Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[OH-].[K+].Cl[O-].[Na+]>C(O)C>[O-:26][N+:25]1[O:27][N:1]=[C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]4)[CH2:9]3)=[CH:4][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3cc([N+](=O)[O-])c(N)cc3C2)CC1
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3cc4c(cc3C2)no[n+]4[O-])CC1

Procedure:
To a solution of tert-Butyl 4-(7-amino-6-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (160 mg, 0.42 mmol) in ethanol (3 mL) was added potassium hydroxide (36 mg, 0.64 mmol). The solution was stirred until all solids dissolved. At that point, sodium hypochlorite (1.3 mL, 1.3 mmol) was dropped into the reaction. LC showed quite slow reaction. Another 1.3 mL of sodium hypochlorite was added to complete the reaction. The desired product was separated by reverse phase HPLC (water: Acetonitrile with 0.1% TFA). LC-MS (IE, m/z): 375 [M+1]+.
Reaction SMILES: [CH2:1]([NH:7][C:8](=S)[NH:9][NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:12][CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[ClH:12].[CH2:1]([NH:7][C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:21])[NH:10][N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCCCCCNC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCCCCCNc1n[nH]c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 28.4 %

Procedure:
A stirred solution of 15.8 g (0.091 mole) of 4-hexyl-3-thiosemicarbazide in 150 mL of absolute ethanol under nitrogen atmosphere was treated with 14.8 g (0.091 mole) of ethyl 2-chloroacetoacetate, stirred for 2.5 hr at ambient temperature, treated with 50 mL of 2N ethanolic hydrogen chloride, heated at reflux for 1 hr, and stirred at ambient temperature ~16 hr. The reaction mixture was heated to dissolve most of the solids, filtered to remove the insoluble sulfur and concentrated in vacuo to give a deep red-orange oil. After standing for 3 weeks at ambient temperature, the oil began to crystallize. Trituration with ethyl acetate and filtration gave 13 g of crude product, which was recrystallized from acetone/diethyl ether to give 7.5 g of white granular product, mp 108°-109° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH2:14]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:11])[CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-nitro-m-cresol (100.0 g) in methylene chloride (1000 ml) was added a 1N aqueous solution of sodium hydroxide (1000 ml). To the resulting two-layer solution were added in turn benzyl bromide (170 ml) and tetra-n-butylammonium bromide (2.17 g) while stirring at room temperature. After stirring at room temperature overnight, the reaction solution was placed into a separating funnel to separate the organic layer from the aqueous layer. The aqueous layer was extracted with methylene chloride. The combined organic layer was washed with saturated saline, dried over magnesium sulfate and the solvent was distilled off to give a yellow oily substance. The solidified yellow oily substance was ground in hexane, filtered and dried. The resulting yellow powder was recrystallized from an ethyl acetate/hexane mixed solvent system to give the title compound (116.7 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:35])=[CH:30][CH:29]=1)(C(C)(C)C)(C)C>C1COCC1>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:34]([C:31]2[CH:30]=[CH:29][C:28]([CH2:27][OH:26])=[CH:33][CH:32]=2)=[O:35])[CH:37]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)c2cccnc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccc(CO)cc1)c1cccnc1
Reaction time: 1 h
Yield: 58 %

