Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])(OCC)=O.C(#N)C.N>C1C=CC=CC=1.C(Cl)(Cl)Cl>[C:14]1(=[O:23])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: NCCCCCO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: N
Solvent: c1ccccc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCCCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
A solution of 5-amino-1-pentanol (5.00 g, 48.5 mmol) in benzene (150 ml) was treated with N-carboethoxyphthalimide (11.0 g, 50.2 mmol) and stirred at room temperature for 5 h. Concentration in vacuo and flash chromatography (25% ethyl acetate/petroleum ether) yielded III-33 (9.6 mg, 84% yield) as a clear, colorless oil: UV (9.65×10-4M, acetonitrile) λmax 292.0 (ε212), 242.4 (226) nm; IR (CHCl3) 3460 (br), 2940 (s), 2860 (s), 1770 (s), 1710 (s), 1610 (s), 1470 (s), 1440 (s), 1400 (s), 1370 (s), 1190 (m), 1170 (m), 1130 (m), 1050 (s), 960 (m), 890 (m), 875 (m), 790 (m), 720 (s) cm-1 ; 1H NMR (500 MHz, CDCl3) δ7.72-7.70 (m, 2 H), 3.69 (t, J=7.2 Hz, 1 H), 3.64 (t, J=6.5 Hz, 1 H), 2.17 (br s, 1 H), 1.74-1.59 (m, 2 H), 1.46-1.40 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ169.39, 133.78, 131.96, 123.05, 62.34, 37.74, 32.03, 28.22, 22.93; high resolution mass spectrum (Cl, NH3) m/z 234.1108 [(M+H)+ ; calcd for C13 H15NO3 : 234.1129].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([OH:22])=O)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=O.CN>O1CCCC1>[CH3:23][NH:25][C:20](=[O:22])[CH2:19][N:18]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.4 %

Procedure:
A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.63 g, 0.0101 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for three hours with a stream of nitrogen bubbling through it and then refluxed overnight under nitrogen. It was cooled to room temperature and a solution of methylamine (0.94 g, 0.0302 mole) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature over the weekend. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed once with water, once with 5% potassium hydroxide solution and once with water. The solid was dissolved in hot isopropyl alcohol, filtered hot cooled in the refrigerator to precipitate a solid. Water was added and the solid was collected by filtration and dried under high vacuum at 70° C. to give 0.42 g (13%) of title compound, mp.>260° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cc(F)ccc3C)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
In THF/methanol (2:1, v/v, 90 ml) was dissolved methyl (2-(5-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (810 mg, 2.44 mmol). To the resulting solution was added 1N NaOH (30 ml). After stirring at room temperature for 12 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(5-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (700 mg, 90%) as a pale brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[SH:12].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:25][CH:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])=[O:23]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[S:12][CH2:28][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[NH:25][S:22]([C:15]1[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH3:13])(=[O:23])=[O:24]
Reactant: Sc1nccn1-c1ccccn1
Reactant: Cc1cc(C)c(S(=O)(=O)NC(Cl)c2ccccc2)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2CSc2nccn2-c2ccccn2)c(C)c1
Yield: 87 %

Procedure:
1-(2-pyridyl)-2-mercaptoimidazole and (2,4,6-trimethylphenyl)sulfonylaminobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 1-(2-pyridyl)-2-[2-(2,4,6-trimethylphenyl)sulfonylaminobenzylthio]imidazole.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]([S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])[CH:28]=2)O)=[C:21]([F:47])[N:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:41]1([S:38]([N:29]2[C:30]3=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[C:35]3[C:27]([CH2:25][C:22]3[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=4)=[N:20][C:21]=3[F:47])=[CH:28]2)(=[O:39])=[O:40])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1cnc2c(c1)c(C(O)c1ccc(N(Cc3ccc(C(F)(F)F)nc3)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cnc2c(c1)c(Cc1ccc(NCc3ccc(C(F)(F)F)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 105 %

