Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:20][CH3:21])=[C:8]([CH:10]2[C:16](=[O:17])[CH:15]3[CH2:18][CH:12]([CH2:13][CH2:14]3)[C:11]2=[O:19])[CH:9]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[CH3:38][O:37][C:35](=[O:36])[O:17][C:16]1[CH:15]2[CH2:18][CH:12]([C:11](=[O:19])[C:10]=1[C:8]1[CH:9]=[C:4]([C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])[CH:5]=[CH:6][C:7]=1[CH2:20][CH3:21])[CH2:13][CH2:14]2
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C2CCC(C2)C1=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1=C(OC(=O)OC)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)-bicyclo[3.2.1]octane-2,4-dione (0.133 g, 0.34 mmol) in dichloromethane (2 ml) is added triethylamine (0.24 ml, 1.72 mmol) followed by stirring at room temperature for 5 minutes. To this solution is added methyl chloroformate (0.132 ml, 1.72 mmol) dropwise, then the mixture is left to stand overnight. The reaction mixture is concentrated in vacuo to afford a crude solid which is purified by flash column chromatography on silica gel (100% to 70% hexane/ethyl acetate eluant ratio) to afford carbonic acid 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester methyl ester.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](Cl)=[O:30])[CH:24]=1>Cl.O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:2][CH2:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]2)=[O:30])[CH:24]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: NCCC1CCN(S(N)(=O)=O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccn2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a mixture of 1.95 g. (0.008 mole) of 4-(2-aminoethyl)-1-piperidinesulfonamide hydrochloride and 2.22 ml. (0.016 mole) of triethylamine in 15 ml. of dry tetrahydrofuran, there were added 1.41 g. (0.008 mole) of 4-chloropicolinoyl chloride dissolved in 15 ml. of tetrahydrofuran. The initial addition step was slightly exothermic (~40° C.) and after completion of same, the resulting reaction mixture was stirred at ambient temperatures for a period of approximately 16 hours. At this point, the thoroughly stirred mixture was poured into 50 ml. of ice water and subsequently acidified with a few drops of 3N aqueous hydrochloric acid. The resulting crystalline precipitate was then recovered by means of suction filtration and thereafter recrystallized twice from acetonitrile to afford 0.997 g. of pure product. In this way, there was ultimately obtained a 36% of 4-[2-(4-chloropicolinamido)ethyl]-1-piperidinesulfonamide, m.p. 186°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[NH:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:7](=[S:30])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)C(=O)Nc1cc(OC)c(OC)c(OC)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(=S)Nc1cc(OC)c(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Ethyl 3,4,5-trimethoxyoxanilate (3.0 g) was dissolved in benzene (20 mL), and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.14 g) was added to the solution. The reaction mixture was stirred at 80° C. for 1 hour, and water was added thereto. After conducting extraction with ethyl acetate, the resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][N:5]([C:7](=[S:9])[NH2:8])[N:4]=[CH:3]1.I[CH3:12]>CO>[CH3:12][S:9][C:7]([N:5]1[CH2:6][C:2]([CH3:10])([CH3:1])[CH:3]=[N:4]1)=[NH:8]
Reactant: CI
Reactant: CC1(C)C=NN(C(N)=S)C1
Solvent: CO
Product: CSC(=N)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.9 %

Procedure:
1.50 g (1 mol equiv.) 4,4-Dimethyl-4,5-dihydro-pyrazole-1-carbothioic acid amide was dissolved in 30 ml methanol; 5.9 mL (10 mol equiv.) iodomethane was added and the reaction mixture was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure, and the residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness, yielding 1.53 g (94%) 4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.24 (s, 6H), 2.32 (s, 3H), 3.65 (s, 2H), 6.63 (s, 1H), 6.66-6.85 (br.s., 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15]O)=[CH:8][C:7]=1[O:21][CH3:22].N1C=CC=CC=1>O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:3])=[CH:8][C:7]=1[O:21][CH3:22]
Reactant: COc1cc(Sc2ccccc2CO)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(Sc2ccccc2CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Thionyl chloride (6.5 g) is added dropwise to a stirred mixture of the alcohol from the preceding preparation (11.2 g) and pyridine (4.0 g) at 10°-20° C. The mixture is stirred at room temperature for 3 hours and, after standing overnight, for one additional hour at 30°-40° C. The cooled mixture is decomposed by dropwise addition of water (20 ml) and the product extracted with benzene. The work-up of the extract, followed by crystallization of the crude residue from a small volume of hexane, yields 10.2 g (85%) of 2-(4-chloro-3-methoxyphenylthio)benzyl chloride which in the pure state melts at 57°-59° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CCN(C(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>C1COCC1>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(C#N)cc2[N+](=O)[O-])c(OC)c1
Reaction time: 24 h

