Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Cu])#[N:12].CN(C=O)C>C(Cl)Cl>[CH3:10][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: COc1cccc(C)c1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C)c1C#N
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 2-bromo-1-methoxy-3-methylbenzene (7.5 g, 37 mmol), CuCN (6.7 g, 75 mmol) followed by addition of DMF (60 mL); the resulting mixture was then refluxed at 150° C. overnight. When the reaction was complete, as evidenced by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately. The solids were filtered, re-dissolved in DCM, absorbed into silica gel and loaded into column with Hexanes:EtOAc (1:1) to afford the title product.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]1([CH3:29])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:12]([C@@H:6]1[CH2:7][CH2:8][C@H:9]([C:10]#[CH:11])[N:5]1[C:3](=[O:4])[CH2:2][NH:14][C:15]1([CH3:29])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)#[N:13]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC1(N)CCN(c2cc(C#N)ccn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(C)CCN(c2cc(C#N)ccn2)CC1
Temperature: 55 °C
Reaction time: 48 h
Yield: 5.1 %

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (170 mg, 0.86 mmol, Example 8D) in acetonitrile (4 mL) at room temperature was added 4amino-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carbonitrile (150 mg, 0.78 mmol) and diisopropylethylamine (250 μL, 1.38 mmol). The reaction mixture was stirred at 55° C. for 48 hours, concentrated under reduced pressure and purified by flash chromatography with a gradient from 1% to 6% methanol in methylene chloride buffered with ammonium hydroxide (0.3%). Combined fractions were concentrated under reduced pressure to afford 15 mg of the desired compound. The residue was subjected to 4N HCl in dioxane (2 mL), and after 0.5 h, the volatiles were removed under reduced pressure. Solidification by trituration with diethyl ether provided the titled compound as the HCl salt. MS (CI) m/z 377 (M+H)+; 1H NMR (300 MHz, MeOH-d4) δ 8.21 (d, 1H), 7.09 (m, 1H), 6.79 (d, 1H), 4.75 (m, 1H), 4.61 (m, 1H), 3.94 (m, 2H), 3.77-3.52 (m, 4H), 3.06 (m, 1H), 2.45-2.22 (m, 4H), 1.65 (m, 4H), 1.19 (m, 3H).
Reaction SMILES: C1COCC1.[NH2:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[O:20][CH3:21].C(=O)(O)[O-].[Na+].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>O>[CH2:31]([O:30][C:28]([NH:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[O:20][CH3:21])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 94.5 %

Procedure:
THF (20 mL) and water (15 mL) were added to tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate (described in Example (1e), 4.6 g, 20 mmol). The mixture was stirred, during which sodium bicarbonate (3.44 g, 40 mmol) and benzyl chloroformate (3.95 g, 22 mmol) were added at room temperature, followed by stirring for one hour. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 6.89 g of the title compound as a colorless solid (95%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[Cl:18][C:19]([Cl:26])([Cl:25])[CH2:20][O:21][C:22](Cl)=[O:23]>ClCCl>[Cl:18][C:19]([Cl:26])([Cl:25])[CH2:20][O:21][C:22]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:23]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Tetrahydroisoquinoline [Aldrich] (39.9 g, 300 mmol) was dissolved in dichloromethane (400 ml) and treated with triethylamine (32 g, 315 mmol). The mixture was cooled in an ice bath and a solution of 2,2,2-trichloroethylchloroformate (65.0 g, 306 mmol) in dichloromethane (100 ml) introduced dropwise over 15 minutes. After addition, the mixture was allowed to warm to room temperature and stirred for a further 30 minutes. The solution was washed with 1M aqueous hydrochloric acid (2×100 ml), then washed successively with water (100 ml), sodium bicarbonate (100 ml) and brine (50 ml), then dried (MgSO4), filtered and evaporated to give the title compound (D6) as a pale orange oil 92.5 g; δH (CDCl3 rotomers observed) ppm 2.90 (2H, app.t), 3.74-3.81 (2H, m), 4.67, 4.72 (2H, 2s), 4.80 (2H, s), 7.12-7.21 (4H, m).
Reaction SMILES: C(OC([N:8]1[CH2:44][CH2:43][C:11]2([N:15]=[C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=4)=[C:30]([CH3:42])[CH:29]=3)[O:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:14]4[O:13][CH2:12][C:11]5([CH2:43][CH2:44][NH:8][CH2:9][CH2:10]5)[N:15]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][C:35]1[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6(CCN(C(=O)OC(C)(C)C)CC6)CO5)cc34)cc2C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6(CCNCC6)CO5)cc34)cc2C)cn1

