Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([Cl:14])[N:6]=1)(=O)C.C([O:18][C@@H:19]1[C@H:23]([O:24]C(=O)C)[C@@H:22]([CH2:28][O:29]C(=O)C)[O:21][CH:20]1N1C2C(N=CN=2)=CN=C1)(=O)C.N>Cl[Hg]>[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:20]2[O:21][C@H:22]([CH2:28][OH:29])[C@H:23]([OH:24])[C@H:19]2[OH:18])=[C:7]([Cl:14])[N:6]=1
Reactant: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OC[C@H]1OC(n2cncc3ncnc2-3)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Hg]
Agent: N
Product: Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)c2n1

Procedure:
The chloromercury derivative of 2-acetamido-6-chloropurine is condensed with 2,3,5-tri-O-acetyl-3-D-ribofuranosylpurine utilizing the method of Lee et. al. (1971), J. Med. Chem., 14:819. The condensation product was treated with ammonia to yield 2-amino-6-chloro-9-(β-D-xylofuranosyl)purine. Further treatment with sodium hydroxyethylmercaptide gives the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=1)[CH2:3][OH:4].[C:18]1([CH:24]2[CH2:26][CH:25]2[C:27](O)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:27]([CH:25]2[CH2:26][CH:24]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:28])[CH2:3][OH:4])=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1
Reactant: O=C(O)C1CC1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(CO)c1ccc(F)c(N2CCOCC2)c1)C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of (R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol (0.1 mmol), 2-phenyl-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.1 mmol), triethylamine (0.4 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography with 3% methanol in ethyl acetate to give the desired product (27 mg) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])(C)(C)C.CCCCC.[CH2:21]([C:28]1([N:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([C:28]1([N:35]([CH3:36])[CH3:37])[CH2:33][CH2:32][C:31]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)([OH:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: Cn1ccc2ccccc21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3n2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A solution of N-methylindole (1.50 mg, 3.81 mmol) in dry THF (20 ml) was cooled to −5° C. under a stream of argon. Thereafter, tert-butyllithium (4.19 mmol, 2.47 ml of a 1.7 molar pentane solution) was added dropwise such that a reaction temperature of 0° C. was not exceeded during the addition. When the addition had ended the reaction mixture was stirred for a further two hours at 0° C. A solution of 4-benzyl-4-dimethylaminocyclohexanone (3.88 mg, 3.81 mmol) in dry THF (7 ml) was then added dropwise at 0° C. The mixture was stirred for 15 minutes at 0° C. and then for four hours at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase was extracted four times with methylene chloride (20 ml). The combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. Purification was carried out by means of flash chromatography over silica gel with cyclohexane/ethyl acetate (v/v=4:1). 456 mg 4-benzyl-4-dimethylamino-1-(1-methyl-1H-indol-2-yl) cyclohexanol with a melting point of 105-107° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([CH:16]=O)[CH2:11]2.[C:19]1([N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26](=[O:29])[NH:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26](=[O:29])[NH:27][N:28]=[CH:16][CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[CH:15][C:6]=3[O:5][CH2:4][C:3]([O:2][CH3:1])=[O:18])[CH2:11]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)COc1cccc2c1CCC(C=O)C2
Reactant: NNC(=O)N(c1ccccc1)c1ccccc1
Solvent: CCO
Product: COC(=O)COc1cccc2c1CCC(C=NNC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of methyl(2-formyl-1,2,3,4-tetrahydronaphthalen-5-yl)oxyacetate (248 mg), prepared by the same procedure as reference example 1, m ethanol (10 ml) was added 4,4-diphenylsemicarbazide (0.27 g) under an atmosphere of argon. After stirred for 1 h at room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:methylene chloride=3:100) to give the title compound (444 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.78 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), Ethyl acetate (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml ethyl acetate. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.78 to 0.80%].
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:20]([S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCBr
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 52.6 %