Procedure:
A solution of 4-fluoro-3-nitrobenzonitrile (5.0 g) in THF (100 mL) was treated with DIEA (6.3 mL) and 2,4-dimethoxybenzylamine (5.0 mL), and then stirred for 24 h. The solvent was evaporated and the crude mixture was dissolved in EtOAc (100 mL). The solution was washed once with 1 M HCl and twice with saturated aqueous NaCl (100 mL each). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (20% EtOAc/DCM) provided 9.25 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4].[OH:9][C:10]1[CH:21]=[CH:20][C:13]2[NH:14]C(=O)[O:16][C:17](=O)[C:12]=2[CH:11]=1>C(#N)C.ClCCl>[NH2:14][C:13]1[CH:20]=[CH:21][C:10]([OH:9])=[CH:11][C:12]=1[C:17]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]([CH3:8])[CH3:7])=[O:16]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: CC(C)NC(=O)CN
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)NC(=O)CNC(=O)c1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a solution of 2-amino-N-isopropylacetamide (INTERMEDIATE I.1) (4.77 g, 41.1 mmol) in acetonitrile (50 mL) was added 6-hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (6.13 g, 34.2 mmol). The mixture was stirred for 16 h at room temperature during which time a very thick precipitate formed. The mixture was diluted with dichloromethane (100 mL) and the solid collected by filtration and washed with dichloromethane (2×20 mL) to afford 2-amino-5-hydroxy-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE II.1) (6.75 g, 32.0 mmol, 78%).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=1>>[CH3:45][N:41]1[C:42]([CH3:44])=[CH:43][C:38]([C:17]2[CH:16]=[CH:15][C:14]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:19][CH:18]=2)=[CH:39][C:40]1=[O:46]
Reactant: Cc1cc(Br)cc(=O)n1C
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(=O)n1C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-1,6-dimethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.173 min, m/z=475.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.16 (s, 3H), 1.51 (d, 3H), 2.18 (m, 3H), 2.21 (m, 1H), 2.42 (m, 4H), 2.86 (m, 1H), 3.54 (s, 3H), 5.66 (m, 1H), 6.21 (s, 1H), 6.60 (s, 1H), 6.97 (m, 2H), 7.23-7.34 (m, 7H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)C1CC1
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Yield: 50 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Intermediate-30 by using (4-chloro-3-nitrophenyl)methanamine hydrochloride (0.700 g, 3.14 mmol), cyclopropylcarbonyl chloride (0.490 g, 4.71 mmol), DIPEA (3.0 mL) and THF (15 mL) to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (d, J=6.0 Hz, 2H), 1.55-1.61 (m, 1H), 4.33 (d, J=6.0 Hz), 7.55 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 8.68 (br s, 1H); MS (m/z): 255.09 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[C:6]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:32](CC)[CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16].[C:42]([C:44](=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][CH2:33][C:34]2[C:35]([CH2:42][CH3:44])=[CH:36][N:37]=[CH:38][CH:39]=2)(=[O:30])=[O:31])(=[O:21])=[O:22])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: N#CC(=Cc1ccc(O)cc1)C(=O)O
Reactant: CCN(Cc1ccncc1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Agent: Cl
Product: CCc1cnccc1CNS(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Yield: 84 %

Procedure:
{3-[5-Methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy) phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 84% yield from N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy) phenoxy]propoxy}guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 1H-NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=4.5 Hz, 2H), 8.23 (d, J=7.9 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.01 (t, J=7.7 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.42 (br s, 4H), 7.34 (d, J=5.8 Hz, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 6.50 (s, 1H), 4.67 (s, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.36 (t, J=7.1 Hz, 2H), 2.21 (s, 3H), 2.00 (pentet, J=6.1 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H31N5O7S2: 578.2 (M+H), 600.2 (M+Na), 616.1 (M+K). Found: 578.1, 599.9, 616.0.
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[CH:13](=[O:16])[CH2:14][CH3:15]>C(O)CO>[CH3:15]/[C:14](=[CH:8]\[C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([CH3:4])[CH:6]=1)/[CH:13]=[O:16]
Reactant: Cc1cccc(C=O)c1
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: C/C(C=O)=C\c1cccc(C)c1
Temperature: 40 °C
Yield: 69.7 %

