Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][CH:26]([F:29])[CH2:27]O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:25][CH:26]([F:29])[CH2:27][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: OCC(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)Cn1cncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of [1,2,4]triazole (7.3 g, 0.11 mol), triphenylphosphine (33 g, 0.13 mol) and 2,2-difluoroethanol (8.0 ml, 10 g, 0.13 mol) in THF (115 ml) was added diethyl azodicarboxylate (20 ml, 22 g, 0.13 mol) dropwise, maintaining the temperature of the mixture between −5 and 0° C. throughout the addition. The resultant solution was allowed to warm to room temperature and was stirred under nitrogen overnight. The solvent was removed it uacuo, and diethyl ether (220 ml) was added to the residue, precipitating a solid. This was separated by filtration, and the filtrate was concentrated in vacuo. The residual oil was purified by distillation under vacuum, yielding 1-(2,2-difluoroethyl)-1H-[1,2,4]triazole as a yellow oil (7.1 g). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 4.56 (2H, td, J=13.5, 4.1 Hz), 6.13 (1H, tt, J=55.1, 4.2 Hz), 8.01 (1H, s), 8.18 (1H, s).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[C:14]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:13]=[CH:12][C:11]=1[N+:23]([O-])=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].CO>[NH2:23][C:11]1[CH:12]=[CH:13][C:14]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:15][C:10]=1[N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1N
Yield: 78.8 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-methyl-N-[2-nitro-5-(pyridine-2-ylthio)phenyl]carbamate (1.08 g), palladium on carbon (10%, 1.00 g) and methanol (20 ml) and the reaction mixture was purified to give the title compound (0.78 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: COc1cccc(C(=O)COC(=O)CC2CCCCN2C(=O)OC(C)(C)C)c1
Yield: 95.2 %

Procedure:
The title compound (3.06 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-bromo-3′-methoxyacetophenone (1.88 g) according to the method of description 36.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH:16]([NH2:18])[CH3:17].[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[N:12][N:11]3[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2cccnn2c1-c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnn2c1-c1ccccn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethylamine (450 mg, 2.09 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (325 mg, 2.09 mmol) in n-butanol (8 mL) was added DIEA (0.6 mL, 3.01 mmol) at rt. The reaction mixture was stirred at 110° C. overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-60% acetone in hexane to provide 4-amino-6-[1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethyl amino]-pyrimidine-5-carbonitrile: 1H NMR (400 MHz, DMSO-d6) δ 1.272 (d, J=6.4 Hz, 3H), 6.047-6.118 (m, 1H), 7.375 (br s, 2H), 7.446-7.477 (m, 2H), 8.022-8.060 (m, 2H), 8.230-8.280 (m, 1H), 8.400-8.490 (m, 2H), 8.727 (s, 1H), 8.878 (s, 1H). LC-MS (ESI) m/z 358.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[N:10]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH3:24])[CH:19]=[CH:18]4)[C:11]([SH:14])=[N:12][N:13]=2)[C:6]([O:25]C)=[CH:5][C:4]=1[O:27]C)[CH3:2].Cl.N1C=CC=CC=1.O>C(OCC)(=O)C>[CH2:1]([C:3]1[C:4]([OH:27])=[CH:5][C:6]([OH:25])=[C:7]([C:9]2[N:10]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH3:24])[CH:19]=[CH:18]4)[C:11]([SH:14])=[N:12][N:13]=2)[N:8]=1)[CH3:2]
Reactant: CCc1nc(-c2nnc(S)n2-c2ccc3c(ccn3C)c2)c(OC)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc(-c2nnc(S)n2-c2ccc3c(ccn3C)c2)c(O)cc1O
Temperature: 220 °C

Procedure:
A flask was charged with 5-(6-Ethyl-3,5-dimethoxy-pyridin-2-yl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazole-3-thiol (30 mg; 0.08 mmol), and pyridine hydrochloride (2 g). The reaction was put under a nitrogen atmosphere, and heated to 220° C. for forty five minutes, and then cooled. To the flask was then added water (10 mL) and ethyl acetate (10 mL), and the contents were stirred until all solids were dissolved. The organic layer was isolated, washed with water, and all solvent was evaporated under vacuum with heating to give 2-ethyl-6-[5-mercapto-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-pyridine-3,5-diol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4](Br)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[NH:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: COC(=O)C(Br)c1ccc(F)cc1
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC(=O)C(NCCCO)c1ccc(F)cc1
Temperature: 45 °C
Yield: 95 %

Procedure:
To a solution of bromo-(4-fluoro-phenyl)-acetic acid methyl ester (16.0 g) in chloroform (100 mL) was added potassium carbonate (17.9 g, finely ground) followed by 3-amino-1-propanol (4.87 g). The reaction was heated to 45° C. for 18 hours. The reaction was filtered and the filtrate was diluted with water and the phases were separated. The aqueous phase was further extracted with chloroform (3×25 mL) and the combined organics were washed with brine. The chloroform phase was dried over sodium sulfate, filtered and evaporated in vacuo to give the desired (4-fluoro-phenyl)-(3-hydroxy-propylamino)-acetic acid methyl ester (14.85 g, MS (ES+): 242.2 (MH+)) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[NH:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[H-].[Li+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44]Cl)=[CH:40][CH:39]=2)=[CH:32][CH:31]=1>C(O)C.O>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][N:22]3[C:23](=[O:25])[N:24]=[C:19]([N:16]4[CH2:17][CH2:18][N:13]([C:10]5[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=5)[CH2:14][CH2:15]4)[NH:20][C:21]3=[O:26])=[CH:40][CH:39]=2)=[CH:32][CH:31]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)[nH]1
Reactant: ClCc1ccc(OCc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)n1Cc1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
In argon atmosphere, to an N,N-dimethylformamide solution (5 mL) of 6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine-2,4(1H,3H)-dione (200 mg, 0.69 mmol) synthesized in Reference Synthesis Example 18, lithium hydride (12 mg, 1.51 mmol) was added at 0° C. and the resultant mixture was stirred for 1 hour. To the mixture, 1-chloro-4-{[4-(chloromethyl)phenoxy]methyl}benzene (183 mg, 0.69 mmol) was added and the resultant mixture was stirred at 50° C. for 2 hours and at 70° C. for 3 days. After the completion of the reaction, water and ethanol were added to the reaction solution and a resultant solid was filtered to obtain a crude product of a precursor (66St) of the title compound, which was used as it was in the next reaction below.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:44])[C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:22]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:47][O:48][C:49](=[O:52])[CH2:50]Br.C1OCCOCCOCCOCCOC1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:32][C:28]1[CH:27]=[C:26]([C:24]2[CH:25]=[C:20]([C:19](=[O:44])[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH:21]=[C:22]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:23]=2[O:33][CH2:34][CH2:35][O:36][CH2:50][C:49]([O:48][CH3:47])=[O:52])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)CBr
Reactant: O=C(NCCCCCCCCn1ccc2ccccc21)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)COCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Reaction time: 6 h

Procedure:
To a stirred solution of N-(8-indol-1-yl-octyl)-3,5-bis(3-chlorophenyl)-4-(2-hydroxyethoxy)benzamide (0.629 g, 1 mmol) in THF (10 ml) under nitrogen at room temperature was sodium hydride (0.055 g, 2.3 mmol). The mixture was refluxed for 45 minutes, cooled and methylbromoacetate (0.189 g, 1.2 mmol), 15-crown-5 ether (0.022 g, 0.1 mmol), and tetrabutylammoniumiodide (0.037 g, 0.1 mmol) were added. The mixture was refluxed. After 6 h, the reaction mixture was quenched with water and then diluted with water (100 ml) and extracted with EtOAc. This gave a thick emulsion which was separated by acidfying the mixture with 1N HCl. The combined