Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>CC(C)=O>[CH3:2][CH2:1][NH:3][C:4](=[O:5])[NH:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][C:13]([O:16][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])=[CH:12][C:10]=2[N:11]=1
Reactant: CCNC(=O)Nc1nc2ccc(O)cc2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCNC(=O)Nc1nc2cc(OS(=O)(=O)c3cccs3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
A stirred solution of 1-ethyl-3-(6-hydroxy-1H-benzoimidazol-2-yl)-urea (35 mg, example 84-c) and thiophene-2-sulfonyl chloride (18 mg) in acetone (3 ml) was treated with triethylamine (25 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give thiophene-2-sulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester (14 mg) as a off-white solid Mass spectrum: 367 [M+H]+; retention time=7.88 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J7) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (326 mg, 82%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[C:38]([NH:40][CH2:41][CH:42]3[CH2:44][CH2:43]3)[N:37]=[C:36]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:35]=2)[CH:31]=[N:32][CH:33]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]([C:28]3[CH:29]=[C:30]([C:34]4[CH:39]=[C:38]([NH:40][CH2:41][CH:42]5[CH2:43][CH2:44]5)[N:37]=[C:36]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=5)[CH:35]=4)[CH:31]=[N:32][CH:33]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cncc(-c2cc(NCC3CC3)nc(-c3ccccn3)c2)c1
Reactant: CC(C)(C)N1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)N1CCN(Cc2cccc(-c3cncc(-c4cc(NCC5CC5)nc(-c5ccccn5)c4)c3)c2)CC1

Procedure:
To a solution of 3-(4-tert-Butyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B11) (1.5 eq, 0.197 mmol, 54 mg) and 2M Na2CO3 (2.0 eq, 0.262 mmol, 0.13 ml) in DME (1 ml) are added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropylmethyl-amine (Example 2.149; step1) (1 eq, 0.131 mmol, 50 mg) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.0131 mmol, 9.6 mg). The reaction mixture is heated using microwave radiation at 90° C. for 3 hours. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The residue is purified by reverse phase chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 533.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11](=O)([O-])[O-].[K+].[K+]>C1(=O)OC(C)CO1>[CH3:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][CH:5]=[N:6]2)=[C:2]([Cl:1])[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ncnc2nc[nH]c12
Agent: [K+]
Solvent: CC1COC(=O)O1
Product: Cc1nc(Cl)c2[nH]cnc2n1

Procedure:
6-Chloropurine (dried over phosphorus pentoxide, 1.13 g), MBTG (3.87 g) and freshly-dried potassium carbonate (1.5 g) are stirred in anhydrous propylene carbonate (30 ml) at room temperature for 24 hours. The dark mixture is filtered and purified by column chromatography over silica 100 g) eluting with a 0-80% gradient of ethyl acetate in chloroform. The main fraction (other than unreacted 6-chlorpurine) is dried and recrystallized from boiling ethanol to yield methyl 6-chloropurine-9-(2',3',4'-tri-O-acetyl-β-D-glucopyranuronate (312 mg) and benzylamine (171 μl) are heated together in 1-butanol (13.5 ml) at 100° C. for 1 hour. The solid dissolves readily to give a clear yellow solution. Most of the butanol is removed under vacuum to yield a whitish solid which is shaken with 5% sodium hydroxide in 50% aqueous ethanol (25 ml) for 1-2 hours at room temperature. After neutralization, the product is dried under vacuum to remove traces of butanol. Crude BA9GN sodium salt is then purified by reverse-phase chromatography as in Method 1.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13]C(C(O)=O)[S:15][CH2:16]2)=[CH:11][CH:10]=1.CN(C=O)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH:1]([C:2]([Cl:4])=[O:3])[S:15][CH2:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)CSC(C(=O)O)C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)CSC(C(=O)Cl)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2.0 M solution of oxalyl chloride (3.57 mL, 7.14 mmol) in CH2Cl2 was added under N2 to a solution of 7-methoxy-isothiochroman-3-carboxylic acid (0.80 g, 3.57 mmol) and a drop of DMF in CH2Cl2 (100 mL). The solution was allowed to stir at room temperature for 3 h and was concentrated under reduced pressure to provide 7-methoxy-isothiochroman-3-carbonyl chloride as a tan oil. The acid halide was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[S:14][CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[CH:19]=[N:18][CH:17]=1.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[C:3]([S:14][CH2:15][C:16]3[N:20]([CH2:21][CH2:22][CH3:23])[CH:19]=[N:18][CH:17]=3)[N:2]([CH3:1])[C:6]=2[CH:7]=1
Reactant: CCCn1cncc1CSc1nc2ccc([N+](=O)[O-])cc2n1C
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1cncc1CSc1nc2ccc(N)cc2n1C
Yield: 81.3 %

