Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:17]=[C:6]2[C:7]3[CH:13]([CH2:14][CH2:15][NH2:16])[CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:2][C:3]1[CH:17]=[C:6]2[C:7]3[CH:13]([CH2:14][CH2:15][NH:16][C:25](=[O:27])[CH3:26])[CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c3c(ccn2n1)CCC3CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1CCc2ccn3nc(C)cc3c21
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a mixture of 2-(2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine hydrochloride obtained in Reference Example 43 and triethylamine (1.36 mL, 9.76 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (115 μL, 1.22 mmol) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (56.6 mg, total yield from Reference Example 43, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[OH:18].CN(C=O)C.[H-].[Na+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:15])[O:13]2)[CH:6]=[CH:5][C:4]=1[O:18][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2OC)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
2-[3-Methoxy-4-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was prepared as follows. To a flame-dried 50 ml round bottomed flask were added 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.00 g, 4.00 mmol) and anhydrous DMF (20 ml). Sodium hydride (251 mg, 6.29 mmol; 60% dispersion in mineral oil) was added in three portions, and the suspension was stirred under nitrogen for 30 minutes para-Methoxy benzyl chloride (655 μl, 3.62 mmol) and tetrabutyl ammonium iodide (10 mg, 0.03 mmol) were added, and the reaction mixture was stirred for an additional 16 hours. The reaction mixture was concentrated, then cooled in an ice-bath, and 50 ml of 1 M citric acid was added followed by 100 ml ethyl acetate. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated to give a tan powder. Trituration with diethyl ether gave 1.34 g (91%) of 2-[3-Methoxy-4-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as a tan powder. 1H-NMR (CDCl3) δ=7.35 (m, 2H), 7.29 (s, 1H), 7.26 (s, 1H), 6.89 (m, 3H), 5.11 (s, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 1.33 (s, 12H); MS m/z: 393 [M+Na]+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:33])[C:15]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([Cl:30])[C:18]([NH:31][NH2:32])=[N:17][CH:16]=1)C.C(N(CC)CC)C.O=P(Cl)(Cl)Cl>C(Cl)Cl.C(Cl)CCl>[CH3:11][O:13][C:14]([C:15]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([Cl:30])[C:18]2[N:17]([C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:32][N:31]=2)[CH:16]=1)=[O:33]
Reactant: CCOC(=O)c1cnc(NN)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cn2c(Cc3ccccc3)nnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 33.4 %

Procedure:
Phenylacetyl chloride (152 μL, 1.148 mmol) was added to a solution of 4-(4-bromo-2-chlorophenylamino)-5-chloro-6-hydrazinonicotinic acid methyl ester (49) (0.233 g, 0.574 mmol) and triethylamine (160 μL, 1.148 mmol) in CH2Cl2 (5.7 mL) at 0° C. After warming to room temperature, an additional 75 μL phenylacetyl chloride was added. After 6 hours, the reaction mixture was concentrated and diluted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated. The residue (50b) was diluted with dichloroethylene (2 mL) and POCl3 (465 μL, 5.082 mmol) was added. After stirring at reflux for 12 hours, the reaction mixture was cooled to room temperature and concentrated. The residue was diluted with EtOAc and saturated NaHCO3 was added and the mixture stirred for 20 minutes. The resulting solid was collected by filtrate to give the desired product (51b) (97 mg, 30%).
Reaction SMILES: [OH-].[K+].[CH:3]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:5]([NH:6][C:7]3=[O:14])[CH2:4]1)[CH2:11]2.[CH2:15](Br)[C:16]#[CH:17]>CO>[CH2:17]([N:6]1[C:7](=[O:14])[CH:8]2[CH2:13][CH:3]3[CH2:11][CH:10]([CH2:12][CH:5]1[CH2:4]3)[CH2:9]2)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: O=C1NC2CC3CC(C2)CC1C3
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#CCN1C(=O)C2CC3CC(C2)CC1C3
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
A solution of potassium hydroxide (0.56 gram, 10 mmol) in 3 ml of absolute methanol was added to 4-azatricyclo[4.3.1.13,8 ]undecan-5one (1.65 gram, 10 mmol) and the solvent was slowly removed under reduced pressure with the internal temperature not exceeding 25° C. When solid began to separate, anhydrous toluene was added and the solvent removal continued (a total of 30 ml of toluene were removed), then the temperature was raised to 90° C. (with the distillation continuing at atmospheric pressure--a total of 10 ml of toluene were distilled). The reaction mixture was cooled to 40° C. and propargyl bromide (0.9 ml, 10 mmol) was added dropwise. The temperature was raised to 65° C. and the mixture stirred for 4 hours. The solid precipitate was filtered off, and the filtrate was evaporated to yield 1.82 gram of compound 5a. Melting point 168°-170° C. (recrystallized from a petr. ether-ethanol 10:1 mixture by volume).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:28]3[C@H:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
N,N'-Carbonyldiimidazole (1 g) is added to a solution of 2-methoxyphenylacetic acid (1 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2 g) and triethylamine (1.7 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.8 cm, height 13 cm), eluting with ethyl acetate and collecting 25 cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (5 cc) and isopropyl ether (10 cc). The crystals are drained, washed with isopropyl ether (25 cc) and dried. (3aR,7aR)-(-)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone (1.7 g) is obtained in the form of white crystals melting at 200° C.; [α]20D =-274° (c=0.49, acetic acid).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:30])=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:16]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])=[CH:15][N:14](C4CCCCO4)[N:13]=3)[NH:9][C:8]=2[CH:29]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]1[C:5]([F:30])=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:16]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])=[CH:15][NH:14][N:13]=3)[NH:9][C:8]=2[CH:29]=1)[CH3:2]
Reactant: CCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)nc2cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)C3CC3)nc2cc1F
Reaction time: 5 h
Yield: 61.4 %

