Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O.C(OCC)(=O)C>[Si:20]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCc1ccccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CO
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
To a solution of 1,2-benzenedimethanol (2 g) and imidazole (1.13 g) in N,N-dimethylformamide (30 mL) was added tert -butyldimethylchlorosilane (2.08 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/2) to give the title compound (1.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:25]1([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH:29]=[N:28][CH:27]=[N:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([N:25]4[CH:29]=[N:28][CH:27]=[N:26]4)=[CH:37][CH:36]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=Cc1ccc(-n2cncn2)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(-n4cncn4)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-[1,2,4]Triazol-1-yl -benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).ESIMS (MH+): 509.1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH2:14][N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1)=[O:12]
Reactant: O=C(Nc1nc2ccccc2s1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(Nc1nc2ccccc2s1)c1cn(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
A solution of 9.66 g of N-(2-benzothiazolyl)-1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxamide in 250 ml of toluene was treated with 39.0 g of activated manganese dioxide and stirred for four hours at room temperature. The slurry was filtered and evaporated. The residue was purified by means of high pressure liquid chromatography (silica gel: dichloromethane as the eluent) followed by recrystallization from dichloromethane to yield 4.6 g (48%) of N-(2-benzothiazolyl)-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxamide, m.p. 295°-297° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@@H:18]2[CH:19]=[CH:20][C@@H:14]([C@@H:15]3[C@H:17]2[CH2:16]3)[C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:11][C@H:12]1[C@@H:18]2[CH2:19][CH2:20][C@@H:14]([C@@H:15]3[C@H:17]2[CH2:16]3)[C@H:13]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@@H]1[C@H]2C=C[C@H]([C@@H]3C[C@H]23)[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@@H](N)[C@@H]2CC[C@H]1[C@H]1C[C@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
rac-Methyl (1R,2R,4S,5S,6R,7S)-7-{[(benzyloxy)carbonyl]amino}tricyclo[3.2.2.02,4]non-8-ene-6-carboxylate (0.35 g, 1.07 mmol) was dissolved in ethyl acetate (10 mL). 5% Palladium on carbon (0.04 g) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford the crude product, rac-Methyl (1R,2R,4S,5S,6R,7S)-7-aminotricyclo[3.2.2.02,4]nonane-6-carboxylate, as a thick clear oil, which was used in the next step without further purification. LC-MS (ESI) calcd for C11H17NO2 (free amine) 195.26, found 196.3 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])#[CH:16].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Pd](Cl)Cl.C(#N)C.C(#N)C>[Cl:14][C:12]1[CH:13]=[C:8]([C:16]#[C:15][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])[CH:9]=[N:10][CH:11]=1
Reactant: C#Cc1cccc(C#N)c1
Reactant: Clc1cncc(Cl)c1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: N#Cc1cccc(C#Cc2cncc(Cl)c2)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
Add cesium carbonate (6.59 g, 20.25 mmol) to a degassed mixture of 3,5-dichloropyridine (1 g, 6.75 mmol), 3-ethynylbenzonitrile, (prepared as described in PREPARATION 8), (1.29 g, 10.12 mmol) 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (X-PHOS) (96.3 mg, 0.202 mmol) and bis(acetonitrile) palladium (II) chloride (17.5 mg, 0.068). Stir at 110° C. in a sealed tube for 16 h. Cool to room temperature. Quench with water, and extract the product with ethyl acetate. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 100:50 hexanes:ethyl acetate, to give the title compound (300 mg, 19%).
Reaction SMILES: CN(C)C(=O)C.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([NH:30][CH3:31])[C:27]([NH2:32])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[NH:32][C:12](=[O:13])[C:8]([CH3:15])([CH3:7])[C:9](=[O:10])[N:30]([CH3:31])[C:28]=2[CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: CNc1cc(OCc2ccccc2)ccc1N
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)C(=O)Nc2ccc(OCc3ccccc3)cc21
Reaction time: 4 h
Yield: 57.8 %