Procedure:
A mixture of 4,5-diphenyl-2-imidazolethiol (2.5 g), 8-bromooctane (3.8 g), anhydrous potassium carbonate (13.7 g) and dry butanone (60 ml) was stirred at reflux for 2 h. The cooled reaction mixture was filtered to remove solid and the filtrate was evaporated to dryness. The residue was mixed with hexane and the resulting precipitate was collected by filtration. Recrystallisation from ethanol and water gave 2-octylthio-4,5-diphenylimidazole (1.9 g, 53%) as a white solid, m.p. 133°-4°.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:11]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([C:2]2[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]3[CH:10]([C:20]4[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=4)[N:11]([CH:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:32][N:31]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N(C1CCOCC1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(C2CCOCC2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 4-[2-bromo-1-isopropyl-4-oxo-5-(tetrahydro-pyran-4-yl)-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AU) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 0.98 min (HPLC 3); ESI-MS: tR=0.92 min, [M+H]+ 488 (LC-MS 1); TLC: Rf=0.20 (EtOAc).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:21][C@@H:22]1[C:38](=[O:39])[N:24]2[C:25]([C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])=[C:26]([CH3:29])[CH2:27][S:28][C@H:23]12>CC(N(C)C)=O.C(#N)C>[CH3:29][C:26]1[CH2:27][S:28][C@@H:23]2[C@H:22]([NH:21][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C:38](=[O:39])[N:24]2[C:25]=1[C:30]([O:32][CH2:33][C:34]([Cl:35])([Cl:37])[Cl:36])=[O:31]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
2,2,2-Trichloroethyl chloroformate (3.15 ml, 22 mmole) was added to a suspension of 2,2,2-trichloroethyl 7β-amino-3-methylceph-3-em-4-carboxylate hydrogen p-toluenesulphonate (10.36 g, 20 mmole) in a mixture of dimethylacetamide (25 ml) and acetonitrile (100 ml.) The mixture was stirred at ca. 25° for 30 minutes, the acetonitrile was evaporated and ethyl acetate (80 ml) was added. The solution was washed with saturated sodium hydrogen carbonate solution (80 ml), dried and evaporated to an oil which could not be crystallised. The oil was taken up in chloroform (50 ml), washed with water (3 × 50 ml) and re-evaporated to an orange foam which on trituration with methanol (20 ml) gave the title ester as an off-white solid, λmax. 262 nm (E1cm1% 113.5). Crystallisation from ethanol gave an analytical sample, m.p. 179° to 181.5°, [α]D + 70°, λmax. 262 nm (ε 6,000), νmax (CHBr3) 3410 (NH), 1780 (azetidin-2-one), 1740 and 1520 (NHCO2R) and 1740 cm-1 (CO2R), τ(CDCl3) 3.98 (1H,d,J 9.5 Hz; NH), 4.34 (1H,dd,J 9.5 Hz; C7 -H) 4.91 (1 H,d J 5 Hz; C6 -H), 4.91, 5.08 (2H, AB-q, J 12 Hz; CO2CH2CCl3), 5.17 (2H, s; NHCO2CH2CCl3), 6.34, 6.73 (2H, AB-q, J 18 Hz; C2 -H2), 7.74 (3H,s; C3 -CH3) (Found: C, 30.3; H, 2.4; Cl, 40.2; N, 5.3; S, 6.5. C13H12Cl6N2O5S (521.1) requires C, 30.0; H, 2.3; Cl, 40.8; N, 5.3; S, 6.2%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(N(CC)CC)C.[I:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([I:28])=[CH:30][CH:31]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(6-Chloronaphth-2-ylsulphonyl)piperazine (0.65 g, 2.1 mmol) was dissolved in dichloromethane (50 mL) and triethylamine (2.9 mL, 21 mmol) was added at room temperature. 4-Iodobenzoyl chloride (0.56 g, 2.1 mmol) was added as a solid in one portion and the reaction mixture stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo, then separated between EtOAc (100 mL) and saturated sodium hydrogen carbonate solution (100 mL). The EtOAc layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The resulting white solid was subjected to chromatography (SiO2: 50% EtOAc/Hexane) to yield 1-(6-chloronaphth-2-ylsulphonyl)-4-(4-iodobenzoyl)piperazine as a white solid (097 g); 1H NMR (DMSO-d6) δ=3.05 ppm (s,4H), δ=3.53 ppm (s,4H), δ=7.11 ppm & 7.74 ppm (dd,4H), δ=7.65 to 7.84 ppm (m,2H), δ8.10 ppm to 8.28 ppm (m,3H), δ=8.47 ppm (s,1H); MS (M+H)+ 540.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:26]=[C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)[S:28][C:21]=34)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:26]=[C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][N:1]6[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]6)=[CH:31][CH:30]=5)[S:28][C:21]=34)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NC(=O)C1CCNCC1
Product: NC(=O)C1CCN(Cc2ccc(-c3cc4nccc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared from piperidine-4-carboxylic acid amide and 4-[7-(1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde by a procedure analogous to example 17. LC-MS: 482 (MH+); HPLC RT: 3.56 minutes.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>[Cl-].[Zn+2].[Cl-].O>[C:1]1(=[N:7][CH:13]2[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1C=CCCC1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: c1ccccc1
Product: C1=CC(N=C2CCCCC2)CCC1
Yield: 69.9 %