Procedure:
An aqueous solution of 1-methyl-6-nitro-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazole (230 mg), reduced iron (194 mg) and anhydrous calcium chloride (38.5 mg) in 85% ethanol (10 ml) was stirred for 1 day under nitrogen atmosphere at 105° C. The mixture was allowed to be at room temperature, the insolubles were filtered off, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate) to give 6-amino-1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazole (170 mg) as colorless oil.
Reaction SMILES: [CH:1]12[BH:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[CH2:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>O1CCCC1>[CH:5]12[B:9]([CH2:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]3)[CH:1]([CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: B1C2CCCC1CCC2
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CB2C3CCCC2CCC3)CC1
Temperature: 25 °C

Procedure:
6.29 ml of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran are added to 620 mg tert-butyl 4-methylene-piperidine-1-carboxylate under an argon atmosphere, and the reaction mixture is refluxed for 1 h. After cooling to ambient temperature the reaction solution is further reacted without any further working up.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[CH:12]([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:11]([CH:12]([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(C(=O)CC(=O)C(F)F)sc2c1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2nc(-c3cc(C(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2c1
Yield: 84 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-methylbenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-methyl-2-[1-(4-methylsulfonylphenyl)-3-difluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 84%). NMR(CDCl3) δ: 2.51 (3H, s), 3.10 (3H, s), 6.80 (1H, t, J=54.8 Hz), 7.19 (1H, s), 7.33 (1H, app d, J=8.3 Hz), 7.68 (1H, bs), 7.71-7.74 (2H, m), 7.81 (1H, d, J=8.6 Hz), 8.01-8.04 (2H, m); mp 183-184° C. (ethanol)
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])=[N:25][C:24]4[C:19](=[CH:20][C:21]([O:37][CH3:38])=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])=[N:25][C:24]4[C:19](=[CH:20][C:21]([O:37][CH3:38])=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc4[nH]ncc4c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of (S)-methyl 2-(1-(tert-butoxycarbonyl)-1H-indazol-5-yl)-7-methoxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (310 mg, crude) in dichloromethane (32 ml) was added trifluoroacetic acid (8 ml). After stirring overnight at room temperature, the pH value was adjusted to 7 with aqueous sodium bicarbonate and extracted with dichloromethane (2×25 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (10% ethyl acetate in petroleum ether) to give (S)-methyl 2-(1H-indazol-5-yl)-7-methoxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (240 mg) as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH:7]1[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:12]=1)=[O:5])[CH3:2].C=O.CO.[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([CH3:27])[CH:7]1[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:12]=1)=[O:5])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)C1CCNC1c1cc(C)nc(-n2ccnc2)n1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C)C1c1cc(C)nc(-n2ccnc2)n1
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
2-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-3-carboxylic acid ethyl ester (300 mg, 0.996 mmol), formaldehyde, 37 wt % in H2O (500 μL), methanol (8 mL) and acetic acid (550 μL) were all combined in a reaction vessel and stirred for 30 mins. Next, sodium triacetoxyborohydride (530 mg, 2.49 mmol) was added and the solution was allowed to stir at room temperature for an additional 30 mins. After this period of time, the reaction mixture was concentrated under vacuum, dissolved in ethyl acetate (75 mL) and poured into ice (25 mL). The pH was adjusted to pH=8 with 1M NaOH. The organic layer was partitioned from the aqueous layer, dried over Na2SO4 and concentrated down to afford the crude product. The product was purified by Flash Chromatography (0-10% methanol/DCM gradient) to afford 130 mg (42%) 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid ethyl ester. [M+H]+ 316.56.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][C@@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([CH3:23])[CH2:13]2)=O)=[N:8][CH:9]=1.[Cl-].[NH4+].[CH2:26]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[N:6][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][C@@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([CH3:23])[CH2:13]2)=[CH2:26])=[N:8][CH:9]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@@H]1CCC(C(=O)c2ncc(Cl)cn2)C[C@@H]1C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Product: C=C(c1ncc(Cl)cn1)C1CC[C@@H](C(=O)OCC)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.22 g, 6.20 mmol) in THF (22 mL) was added sodium hydride (0.24 g, 6.2 mmol, 10 wt %) at 0° C. After being stirred at 25° C. for 3 hours, ethyl rel-(1R,2S)-4-[(5-chloropyrimidin-2-yl)carbonyl]-2-methylcyclohexanecarboxylate (0.62 g, 2 mmol) was added in one portion at 0° C. The reaction mixture was stirred at 20° C. for 6 hours and then saturated aqueous ammonium chloride was added. The reaction mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give ethyl rel-(1R,2S)-4-[1-(5-chloropyrimidin-2-yl)ethenyl]-2-methylcyclohexanecarboxylate. MS ESI calc'd for C16H22ClN2O2[M+H]+ 309. found 309. 1H NMR: (400 MHz, CD3OD) δ 8.80-8.74 (m, 2H), 6.45-6.40 (m, 1H), 5.55-5.49 (m, 1H), 4.19-4.12 (m, 2H), 2.72-2.47 (m, 2H), 1.87-1.74 (m, 3H), 1.73-1.58 (m, 2H), 1.31-1.25 (m, 4H), 1.22-1.18 (m, 1H), 1.04-1.00 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[N:10]=NC1C=CC(Cl)=CC=1>C(O)C.O.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10]
Reactant: Nc1nc(N)c(N=Nc2ccc(Cl)cc2)c(Cl)n1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N)c(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.7 %