Procedure:
N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diazaspiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS ESI (+) m/z 496 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 8.43 (s, 1H), 8.39 (s, 1H), 8.12 (d, 1H), 7.70 (m, 3H), 7.61 (dd, 1H), 7.28 (m, 2H), 6.98 (d, 1H), 3.45 (m, 2H), 3.32 (m, 2H), 3.25 (m, 2H) 2.50 (s, 3H), 2.32 (m, 2H), 2.25 (s, 3H), 2.01 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].O(Cl)[Cl:19].[P+5]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:19])=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(Cl)cc2c1=O
Reactant: ClOCl
Agent: [P+5]
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Temperature: 125 °C

Procedure:
Ethyl-6-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate (19.8 mmol) and phosphorus (V) oxychloride (99.3 mmol) was stirred and heated to 125° C. for 12 hours. The mixture was cooled to ambient temperature and the phosphorus (V) oxychloride was evaporated. The crude product was used without further purification. MS m/z 271.80 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.[F:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH2:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(=O)C.C(OCC)(=O)C>[F:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:9][C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:17]1
Reactant: Fc1ccccc1OCC1CCNC1
Reactant: COc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1nccnc1CN1CCC(COc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
After dissolving 148 mg of 3-methoxypyrazine-2-carboxaldehyde and 200 mg of 3-(2-fluorophenoxymethyl)pyrrolidine in 5 ml of dichloromethane, 0.07 ml of acetic acid and 297 mg of sodium triacetoxyborohydride were added and the mixture was stirred overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (245 mg, 77% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]#[N:16].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl>[CH3:13][N:5]1[C:6]2[C:11](=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[C:2]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:3]([C:15]#[N:16])[C:4]1=[O:14]
Reactant: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2C
Reactant: C1CNCCN1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A solution of Compound 23 (1 g, 4.3 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (1.1 g, 12.9 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.07 g (88%) yellow solids. M.P. 274° C. 1H NMR (DMSO-d6): δ 2.39 (s, 3H), 2.94 (m, 4H), 3.48 (m, 4H), 3.54 (s, 3H), 7.45 (d, J=8.6 Hz, 1H), 7.56 (dd, J=1.3, 8.6 Hz, 1H), 7.64 (s, 1H). EIMS m/z 283 (M+1).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1([N:23]([CH3:25])[CH3:24])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14](C)[C:15](=O)OC(C)(C)C)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].CO.C(Cl)(Cl)[Cl:29]>C(Cl)(Cl)Cl>[ClH:29].[ClH:1].[ClH:29].[CH2:2]([C:6]1([N:23]([CH3:24])[CH3:25])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][CH3:15])[CH2:10][CH2:11]1)[CH2:3][CH2:4][CH3:5]
Reactant: ClC(Cl)Cl
Reactant: CCCCC1(N(C)C)CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CCCCC1(N(C)C)CCN(CCNC)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