Procedure:
A mixture of 2-cyclohexenylamine (9.7 g, 0.1 mole), cyclohexanone (9.8 g, 0.1 mole), zinc chloride (0.16 g) and benzene (50 ml) was heated under reflux, and resulting water was removed by azeotropic distillation. The mixture was concentrated and distilled to obtain 12.4 g of N-cyclohexylidene-2-cyclohexenylamine [Compound (344)].
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)=CC=1.[CH:34]([C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:40]2[CH:41]=[CH:42][C:37]([CH:34]([CH3:36])[CH3:35])=[CH:38][CH:39]=2)=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19]1(=[O:27])=[O:28])([CH3:31])([CH3:32])[CH3:30]
Reactant: CC(C)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: CC(C)c1ccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1

Procedure:
The title compound was prepared from 3-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate and 4-isopropylphenol in a similar manner as described for Example 12. 1H NMR (500 MHz CDCl3): δ 7.56-7.50 (m, 2H), 7.48-7.42 (m, 3H), 7.16 (d, 2H), 6.80 (d, 2H), 5.78 (t, 1H), 3.88 (t, 2H), 3.10-3.05 (m, 2H), 2.92-2.82 (m, 1H), 1.85-1.80 (m, 2H), 1.75 (s, 9H), 1.24 (d, 6H); 13C NMR (125 MHz CDCl3): δ 159.8, 156.6, 141.8, 135.4, 131.8, 129.7, 128.8, 127.5, 125.4, 114.4, 107.1, 66.1, 61.7, 42.6, 33.5, 29.0, 27.9, 24.4; Mass Spectrum: M+H+ 457.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=2)[CH2:16][C:15]1([CH3:26])[CH3:25].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CNC>CN(C=O)C>[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][C:15]([CH3:26])([CH3:25])[C@H:14]2[NH:13][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1N
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 72.9 %

Procedure:
A mixture of 1H-indole-2-carboxylic acid (44.0 mg, 0.273 mmol), (R)-3-amino-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (34.0 mg, 0.182 mmol), BOP reagent (157 mg, 0.355 mmol), N-methylmorpholine (0.12 mL, 1.09 mmol) in DMF (0.5 mL) was stirred at 50° C. for 50 min. Dimethylamine (2.0 M in THF, 0.2 mL) was added to the mixture and the resulting mixture was stirred at 50° C. for 30 min. The desired title product (43.7 mg, 73% yield) was isolated as a white solid by prep. LCMS (M+H)+=330.33; HPLC. 1H NMR (500 MHz, DMSO-d6) δ: 11.6 (s, 1H), 8.53 (d, J=9.35 Hz, 1H), 7.70 (d, J=70 Hz, 1H), 7.60 (d, J=7.70 Hz, 1H), 7.62 (s, 1H) 7.46 (d, J=7.70 Hz, 1H), 7.44 (d, J=9.35 Hz, 1H), 7.29 (s, 1H), 7.18 (t, J=7.70 Hz, 1H), 7.03 (t, J=7.70 Hz, 1H), 5.38 (d, J=9.35 Hz, 1H), 2.86 (dd, J=22.5, 16.5 Hz, 2H), 1.21 (s, 3H), 0.94 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ: 161.1, 148.2, 144.1, 136.2, 131.4, 131.0, 127.9, 126.7, 125.7, 123.0, 121.2, 119.4, 118.8, 111.9, 108.8, 103.2, 61.0, 39.4, 39.2, 39.1, 38.9, 27.1, 22.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:25]([O:29][N:30]1N=NC2C=CC=C[C:31]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.CNOC>ClCCl>[CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:9]([CH2:13][CH3:14])[C:10]([N:30]([O:29][CH3:25])[CH3:31])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@@H](C(=O)N(C)OC)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, (S)-2-(dibenzylamino)butanoic acid (27 g, 80.0 mmol, Eq: 1.00) was combined with dichloromethane (250 ml) to give a white suspension. At 0° C., TBTU (36.0 g, 112 mmol, Eq: 1.4) was added. The reaction was stirred for 2 h at 0° C. Then N-methylmorpholine (24.3 g, 26.4 ml, 240 mmol, Eq: 3) and N,O-dimethylhydroxylamine hydrochloride (19.5 g, 200 mmol, Eq: 2.5) were added. The reaction was stirred overnight at RT. The reaction mixture was extracted with water (2×75 ml) and brine (50 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The residual solvent was removed under vacuum. The title compound was obtained as a light yellow oil (35.5 g, 95.1%, MS (m/e)=327.3 [M+H+]).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>ClCCl>[C:22](=[O:23])([O:24][CH3:25])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: Oc1ccc(Cl)cc1C1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(Cl)cc1C1CCCC1
Temperature: 0 °C