extracts were washed with water (2×15 ml), brine (2×15 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by flash chromatography (15%, 20% EtOAc/Hex) and then preparatory plate chromatography (50% EtOAc/Hex) to give the desired product as a viscous, hazy oil (0.400 g, 57%); 1H NMR (400 MHz, DMSO-d6) δ 1.16–1.31 (m, 8H), 1.45–1.53 (m, 2H), 1.68–1.76 (m, 2H), 3.20–3.26 (m, 4H), 3.45–3.48 (m, 2H), 3.58 (s, 3H), 3.71 (s, 2H), 4.12 (t, J=6.8 Hz, 2H), 6.37 (dd, J=0.8, 3.1 Hz, 1H), 6.95–6.99 (m, 1H), 7.06–7.10 (m, 1H), 7.32 (d, J=3.1 Hz, 1H), 7.40–7.52 (m, 6H), 7.57–7.60 (m, 2H), 7.67–7.70 (m, 2H), 7.87 (s, 2H), 8.52 (t, J=4.83 Hz, 1H); IR (film) 3300, 2800, 1750, 1630, 1540, 1470, 1220 cm−1; mass spectrum [(+)APCI], m/z 701 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[C:8]([C:33]#[N:34])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([C:33]#[N:34])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3C#N)c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
Potassium thiocyanate (1.84 g, 18.9 mmol) was suspended in acetic acid (20 mL), and the mixture was stirred at room temperature for 10 min. N-[3-(4-Amino-2-cyanophenoxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (1.5 g, 3.78 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (635 mg, 3.97 mmol) in acetic acid (10 mL) was added dropwise to the obtained solution over 15 min. After the completion of the dropwise addition, and the mixture was stirred at room temperature for 4 hr. A solution of potassium thiocyanate (0.734 g, 7.56 mmol) and bromine (241 mg, 1.51 mmol) in acetic acid (5 mL) was added, the mixture was further stirred for 1 hr. Insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (200 mL)/tetrahydrofuran (20 mL), washed successively with 1N aqueous sodium hydroxide solution (100 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (1.38 g, 81%) as a yellow powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][S:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+]>C1COCC1>[OH:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1CSCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CSCCC1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (3.00 g, 17.2 mmol) in THF (57 mL) was stirred at 0° C. Sodium borohydride (1.30 g, 34.4 mmol) was added and the resulting mixture was stirred at ambient temperature for 4 hours. The mixture was thermally stabilized with a water bath and carefully quenched with 1N aqueous HCl. The reaction mixture was then diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][N:29]=[C:28]3[N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=3)[CH2:37][CH2:36]2)[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50].C(N(CC)CC)C.CN(C)C=O>O>[CH3:50][C:49]([CH3:52])([CH3:51])[C:48]([NH:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([N:38]2[CH2:39][CH2:40][N:35]([C:28]3[C:27]4[C:32](=[CH:33][CH:34]=[C:25]([C:23]5[CH:22]=[N:21][N:20]([C:1]([C:14]6[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=6)([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[C:8]6[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=6)[CH:24]=5)[CH:26]=4)[N:31]=[CH:30][N:29]=3)[CH2:36][CH2:37]2)[CH:42]=1)=[O:53]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cccc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A mixture of 100 mg 3-{4-[6-(1-trityl-1H-pyrazol-4-yl)quinazolin-4-yl]piperazin-1-yl} phenylamine obtained in Example 825, 30 mg pivaloyl chloride, 50 μl triethylamine and 10 mL N,N-dimethyl formamide was stirred at room temperature for 15 minutes. Water was added to the mixture which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 91 mg of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)[CH3:24]>>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8])[CH3:24]
Reactant: CCOc1ccccc1B(O)O
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CCOc1ccccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-ethoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2′-ethoxy-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (6 mg, 5%): m/z (ES+) 409 [MH+].
