10]=1)/[CH3:7])C>C(O)C.[OH-].[Na+]>[C:15]12([C:12]3[CH:11]=[CH:10][C:9]([O:8]/[C:6](/[CH3:7])=[CH:5]\[C:4]([OH:25])=[O:3])=[CH:14][CH:13]=3)[CH2:22][CH:21]3[CH2:23][CH:17]([CH2:18][CH:19]([CH2:20]3)[CH2:24]1)[CH2:16]2
Reactant: CCOC(=O)/C=C(/C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C/C(=O)O)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A solution of 12.2 g of 3-[4-(1-adamantyl)-phenoxy]crotonic acid ethyl ester in 120 ml of ethanol and 24 ml of 2 N sodium hydroxide solution is stirred for 5 days at about 25°C. It is then evaporated in vacuo to a volume of approx. 20 ml and the residue is partitioned between twice 200 ml of methylene chloride and 200 ml of 2 N hydrochloric acid. The organic phases are washed until neutral, treated with active charcoal, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from ethanol gives 3-[4-(1-adamantyl)-phenoxy]-crotonic acid of melting point 215°-218°C (decomposition).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=[CH:4][N:3]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#CCc1ccnc(Cl)c1[N+](=O)[O-]
Product: N#CCc1ccnc(N2CCN(Cc3ccccc3)CC2)c1[N+](=O)[O-]

Procedure:
A solution of 15 g of (2-chloro-3-nitropyridin-4-yl)acetonitrile and 1.1 equivalents of N-benzyl-piperazine is heated for 10 minutes, at 80° C., under a stream of argon, and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 100/0 to 95/5) enables the expected product to be isolated.
Reaction SMILES: ClCC(C1C=CC(OC)=C(OC)C=1OC)=O.[Cl:17][CH2:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)=[O:20]>C(OCC)(=O)C>[Cl:17][CH2:18][CH:19]([C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=1)[OH:20]
Reactant: COc1cc(C(=O)CCl)cc(OC)c1OC
Agent: COc1ccc(C(=O)CCl)c(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(C(O)CCl)cc(OC)c1OC

Procedure:
Cultivation and reaction were carried out in the same way as described in Example 9 except that 2-chloro-1-(2',3',4'-trimethoxyphenyl) ethanone, 2-chloro-1-(3',4',5'-trimethoxyphenyl) ethanone were used as substrate and after completion of reaction, extraction was done twice using 300 ml of ethyl acetate. After dehydration of the ethyl acetate layer, the solvent was removed under reduced pressure, the resulting oily substance was refined by silica gel chromatography (hexane/ethyl acetate=7/1) and (-)-2-chloro-1-(2',3',4'-trimethoxyphenyl) ethanol, (-)-2-chloro-1-(3',4',5'-trimethoxyphenyl) ethanol were obtained. Their yield and specific rotation were as shown in Table 11.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].S(Cl)(O[CH2:23][Cl:24])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl.C(OCC)(=O)C>[Cl:24][CH2:23][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:13]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=S(=O)(Cl)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)OCCl
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-propionic acid (0.507 g, 2.68 mol), sodium bicarbonate (1.13 g, 13.4 mmol) and tetrabutylammonium hydrogen sulfate (0.090 g, 0.268 mmol) in H2O (21 mL) at 0° C. was added dichloromethane (12 mL) and the mixture was stirred vigorously. Chloromethyl chlorosulfate (0.326 mL, 3.22 mmol) in dichloromethane (7 mL) was added and the mixture was warmed to rt overnight. The reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The resulting oil was purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexane) to give a colorless oil (4) (0.6207 g, 97%). 1H NMR (300 MHz, CDCl3): 5.75 (d, J=5.4 Hz, 1H), 5.57 (d, J=5.4 Hz, 1H), 5.04 (br s, 1H), 4.28 (m, 1H), 1.37 (s, 9H), 1.32 (s, 3H).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13]2[C:27]3[CH2:28][CH2:29][N:30]([C:32](=[S:45])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[N+:42]([O-:44])=[O:43])[CH2:31][C:26]=3[S:25][C:14]=2[N:15]([CH:20]([CH2:22][CH2:23][CH3:24])[CH3:21])[C:16](=[O:19])[CH2:17][N:18]=1.C(O)C.C([BH3-])#N.[Na+]>O>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[NH:18][CH2:17][C:16](=[O:19])[N:15]([CH:20]([CH2:22][CH2:23][CH3:24])[CH3:21])[C:14]2[S:25][C:26]3[CH2:31][N:30]([C:32](=[S:45])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[N+:42]([O-:44])=[O:43])[CH2:29][CH2:28][C:27]=3[C:13]1=2
