Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]4[CH:27]=[CH:28][C:23]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: CCCCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)cc1
Yield: 76.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-n-butylphenylboronic acid (139 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 180 mg (77%) of the title compound as a white solid. mp 102°-108°. FDMS: m/e=361. α[D]589 =+68.70 (c=1.05, chloroform).
Reaction SMILES: Cl.N[CH2:3][C:4]1[C:12]([OH:13])=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2.C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:31]>>[CH:3]([C:4]1[C:12]([OH:13])=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)=[O:31]
Reactant: CS(=O)(=O)c1cc2c(c(CN)c1O)CCC2
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CS(=O)(=O)c1cc2c(c(C=O)c1O)CCC2

Procedure:
0.83 g (0.003 mol) of 4-aminomethyl-5-hydroxy-6-methylsulfonylindane hydrochloride is reacted with 0.42 g of urotropine in 6 ml of trifluoroacetic acid in analogy to Example 1. Melting point: 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26].Cl.C(OCC)C>CC(O)C>[ClH:1].[N+:18]([C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[N:7][C:2]([NH:26][C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[N:3][CH:4]=1)([O-:20])=[O:19]
Reactant: NC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3C(N)=O)n2)cc(OC)c1OC
Temperature: 90 °C
Yield: 35.3 %

Procedure:
To a mixture of 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]benzamide (52 mg, 0.178 mmol) and 3,4,5-trimethoxyaniline (34 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for approx. 18 hours. After the reaction was cooled to room temperature cold diethyl ether was added to precipitate out the product. The precipitate was filtered and washed with cold diethyl ether, then dried under vacuum to give 2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)benzamide hydrochloride (30 mg, 35%) as a dark brown solid. 1H NMR (DMSO-d6/D2O): δ 9.07 (s, 1H), 8.26 (m, 1 H), 7.69 (d, 1 H), 7.34 (t, 1 H), 7.19 (t, 1 H), 6.92 (s, 2 H), 3.77 (s, 3 H), 3.59 (s, 6 H). MS m/z 440 (M+1).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](OB(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)(O)[O-].[Na+].B(O)(O)O>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.O>[NH2:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: Nc1cccc(OB(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: OB(O)O
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
A suspension of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea (0.300 g, 1.00 mmol), 3-aminophenyl boric acid (0.237 g, 1.50 mmol, 1.5 eq), and sodium bicarbonate (0.210 g, 2.50 mmol, 2.5 eq) in 8 mL of mixed solvent DMF/water (5/1) was purged with nitrogen gas. To the mixture, the catalyst Pd(PPh3)4 (0.058 g, 0.05 mmol, 0.05 eq) was added. It was purged with nitrogen gas again, and was heated at about 100° C. in a sealed tube for about 48 hours. More Pd(PPh3)4 (0.025 g, 0.02 mmol, 0.02 eq) and more boric acid (0.080 g, 0.50 mmol, 0.50 eq) were added after the first 24 hours. The mixture was taken up in MeOH, concentrated, dissolved in methylene chloride, washed with sodium bicarbonate solution, dried (MgSO4), evaporated, and purified by flash chromatography on SiO2 with MeOH and methylene chloride (1/50) to give the desired compound 0.073 g (23%). LC/MS 313.2 (M+1); LC retention time 2.11 min.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]2=O)[CH2:4][CH2:3][CH2:2]1.[CH3:16][NH2:17]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:16][N:17]=[C:9]1[CH:10]2[N:5]([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]1=2
Reactant: CN
Reactant: O=C1c2ccccc2CN2CCCCC12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CN=C1c2ccccc2CN2CCCCC12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of the ketone of example 5 (1.10 g, 5.47 mmol) in CH2Cl2 (20 mL) was added to methylamine (5 mL) followed by the addition of TiCl4 (2.74 mmol, 2.74 mL of 1.0 M solution in toluene). The mixture was stirred at room temperature for 10 h. It was filtered through a pad of diatomaceous earth (sold under the brand name CELITE) and rinsed with CH2Cl2. The filtrate was concentrated in vacuo to give a mixture of red solid and oil (1.29 g, 100%) which was directly used for the next step without purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:8][CH3:9])[NH:5][C:6]=1[Br:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1>CN(C=O)C.CCOC(C)=O.CCCCCC>[CH2:19]([O:18][CH2:17][N:3]1[C:2]([Br:1])=[C:6]([Br:7])[N:5]=[C:4]1[CH2:8][CH3:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCOCc1ccccc1
Reactant: CCc1nc(Br)c(Br)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1nc(Br)c(Br)n1COCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
To a mechanically stirred solution of 4,5-dibromo-2-ethylimidazole (25.4 g, 0.1 mole,) in anhydrous DMF (250 mL) was treated with K2CO3 (69.1 g, fw=138.2, 0.5 moles, 5 equiv.) followed by dropwise addition of benzyl chloromethyl ether (18.5 g, 0.11 moles, 93% pure, TCI, fw=156.61) and stirred overnight at room temp under nitrogen for 20 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material imidazole (Rf=0.2) along with formation of product (Rf=0.71). The reaction mixture was filtered, washed the solid with dichloromethane and the combined filterate was evaporated under reduced pressure and purified the crude (47 g) by flash column chromatography (dichloromethane eluent) to afford 31.75 g (85%) of colorless oil. Mass spectrum (m/z=375, M+H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:26])[N:6]=1)[CH:2]([CH3:4])[CH3:3].Cl.[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1>>[CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([N:28]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]4)=[O:24])=[CH:20][CH:21]=3)[N:12]=2)[CH:8]=[C:7]([CH3:26])[N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C1CCNC1
Reactant: Cc1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cc(CC(C)C)n1
Agent: Cl
Product: Cc1cc(-c2nc(-c3ccc(CC(=O)N4CCC(C(=O)O)C4)cc3)no2)cc(CC(C)C)n1