Procedure:
To 5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2, 3-1)]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (576, 0.100 g, 0.15 mmol) in acetonitrile (12.6 mL) were added triethylsilane (0.34 mL, 2.10 mmol) and trifluoroacetic acid (0.17 mL, 2.20 mmol). The reaction was heated to 80° C. for 2 hours. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude compound (577, 90 mg, 100%) that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:38][CH2:37][C:34]2[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:36][CH:35]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CS(=O)(=O)c1ccc(CNC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)cc1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (4-(methylsulfonyl)phenyl)methanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(4-(methylsulfonyl)benzyl)terephthalamide. MS (Q1) 554 (M)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.Cl.O1CCOCC1.Cl.[CH:26]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2.C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([N:32]2[CH:26]3[CH2:31][CH2:30][CH:29]2[CH2:28][CH2:27]3)=[O:15])[CH:11]=[N:10][C:9]=1[Cl:17]
Reactant: C1CC2CCC1N2
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(c1cnc(Cl)c(Cl)c1)N1C2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g, 30.0 mmol) and 4M hydrogen chloride in dioxane (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2×15 mL) and added to a solution of 7-azabicyclo[2.2.1]heptane hydrochloride (4.75 g; 36.0 mmol) and triethylamine (15.1 mL; 108 mmol) in DCM (150 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo and the residue partitioned between water (75 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to give a solid which was crystallised from ethyl acetate to give the desired compound (5.45 g).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:9][P:10]([CH2:15][CH2:16][NH2:17])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:8].[C:18]([CH:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[C:34]([CH:39]=O)[CH:33]=[CH:32]3)[CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:12]([O:11][P:10]([CH2:15][CH2:16][NH:17][CH2:39][C:34]1[CH:33]=[CH:32][C:31]2[C:36](=[CH:37][CH:38]=[C:29]([O:28][C@H:25]3[CH2:26][CH2:27][C@H:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:23][CH2:24]3)[CH:30]=2)[CH:35]=1)(=[O:14])[O:9][CH2:7][CH3:8])[CH3:13]
Reactant: CCOP(=O)(CCN)OCC
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOP(=O)(CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-amino-ethyl)-phosphonic acid diethyl ester oxalic acid salt (200 mg, 0.74 mmol) in 1,2-dichloroethane (3 mL) was added 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (343 mg, 1.1 mmol). The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (329 mg, 1.5 mmol) was added. After being stirred at room temperature overnight, the reaction mixture was quenched with water, stirred at room temperature for 30 min, then diluted with ethyl acetate, and washed with aqueous NaHCO3. The organic layer was dried over MgSO4 and purified with a silica gel column eluted with ethyl acetate (100%), then eluted with methanol in dichloromethane from 0 to 15% to give sticky oil (130 mg, yield: 25%). ESI-MS: 476.3 (M+H)+.
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[CH:13]=[O:14]>>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[C:13]([OH:2])=[O:14]
Reactant: CC1CCCC(C)(C)C1C=O
Reactant: O=[N+]([O-])O
Product: CC1CCCC(C)(C)C1C(=O)O
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 39 g of nitric acid (aqueous 60% solution), and the temperature was raised to 55° C. Then, 93 g (0.60 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde [composition: 90.2% of the trans-form, 9.8% of the cis-form] synthesized in Synthesis Example 6-A) was added dropwise thereto over a period of 2 hours. Thereafter, the reaction was carried out for 3 hours at the same temperature, and the reaction mixture obtained was washed with of 100 g of toluene and 100 g of water, followed by separating an organic layer from an aqueous layer. After further washing thrice the organic layer with 100 g of a saturated aqueous sodium chloride solution, the organic layer formed was separated from an aqueous layer. The toluene was distilled off from the organic layer by an evaporator under reduced pressure to provide 101 g of crude 2,2,6-trimethylcyclohexanecarboxylic acid (5) [composition: 90.5% of the trans-form, 9.5% of the cis-form].
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.O.[SH2:13].[Na].O.C(O)(=O)C>CN(C)C=O>[CH3:11][N:10]1[C:6]2[CH:5]=[CH:4][NH:3][C:2](=[S:13])[C:7]=2[N:8]=[CH:9]1
Reactant: S
Reactant: Cn1cnc2c(Cl)nccc21
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc2c(=S)[nH]ccc21
Temperature: 5 °C
Yield: 94.5 %