Procedure:
4-Chloro-2-cyclopentylphenol (2.366 g, 7.94 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (2.2 mL, 15.9 mmol). The solution was cooled to 0° C. and treated with methyl chloroformate (920 μL, 11.91 mmol) and allowed to warm to room temperature over 16 h. The reaction was quenched with 3 mL saturated NaHCO3, washed with 50% saturated NaHCO3 (1×50 mL) and brine (1×50 mL), then dried over Na2SO4. Filtration, followed by concentration in vacuo yielded an oil that was purified by silica gel chromatography (20% ethyl acetate/hexane) to yield 4-chloro-2-cyclopentylphenyl methyl carbonate as a colorless oil. 1H NMR (400.0 MHz, DMSO-d6) δ 7.31-7.28 (m, 1H), 7.20-7.13 (m, 1H), 7.06 (d, J=8.6 Hz, 1H), 3.93 (d, J=3.1 Hz, 3H), 3.18-3.09 (m, 1H), 2.08-2.01 (m, 2H), 1.87-1.78 (m, 2H), 1.75-1.65 (m, 2H), 1.61-1.51 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[C:13]([OH:23])=[CH:14][C:15]([OH:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:11][C:12]1[C:13]([O:23][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)=[CH:14][C:15]([OH:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(Cl)c(O)cc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1O
Yield: 46.2 %

Procedure:
A mixture of 1-(chloromethyl)-4-methoxybenzene (1.53 g, 9.8 mmol), methyl 5-chloro-2,4-dihydroxybenzoate (1.98 g, 9.8 mmol) and potassiumcarbonate (1.35 g, 9.8 mmol) in acetone (15 mL) was stirred at reflux overnight. The mixture was filtered, solvent was removed in vacuo, the residue was dissolved in ethyl acetate and was washed with brine two times. The organic layer was dried over sodium sulphate, solvent was removed in vacuo and the residue was purified by recrystillaziation from methanol. (1.46 g, 46%) of the title compound was obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:18].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>CS(O)(=O)=O.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3=[N:11][C:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[O:19][CH2:17][CH3:18])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOc1ccccc1C=O
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Yield: 44.5 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9 mmol), o-ethoxybenzaldehyde (2.7 g, 18 mmol), methanesulfonic acid (5 drops), and xylenes (50 ml) was refluxed for 48 hours. The reaction mixture was stripped to dryness, and treated with 10% K2CO3 and CHCl3 (100 ml). The layers were separated and the aqueous layer was extracted with chloroform (2×100 ml). The organic layers were combined, and concentrated in vacuo. The dark oil thus obtained was dissolved in CH2Cl2 (30 ml) and combined with silica gel (30 g). The preloaded silica gel was placed on a silica gel column and eluted with Et2O/hexanes (20/80) to Et2O (100%) to afford 1.41 g (45%) of 1-cyclopentyl-3-ethyl-6-(2-ethoxyphenyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 146°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([SH:21])[CH:18]=[CH:19][CH:20]=1.CN(C=O)C.[H-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([S:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: COc1cccc(S)c1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cc(Br)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-bromo-3-nitropicolinonitrile (300 mg, 1.31 mmol), 3-methoxybenzenethiol (0.150 mL, 1.31 mmol), and DMF (12 mL). NaH (37.8 mg, 1.58 mmol) was added and reaction stirred at room temperature for 10 minutes. The reaction was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on silica gel (10% EtOAc in Hexanes) to afford the title compound (345 mg, 81%).