Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)(=O)[CH2:2][CH3:3].C(OCC)(=O)C>C1COCC1>[CH2:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1
Yield: 53.2 %

Procedure:
Following the same procedure as described in Example 47.2, N-[4-(1-propionyl-azetidin-3-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (170 mg, 0.39 mmol) in THF (20 ml) was then treated with 1M BH3. THF (3.9 ml). The crude material was chromatographied (ethyl acetate) to afford the title compound (86 mg, 52%) as a pale yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][S:2]1(=[O:11])=[O:10].[CH3:12][NH2:13]>C1COCC1.C(OCC)(=O)C>[CH3:12][NH:13][S:2](=[O:11])(=[O:10])[O:1][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[OH:3]
Reactant: O=S1(=O)Oc2ccccc2O1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)Oc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,3,2-benzodioxathiol 2,2-dioxide (300 mg) in THF (6 mL) was added methylamine (0.871 mL, 2 M THF solution) at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (86 mg).
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH:9]O>>[O:9]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:1]12
Reactant: C1=CCCCCCC1
Reactant: OO
Product: C1CCCC2OC2CC1
Reaction time: 24 h

Procedure:
The solid mixed phase after extraction in Example 1 was dried under reduced pressure for about 12 hours. 0.110 g (1.00 mmol) of cyclooctene was added to the solid mixed phase after drying under reduced pressure, and stirred well. Further, 0.10 mL (0.90 mmol) of 31% aqueous hydrogen peroxide was added and stirred well. Then, the mixture was allowed to stand still at 25° C. for 24 hours. Thereafter, a colorless solid of epoxycyclooctane was obtained in the same manner as in Example 1. The epoxide yield was 83%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=O.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.O>C1(C)C=CC=CC=1>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[N:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:33])[F:32])=[CH:25][CH:26]=3)[N:31]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: NNc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2cccnc2c(-c2cccc(C(F)(F)F)c2)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
A suspension of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.5 g) and 4-trifluoromethylphenylhydrazine (1.34 g) in toluene was stirred at reflux temperature for 3 hours (water was removed azeotropically from the mixture).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([N:6]1[CH2:10][CH2:9][CH:8]([O:11][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCNC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
Methanesulphonyl chloride (1.95 ml, 25.3 mmol) was added dropwise to an ice-cooled, stirred solution of 3(R,S)-pyrrolidinol (1.0 g, 11.5 mmol), triethylamine (3.5 ml, 25.3 mmol) and 4-dimethylaminopyridine (70 mg, 0.575 mmol) in dichloromethane (10 ml) under nitrogen. The resulting slurry was stirred at room temperature for 24 hours, then diluted with dichloromethane (50 ml), washed successively with saturated aqueous sodium bicarbonate solution (50 ml) and water 50 ml), dried (Na2SO4) and filtered. Dilution of the filtrate with ethyl acetate provided the title compound (1.67 g) as a white crystalline solid. Rf 0.84 (SS 1). Found: C,29.89; H,5.12; N,5.74. C6H13NO5S2 requires C,29.62; H,5.39; N,5.76%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH:17][C:18](=[O:20])[CH3:19])[C:7]([CH2:9][CH2:10][C:11](O)=[O:12])=O)([O-:3])=[O:2].O.[NH2:22][NH2:23]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[CH2:9][CH2:10][C:11](=[O:12])[NH:22][N:23]=2)[CH:14]=[CH:15][C:16]=1[NH:17][C:18](=[O:20])[CH3:19])([O-:3])=[O:2]
Reactant: NN
Reactant: CC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]