HCl gas was passed for approximately 1 hour through a solution at 0° C. of 10.5 g (1 equiv.) of tert-butyl 2-(4-butyl-4-(dimethylamino)piperidin-1-yl)ethyl(methyl)-carbamate in 1000 ml of chloroform. The reaction mixture was then stirred for 12 hours at room temperature. The progress of the reaction was monitored by thin-layer chromatography (20% MeOH/CHCl3). When the reaction was complete, the solvent was removed under reduced pressure and the residue was washed with hexane (3×50 ml) and ethyl acetate (3×50 ml) and dried. 9 g (87%) of product were obtained in the form of a white solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([N:21]1[C@@H:25]([CH2:26][CH2:27][OH:28])[CH2:24][O:23][C:22]1([CH3:30])[CH3:29])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:18][C:19]([N:21]1[C@@H:25]([CH2:26][CH:27]=[O:28])[CH2:24][O:23][C:22]1([CH3:30])[CH3:29])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OC[C@H](CCO)N1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C)OC[C@H](CC=O)N1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A solution of dimethyl sulfoxide (6.39 g, 81.8 mmol) in DCM (25 mL) was added at −70° C. to a solution of oxalyl chloride (5.59 g, 44.1 mmol) in DCM (90 mL), then after 15 min a solution of (S)-4-(2-hydroxy-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid benzyl ester (8.79 g, 31.5 mmol) in DCM (45 mL) was added dropwise. After 60 min Et3N (15.9 g, 157 mmol) was added, then after 20 min the cooling bath was removed and the reaction mixture was stirred for 2 h. The reaction mixture was poured onto water and extracted five times with DCM. The combined organic phases were dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 1:1) produced the title compound (8.52 g, 98%) as light yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.ClC(OCC)=O.Cl.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH2:38]([O:45][NH:46][C:14](=[O:15])[CH:13]([CH2:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:10])=[O:11])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)O)cc1
Reactant: NOCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)NOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-[(4-methoxybenzenesulfonyl)methyl]-3-phenyl-propionic acid (1.05 g, 3.14 mmol) and 0.69 mL (6.3 mmol) of NMM in dry THF, under nitrogen, is cooled in an ice bath. Ethyl chloroformate (0.33 mL, 3.5 mmol) in 7 mL of THF is added dropwise over 5 minutes. The suspension is stirred at 0° C. for 10 minutes, after which a slurry of O-benzylhydroxylamine hydrochloride (0.64 g, 4 mmol) and NMM (0.44 mL, 4 mmol) in 7 mL of THF is introduced in several portions. The mixture is stirred for 10 minutes and stored at 10° C. overnight. The mixture is allowed to warm to room temperature for 0.5 hours, and is then partitioned between ethyl acetate and aqueous 10% HCl. The organic phase is washed with water, three portions of 1M sodium bicarbonate and brine. It is dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel, eluting with 40%-50% ethyl acetate in hexanes. This affords 1.26 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[N:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23]>CCOCC.CCOC(C)=O>[C:21]([O-:26])(=[O:25])[C:22]([O-:24])=[O:23].[C:1]1([C:7]2[CH:11]=[N:10][N:9]([CH2:12][CH2:13][NH+:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]2[CH:11]=[N:10][N:9]([CH2:12][CH2:13][NH+:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnn(CCN3CCCCCC3)n2)cc1
Reactant: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C([O-])C(=O)[O-]
Product: c1ccc(-c2cnn(CC[NH+]3CCCCCC3)n2)cc1

