Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(Br)cn1
Reactant: CN1CCNCC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)NC3CCC(CCN4CCC(C(=O)c5ccc(F)cc5)CC4)CC3)nc2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
5-Bromo-pyridine-2-carboxylic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide (80 mg, 0.15 mmol) and 1-methylpiperazine (31 μl, 0.28 mmol) were dissolved in 2 ml dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9 mg, 0.016 mmol), cesium carbonate (76 mg, 0.23 mmol), water (1 μl, 0.078 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (8 mg, 0.008 mmol) were added and the reaction mixture was stirred for 16 hrs at 110° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The desired product was obtained as a light red solid (33 mg, 40%), MS: m/e=536.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14]C2C=CC(C(OC)=O)=CC=2)[C:12]=1[Cl:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C=NN(C[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([O:47][CH3:48])=[O:46])[CH:40]=2)C=1N)=O)(C)(C)C>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([O:47][CH3:48])=[O:46])[CH:40]=2)[C:12]=1[Cl:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cn2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Reactant: COC(=O)c1cccc(Cn2ncc(C(=O)OC(C)(C)C)c2N)c1
Product: COC(=O)c1cccc(Cn2ncc(C(=O)OC(C)(C)C)c2Cl)c1

Procedure:
Compound prepared in an analogous manner to Intermediate #48, replacing 5-Amino-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester with 5-Amino-1-(3-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester (Intermediate #51)
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:27]1[CH:28]=[CH:29][CH:30]=[N:31][C:26]=1[N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: Clc1ncccn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(c2ccccc2)CCN(c2ncccn2)CC1
Yield: 47 %

Procedure:
To a mixture of 4.0 gms (0.017 mole) 4-phenyl-4-carboethoxy-piperidine and 1.72 gms (0.017 mole) of triethylamine in 50 ml. toluene was added dropwise 2.0 gms (0.017 mole) 2-chloropyrimidine. Triethylamine hydrochloride started to precipitate out almost immediately. The reaction mixture was warmed to 70°-80° for a period of two hours, and then allowed to cool. The triethylamine hydrochloride was filtered off and the filtrate washed with water (to remove the last traces of triethylamine hydrochloride). The residue was recrystallized from acetone to yield 2.5 gms (47% yield), m.p. 119°-120°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:22])[C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH3:10].S(=O)(=O)(O)O>C(=S)=S>[CH2:9]([O:11][C:12](=[O:22])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:5](=[O:7])[CH3:6])=[CH:17][CH:16]=1)([CH3:21])[CH3:14])[CH3:10]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C(C)(C)c1ccc(C(C)=O)cc1
Yield: 46.8 %