Procedure:
A solution of potassium hydroxide (24 g, 0.36 mol, 0.6 eq, with a purity of 85%) in ethylene glycol (120 g) and water (12 g) was charged into a 500 mL three-necked round-bottom flask equipped with a reflux condenser and a mechanical stirrer. 3-methyl benzaldehyde (70 g, 0.59 mol) was added dropwise. The stirred reaction mixture was heated at 38-42° C. and propionaldehyde (41 g, 0.71 mol, 1.2 eq) was dosed in over 3.25 h. After a further hour at 40° C., the reaction mixture was cooled to ambient temperature and the two layers separated. The organic layer thus obtained was washed with water (2×100 mL), dried over magnesium sulphate and concentrated. The resulting crude product was distilled via a Vigreux column (1.0 mBar, 87-92° C.), to give (2E)-2-methyl-3-(3-methylphenyl)acrylaldehyde (65.9 g, gc purity>95%; yield 70%).
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][OH:3].C[Na].[CH2:8]([O:10][CH:11]([O:18][CH2:19][CH3:20])/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH3:9].O>CS(C)=O>[CH2:19]([O:18][CH:11]([O:10][CH2:8][CH3:9])[CH:12]1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:2](=[O:3])[CH2:1][O:4]1)[CH3:20]
Reactant: CCOC(/C=C/C(=O)OC)OCC
Reactant: O=C(O)CO
Agent: C[Na]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(OCC)C1OCC(=O)C1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: To the suspension of 7.15 g of methyl sodium glycolate in 50 ml of dimethylsulfoxide and 25 ml of diemthylformamide, cooled to 0°, are added at once 9.5 g of methyl 4,4-diethoxy-crotonate and the mixture is stirred at room temperature for 3 hours. It is poured into water, washed with diethyl ether and the aqueous layer is acidified with cold N hydrochloric acid. It is extracted twice with diethyl ether, the extract dried, evaporated and the residue distilled, to yield the methyl 2-diethoxymethyl-4-oxo-tetrahydrofuran-3-carboxylate boiling at 123°-126°/0.5 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34](Cl)=[C:29]3[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34]([O:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])=[C:29]3[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Temperature: 160 °C
Yield: 47.5 %

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 112 mg, 0.6 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.6 mmol) and potassium carbonate (180 mg, 1.3 mmol) in DMF (2 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture to give a precipitate which was filtered off and dissolved in ethyl acetate. The organic solution was dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 20% ethyl acetate/hexanes, to give 4-[4-(2-fluoro-4-methane-sulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (140 mg, 47%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.CCOCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)c5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 90 °C
Yield: 95.3 %

Procedure:
To 3α-hydroxy-5α-pregnan-20-one (464 mg, 318.5 g/m, 1.5 mmol) and 4-dimethylaminopyridine (DMAP, 195 mg, 122.17 g/m, 1.6 mmol) dissolved in 10 mL of dry pyridine was added nicotinoyl chloride hydrochloride (285 mg, 178.02 g/m, 1.6 mmol). The reaction mixture was heated at 90° C. for 5 hours and poured into 300 mL of ether. The organic layer was washed twice with saturated sodium bicarbonate, twice with water, dried over magnesium sulfate, and concentrated in vacuo to give the crude product. The crude material was filtered through a bed of silica gel using hexane/ethyl acetate (50:50) elution. The first two fractions gave the titled compound (604 mg, 421 6/m, 1.43 mmol, 96%).
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].O>CS(O)(=O)=O>[Cl:11][CH2:12][C:13]1[C:5]2[C:3](=[C:2]([F:1])[C:8]([OH:9])=[C:7]([F:10])[CH:6]=2)[O:4][C:15](=[O:16])[CH:14]=1
Reactant: Oc1ccc(F)c(O)c1F
Reactant: CCOC(=O)CC(=O)CCl
Agent: CS(=O)(=O)O
Solvent: O
Product: O=c1cc(CCl)c2cc(F)c(O)c(F)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
A solution of 2,4-difluororesorcinol (0.8 g) in 8 mL of methyl sulfonic acid is introduced into a flask and then 1.3 equivalents (963 μL) of ethyl 4-chloroacetoacetate are added dropwise. After 3 hours of stirring at room temperature, the mixture is cooled to 0° C. and then 100 mL of water are added. The residue is then filtered, dried and washed with diethyl ether in order to obtain 0.34 g (25%) of the compound 1.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[CH:13]=1>>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:14]2[CH:13]=[C:12]([CH2:11][N:3]3[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]3)[CH:17]=[CH:16][N:15]=2)[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Piperidone hydrochloride monohydrate (3.07 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2.94 g) were coupled by the same manner as described in Example 2 to give the title compound.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1)=[CH2:14].[Cl-].[Na+]>O.C(O)C>[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[CH:17][CH:16]=1)=[CH2:14]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C=Cc1ccc(CC(C(=O)OCC)C(=O)OCC)cc1
Yield: 70.1 %