Procedure:
Under ice cooling, a N,N-dimethylacetamide (3 mL) solution of dimethylmalonic acid dichloride (0.68 g, 4.0 mmol) was added dropwise to a N,N-dimethyl acetamide (5 mL) suspension of 5-benzyloxy-N1-methylbenzene-1,2-diamine 1/2 sulfate (1.11 g, 4.0 mmol). After the reaction solution was stirred at the same temperature for 4 hours, water (8 mL) was added. The mixture was stirred at 10° C. or less for 30 minutes, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 60° C., thereby obtaining 0.75 g of a slightly pink, powdery target compound (yield: 57.8%).
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:57].Cl.[NH2:59][C@@H:60]([CH2:76][C:77]1[CH:82]=[C:81]([F:83])[CH:80]=[C:79]([F:84])[CH:78]=1)[C@H:61]([OH:75])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:73])[F:72])[CH:66]=1>CN(C=O)C.C(Cl)(Cl)Cl>[ClH:57].[ClH:57].[F:84][C:79]1[CH:78]=[C:77]([CH:82]=[C:81]([F:83])[CH:80]=1)[CH2:76][C@H:60]([NH:59][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:61]([OH:75])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:72])([F:73])[F:74])[CH:66]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(C(F)(F)F)c2)cc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoic acid is dissolved in DMF (10 mL), and diisopropylethylamine (364 μL, 2.1 mmol), HATU (237 mg, 0.62 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-311 (250 mg, 0.52 mmol) are added. The reaction stirred at room temperature 4 h. The reaction mixture is diluted with chloroform, washed with water, saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 689.3 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.I[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>[Cu]=O.CN1CCCC1=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C(O)c1cccc(I)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc(Sc2ccc(F)cc2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Copper(II) oxide (4.01 g) and cesium carbonate (19.7 g) were added in that order to an N-methylpyrrolidinone (100 mL) solution of 4-fluorobenzenethiol (3.10 g) and 3-iodobenzoic acid (5.00 g), and stirred overnight at 160° C. After left cooled, the solid in the reaction solution was removed through filtration. 1 M hydrochloric acid was added to the filtrate, extracted three times with ethyl acetate and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was suspended in a mixed solvent of chloroform/hexane, and the solid was collected through filtration to give the intended product (4.08 g, 82%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH2:19][CH2:20][CH2:21][CH3:22])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(O)C.O.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:3]=1
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(Br)cc1
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1oc2ccccc2c1Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A solution of (4-bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone (2.25 g, 6.32 mmol) in ethanol (20 mL, 0.3 M) was cooled to 0° C. and treated with NaBH4 (0.263 g, 1.1 equiv, 6.95 mmol). After stirring for 1 h, the mixture was poured into a 50% ether in water solution (200 mL). After separation, the aqueous layer was extracted with ether (50 mL) and the combined organic layers were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting alcohol was subsequently dissolved in dry dichloromethane (50 mL), cooled to 0° C. and treated with triethylsilane (2.0 mL, 2.0 equiv., 12.64 mmol) dropwise via syringe. After stirring an additional 5 min, trifluoroacetic acid (2.43 mL, 5.0 equiv., 31.6 mmol) was added over 2 min and the mixture was stirred for 3 h. Once complete, the solution was washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (0-2% ethyl acetate in heptane) afforded 3-(4-bromo-benzyl)-2-butyl-benzofuran as a pale yellow oil (1.34 g, 63%).
Reaction SMILES: [C:1]([O:6]CCO)(=[O:5])[C:2]([CH3:4])=[CH2:3].S(C1C=CC=C[C:15]=1[C:16]([O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([OH:29])(=[O:28])=[O:27])=O)(O)(=O)=O.COC.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([O:18][CH2:16][CH2:15][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:30])([OH:29])(=[O:27])=[O:28]
Reactant: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Reactant: C=C(C)C(=O)OCCO
Agent: COC
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCOC(=O)c1ccccc1S(=O)(=O)O
Temperature: 110 °C

Procedure:
Hydroxyethyl methacrylate (65 g.), o-sulfobenzoic anhydride (92 g.), the monomethyl ether of hydroquinone (0.2 g.) and toluene (157 g.) are stirred, sparged with dry air, and heated at 110° C. for 2 hours and then cooled to room temperature. Analysis indicates an approximately 74% conversion of anhydride into methacryloxyethyl sulfobenzoate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][N+:12]([O-])=O)=[CH:6][CH:5]=1.[H][H].[ClH:19]>CO.[Pd]>[ClH:19].[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])C=Cc1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCc1ccc(OC(F)(F)F)cc1
Yield: 57 %

Procedure:
A solution of 4-trifluoromethoxy benzaldehyde (1 g, 5.26 mmol) and nitromethane (0.96 g, 15.8 mmol) in acetic acid (10.6 mL) is treated with ammonium acetate (1.01 g, 13.2 mmol) is heated under microwave to 150° C. for 15 minutes. The reaction mixture is diluted with water, and extracted three times with DCM (50 mL). The combined extracts are washed sequentially with 2 N sodium hydroxide, water, and brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to yield 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (1.23 g) as a solid. A portion of 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (0.504 g, 2.16 mmol) is hydrogenated with hydrogen in a balloon, 10% Pd/C (115 mg, 5 mol %) in MeOH (22 mL) containing concentrated hydrochloric acid (0.27 mL) at room temperature for 15 hours. The mixture is filtered and filtrate is concentrated to a solid that is washed with diethyl ether to obtain 2-(4-trifluoromethoxy-phenyl)-ethylamine hydrochloride [0.3 g, 57%, Intermediate (12)] as a solid. LC/MS: MS: 206 (M+H).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH3:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1.C(OCC)(=O)C.N>ClCCl.C(OCC)(=O)C.C1CCCCC1.CO>[CH3:32][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN(C)CCCCC1CCCCN1
Agent: N
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CCCCC1CCCCN1C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 55 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-(dimethylamino)butyl]piperidine in a yield of 55% of theory. Colourless crystals, m.p. 145°-147° C. (from ethyl acetate), Rf 0.1 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 58/25/8/8/1, v/v/v/v/v)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH2:13][CH3:14])[CH:8]=[C:7]2[OH:15].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCSc1cc(O)c2cccc(Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1cc(OCc2ccc(OC)cc2)c2cccc(Cl)c2n1
Temperature: 65 °C
Yield: 72.3 %