Procedure:
A suspension of 6-chloro-5-[(4-chlorophenyl)-azo]-2,4-pyrimidinediamine (24.55 g, 0.0906 mol) in ethanol (640 ml), water (640 ml) and acetic acid (64 ml) was heated to 70° under nitrogen. Zinc dust (75 g) was added slowly over 1 hour, and then the reaction was stirred an additional hour at 70°. Then the reaction was cooled to room temperature and filtered under nitrogen. The filtrate was cooled to 0° and the pH was raised to 10 with 10% sodium hydroxide (400 ml). The precipitated zinc hydroxide was removed by filtration through Celite, and the dark red filtrate was netralized to pH 7 with glacial acetic acid and concentrated to 00 ml. Water (50 ml) was added, the reaction was cooled to 0° , and the pH raised to 9 with 10% NaOH. The solution was allowed to stand at 5° for 3 days. The crystals were collected, washed with water (50 ml) and then ether (50 ml), and dried at 35° for 16 hours in vacuo to give 10.94 g of desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[NH2:1][C:2]1[S:3][C:4]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1
Reactant: CC(C)(C)c1nc(N)sc1Br
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1nc(N)sc1N1CCCCC1
Yield: 79.3 %

Procedure:
A mixture of 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (0.10 g, 0.42 mmol), piperidine (0.1 mL), potassium carbonate (0.20 g) and acetonitrile (4 mL) was refluxed for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (80.7 mg, 79.3%) as a yellow crystal.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[CH:17]1[C:29]2[CH:28]([O:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[CH:26]1[C:27]2[CH:28]([O:30][CH:31]3[CH2:36][CH2:35][N:34]([CH2:2][C:3]4([CH3:16])[CH2:7][C:6]5[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=5[O:4]4)[CH2:33][CH2:32]3)[C:29]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1ccc2c(c1)-c1ccccc1C2OC1CCNCC1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(OC3c4ccccc4-c4ccccc43)CC1)O2
Yield: 63 %