Procedure:
(RS)-1-(2-{4-[5-(2-Isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetyl)-pyrrolidine-3-carboxylic acid is prepared from {4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetic acid and (RS)-pyrrolidine-3-carboxylic acid hydrochloride in analogy to Example 65; LC-MS: tR=0.82, [M+1]+=448.10.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30](C)(C)[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(OCC)=O>C(Cl)Cl.O>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
Tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 148 (300 mg, 0.65 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and then added methylene chloride (5 ml), triethylamine (2 ml) and ethyl chloroformate (0.11 ml, 1.31 mmol) followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford ethyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (182 mg, yield 65%) as a white powder.
Reaction SMILES: [ClH:1].C[O:3][C:4](=[O:38])[CH2:5][NH:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[N:37]=[CH:36][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:24][CH:23]=4)[C:15]=3[CH:14]=2)=[CH:11][CH:12]=1.[OH-].[Na+]>CC(C)=O>[ClH:1].[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:10]4[O:9][C:8]([CH2:7][NH:6][CH2:5][C:4]([OH:38])=[O:3])=[CH:12][CH:11]=4)[N:37]=[CH:36][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:23][CH:24]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)CNCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)CNCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
((5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-ylmethyl)-amino)acetic acid methyl ester hydrochloride (0.04 g) was suspended in acetone (5 ml) and 2N sodium hydroxide solution (5 ml) added. The resulting solution was stirred at room temperature for 30 mins. The acetone was removed under vacuum and the solution acidified with 2N HCl. The mixture was chilled in an ice-bath and the precipitate filtered off and washed with a little cold water and then acetone. The residue was dried at 60° C. under vacuum to give the product as an orange solid (0.03 g); δH [2H6]-DMSO 10.30 (1H, b), 9.10 (1H, s), 8.71 (11H, s), 8.59 (11H, s), 7.75 (2H, d), 7.53−7.28 (5H, m), 7.15−7.00 (3H, m), 6.62 (1H, d), 5.12 (2H, s), 4.07 (2H, s); m/z 482 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH:16]1([CH2:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:23][CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: NCC1CCCCC1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC1CCCCC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and cyclohexanemethylamine.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][C:33]([F:32])([F:44])[F:45])[CH:36]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(OC(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-(trifluoromethoxy)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (61%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:23]=[CH:22][C:11]([C:12]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[O:13])=[CH:10][CH:9]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>Cl.O1CCCC1>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[O:13])=[CH:22][CH:23]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)c2cncc(C#N)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cncc(C(=O)c2ccc(CO)cc2)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Dissolve 5-[4-(tert-butyl-dimethyl-silanyloxymethyl)-benzoyl]-nicotinonitrile (510 mg, 1.45 mmol) in 10% aqueous hydrochloric acid (10 mL) and tetrahydrofuran (50 mL) and stir. After 1 hour, add saturated aqueous sodium bicarbonate (50 mL) and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title product as a white solid (325 mg, 94%): 1H NMR (DMSO-d6) δ 4.64 (d, 2H), 5.44 (t, 1H), 7.53 (d, 2H), 7.80 (d, 2H), 8.59 (t, 1H), 9.09 (d, 1H), 9.27 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].CC(C)([O-])C.[K+].[C:20]1([S:26][CH2:27]Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[N:5]([CH2:27][S:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:6]2(=[O:8])=[O:7]
Reactant: O=C1NS(=O)(=O)c2cccc(Br)c21
Reactant: ClCSc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2c(Br)cccc2S(=O)(=O)N1CSc1ccccc1
Yield: 83.7 %