Procedure:
Ex-77A: To a mixture of aluminum chloride (2.8 g, 20.8 mmol) in carbon disulfide (50 mL) was added acetyl chloride (0.74 mL, 10.4 mmol) followed by addition of 2-methyl-2-phenyl-propionic acid ethyl ester (1.0 g, 5.2 mmol). The reaction mixture was refluxed for 2 hours and then poured into ice containing sulfuric acid (6M). The mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (0.5M), saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave 2-(4-acetyl-phenyl)-2-methyl-propionic acid ethyl ester (0.57 g, 47%). 1H NMR (CDCl3) δ 7.92 (d, J=7.6 Hz, 2H), 7.42 (d, J=7.6 Hz, 2H), 4.13 (q, J=7.2 Hz, 2H), 2.59 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.18 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:16][C:17]([CH3:19])=[O:18]>O1CCCC1>[Br:9][C:10]1[C:15]([C:17]([OH:18])([CH3:19])[CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)=O
Reactant: Brc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cccnc1Br
Temperature: -78 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
Lithium diisopropylamide (2M, 12.5 mL, 25 mmol) is dissolved in tetrahydrofuran (40 mL) and cooled to −78° C. 2-Bromopyridine (3.9 g, 25 mmol) is added dropwise and the reaction is stirred for 3 hr. before adding acetone (1 mL, dried over freshly activated molecular sieves) and allowing warming to room temperature. The reaction is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated. The residue is purified by flash column chromatography on silica, eluting with 20% hexane/tert-butyl methyl ether to give the title compound (1.4 g, 26%). 1H-NMR (d6-dimethyl sulfoxide): 8.23 (dd, J=1.9, 4.5 Hz, 1H), 8.19 (dd, J=2.0, 7.8 Hz, 1H), 7.44 (dd, J=4.5, 7.7 Hz, 1H), 5.43 (s, 1H), 2.12 (s, 1H), 1.46 (s, 6H).
Reaction SMILES: CC1C=CC=C(C)N=1.[Cl:9][C:10](=[N:19][OH:20])[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18].[Cl:21][CH2:22][CH2:23][CH2:24]S(Cl)(=O)=O>C1C=CC=CC=1>[Cl:21][CH2:22][CH2:23][CH2:24][O:20][N:19]=[C:10]([Cl:9])[C:11]1[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(Cl)CCCCl
Solvent: Cc1cccc(C)n1
Solvent: c1ccccc1
Product: ClCCCON=C(Cl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A 3.6 g (0.034 mol) sample of 2,6-dimethylpyridine was added dropwise to a cooled solution (ice bath) of 7.4 g (0.033 mol) alpha-chloro-2,6-dichlorobenzaldoxime and 5.9 g (0.03 mol) 3-chloropropylsulfonyl chloride in 75 ml benzene. The reaction mixture was allowed to warm to 25° C., stirred for 2 hours (a red solid formed) and allowed to stand overnight. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed through a silica gel column with dichloromethane. A semi-crystalline yellow product was eluted from the column. The product was recrystallized from ether/hexane to give 4.3 g of O-(3-chloropropyl)-alpha-chloro-2,6-dichlorobenzaldoxime as a white solid, m.p. 69°-71° C. Elemental analysis for C10H9Cl4NO3S showed: %S, calc. 8.8, found 9.2; %Cl, calc. 38.8, found 37.9.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.[CH2:20]([SH:22])[CH3:21].[H-].[Na+].O>CN(C=O)C>[CH2:20]([S:22][C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1)[CH3:21]
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(-n2[nH]cc(-n3ccnn3)c2=O)ncn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
200 mg (0.7 mmol) of the compound from Example 52A are suspended in 1.1 ml DMF under argon. 61 mg (1.0 mmol) ethanethiol are added. 35 mg (0.8 mmol, 60% strength in mineral oil) sodium hydride are added cautiously, while cooling with ice. The mixture is stirred at RT for 2.5 h. 1 ml water is subsequently added dropwise and the mixture is subsequently stirred at RT for 15 min. The clear reaction solution obtained is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined, the mixture is concentrated and the residue is dried under a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH2:20][CH2:19][CH2:18][C:12]=3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4].[Mg]>CO.C1COCC1>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4]
Reactant: COC(=O)C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
A solution of 550 mg (2.0 mmol) of 7-(methoxycarbonyl-ethenyl)-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one in 130 ml of methanol-THF 3:1 is mixed with 972 mg (40.0 mmol) of magnesium and stirred for 24 hours at room temperature. The reaction mixture is filtered over glass fibers, the filter residue is washed with dichloromethane-methanol, and the combined filtrates are concentrated by evaporation in a vacuum. Purification of the residue on silica gel yields 120 mg of product.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH3:2].[CH3:9][S:10]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][C:20]=1[NH2:29])(=[O:12])=[O:11].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:18]([CH2:17][CH2:16][O:15][CH2:14][CH2:13][S:10]([CH3:9])(=[O:12])=[O:11])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Reactant: COC(C)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Yield: 70.9 %