Procedure:
Add tetrabutylammonium fluoride (1.37 mL, 1.37 mmol, 1M solution in THF) to a solution of [4-(tert-butyldimethylsilyloxymethyl)-phenyl]-pyridin-3-yl-methanone (225 mg, 0.687 mmol) in anhydrous THF (10 mL) at 0° C. and stir at this temperature for 1 h. Concentrate the solvent in vacuo and purify the crude mixture by chromatography on silica gel eluting with EtOAc to provide the desired intermediate (85 mg, 58%). MS (ES+) m/z: 214 (M+H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21](CC2C=CC(OC)=CC=2)CC2C=CC(OC)=CC=2)[N:15]=1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[CH:44]=[N:45][C:46]=1[O:47][CH3:48]>>[NH2:21][C:16]1[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:7][C:2]=2[NH:49][C:43]2[CH:44]=[N:45][C:46]([O:47][CH3:48])=[C:41]([F:40])[CH:42]=2)[N:15]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4cccnc4)nc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Product: COc1ncc(Nc2nc(-c3cccnc3)ccc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared in an analogous manner to that described in Example 254 using 4-(6-fluoro-2,3′-bipyridin-5-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 5-fluoro-6-methoxypyridin-3-amine (Anichem), and was isolated as an orange amorphous solid (5.7%). m/z (ESI, +ve ion) 405.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.03 (1H, s); 9.27 (1H, d, J=2.0 Hz); 8.91 (1H, d, J=8.2 Hz); 8.67 (1H, dd, J=4.8, 1.5 Hz); 8.55 (1H, d, J=2.2 Hz); 8.39-8.43 (1H, m); 8.36 (1H, dd, J=12.7, 2.3 Hz); 7.93 (1H, br. s.); 7.79 (1H, br. s.); 7.62 (1H, d, J=8.2 Hz); 7.57 (1H, dd, J=7.9, 4.8 Hz); 3.96 (3H, s); 2.45 (3H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[C:11]2[CH3:23])=[O:7])[CH3:4].S(OC)(O[CH3:28])(=O)=O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:28])[C:12]([CH2:17][C:18]1[NH:22][CH:21]=[CH:20][N:19]=1)=[C:11]2[CH3:23])=[O:7])[CH3:4]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1ccc2[nH]c(Cc3ncc[nH]3)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(Cc1ncc[nH]1)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Sodium hydride (0.11 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 2-[1-imidazolylmethyl]-3-methylindole-5-carboxylic acid ethyl ester (0.57 g) in dry N,N-dimethylformamide (20 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of dimethyl sulphate (0.26 g) in dry N,N-dimethyl-formamide (2.5 ml) was added dropwise and the mixture was stirred at room temperature for 18 hours and then evaporated. The residue was chromatographed on silica gel. Elution with chloroform first gave mineral oil and impurity followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallised froml ethyl acetate/petrol (b.p. 60°-80°) to give 1,3-dimethyl-2-[1-imidazolylmethyl]indole-5-carboxylic acid ethyl ester (0.40 g), m.p. 109°-110°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:21])[CH:3]=1.[N+:22]([C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CC(O)=O.CO>[F:21][C:4]1[CH:3]=[C:2](/[N:1]=[CH:30]/[C:28]2[O:29][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=2)[CH2:10][CH2:9]1
Reactant: Cn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Solvent: CC(=O)O
Product: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 85 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7f, 0.29 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (9f, 352 mg, 85%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][Cl:10].[OH-].[K+].[CH2:13]([OH:16])[CH2:14][OH:15]>>[Cl:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:15][CH2:14][CH2:13][OH:16]
Reactant: OCCO
Reactant: ClCCOCCOCCCl
Agent: [K+]
Agent: [OH-]
Product: OCCOCCOCCOCCCl
Yield: 30 %