Procedure:
A mixture of 3.27 g (0.012 mol) of 4-bromosaccharin [Japanese Pat. Publcn. 58/79,034, published May 12, 1983; C. A. 100, 7773w (1984)], 1.63 g (0.015 mol) of potassium t-butoxide, 0.39 g (0.0012 mol) of tetrabutylammonium bromide and 3.0 ml (0.022 mol) of chloromethyl phenyl sulfide in 100 ml of toluene was heated under reflux under a nitrogen atmosphere for eight hours and then at ambient temperature for about sixteen hours. The reaction mixture was then cooled, diluted with ethyl acetate and the organic layer washed with bicarbonate, water and brine and then dried over magnesium sulfate and taken to dryness in vacuo. The residual solid was recrystallized from toluene-hexane to give 3.86 g (84%) of 4-bromo-2-phenylthiomethylsaccharin, mp 174.5°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 97 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 97%). 1H NMR (300 MHz, CDCl3): δ 2.17 (s, 3H), 2.54 (s, 3H), 3.39-3.58 (m, 4H), 3.71-3.90 (m, 4H), 4.14 (s, 3H), 6.89 (d, J=6.4 Hz, 2H), 7.21-7.54 (m, 4H), 7.90 (d, J=6.4 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3=CC=CC=C3C2=O)=[CH:3][CH:2]=1.O.NN>CO>[NH2:10][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccncc1
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCc1ccncc1
Yield: 59.7 %

Procedure:
N-[3-(4-Pyridyl)propyl]phthalimide (67.1 g, 252 mmol) was mixed with methanol (504 ml) and hydrazine monohydrate (18.3 ml, 378 mmol), and the mixture was refluxed for three hours. The reaction mixture was allowed to stand, then an insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure. Chloroform (1 liter) and a 4 N aqueous sodium hydroxide solution (500 ml) were added to the residue, layers were separated, and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure and then distilled under reduced pressure to give 20.5 g (60%) of the titled compound as a colorless oily matter.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]4[O:12][C:13]([CH3:16])=[N:14][N:15]=4)[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3c2)o1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(F)cc4)c3c2)o1
Yield: 68.7 %