Procedure:
Using 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 4-[(9-fluorenyl)oxy]piperidine, the procedure of Example 1, presented below, was followed to provide 2-[[4-[(9-fluorenyl)oxy]-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine. Yield 63%. A portion of the product was converted to the oxalate and recrystallized from ethanol to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2ccccc2Cl)ccn1
Yield: 64.7 %

Procedure:
Using the method of Example 3, Step A, 2-chlorophenol (811 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(2-chlorophenoxy)pyridine (0.98 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.25 (d, 1H), 7.52 (d, 1H), 7.36 (t, 1H), 7.28 (t, 1H), 7.17 (d, 1H), 6.74-6.77 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16](/[CH:18]=[CH:19]/[C:20]([O:22]C(C)(C)C)=[O:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.4 %

Procedure:
tert-Butyl (E)-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]acrylate (0.14 g, 0.44 mmol) was dissolved in trifluoroacetic acid (2.0 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and recrystallized from tetrahydrofuran-ethanol to give the titled compound (0.088 g, 64%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:23][CH:24]2[CH2:29][CH2:28]S[CH2:26][CH2:25]2)=[C:8]([CH:22]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])([O-:3])=[O:2].ClC1C=CC=C(C(OO)=O)C=1.[S:41]([O-:45])([O-])(=[O:43])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[O:43]=[S:41]1(=[O:45])[CH2:28][CH2:29][CH:24]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[O:10])[CH2:25][CH2:26]1
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCSCC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(tetrahydro-2H-thiopyran-4-ylamino)benzamide (50.0 mg) in anhydrous dichloromethane (1 mL) was added m-chloroperbenzoic acid (41.5 mg), and the mixture was stirred for 4 hours at ambient temperature. To the mixture were added an aqueous saturated sodium thiosulfate solution and an aqueous sodium bicarbonate solution. The resulting precipitates were collected by filtration and washed with water, methanol and ethyl acetate to give 2-(1,1-dioxotetrahydro-2H-thiopyran-4-ylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (40.0 mg).
Reaction SMILES: [H-].[K+].[C:3]([O:7][C:8](=[O:19])[NH:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[O:17][CH3:18])([CH3:6])([CH3:5])[CH3:4].C([Li])(C)(C)C.[CH2:25]([Si:28](Cl)([CH3:30])[CH3:29])[CH:26]=[CH2:27]>C1COCC1.CCCCCC.CCOC(C)=O.O>[C:3]([O:7][C:8](=[O:19])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([Si:28]([CH2:25][CH:26]=[CH2:27])([CH3:30])[CH3:29])=[CH:12][C:11]=1[O:17][CH3:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1cc(Br)ccc1NC(=O)OC(C)(C)C
Reactant: C=CC[Si](C)(C)Cl
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC[Si](C)(C)c1ccc(NC(=O)OC(C)(C)C)c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To 2.4 g (20.6 mmol, 1.2 eq) of 35% potassium hydride suspended in 70 ml of anhydrous THF under an argon atmosphere, at room temperature 5.2 g (17.2 mmol) of tert-butyl-N-(4-bromo-2-methoxyphenyl)carbamate 4 diluted in 60 ml of anhydrous THF is added dropwise. This mixture is shaken for 10 min before cooling to −78° C. When this temperature is reached, 23.5 ml (35.3 mmol, 2.05 eq) of 1.5 M tert-butyllithium is added through a cannula in hexane diluted in 50 ml of anhydrous THF and previously cooled to −78° C. The reaction is allowed to progress for 20 min at −78° C. before adding 6.2 ml (41.3 mmol, 2.4 eq) of allyl(chloro)dimethylsilane all at once. The temperature is allowed to rise to −10° C. then the medium is hydrolyzed with a small amount of water. Next, 90 ml of AcOEt is added and the organic phase is washed with H2O (3×90 ml), 1 M NaHSO4 (2×90 ml), then a saturated aqueous solution of NaCl (1×90 ml), and lastly, dried on MgSO4. Concentration under vacuum gives an orange oil which is purified by column chromatography (eluent petroleum ether/AcOEt 9:1), producing 4.28 g of a colorless oil (yield: 77%).