Procedure:
Into a flask containing 100 ml of dry ethanol were fed 2.43 g (0.106 mole) of metallic sodium, 50.77 g (0.317 mole) of diethyl malonate and 16.12 g (0.106 mole) of p-vinylbenzyl chloride in dry nitrogen gas atmosphere. The mixture was subjected to reaction at the reflux temperature for 3 hours. 100 ml of pure water was added to the reaction mixture to dissolve the sodium chloride (NaCl) generated by the reaction. Extraction was carried out with three 100 ml-portions of methylene chloride to obtain a methylene chloride solution of the product, i.e., diethyl 2-(p-vinylbenzyl)malonate.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)#[N:2].ClC1C=C(NC(=NC#N)OC2C=CC=CC=2)C=CC=1.[CH3:39][C:40]1[C:48]2[C:47]([N:49]3[CH2:54][CH2:53][NH:52][C@@H:51]([CH3:55])[CH2:50]3)=[N:46][CH:45]=[N:44][C:43]=2[NH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([N:3]=[C:4]([N:52]1[CH2:53][CH2:54][N:49]([C:47]2[C:48]3[C:40]([CH3:39])=[CH:41][NH:42][C:43]=3[N:44]=[CH:45][N:46]=2)[CH2:50][C@@H:51]1[CH3:55])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)#[N:2]
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reactant: N#CN=C(Nc1cccc(F)c1)Oc1ccccc1
Agent: N#CN=C(Nc1cccc(Cl)c1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(F)c4)[C@@H](C)C3)c12
Temperature: 85 °C
Yield: 27 %

Procedure:
Phenyl N′-cyano-N-(3-fluorophenyl)carbamimidate, prepared analogously to phenyl N-3-chlorophenyl-N′-cyanocarbamimidate from Example 6, step A, (0.55 g, 2.2 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, from example 1, step B, (0.50 g, 2.2 mmol), and N,N-diisopropylethylamine (1 ml) were added to acetonitrile (10 ml). The mixture was heated at 85° C. in a sealed pressure tube for 4 hours. The solvent was evaporated, and the residue was purified prep HPLC (Sunfire C18 30×250 mm column. 10-100% MeCN:H2O (10 mM NH4OAc), 18 min., 45 ml/min) to give (S)—N′-cyano-N-(3-fluorophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (0.23 g, 0.58 mmol, 27%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.O>CC#N>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1
Reactant: BrCCCOC1CCCCO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Ic1cnn(CCCOC2CCCCO2)c1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a mixture of 4-iodo-1H-pyrazole (2.0 g, 10.3 mmol) and Cs2CO3 (5.04 g, 15.5 mmol) in MeCN (28 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.84 mL, 10.8 mmol) and the mixture stirred overnight. The crude reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-80% EtOAc in cyclohexane, to give the title compound (2.95 g, 81%). 1H NMR (300 MHz, CDCl3): 150-1.58 (4H, m), 1.65-1.90 (2H, m), 2.12 (2H, qn, J=6.4 Hz), 3.35 (1H, dt, J=10.2, 5.9 Hz), 3.46-3.54 (1H, m), 3.73 (1H, dt, J=10.2, 5.9 Hz), 3.80-3.88 (1H, m), 4.26 (2H, td, J=6.9, 1.5 Hz), 4.54 (1H, dd, J=4.5, 3.1 Hz), 7.46 (1H, s), 7.50 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Br:12])=[CH:5][N:6]=[CH:7]2.[CH2:13]([CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:20](O)=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[Br:12][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:20](=[S:21])[CH:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[N:6][CH:5]=1
Reactant: CCCCCCCCC(CCCCCC)C(O)=S
Reactant: Nc1cccc2cncc(Br)c12
Product: CCCCCCCCC(CCCCCC)C(=S)Nc1cccc2cncc(Br)c12

Procedure:
5-Amino-4-bromoisoquinoline (prepared according to the process described by Gordon et al., J. Het. Chem., 4, 410 (1967)) was coupled with 2-hexylthiodecanoic acid (prepared by the procedures described in Examples 1 and 3) using the procedure described in Example 25 to give the title compound.