Procedure:
A solution of 1,8-dichloro-3, 6-dioxaoctane (40 g) and potassium hydroxide (11.8 g) in ethylene glycol (100 ml) was stirred at 100° C. for 18 h. The mixture was then cooled, filtered and the residue washed with acetone (2×35 ml). The combined filtrate was then distilled to yield the product as a clear oil (13.5 g, 30%), b.p. 120°-122° C. /0.2 mm Hg; I.r. (liquid film) 3430 cm-1.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1[C:14]([CH:15]=O)=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:17])=[N:12]2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)(=O)C>[OH:4][C:5]1[C:14]([CH:15]=[N:2][OH:3])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:17])=[N:12]2)=[CH:7][CH:6]=1
Reactant: NO
Reactant: Cc1ccc2ccc(O)c(C=O)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2ccc(O)c(C=NO)c2n1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Referring to FIG. 19, hydroxylamine hydrochloride (0.106 g, 1.52 mmol) was added to a mixture of 6 (0.200 g, 1.06 mmol) in a solution of NaOH (0.3 in 6 mL water). The reaction was stirred at 95° C. for 15 min followed by the addition of glacial acetic acid until it reached pH 6. The resulting mixture was cooled in an ice bath and vacuum filtered to afford 7 (0.176 g, 0.869 mmol, 82% yield) as a yellow solid, which was carried to the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]1[C@@H:13]([OH:14])[CH2:12][C@H:11]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:9]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:60]([C:63]1[CH:71]=[CH:70][C:66]([C:67](O)=[O:68])=[CH:65][CH:64]=1)([O-:62])=[O:61].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:60]([C:63]1[CH:64]=[CH:65][C:66]([C:67]([O:14][C@@H:13]2[CH2:12][C@H:11]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:10]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:9]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:8]2[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:40])=[O:68])=[CH:70][CH:71]=1)([O-:62])=[O:61]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of tert-butyl((1S,2R,3R,4R,6S)-2,3-bis(benzyloxy)-4-((benzyloxy)methyl)-6-hydroxycyclohexyl)carbamate (3.20 g, 5.85 mmol), triphenylphosphine (1.92 g, 7.31 mmol) and 4-nitrobenzoic acid (1.37 g, 8.19 mmol) in anhydrous THF (50 mL), at 0° C., was added DIAD (1.42 g, 7.02 mmol) slowly. After addition the mixture was stirred at room temperature for 3 h. The solvent were evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording the title compound as a white solid (2.80 g, 69%). 1H NMR (400 MHz, CDCl3) δ 8.26-8.20 (m, 4H), 7.33-7.25 (m, 15H), 4.90-4.86 (m, 3H), 4.71 (d, J=11.3 Hz, 1H), 4.57 (d, J=10.8 Hz, 1H), 4.45 (s, 2H), 4.24 (d, J=9.7 Hz, 1H), 3.97-3.93 (m, 1H), 3.68-3.63 (m, 2H), 3.49 (dd, J=2.0, 8.8 Hz, 1H), 3.38 (t, J=10.1 Hz, 1H), 2.22-2.17 (m, 1H), 1.84-1.76 (m, 2H), 1.28 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([CH3:16])[CH:18]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2cc(Nc3ccc(O)cc3)ncn2)c1

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(4'-hydroxyanilino)pyrimidine (3.2 g) was reacted with 3-methylaniline (5 ml). The product so obtained was triturated under methylene chloride. The solid so obtained was filtered off and extracted with hot water. On cooling a solid precipitated from the aqueous solution. The solid was extracted from the aqueous solution with ethyl acetate, washed with water and with brine, dried (MgSO4) and recrystallised from a mixture of ethyl acetate and hexane to give 4-(4'-hydroxyanilino)-6-(3'-methylanilino)pyrimidine (0.15 g), m.p. 242°-245° C.;
Reaction SMILES: C([O:3][P:4]([C:9]1[C:10](=[O:28])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1)=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=2)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(#N)C>[O:28]=[C:10]1[C:9]([P:4](=[O:3])([OH:8])[OH:5])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([N:19]3[CH:20]=[CH:21][CH:22]=[CH:23]3)[CH:16]=2)[NH:11]1
Reactant: CCOP(=O)(OCC)c1cc2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=c1[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc2cc1P(=O)(O)O
Reaction time: 0.5 h