Procedure:
8-Chloro-2-ethylsulfanyl-quinolin-4-ol (10.26 g, 42.8 mmol) was dissolved in anhydrous dimethylformamide (100 mL). Cesium carbonate (27.9 g, 85.6 mmol) was added, followed by p-methoxybenzyl chloride (8.0 g, 51.36 mmol). The mixture was then heated at 65° C. for 2 hours and then cooled to room temperature and diluted with ethyl acetate. The diluted reaction mixture was washed with brine 2 times, dried over Mg2SO4 and concentrated in vacuo. The residue was recrystallized from EtOAc/Hexanes to afford 8-chloro-2-ethylsulfanyl-4-(4-methoxy-benzyloxy)-quinoline (11.14 g, 67% yield). LCMS found 360.21 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C[Si]([C:15]#[N:16])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:15]#[N:16])=[N:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(=O)c1ccc[n+]([O-])c1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(=O)c1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.7 %

Procedure:
3-Acetylpyridine N-oxide (2.0 g, 14.6 mmol) was dissolved in nitroethane (20 ml), and trimethylsilyl cyanide (1.7 g, 16.7 mmol) and N,N-dimethylcarbamoyl chloride (1.8 g, 16.7 mmol) were added thereto. The reaction mixture was stirred at room temperature for 16 hrs, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (0.40 g, 21%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:19]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:12])[C:9]([O:11][CH2:19][C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)=[CH:10][C:2]=1[O:1][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 189.9 %

Procedure:
The mixture of 2,4-dihydroxy-5-bromobenzoic acid (23.3 g, 0.1 mol), BnBr (54 g, 0.33 mol) and excess K2CO3 (80 g, 0.58 mol) was stirred in acetone (500 ml) at 85° C. overnight. HPLC indicated the completion of the reaction. After cooling to r.t, the reaction was filtered, and the filtrate was concentrated to give 2,4-bis-benzyloxy-5-bromo-benzoic acid benzyl ester as a white solid (47.8 g, 95%). M.p.: 74-76° C.; 400 MHz 1H NMR (CDCl3) δ: 8.13 (s, 1H), 7.41-7.28 (m, 15H), 6.53 (s, 1H), 5.32 (s, 2H); 5.12 (s, 2H), 5.08 (s, 2H); LCMS: 503, 505 [M+H].
Reaction SMILES: [C:1]12([S:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:16]1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([NH:14][S@:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[O:12])[CH2:16]2)=[CH:23][CH:24]=1
Reactant: O=S(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=[S@](NC1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanesulfinyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanesulfinamide.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:33][CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:35][CH:36]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2c(N)ncnc2Cl)cc1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CNS(=O)(=O)c1ccc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 23 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.33 mmol), 4-amino-6-chloro-N-(4-(N-methylsulfamoyl)phenyl)pyrimidine-5-carboxamide (123 mg, 0.36 mmol), DIEA (344 μl, 1.97 mmol) and cesium fluoride (150 mg, 0.99 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase chromatography using SP1® Purification System to give 47 mg (23% yield) as a solid. Purity 94%.
Reaction SMILES: N([C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([O:12][CH3:13])[N:6]=[CH:5][N:4]=1)N>CO.[Ag-]=O>[CH3:13][O:12][C:7]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:3][N:4]=[CH:5][N:6]=1
Reactant: COc1ncnc(NN)c1[N+](=O)[O-]
Agent: O=[Ag-]
Solvent: CO
Product: COc1ncncc1[N+](=O)[O-]
Yield: 89.5 %

Procedure:
14 g 4-hydrazino-6-methoxy-5-nitropyrimidine are dissolved in 3.6 liters of methanol and stirred for 10 hours at 40° C. with 61.9 g of freshly prepared silver (I) oxide. Then the mixture is filtered and the solution evaporated. 10.5 g 4-methoxy-5-nitropyrimidine with a melting point of 193° to 195° C. is obtained.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH2:11])=[CH:4][C:3]=1[CH3:12].[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:31]=[C:32]([C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH2:11])=[CH:4][C:3]=3[CH3:12])[CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(N)cc([N+](=O)[O-])c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2[N+](=O)[O-])c1

Procedure:
Following the procedure used for Example 295, step h, reaction of 4-bromo-3-methyl-5-nitro-phenylamine (350 mg, 1.5 mmol, as prepared in Example 135, step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (1.0 gm, 2.27 mmol, as prepared in Example 140, step a), tetrakis(triphenylphosine)palladium(0) (433 mg, 0.375 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (6 mL, 2M), and toluene/EtOH mixture (2:1, 18 mL) at 80° C. for 24 h afforded 250 mg (30%) after purification (SiO2, flash elution: 5% to 50% EtOAc in hexanes) of the title compound as a yellow solid. ESI-MS (m/z): Calcd. for C24H26N4O6S3: 563.1 (M+H); found: 562.8, 463.1 (M−Boc).