Procedure:
Trimethyl orthoacetate (1 g, 8.1 mmol) was added to a mixture of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (˜2.3 g, ˜7.4 mmol) and toluene (45 mL). Pyridine hydrochloride (0.25 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. Pyridine was added to help solubilize the starting material. After 2 hours the reaction mixture was concentrated under reduced pressure to provide a dark oil. This material was purified by column chromatography (silica gel eluting sequentially with 95/5 dichloromethane/methanol and 9/1 dichloromethane/methanol) to provide 1.75 g of 2-methyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as a white foam.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](=[O:30])[C:27]([OH:29])=[O:28])=[CH:18]1.[F:31][C:32]1[C:37](O)=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42].C(O)(=O)C>O1CCCC1>[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](=[O:30])[C:27]([O:29][C:37]2[C:36]([F:39])=[C:35]([F:40])[C:34]([F:41])=[C:33]([F:42])[C:32]=2[F:31])=[O:28])=[CH:18]1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 21.9 %

Procedure:
1.13 g (5.5 mol) of dicyclohexylcarbodiimide were added to a solution, cooled in ice, of 1 g (5 mmol) of 1-methylindole-3glyoxylic acid and 1.01 g (5 mmol) of pentafluorophenol in 50 ml of dry tetrahydrofuran. After stirring for 4 hours under a nitrogen atmosphere at 0° C., the mixture was allowed to warm to room temperature and left to stand for 60 hours. Then, 3 ml of glacial acetic acid were added and the mixture obtained was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane for the elution to give 404 mg (22%) of pentafluorophenyl 1-methylindole-3-glyoxylate in the form of a pale yellow solid of melting point 168°-9° C.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:26][CH2:27][NH2:28])=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:25][CH2:26][CH2:27][NH:28][C:9](=[O:11])[C@@H:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:20][CH:19]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@H](NC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC1CCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (108 mg, 0.51 mmol) and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (151 mg, 0.51 mmol) in dry DMF (4 mL) was treated with Triton® B (0.92 mL, 2.0 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.), then sonicated for a few seconds, a clear solution was obtained. The clear solution was concentrated in vacuo to remove most of the methanol, then cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.19 g, 0.51 mmol) was then added. After stirring at 0° C. for 20 minutes the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (60% EtOAc in hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 150 mg (60%) of the pure titled compound as a white foam; mp 75-85° C. APCI-MS m/z 457.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[CH:6]1.[OH-].[K+:25]>C(O)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[CH:6]1.[K+:25]
Reactant: Cc1cccc(C)c1Cn1cc(C)c2ccc(CC(=O)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1Cn1cc(C)c2ccc(CC(=O)[O-])cc21

Procedure:
To a solution of the compound [64](226 mg) in ethanol (5 mL) was added an aqueous solution of 1N-potassium hydroxide (0.74 mL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (254 mg) as a yellow solid.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][OH:15].CCCCCC>O1CCCC1>[CH2:16]([C:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11])([CH2:14][OH:15])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(N)(CC)CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)(CO)NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Benzoyl isothiocyanate (4.28 mL, 31.8 mmol) was added under nitrogen to a solution of 2-amino-2-ethylbutan-1-ol (3.7315 g, 31.8 mmol), prepared in the previous step, in 100 mL of anhydrous tetrahydrofuran (exotherm on addition). After the addition, the reaction was refluxed for 2.5 h. After cooling to room temperature, 100 mL of hexane was added. The solid that formed was collected by filtration and dried under reduced pressure to give N-({[1-ethyl-1-(hydroxymethyl)propyl]amino}carbonothioyl)benzamide (7.1406 g, 80%) as a white solid, mp 161-163° C.; MS (ESI) m/z 281 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[N:26][CH:27]=4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:36][C:37]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[N:26][CH:27]=4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH:36]=[CH2:37])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: CN(C)C=O
Solvent: O
Product: C=Cc1nn(C(C)c2cc(Cl)c(C)c(-c3ccc(C(=O)N(C)C)nc3)c2OCC)c2ncnc(N)c12
Temperature: 100 °C
Yield: 88.5 %