Procedure:
A mixture of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole (251 mg, 0.900 mmol), (4-fluorophenyl)boronic acid (140 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium(0) (31.2 mg, 0.0270 mmol), sodium carbonate (212 mg, 2.00 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was heated overnight under reflux under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (182 mg, yield 69%) as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:18][N:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[O:21])[C:9]1=[O:30])(C)(C)C.C(O)(C(F)(F)F)=O>C(O)=O>[CH2:23]([O:22][N:19]([CH2:18][CH:10]1[C:9](=[O:30])[N:8]([CH2:7][C:6]([OH:31])=[O:5])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11]1)[CH:20]=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(CN(C=O)OCc2ccccc2)Sc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Product: O=CN(CC1Sc2ccccc2N(CC(=O)O)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
The {2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-acetic acid tert-butyl ester obtained in the previous step is treated with TFA (2.4 mmol) in 12 mL of formic acid. The reaction is stirred at room temperature for 3 hours. The solvent is removed and the mixture is purified by column chromatography (hexane/EtOAc) yielding {2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-acetic acid. Yield: 50%. MS: (ES+): 359.2 [M+1].
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[NH:40]1[CH2:48][CH2:47][CH2:46][CH:42]([C:43]([NH2:45])=[O:44])[CH2:41]1>>[C:43]([CH:42]1[CH2:46][CH2:47][CH2:48][N:40]([C:36]([C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([C:23]4[CH:22]=[C:21]([N:15]5[C:14](=[O:39])[C:13]6[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=6)[C:16]5=[O:20])[CH:26]=[CH:25][CH:24]=4)[O:28][C:29]=3[CH:35]=2)=[O:37])[CH2:41]1)(=[O:44])[NH2:45]
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Reactant: NC(=O)C1CCCNC1
Product: NC(=O)C1CCCN(C(=O)c2ccc3nc(-c4cccc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)c4)oc3c2)C1

Procedure:
Prepared by the method of Example 76 g), from 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) and nipecotamide (18 mg, 0.14 mmol) the title compound was obtained (18 mg, 37%). 1H NMR (DMSO) δ 8.44(dd, 1H), 8.36(m, 2H), 8.29(dt, 1H), 7.95–7.76(m, 4H), 7.44(dd, 1H), 4.02(m, 1H), 3.18(bm, 2H), 2.87(bm, 2H), 1.70–1.38(m, 4H). MS 536.8 m/z (M−H)−.
Reaction SMILES: CS([C:4]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N+:21]3([O-])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[N:5]=1)=O.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.S([O-])(O)=O.[Na+].N>C(Cl)(Cl)Cl>[CH:28]1([NH:31][C:4]2[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)[N:5]=2)[CH2:30][CH2:29]1
Reactant: CS(=O)c1nc(Nc2ccc(C[N+]3([O-])CCOCC3)cc2)ncc1C(N)=O
Reactant: NC1CC1
Agent: N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cnc(Nc2ccc(CN3CCOCC3)cc2)nc1NC1CC1
Temperature: 90 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
A 1 ml portion of chloroform solution containing 11.7 mg of 4-methylsulfinyl-2-({4-[(N-oxidomorpholin-4-yl)methyl]phenyl}amino)pyrimidine-5-carboxamide was mixed with 5.1 mg of cyclopropylamine and 5.8 mg of diisopropylethylamine, followed by stirring at 90° C. for 15 hours. A 1 ml portion of aqueous solution containing 50 mg of sodium hydrogen sulfite was added to the reaction mixture, followed by stirring at room temperature for 4 hours. This was mixed with 0.1 ml of aqueous ammonia and extracted with 2 ml of chloroform. By evaporating the solvent under a reduced pressure and fractionating the residue by an HPLC (Wakosil-II 5C18AR, 0.1% HCOOH—H2O/MeOH=7/3−0/10), 2.6 mg of 4-cyclopropylamino-2-(4-morpholin -4-ylmethylphenylamino)-pyrimidine-5-carboxamide was obtained.