Procedure:
A suspension in acetonitrile of 235 mg (0.567 mmol) of the compound obtained in Example 29 and 0.75 ml (5.67 mmol) of bromotrimethylsilane is heated for 1 hour 30 minutes at reflux of the acetonitrile (3 ml). Evaporation to dryness is carried out, the residue is taken up in methanol, and the solution is stirred for 30 minutes and then evaporated to dryness again. The residue is triturated in acetonitrile and the precipitate corresponding to the title product is filtered off.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccn1
Yield: 34.8 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (250 mg, 0.81 mmol) and 2-bromopyridine (76 μL, 0.79 mmol) according to the method of Example 6 Step 4. Purification by flash column chromatography eluting with a 20-40% ethyl acetate/isohexane gradient gave 2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}pyridine (0.10 g, 34%). 1H NMR (400 MHz, CDCl3) δ 8.70 (1H, s), 8.68-8.65 (1H, m), 8.33-8.22 (1H, m), 8.07 (1H, d, J=8.6 Hz), 8.04-7.92 (4H, m), 7.82 (1H, dd, J=1.8, 8.6 Hz), 7.69-7.65 (2H, m), 7.46-7.44 (1H, m), 7.22-7.16 (2H, m); m/z (ES+) 364 [MH+].
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Cl.N([O-])=O.[Na+].[S:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[OH-].[Na+]>O>[CH3:8][C:4]1[CH:3]=[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: c1ccsc1
Reactant: Cc1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(-c2cccs2)c1
Temperature: 25 °C
Yield: 5.7 %

Procedure:
To a stirred solution of 107.0 g (1.0 mol) of m-toluidine and 185 mL of concentrated hydrochloric acid in 50 mL of water at 0° C. ±5° C. was added 75.9 g (1.1 mol) of sodium nitrite in 150 mL of water at such a rat as to maintain the reaction mixture temperature at 0° C. ±5° C. Upon complete addition, the reaction mixture was transferred to a Morton flask equipped with a mechanical stirrer, and 500 g (5.94 mol) of thiophene was added dropwise at 0° C. with stirring. A 1 molar aqueous solution of sodium hydroxide (275 mL) was then added, the reaction mixture temperature being maintained at 0° C. ±5° C. The reaction mixture was allowed to warm to ambient temperature and the resulting two phase mixture was separated. The aqueous phase was extracted with four portions of 300 mL each of toluene. The extracts were combined with the organic phase from above, and the whole was washed with two portions of a saturated aqueous solution of sodium chloride. The organic phase was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a dark residual oil. The residual oil was distilled under reduced pressure to give 31.4 g of crude product, b.p. 90°-108° C./0.075-0.35 mm. Purification by redistillation at 60° C./0.05 mm using a Kugelrohr distilling system, followed by column chromatography on silica gel using hexane as an eluent, gave 10.0 g of 2-(3-methylphenyl)thiophene.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:3]([NH2:5])=[O:4].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C:6]2[C:11](=[CH:10][C:9]3[O:12][CH2:13][O:14][C:8]=3[CH:7]=2)[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:5][C:3]1=[O:4]
Reactant: O=Cc1ccccc1
Reactant: CN(C(N)=O)c1ccc2c(c1)OCO2
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3
Yield: 20 %

Procedure:
A mixture of N-methyl-N-[3,4-(methylenedioxy)phenyl]urea (240 mg), benzaldehyde (140 μL) and methanesulfonic acid (50 μL) and toluene (60 mL) was refluxed for 2 h in a flask equipped with a Dean-Stark water separator. After cooling, the solution was washed with water thoroughly, dried over Na2SO4 and concentrated in vacuo. The resulting solid was recrystallized from chloroform/hexane to provided the title compound as a tan solid (70 mg, 20%), mp: 228-230° C. 1H NMR (CDCl3): 7.37-7.30 (m, 5H), 6.53 (s, 1H), 6.28 (s, 1H), 5.91 (d, 1H, J=1.4), 5.89 (d, 1H, J=1.4), 5.46 (s, 1H), 5.11(br s, 1H), 3.33 (s, 3H). Anal. calcd. for C16H14N2O3: C, 68.08; H, 5.00; N, 9.92. Found: C, 68.06; H, 4.91; N, 9.71.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:15])[CH2:11][N:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[NH:16]1C=CN=[CH:17]1>C(O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:15])[CH2:11][N:12]2[CH:14]=[CH:17][N:16]=[CH:13]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: CN(C)CC(=O)Cc1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)Cn1ccnc1
Yield: 54.1 %