Procedure:
A solution of cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide [90 mg, Reference Example 48(d)] in a 1/1 mixture of trifluoroacetic acid and dichloromethane (30 mL) was stirred for 5 hours and then evaporated. The residue was mixed with ethyl acetate (30 mL) and aqueous sodium bicarbonate (30 mL). The organic layer was evaporated to give cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide (44 mg). LC-MS (Method E): RT=2.34 minutes, 330 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]#[N:41].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:39][C:40]#[N:41])=[C:22]([O:27][CH3:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(O)c(OC)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OCC#N)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After dissolving 520 mg of {2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (18d)) in 5 ml of DMF, 262 mg of potassium carbonate and 107 μl of bromoacetonitrile were added and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (514 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(#N)C.[Cl:20][Si:21](Cl)([CH3:23])[CH3:22]>C(N(CC)CC)C>[C:12]([C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:16][Si:21]([CH3:23])([CH3:22])[Cl:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[Si](C)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(C)(C)C)c(O[Si](C)(C)Cl)c(C(C)(C)C)c1

Procedure:
A mixture of 2,6-di-t-butyl-4-methylphenol (110 g, 0.5M), acetonitrile (500 ml), triethylamine (70 ml, 0.5M) and dichlorodimethylsilane (61 ml, 0.5M) was refluxed for 16 hours. The solvent was evaporated and the residue extracted with toluene (500 ml). The toluene extract was evaporated and the residue recrystallised from acetonitrile to give the title compound (90 g, 57%) m.p. 119°-121° (Found: C, 65 65; H, 9.4%. C17H29ClOSi requires C, 65.2; H, 9.3%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[C:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:13]([Cl:15])=[CH:14][C:8]=2[O:7]1)=[O:5])C.NC(N)=N.O>CN(C)C=O>[Cl:15][C:13]1[C:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][C:9]2[O:10][CH:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)C1Oc2cc(Cl)c(S(=O)(=O)c3ccc(Cl)cc3)cc2O1
Agent: N=C(N)N
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C1Oc2cc(Cl)c(S(=O)(=O)c3ccc(Cl)cc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.88 g (0.0069 mol) of 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester are dissolved in 20 ml of dimethylformamide and are added to 0.71 g (0.012 mol) of guanidine at room temperature. The mixture is stirred for 2 hours at room temperature, then poured out onto 200 ml of water. After stirring for 1/2 hour, a crystalline suspension has formed. This is filtered, washed with water, and the crude product is dried in a vacuum drying chamber at 30°-40°. The crude product is then digested with 25 ml of ethyl acetate, partial dissolution and recrystallisation occurring. The whole is cooled for 1/2 hour in an ice-bath, filtered and dried, yielding, in the form of beige crystals, 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid guanidide having a melting point of from 215° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>CN(C)C=O>[Cl:9][CH2:10][CH2:11][NH:12][C:13]([N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])=[O:14]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C=NCCCl
Solvent: CN(C)C=O
Product: O=C(NCCCl)n1cc(Cl)cnc1=O
Yield: 40 %