Reaction SMILES: CN1CC[O:5]CC1.[F:8][C:9]1[CH:10]=[C:11]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][S:18](=[O:21])[CH2:17][CH2:16]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:21]=[S:18]1(=[O:5])[CH:17]=[CH:16][N:15]([C:14]2[CH:13]=[CH:12][C:11]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]3=[O:32])=[CH:10][C:9]=2[F:8])[CH2:20][CH2:19]1
Reactant: CN1CCOCC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=O)CC3)c(F)c2)C(=O)O1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-Methylmorpholine (1.2 mL, 11.1 mmol) is added to a solution of N-[[(5S)-3-[3-fluoro-4-(1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.690 g, 1.87 mmol; prepared as described in U.S. Pat. No. 5,688,792) in DCM (40 mL), followed by trifluoroacetic anhydride (1.06 mL, 7.5 mmol). The solution is stirred at r.t. for about 20 h, and is concentrated under vacuum, then dissolved in 100 mL of EtOAc—2.5% aq. NaHCO3 (1:1). Aqueous phase is extracted with EtOAc (2×50 mL). The combined organic layers are washed with brine, and dried (MgSO4). Solvent is removed under vacuum to afford the title compound that is used directly without further purification. Step 2: Preparation of N-[[(5S)-3-[4-[2,3-dihydro-1,1-dioxido-6-(trifluoroacetyl)-4H-1,4-thiazin-4-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:13][C:14]([F:27])([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[CH:15]([F:17])[F:16].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:13][C:14]([F:27])([O:18][C:19]1[CH:20]=[C:21]([CH2:22][NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:24]=[CH:25][CH:26]=1)[CH:15]([F:16])[F:17]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Ethyl 3-aminobenzoate (6.75 mL, 0.045 mol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (10 g, 45 mmol) were dissolved in 100 mL of dichloroethane and acetic acid (2.7 mL, 47 mmol), then solid NaBH(OAc)3 (14.3 g, 67 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was wa shed with brine, then dried over MgSO4, and evaporated to give 16.7 g (98%) of the desired ethyl 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzoate product as a yellow oil. 1H NMR (CDCl3) δ1.3 (t, 3H), 4.3 (q, 2H), 4.5 (s, 2H), 6.5 (tt, 1H), 6.9 (d, 1H), 7.1-7.4 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[O-:14][C:15]#[N:16].[Na+]>CO.C(O)(=O)C>[NH:1]([C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)[C:15]([NH2:16])=[O:14]
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2
Temperature: 0 °C
Yield: 169.6 %

Procedure:
To a solution of 5-aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.75 g.) in methanol (10 ml.) and acetic acid (5 ml.) was added dropwise 2 ml. of aqueous solution of sodium cyanate (130 mg.), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added ice-water, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give colorless needles of 5-ureidospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.74 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>O.CCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(N)cc1OCc1ccccc1
Temperature: 80 °C
Yield: 33.3 %

Procedure:
In a 50 mL 3-neck RBF equipped with a magnetic stirrer, reflux condenser, and thermo pocket were charged 2-(benzyloxy)-1-(2-methoxyethoxy)-4-nitrobenzene (2.00 g), ethanol (15 mL) and SnCl2 (4.49 g). The reaction mixture was heated to 80° C. for 3 hr. The reaction was monitored by TLC using hexane:ethyl acetate (5:5) as mobile phase. After completion, the reaction mixture was allowed to cool at room temperature. The reaction mixture was poured in water and basified by using saturated sodium bicarbonate solution. Product was extracted with ethyl acetate (50 mL×3) and the organic layer was washed with 50 mL brine solution. Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by using Combiflash chromatography. Product was eluted with 30% ethyl acetate in hexane to give 0.600 g of 3-(benzyloxy)-4-(2-methoxyethoxy)aniline. 1H NMR: DMSO-d6 (400 MHz): 3.348 (s, 3H), 3.556-3.580 (t, 2H, J=4.8), 3.928-3.951 (t, 2H, J=4.4), 4.702 (s, 2H), 5.006 (s, 2H), 6.004-6.031 (dd, 1H, J=2.4, 6), 6.334-6.340 (d, 1H, J=2.4), 6.676-6.697 (d, 1H, J=8.4), 7.303-7.339 (m, 1H), 7.373-7.410 (m, 2H), 7.438-7.747 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Brc1cccc2c1CCCN2
Product: COc1cc2ncnc(N3CCCc4c(Br)cccc43)c2cc1OC
Yield: 4 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 4% yield from 5-bromo-1,2,3,4-tetrahydroquinoline and 4-chloro-6,7-dimethoxy-quinazoline. (film; LC-MS: 399 (MH+)).