Procedure:
A solution of product from step B (7.80 g, 36.6 mmol) in ethanol (30 ml) and water (30 ml) containing imidazole (12.4 g, 183.0 mmol) was heated under reflux for 6 hrs. The mixture was allowed to cool and partitioned between dichloromethane (100 ml) and water (100 ml), the organic phase was washed with brine (5×100 ml) separated and dried (MgSO4). Evaporation of the residue left a yellow oil. This was purified by chromatography (Biotage flash 40, 90 g, SiO2 cartridge) eluting with a gradient of 0-5% methanol/dichloromethane to give 1-(4-fluorophenyl)-3-(imidazol-1-yl)propanone as a yellow oil 4.32 g (54%).
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:20]([O-:22])=[O:21])=[CH:7][C:8]([Br:19])=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15]C(=O)C)[CH2:11][CH2:10]2)(=O)C.Cl>C(O)(=O)C>[NH2:4][C:5]1[C:6]([N+:20]([O-:22])=[O:21])=[CH:7][C:8]([Br:19])=[C:9]2[C:14]=1[CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CC(OC(C)=O)CC2
Agent: Cl
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CC(O)CC2
Temperature: 90 °C
Reaction time: 18 h
Yield: 103.2 %

Procedure:
A mixture of acetic acid 8-acetylamino-5-bromo-7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl ester (2 g, 5.4 mmol), acetic acid (15 mL) and 6N HCl (30 mL) was stirred at 90° C. for 18 h. The solvent was removed by rotoevaporation to give the product (1.6 g) as an orange solid in quantitative yield.
Reaction SMILES: [CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>O1CCOCC1>[CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([SiH:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: C[SiH](C)c1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: C1COCCO1
Product: C[SiH](C)c1ccc(C(=O)Oc2ccc(-c3ccc(OC(=O)c4ccc([SiH](C)C)cc4)cc3)cc2)cc1

Procedure:
A solution of 49.7 g (0.250 mol) of p-dimethylsilylbenzoyl chloride and 18.6 g (0.100 mol) of 4,4'-dihydroxybiphenyl in 40 ml of dry dioxane was boiled for 15 hours. The completeness of the reaction was checked by thin-layer chromatography. After the solvent had been stripped off in vacuo on a rotary evaporator, the crude product was recrystallized from toluene, to give 4,4'-bis-(4-dimethylsilylbenzoyloxy)biphenyl, [-4 s 146 n 184 i].
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.BrC1C=CC=C(OC)N=1.O1C2(CCC(=O)CC2)OCC1.[NH:37]1[CH2:40][CH:39]([NH:41][C:42](=[O:59])[CH2:43][NH:44][C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[C:52]([C:55]([F:58])([F:57])[F:56])[CH:53]=3)[N:48]=[CH:47][N:46]=2)[CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=2)[CH2:7][CH2:6][CH:5]([N:37]2[CH2:38][CH:39]([NH:41][C:42](=[O:59])[CH2:43][NH:44][C:45]3[C:54]4[C:49](=[CH:50][CH:51]=[C:52]([C:55]([F:56])([F:58])[F:57])[CH:53]=4)[N:48]=[CH:47][N:46]=3)[CH2:40]2)[CH2:4][CH2:3]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: COc1cccc(C2(O)CCC(=O)CC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1cccc(Br)n1
Agent: O=C1CCC2(CC1)OCCO2
Product: COc1cccc(C2(O)CCC(N3CC(NC(=O)CNc4ncnc5ccc(C(F)(F)F)cc45)C3)CC2)n1

Procedure:
Reaction of 4-hydroxy-4-(6-methoxypyridin-2-yl)cyclohexanone (prepared by the reaction of 2-bromo-6-methoxypyridine with 1,4-dioxaspiro[4.5]decan-8-one using the sequence described in Example 24 Step A-B) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.