Procedure:
was prepared from 5-chloropyrimidin-2-one and 2-chloroethylisocyanate in dimethyl formamide as described above; yield 40%. 1H NMR (DMSO-d6): δ3.6 (CH2CH2, broad m), 8.41 (2H-4,6), 9.5 (NH).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[CH3:23][CH:24]([CH3:47])[C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26]>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:27][C:25](=[O:26])[CH:24]([CH3:47])[CH3:23])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)C(C)C)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 5.4 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 100 ml of benzene is treated at room temperature with 8.8 g of dimethylacetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There is obtained methylene-(2S,5R)-3,3-dimethyl-6-(3-methyl-2-oxobutylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as a yellow oil [Rf: 0.35; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm): 1.12 (6H); 1.25 (9H); 1.51 (3H); 1.6 (3H); 2.77 (2H); 4.6 (1H); 5.89 (2H); 6.05 (1H); 6.72 (1H)].
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:20])[CH:16]=3)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.Cl[CH2:22][CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:26].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1>[Cl:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH2:22][CH2:23][CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[O:26])[CH2:3][CH2:4]1)=[O:9])[CH:19]=[CH:18]2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: Cc1ccccc1
Product: O=C(CCCN1CCC(C(=O)c2ccc3cc(Cl)ccc3c2)CC1)c1ccc(F)cc1

Procedure:
A solution of 3.43 g (12.5 mmoles) of 6-chloro-2-naphthyl 4-piperidyl ketone hydrochloride, 2.63 g (13.1 mmoles) of 4-chloro-1-(4-fluorophenyl)-1-butanone, 2.6 g (26 mmoles) of potassium bicarbonate and a pinch of potassium iodide in 60 ml of toluene is heated at reflux for 80 hours. The mixture is partitioned between toluene and water and the organic phase washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 4-[4-(6-chloro-2-naphthoyl)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH2:18][CH3:19])[C:3]=1[C:20]#[N:21].N.[OH:23]O>C(O)C>[NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:5]=[C:4]([CH2:18][CH3:19])[C:3]=1[C:20]([NH2:21])=[O:23]
Reactant: OO
Reactant: CCc1nn(C(C)CCCc2ccccc2)c(N)c1C#N
Agent: N
Solvent: CCO
Product: CCc1nn(C(C)CCCc2ccccc2)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.08 g (18 mmol) of 5-amino-3-ethyl-1-(1-methyl-4-phenyl-butyl)-1-H-pyrazole-4-carbonitrile are dissolved in 100 ml of ethanol and, after 100 ml of concentrated NH3 solution (25% strength) and 50 ml of hydrogen peroxide solution (30% strength) have been added, the solution is stirred for 16 hours at room temperature. After the non-aqueous solvents have been removed, the pH is brought to 5 with 1N HCl. The aqueous phase is extracted three times with dichloromethane, and the organic phase is dried over sodium sulphate and evaporated on a rotary evaporator. This gives 3.58 g of a brown oil (66%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([C:13]([F:16])([F:15])[F:14])[C:4]=1[CH2:17]Br.C(O)C.[Na].CC1C=CC(S([NH2:33])(=O)=O)=CC=1>C(O)(=O)C.CO>[F:14][C:13]([F:16])([F:15])[C:5]1[C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=[C:3]2[C:4]=1[CH2:17][NH:33][CH2:2]2
Reactant: FC(F)(F)c1ccc(CBr)c(CBr)c1C(F)(F)F
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1C(F)(F)F)CNC2

Procedure:
1,2-Bis(bromomethyl)-3,4-bis(trifluoromethyl)benzene (120 g., 0.3 mol.) in 450 ml. of ethanol is refluxed and treated with a solution of the sodium salt of p-methyl-benzene sulfonamide prepared by dissolving sodium (15.2 g., 0.66 mol.) in a mixture of p-methylbenzenesulfonamide (51.2 g., 0.3 mol.) in 650 ml. of methanol. The mixture is refluxed for two hours, cooled, neutralized with acetic acid and filtered to give 4,5-bis(trifluoromethyl)-2,3-di-hydro-1H-isoindole.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13](=[O:15])[NH2:14])=[CH:5][C:6]=1[CH2:7][C:8](OCC)=[O:9].C[Al](C)C>ClCCl>[O:9]=[C:8]1[NH:1][C:2]2[S:3][C:4]([C:13]([NH2:14])=[O:15])=[CH:5][C:6]=2[CH2:7]1
Reactant: CCOC(=O)Cc1cc(C(N)=O)sc1N
Agent: C[Al](C)C
Solvent: ClCCl
Product: NC(=O)c1cc2c(s1)NC(=O)C2
Temperature: 25 °C
Yield: 52.6 %