Reactant: CCCC(C)N1C(=O)CN=C(c2ccccc2Cl)c2c1sc1c2CCN(C(=S)Nc2ccc(OC)cc2[N+](=O)[O-])C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCC(C)N1C(=O)CNC(c2ccccc2Cl)c2c1sc1c2CCN(C(=S)Nc2ccc(OC)cc2[N+](=O)[O-])C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.5 ml) is added to 0.16 g of 5-(2-chiorophenyl)-1,2,3,6,7,9-hexahydro-N-(4-methoxy-2-nitrophenyl)-2-oxo-1-(2-pentyl)-8H-pyrido[4′,3′:4,5]thieno[2,3-e]-1,4-diazepine-8-carbothioamide (0.26 mmol). Ethanol (3.5 ml) is added to this yellow suspension then acetic acid (1 ml) and finally sodium cyanoborohydride (0.033g, 0.52 mmol) are added dropwise. The reaction mixture is agitated for one hour then it is heated for one hour at 40° C. until solubilization. Then agitation is carried out for 2 hours at 22° C. The reaction medium is poured into ice-cooled water (30 ml), followed by agitation, filtering then washing abundantly with water. After drying under vacuum without heating, the desired product is obtained in the form of an orange powder (0.145 g, 83%)
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:13][C:14]([O:23][OH:24])([CH2:16][CH2:17][C:18]([CH3:22])([O:20]O)[CH3:19])[CH3:15].S([O-])([O-])=O.[Na+].[Na+]>>[C:1]([O:24][O:23][C:14]([CH3:15])([CH3:13])[CH2:16][CH2:17][C:18]([OH:20])([CH3:22])[CH3:19])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)CCCCCC(=O)Cl
Reactant: CC(C)(CCC(C)(C)OO)OO
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)CCCCCC(=O)OOC(C)(C)CCC(C)(C)O
Yield: 55.1 %

Procedure:
Reacting neodecanoyl chloride with 2,5-dimethyl-2,5-dihydroperoxyhexane followed by reducing the intermediate product with a buffered sodium sulfite solution employing the same procedure as used in preparation of C-5 resulted in the preparation of 4-hydroxy-1,1,4,4-tetramethylbutyl peroxyneodecanoate. The liquid product had an assay of 91.7% and was obtained in a corrected yield of 55.1%. An infrared spectrum of the product showed a broad OH band centered at 3300 to 3500 cm-1.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl[CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][CH:14]=[CH2:13])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: C=CCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(C)(C)C)cc1

Procedure:
A mixture of 45 g 4-(1,1-dimethylethyl)phenol, 30 g 3-chloro-1-propene, 50 g anhydrous potassium carbonate and 250 ml 2-butanone was refluxed for 15 hours, after which time the solvent was removed in a rotary evaporator. Water was added to dissolve the potassium salts and the product extracted twice with ether. The ether layer was dried, removed, and the product distilled. The 50 grams of 1-(1,1-dimethylethyl)-4-(2-propenyloxy)benzene was found to boil at 70°-75° C. at 0.2 mm Hg, listed in Table 1 as compound I-4)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C.O1CCCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:21])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(CCCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(CCCC(=O)c2ccc(F)cc2)cc1
Yield: 77.7 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(4-nitrophenyl)butan-1-one (0.5 g, 1.7 mmol) and 10% palladium on carbon (0.06 g) in ethyl acetate (15 mL) and tetrahydrofuran (5 mL) was hydrogenated at room temperature using the hydrogen balloon. The catalyst was removed by filtration, and the filtrate concentrated in vacuo. Purification by silica gel chromatography, eluting with 10% ethyl acetate/hexane gave the title compound as a white solid (0.34 g, 78%). The product was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.[C:35]([NH:38][NH2:39])(=[O:37])[CH3:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:35]([NH:38][NH:39][C:8]([C:6]1[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])(=[O:37])[CH3:36]
Reactant: CC(=O)NN
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)O)c12
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NNC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid (36B, 96 mg, 0.204 mmol), acethydrazide (22.70 mg, 0.306 mmol), EDC (58.7 mg, 0.306 mmol), and HOBT (46.9 mg, 0.306 mmol) were taken up in DMF (2043 μl). DIPEA (143 μl, 0.817 mmol) was added and the reaction mixture was allowed to stir at rt overnight. The reaction was heated to 60 C for 1 hour. Saturated NH4Cl and EtOAc were added. The products were extracted into EtOAc (2×). The combined organics were then washed with saturated NaHCO3 and brine, then dried over MgSO4, and concentrated in vacuo to give N′-acetyl-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide. MS: [M+H]+ m/z 526.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[BH4-].[Na+]>C1COCC1.O.CCO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(F)c(Br)n1