Procedure:
4.00 g (23.9 mmol) of 4-chloro-1-methyl-1H-imidazo[4,5-c]pyridine in 27 ml of dimethylformamide were stirred at 115° C. for 18 hours with 8.10 g (95.6 mmol) of sodium hydrogen sulphide hydrate. After cooling the mixture was treated with 110 ml of water, adjusted to pH 4 with acetic acid and stirred at 5° C. while cooling with ice for 15 min. The precipitate was filtered off and washed with water. After drying there were obtained 3.73 g (95%) of 1-methyl-1,5-dihydro-imidazo[4,5-c]pyridine-4-thione as white crystals with m.p.>300° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1>>[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][C:20](/[CH:21]=[CH:22]/[C:23]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cc(C=CC(=O)O)c([N+](=O)[O-])cc1OC
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3[N+](=O)[O-])nc2n(CC)c1=O
Yield: 38.8 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 1.50 g (7.57 mmol) of 5,6-diamino-1,3-diethyluracil and 2.11 g (8.33 mmol) of 4,5-dimethoxy-2-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 1.22 g (yield 39%) of Compound 119 as orange needles.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:32](=[O:33])[CH2:31][O:30][CH3:29])[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Triethylamine (0.5 g, 5.0 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and methoxyacetyl chloride (0.3 g, 2.7 mmol) in THF (30 mL) at room temperature. The mixture was stirred at room temperature overnight. Reaction mixture was quenched with methanol (1 mL) and then concentrated. The residue was stirred with 1N HCl (30 mL) for 30 minutes and filtered. The solid was slurried with ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-methoxy-acetamide (0.4 g, 57%) as a white solid: mp 232-234° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.32-2.64 (m, 2H), 2.85-3.00 (m, 1H), 3.31 (s, 3H, CH3), 3.87 (s, 2H, CH2), 4.35 (d, J=6.2 Hz, 2H, CH2), 4.41 (d, J=17.3 Hz, 1H), 4.49 (d, J=17.3 Hz, 1H), 5.10-5.17 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.45-7.64 (m, 3H, Ar), 8.46 (t, J=5.8 Hz, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.16, 38.42, 46.18, 51.54, 58.61, 71.46, 121.60, 128.23, 130.69, 131.56, 134.65, 140.01, 168.03, 169.20, 170.97, 172.82, Anal. calcd. for C17H19N3O5: C, 59.12; H, 5.55; N, 12.17. Found: C, 59.10; H, 5.51; N, 12.05.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH2:17])=[N:9]3)[CH:7]=1.[C:19](=[O:22])(O)[O-:20].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:19](=[O:22])[O:20][C:6]([CH3:8])([CH3:7])[CH3:5])=[N:9]3)[CH:7]=1
Reactant: NC1=N[C@@]2(c3cc(Br)ccc3F)OCC[C@H]2CS1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)ccc3F)OCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of (4aR,7aR)-7a-(5-bromo-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-amine (4.8 g, 14.5015 mmol) in 1,4-Dioxane (40 mL) was added di-tert-butyl bicarbonate (6.19 mL, 29.003 mmol) followed by addition of saturated sodium bicarbonate (33.6 mL) and water (4.8 mL) at rt, and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×100 mL), and the combined organics were dried over the sodium sulphate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting with 30-40% ethyl acetate-hexanes (combiflash) to give the title compound as a white solid (3.5 g, 56% yield). 1H NMR (400 MHz, CDCl3) δ 7.67 (1H, dd, J=2.4, 6.8 Hz), 7.43 (1H, dt, J=1.2, 6.8 Hz), 6.96 (1H, dd, J=8.4, 11.2 Hz), 4.13 (1H, m), 4.03 (1H, m), 3.26 (1H, m), 2.86 (2H, m), 2.36 (1H, m), 2.21 (1H, m), and 1.47 (9H, s). MS (M+H)+:431.0, 435.0
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[NH2+:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[O:1]=[CH:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6]
Reactant: O=CCCC(=O)O
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: C1CC[NH2+]CC1
Product: O=CCCC(=O)[O-]
Reaction time: 1 h