Procedure:
Ethyl 2-amino-5-carbamoylthiophene-3-acetate (500 mg, 2.19 mmol) was dissolved in dry dichloromethane (20 ml) and treated at 0° C. with trimethyl-aluminium (2M in heptane, 3.5 ml, 7.22 mmol). The reaction mixture was allowed to warm slowly to room temperature over 3 hours, cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution. The solution was extracted with ethyl acetate, the organic phase was dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate as eluent to give 210 mg of 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide as a pale grey solid. MS(ES): m/e 183 [M+H].
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:10]([OH:18])([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2([O:18][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[N:9]2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: OCCCCO
Reactant: N#Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Product: N#Cc1ccc(CN2C(=O)c3ccccc3C2(OCCCCO)c2ccc(Cl)cc2)cc1
Yield: 49.3 %

Procedure:
The named compound was synthesised from 2-(4-(aminomethyl)benzonitrile)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (513 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure B and obtained as a white solid (302 mg, 67%). 1H NMR (300 MHz, CDCl3): 7.94-7.91 (m, 1H, C(O)═C═CH), 7.55-7.52 (m, 2H, Ar—H), 7.47 and 7.33 (d: A2B2, J=8.4 Hz, 4H, Ar—H), 7.20 (m, 4H, Ar—H), 7.13-7.10 (m, 1H, Ar—H), 4.60 and 4.24 (d: AB, J=15.0 Hz, 2H, NCH2), 3.56 (t, J=5.4 Hz, 2H, HOCH2), 2.80-2.74 (m, 2H, OCH2), 1.53-1.16 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3): 168.18, 145.32, 142.86, 137.20, 134.77, 132.90, 131.86, 131.46, 129.99, 129.85, 128.61, 127.95, 123.77, 123.08, 118.41, 111.33, 94.78, 62.82, 62.34, 42.68, 29.41, 25.67. Anal.: calc. for C29H23ClN2O3+0.2 H2O: C, 69.37; H, 5.16; N, 6.22. Found: C, 69.29; H, 5.20, N: 6.04.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@H:12]([O:13]C(C3C=CC=CC=3)=O)[C@@H:8]2[O:7][C@H:4]1[O:5][CH3:6].[OH-].[Na+].N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CO.C(OCC)(=O)C.ClCCl>[CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@H:12]([O:13][S:31]([CH3:30])(=[O:33])=[O:32])[C@@H:8]2[O:7][C@H:4]1[O:5][CH3:6]
Reactant: CO[C@@H]1O[C@@H]2[C@@H](OC[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CO[C@@H]1O[C@@H]2[C@@H](OC[C@@H]2OS(C)(=O)=O)[C@@H]1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-α-L-glucofuranoside (230 mg, 0.92 mmol) and 50% sodium hydroxide (74 mg, 0.92 mmol) in methanol (5 mL) was stirred at room temperature for 30 minutes. The mixture was adsorbed on silica gel (2 g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to afford a colorless oil which was employed directly in the next step, 140 mg, 0.72 mmol, 95% yield. The alcohol was dissolved in dichloromethane (5 mL) and pyridine (121 μL, 1.03 mmol) was added at 0° C. Methanesulfonyl chloride (27 μL, 0.88 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-α-L-glucofuranoside as a colorless oil, 190 mg, 96% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>>[C:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)=[CH:7][CH:6]=2)[CH2:36][CH2:35]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: CC(=O)N1CCN(CCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CC1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 4-acetylpiperizine according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.3 (dd, 1H, J=1.8 and 8.7 Hz), 7.9 (s, 1H), 7.84 (d, 1H, J=7.5 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.54 (m, 2H), 7.31 (s, 1H), 6.99 (d, 1H, J=7.5 Hz), 6.84 (d, 1H, J=8.1Hz), 6.76 (d, 1H, J=11.7 Hz), 4.32 (t, 2H, J=5.7 Hz), 3.66 (t, 2H, J=5.4), 3.5 (t, 2H, J=5.4 Hz), 3.28 (m, 4H), 3.0 (t, 2H, J=5.7 Hz), 2.65 (m, 4H), 2.05 (s, 3H), 1.62-1.8 (m, 6H).