Procedure:
1-[2-(4-Phenyl-[1,2,3]triazol-2-yl)-ethyl]azepane (compound 22) (0.25 mmol) was dissolved in ether (0.5 mL) and mixed with a solution of oxalic acid (0.25 mmol) in AcOEt (0.1 mL) to give 1-[2-(4-Phenyl-[1,2,3]triazol-2-yl)-ethyl]azepanium oxalate as a white precipitate which was filtered off and dried in vacuum. 1H NMR (500 MHz, DMSOd6, 25° C.) δ=8.32 (1H, s), 7.85 (2H, d, 3J=7.4 Hz), 7.47 (2H, t, 3J=7.4 Hz), 7.38 (1H, t, 3J=7.4 Hz), 4.78 (2H, t, 3J=6.2 Hz), 3.52 (2H, sw), 3.09 (4H, sw), 1.70 (4H, sw), 1.55 (4H, sw) ppm. ES-MS m/z=271.0; C18H24N4O4×½ H2O (369.4): caldc. C, 58.52; H, 6.82; N, 15.17. found C, 58.08; H, 6.61; N, 14.71.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](C)[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:30])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(CO)o2)c1
Reactant: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C=O)o2)cc1
Yield: 59.62 %

Procedure:
N-(5-Benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (11-06) (2.2 g, 59.62%) was synthesized as a yellow sticky solid from N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (10-06) (3.7 g, 8.92 mmol) following the procedure described for N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (11-01).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To an ice-cooled solution of 125 mL of 4-fluoroaniline and 18.4 mL of triethylamine in 300 mL of methylene chloride was added dropwise over 30 min 14.8 mL of trimethylacetyl chloride. After addition was complete, the cooling bath was removed and stirring was continued at ambient temperature for 1 h. The reaction mixture was brought to pH 3 with 6N HCl and was partitioned between methylene chloride and water. Evaporation of the organiclayer afforded a solid which was collected and washed with hexane to afford 21.35 g (83%) of the title compound as a crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C:4]([C:11]([O:13]CC)=[O:12])([C:6]([O:8]CC)=[O:7])[NH:3]1.[OH-].[Na+:17]>CO>[O:1]=[C:2]1[CH2:5][C:4]([C:6]([O-:8])=[O:7])([C:11]([O-:13])=[O:12])[NH:3]1.[Na+:17].[Na+:17]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(C(=O)[O-])(C(=O)[O-])N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1l(c) 5.72 g of diethyl 2-oxoazetidine-4,4-dicarboxylate (prepared as described above) were dissolved in 25 ml of methanol. 53.2 ml of a 1N aqueous solution of sodium hydroxide were added to the resulting solution, and the mixture was stirred at room temperature for 1 day. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to give crystals, which were washed with methanol and with diethyl ether to give 5.3 g of the title compound as crystals.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH:8]=[CH:7][CH2:6][CH2:5][C@H:4]1[C:9]([OH:11])=[O:10].[CH3:12][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO.C1C=CC=CC=1>[ClH:1].[CH3:12][O:10][C:9]([CH:4]1[CH2:5][CH2:6][CH:7]=[CH:8][CH:3]1[NH2:2])=[O:11]
Reactant: N[C@H]1C=CCC[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C1CCC=CC1N
Temperature: 0 °C
Reaction time: 6 h

Procedure:
cis-2-Amino-cyclohex-3-enecarboxylic acid hydrochloride (0.5 g, 2.8 mmol) was dissolved in a mixture of methanol (12 mL) and benzene (12 mL) at 25° C., cooled to 0° C., a 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (4.2 mL, 8.4 mmol) was added slowly, and, after removing the ice-bath, the reaction mixture was stirred at 25° C. for 6 h. The reaction mixture was concentrated in vacuo, to afford the desired crude product, 2-amino-cyclohex-3-enecarboxylic acid methyl ester hydrochloride, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH3:15][N:16]=[C:17]=[S:18]>ClCCl>[CH3:15][NH:16][C:17]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[S:18]
Reactant: Cc1ccc(N2CCOCC2)c(N)c1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)Nc1cc(C)ccc1N1CCOCC1
Reaction time: 144 h

Procedure:
A solution of 4-(2-amino-4-methylphenyl)morpholine (5.7 g) in dichloromethane (30 ml) was treated with methylisothiocyanate (2.8 g) and the reaction mixture kept at room temperature for 6 days to yield 1-methyl-3-(5-methyl-2-morpholinophenyl)thiourea as a colourless solid (m.p. 107° C.).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=1)[C:32]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])=[O:33]>>[C:38]1([S:35]([NH:34][C:32]([C:31]2[CH:30]=[C:29]([NH:28][C:25]([C:14]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[NH:17][C:13]=3[CH2:12][CH2:11][C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[O:26])[CH:46]=[CH:45][CH:44]=2)=[O:33])(=[O:37])=[O:36])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1cccc(C(=O)NS(=O)(=O)c2ccccc2)c1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(C(=O)NS(=O)(=O)c3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole-4-carboxylic acid (Example 93) was reacted with N-(3-amino-benzoyl)-benzenesulfonamide using essentially the same procedure as in Example 20, step d. The crude product was purified by flash column chromatography (silica, ethyl acetate/hexane 2:1) to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.52 (1H, br s), 9.70 (1H, br s), 8.29 (1H, s), 7.98 (3H, m), 7.68-7.52 (SH, m), 7.42-7.28 (4H, m), 2.98 (2H, m), 2.54 (3H, s), 1.95 (3H, s), 1.67-1.35 (14H, m). Found: C, 67.65; H, 6.34; N, 8.49%; C36H38N4O4S.1.0 H2O requires: C, 67.48; H, 6.29; N, 8.74%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added 4-(2-aminoethyl)morpholine (32 mg, 0.25 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl) (38 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 10% MeOH/ethyl acetate) yielding Compound 50 as a solid (10 mg).