Procedure:
100 Mg. of 4-(8-methoxy-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)-4-oxobutyric acid in 10 ml. of benzene is treated with 60 mg. of piperidine. The solution obtained is allowed to stand for one hour and the crystalline material which forms is filtered, washed with ether and air dried to yield piperidinium 4-(8-methoxy-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)-4-oxobutyrate.
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]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=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:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=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: OB(O)c1cccc(F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
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(F)c1)N1CCN(C2CCC2)CC1
Yield: 35 %

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-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (35%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[B:33](OC(C)C)([O:38]C(C)C)[O:34]C(C)C.Cl>C(OCC)C>[CH:1]([C:4]1[CH:5]=[C:6]([B:33]([OH:38])[OH:34])[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)c1cc(B(O)O)cc(C(C)C)c1
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
To the solution of 3,5-diisopropylbromobenzene (5.76 g, 23.9 mmol) and tetramethylethylenediamine (3.6 mL, 23.9 mmol) in diethyl ether (30 mL), solution of n-butyllithium in n-hexane (14.5 mL, 23.9 mmol) was dropped at −60° C. Reaction solution was stirred for 1.5 hours at −60° C., and further was stirred for 30 minutes at 0° C., then, solution of triisopropyl borate (6.6 mL) in diethyl ether (5 mL) was dropped at −60° C. Reaction solution was stirred for 30 minutes at −60° C., and further, was stirred overnight at room temperature, then, diluted hydrochloric acid (50 mL) was added. Resulting solid part was filtered to obtain the crude product of 3,5-diisopropylphenylboronic acid (5.9 g).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)=[N:5][N:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>ClCCl.CO>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[N:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nnc(Cc2ccncn2)c2ccccc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Clc1ccc(Nc2nnc(Cc3ccncn3)c3ccccc23)cc1

Procedure:
A mixture of 100 mg (0.45 mmol) 1-chloro-4-(4-pyrimidinylmethyl)phthalazine hydrochloride and 149 mg (1.17 mmol) 4-chloroaniline is heated for 1.5 h to 100° C. The reaction mixture is distributed between dichloromethane/CH3OH 19:1 and sat. NaHCO3solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4), and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH 19:1) and crystallization from ethyl acetate/ether yield the title compound: m.p.: 174-176° C.; FAB MS (M+H)+=348.
Reaction SMILES: [CH2:1]([C:8]1[C:17]([OH:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([C:19]#N)=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[K+].O.Cl.[CH2:25]([OH:27])[CH3:26]>>[CH2:1]([C:8]1[C:17]([OH:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([C:19]([O:27][CH2:25][CH3:26])=[O:21])=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc2cc(O)c(Cc3ccccc3)nc2c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1ccc2cc(O)c(Cc3ccccc3)nc2c1

Procedure:
A mixture of 203 mg of 2-benzyl-7-cyano-3-hydroxyquinoline, 2.6 g of potassium hydroxide, 5.5 ml of water and 20 ml of ethanol was heated under reflux for 2 hours. After cooling as it was, dilute hydrochloric acid was added thereto. The mixture was extracted with diethyl ether and the solvent was removed. To the residue were added 30 ml of ethanol and 3.0 ml of concentrated sulfuric acid, followed by heating under reflux for one hour. After cooling as it was, the solvent was removed. Diethyl ether and an aqueous potassium carbonate solution were added thereto, followed by extracting with diethyl ether. The organic phase was washed with brine and the solvent was removed, to give 204 mg of the target compound.