Reactant: OB(O)c1c(F)cccc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1ccc(F)c(-c2c(F)cccc2F)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in THF and Water (10:1, 0.2 M) was added 2,6-difluorophenylboronic acid (2.0 equiv.) and potassium fluoride (3.3 equiv.). The reaction was degassed for 10 minutes, then Pd2(dba)3 (0.05 equiv.) was added, followed by tri-t-butylphosphine (0.1 equiv.). The reaction was stirred to 60° C. for 1 hour at which point, all starting material was consumed as indicated by LC/MS. The reaction was allowed to cool to room temperature, partitioned with ethyl acetate and water, the organic phase was dried with sodium sulfate, filtered, and concentrated. The crude material was diluted in EtOH to 0.1 M, and 0.5 equiv. of NaBH4 was added to reduce the dba. The reaction was stirred for one hour at room temperature, then quenched with water and concentrated under vacuo to remove the ethanol. The product was extracted in ether, washed with brine, the organics were dried over sodium sulfate, filtered, and concentrated. The crude material was loaded on silica gel and purified via column chromatography (ISCO) eluting with hexanes and ethyl acetate (0%-10% ethyl acetate). The pure fractions were combined, and concentrated to yield 2-(2,6-difluorophenyl)-3-fluoro-6-methylpyridine as a light yellow oil in 86% yield. LC/MS=224.0 (M+H), Rt=0.84 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([CH3:31])[C:19]([CH3:30])([CH2:21][CH2:22][C:23]#[C:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH3:20])=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:33][CH3:34].C([O-])(=O)C.[Na+].[NH4+].[OH-].C(OC(C)C)(C)C>C(OC(=O)C)(=O)C.O>[CH3:31][N:18]1[C:19]([CH3:20])([CH3:30])[CH2:21][CH2:22][C:23]2[C:24]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[C:9]3[C:10]4[CH:11]=[C:2]([Br:1])[C:3]([O:33][CH3:34])=[CH:4][C:5]=4[CH2:6][CH2:7][N:8]3[C:15]=2[C:16]1=[O:17]
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(C)C(C)(C)CCC#Cc1cccs1)CC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C)C(C)(C)CC3
Temperature: 102.5 °C
Reaction time: 1 h

Procedure:
A mixture of 100 mg of 12j and 150 mg of anhydrous sodium acetate in 4 ml of acetic anhydride was heated at 100-105° C. for 2 h. The mixture was cooled and diluted with 10 ml of water and stirred at ambient temperature for 1 hr in order to decompose excess anhydride. The reaction mixture was neutralized by addition of cold conc. aq. NH4OH and then extracted with ethyl acetate. The extract was washed twice with water, dried, concentrated and the residue was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate. The purified product thus isolated was treated with diisopropyl ether, to give 65 mg of crystalline 12k; Mp 173-175° C.; Rf 0.45 (heptane/ethyl acetate 1/1). MS-ESI: [M+1] 484.96, 586.98.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[Cl:20])=[O:28]
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CNC(=O)c3[nH]cnc3Cl)c2Cl)c1
Yield: 75.8 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(aminomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (40 mg, 0.129 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (35.6 mg, 0.129 mmol), EDC (29.6 mg, 0.154 mmol) and HOBT (29.5 mg, 0.193 mmol) in DMF (3.0 ml) to give the title compound as a white solid (43 mg, 76%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.62 (1H, s) 7.40 (1H, dd, J=8.5, 5.4 Hz) 7.35 (2H, br. s.) 7.12-7.22 (2H, m) 7.00 (1H, s) 4.75 (2H, d). LCMS: m/z 439 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.[OH-].[K+].[Cl-].Cl[CH2:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:23][CH3:24])=[CH:17][NH+:16]=1>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH2:23]([C:18]1[C:19]([O:21][CH3:22])=[CH:20][C:15]([CH2:14][S:8][C:6]2[NH:5][C:4](=[O:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:16][CH:17]=1)[CH3:24]
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Reactant: CCc1c[nH+]c(CCl)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1cnc(CSc2nc(C)cc(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.7 %

Procedure:
0.71 g (5 mmol) of 6-methyl-2-thiouracil and 0.65 g (11.7 mmol) of potassium hydroxide are dissolved in 10 ml of water. Simultaneously, 1.22 g (5.5 mmol) of 2-chloromethyl-5-ethyl-4-methoxypyridinium chloride (m.p.: 123°-125° C.) and 0.1 g of tetrabutylammonium chloride are dissolved in 10 ml of chloroform. After combining the two solutions the reaction mixture is vigorously stirred at room temperature for 20 hours. After separating the phases the aqueous layer is extracted 3 times with 5 ml of chloroform each, the combined organic phase is washed with sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is thoroughly triturated with ethyl acetate, filtered and the crude product obtained is recrystallized from ethanol to obtain 0.68 g (47%) of the title compound in the form of white crystals, m.p.: 167°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[CH:15]=[CH:14][O:13]2.CN(C=O)C.C1C(=O)N([I:30])C(=O)C1>O>[I:30][C:17]1[N:16]2[C:12]([O:13][CH:14]=[CH:15]2)=[N:11][C:10]=1[C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1cc(F)c(-c2cn3ccoc3n2)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(F)c(-c2nc3occn3c2I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a round bottom flask containing 6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole (11.7 g, 49.1 mmol) and DMF (120 mL) was added NIS (11.4 g, 50.6 mmol). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction mixture was poured into water (300 mL) and the resulting precipitate was collected by vacuum filtration. The solid was dissolved into DCM (500 mL) and the organic suspension was washed sequentially with saturated NaHCO3 solution, 5% sodium thiosulfate solution, and brine. The resulting solution was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give the title compound as a pale yellow solid (13.1 g, 73%): LC/MS (Table 1, Method b) Rt=2.17 min; MS m/z 365.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C1C=CC=CC=1.[CH3:25][CH:26]([N:28]1[C:32]([NH2:33])=[CH:31][CH:30]=[N:29]1)[CH3:27]>C(O)(=O)C>[CH3:25][CH:26]([N:28]1[C:32]2[N:33]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:31]=2[CH:30]=[N:29]1)[CH3:27]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(SC)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate (851 mg, 3.20 mmol), benzene (6 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 3.20 mmol), and acetic acid (3 mL). The crude product was purified by column chromatography (Silica gel, eluent; 0 to 100% EtOAc/hexanes) to give 870 mg (63%) of product. LCMS E-S (M+H)=433.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.57 (m, 3 H), 1.66 (d, J=6.8 Hz, 6 H), 2.58 (s, 3 H), 4.56 (q, J=7.2 Hz, 2 H), 5.38-5.55 (m, 1 H), 7.36-7.46 (m, 2 H), 8.12-8.19 (m, 2 H), 8.22 (s, 1 H), 8.40 (s, 1 H).
Reaction SMILES: CCOCC.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[N:18]=[CH:19][C:20]1[N:25]=[C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][NH:37][C:38]2[C:43]([CH3:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=2[CH3:46])[CH:23]=[CH:22][CH:21]=1)([CH3:8])[CH3:7].[CH:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Li])([CH3:49])[CH3:48]>O>[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[NH:18][CH:19]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH:47]([CH3:49])[CH3:48])[C:20]1[N:25]=[C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][NH:37][C:38]2[C:39]([CH3:46])=[CH:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])[CH:23]=[CH:22][CH:21]=1)([CH3:8])[CH3:7]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Reactant: [Li]c1ccccc1C(C)C
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C(Nc3c(C(C)C)cccc3C(C)C)c3ccccc3C(C)C)n2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et2O (40 mL) was added to compound 6b (1.48 g, 2.74 mmol) to form a yellow suspension. At −80° C. an Et2O (5 mL) solution of 2-isopropylphenyllithium (0.690 g, 5.47 mmol) was added dropwise over 5 minutes. Upon the start of the addition the mixture became dark purple. The mixture was allowed to slowly warm to ambient temperature while stirring overnight. Then water was added (30 mL) and the yellow organic layer was separated and dried with brine. Further drying over MgSO4 followed by filtration and evaporation afforded crude diamine 7p as a yellow oil that was found by 1H NMR spectroscopy to be contaminated with about 10% of the imine 6b. The product was purified on basic alumina eluted with 5:1 hexanes:dichloromethane, gradually increasing the amount of ethyl acetate to 8%. The product eluted just before the imine impurity. Yield: 1.5 g, 83%. The 1H NMR spectrum of 7p in CD2Cl2 solution is complex due to the presence of more than one diastereoisomer.