Procedure:
To a solution of 5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (130 mg, 0.21 mmol, racemic intermediate from Example 15), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (66 mg, 0.43 mmol), sodium carbonate (136 mg, 1.29 mmol) in N,N-dimethylformamide (1 mL)/water (0.64 mL) under N2 was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.021 mmol). The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with water, and extracted with dichloromethane. The organic layers were concentrated and purified on silica gel (eluting with 0 to 100% EtOAc in hexanes followed by 0 to 10% MeOH in dichloromethane) to give the desired product (94 mg, 86%), LCMS calculated for C26H29ClN7O2 (M+H)+: m/z=506.2; Found: 506.2.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH:59]([CH3:61])[CH3:60]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH:59]([CH3:61])[CH3:60])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg of compound (6) was dissolved in 1.0 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 3 mg of sodium hydride under cooling with ice. After 30 minutes, 12.2 μl of 2-bromopropane was added, and the reaction solution was stirred at room temperature. The reaction solution was allowed to react for 63 hours, while about 3 mg of sodium hydride and 12.2 μl of 2-bromopropane were added after 40 hours and further after 46 hours. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with n-hexane-ethyl acetate (2:1). The fraction containing the desired product was concentrated to dryness to give 13.6 mg of compound (33).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CO)nc3N21
Yield: 93.4 %

Procedure:
To a solution of 5.00 g (4R,9aR)-6-Hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 50 ml tetrahydrofuran was added at 0°° C. 2.75 g N-bromosuccinimide at once and the mixture was stirred at 0° C. for 1 h. The reaction mixture was partitioned between 10% sodium thiosulfate and ethyl acetate. The phases were separated and the organic phase was washed with 10% sodium bicarbonate and brine dried over magnesium sulfate and evaporated. The residue was triturated in ca 20 ml heptane:ethyl acetate 1:3 to yield 5.75 g of the title compound as white crystals melting at 110-112° C.
Reaction SMILES: CCCCCC.C([Li])CCC.N12CCN(CC1)CC2.[F:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.CN([CH:30]=[O:31])C>C(OCC)C>[F:20][C:21]1[C:22]([CH:30]=[O:31])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cccnc1
Reactant: CN(C)C=O
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ncccc1F
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a mixture of a 1.6M n-butyl lithium hexane solution (35 ml) and diethyl ether (200 ml) was added, at -78° C. under argon atmosphere, a solution of 1,4-diazabicyclo[2,2,21octane (6.35 g) in diethyl ether (200 ml), which was stirred for one hour at temperatures ranging from -70° to -50° C. To the mixture was added 3-fluoropyridine (5.00 g) at -70° C., and the mixture was stirred for one hour at temperatures ranging from -70° to -60° C. To the reaction mixture was added at -70° C. DMF (9.41 g). The mixture was stirred for one hour at temperatures ranging from -70° to -50° C., which was then poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate/chloroform (about 4:1). The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-fluoro-2-formylpyridine (2.75 g, m.p. 52°-53° C.). Reference Example 47 (Production of Compound D-6)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15])[CH:2]=[CH2:3].C[Si]([C:20]#[N:21])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:21][CH2:20][C:10]1([OH:15])[C:11]2[C:6](=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: C=CCOc1cccc2c1CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=CCOc1cccc2c1CCCC2(O)CN

Procedure:
5 g. of 5-allyloxy-1,2,3,4-tetrahydro-1-naphthalenone is reacted with trimethylsilylcyanide and then with lithium aluminum hydride as described in Example 1 to give 1-aminomethyl-1-hydroxy-5-allyloxy-1,2,3,4-tetrahydronaphthalene. The latter compound is treated with HCl in ethanol as described in Example 3 to give 1-aminomethyl-5-allyloxy-3,4-dihydronaphthalene HCl; m.p. 166°-167° C.