Procedure:
32.5 gm of 3-(3'-nitro-4'-acetylamino-benzoyl)-propionic acid were added toa solution of 32.5 gm of hydrazine hydrate in 180 ml of glacial acetic acid, and the mixture was heated on a steam bath. After cooling, the precipitate formed thereby was suction-filtered off and washed with ether,yielding the desired compound; m.p. 223° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C3CCCCO3)[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][OH:28]>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:23][C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([CH2:27][OH:28])[CH:25]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CO)c1
Reactant: Clc1ncc(Cl)c(Nc2cccc(OC3CCCCO3)c2)n1
Product: OCc1cccc(Nc2ncc(Cl)c(Nc3cccc(O)c3)n2)c1
Yield: 53 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using 2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 3-aminobenzyl alcohol as the starting materials in 53% yield. LCMS for C17H16ClN4O2 (M+H)+: m/z=343.0.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[C:33]([O:34]COCC[Si](C)(C)C)=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[O:22][CH2:23][C:24]2[C:33]([OH:34])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cc3ccccc3cc2OCOCC[Si](C)(C)C)C1
Agent: Cl
Product: Oc1cc2ccccc2cc1COC1CNCCC1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Examples 3 and 5 (g), by cleaving off the two protecting groups with methanolic hydrochloric acid from tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[3-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate there was obtained (3RS,4RS)-4-(4-fluorophenyl)-3-(3-hydroxy-naphthalen-2-yl-methoxy)-piperidine as a colourless solid, MS: 351 (M)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([Cl:26])=[CH:8][C:9]([F:25])=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:11]=1.C(N(CC)CC)C.[CH:34](O)=[O:35]>>[Cl:26][C:7]1[CH:8]=[C:9]([F:25])[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][NH:2][CH:34]=[O:35]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCN)c(Cl)cc2F)c1=O
Reactant: O=CO
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCNC=O)c(Cl)cc2F)c1=O

Procedure:
A mixture of 2.0 g of 3-[5-(2-aminoethoxy)-4-chloro- 2-fluorophenyl]-1-methyl-6 -trifluoromethyl-2,4(1H.3H)pyrimidinedione hydrochloride in 20 ml of formic acid are heated to boiling temperature for 20 hours with 0.47 g of triethylamine. The reaction mixture is subsequently evaporated to dryness under reduced pressure, the residue is dissolved in ethyl acetate and extracted with water and thereafter with aqueous sodium bicarbonate solution, and the organic phase is dried over anhydrous sodium sulphate. The solution is thereafter evaporated to dryness under reduced pressure, and the resinous residue is dissolved in ethyl acetate and largely concentrated by evaporation. The residue, still in the liquid state, is treated with diethyl ether until slightly turbid and is seeded. The crystals are filtered off under suction, washed with diethyl ether and dried. There is obtained N-[2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenoxy}-ethyl]-formamide, m.p. 128°-131° C.
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[CH:7]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1>>[C:1]([C:18]1([OH:20])[C:19]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)[Mg]Cl
Product: CC(C)(C)C1(O)c2ccccc2-c2ccccc21

Procedure:
from t-butylmagnesium chloride and 9-fluorenone;
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:8])[CH3:7]>OS(O)(=O)=O>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: -10 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To KNO3 (7.5 g, 73.8 mmol) in conc. H2SO4 (50 mL) was slowly added to a mixture of 2-tert-butylaniline (11.0 g, 73.8 mmol) in conc. H2SO4 (50 mL) at −10° C. The mixture was stirred at −10° C. for 1 hour and poured into ice-water. The mixture was extracted with EtOAc (150 mL×3). The combined organics were washed with brine, dried over anhydrous Na2SO4, and purified by chromatography on silica gel to obtain 2-tert-butyl-5-nitroaniline (9.0 g, 63%). 1HNMR (400 MHz, CDCl3) δ 7.53 (dd, J=2.8, 8.8 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 4.12 (br s, 2H), 1.44 (s, 9H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(I)cc1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(I)cc2)cc1C(F)(F)F
Yield: 68.7 %

Procedure:
4-Fluoro-2-(trifluoromethyl)benzonitrile (53 g, 280.4 mmol, AK Scientific) was treated with 4-iodophenol (61.7 g, 280.4 mmol, Aldrich) and sodium carbonate (44.6 g, 420.6 mmol) in 90 mL anhydrous DMF at 100° C. for 20 hours. The reaction mixture was diluted with 250 mL water and extracted with 2×200 mL EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 4-(4-iodophenoxy)-2-(trifluoromethyl)benzonitrile as a white solid (75 g, 69%). 1H NMR (400 MHz, CDCl3): 7.80-7.72 (3 H, m), 7.36-7.32 (1 H, m), 7.17-7.10 (1 H, m), 6.89-6.82 (2 H, m).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][N:23]=[C:3]12.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][N:23]=[C:3]2[CH:2]([NH:1][C:39]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[O:40])[N:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCc1cc2c(s1)-n1c(C3CCCCC3)nnc1C(N)N=C2c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(C3CCCCC3)nnc1C(NC(=O)Nc1ccc(OC)cc1)N=C2c1ccccc1Cl
Reaction time: 0.5 h

Procedure:
6-Amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (0.6 g) was dissolved in chloroform (15 ml) and 4-methoxyphenyl isocyanate (0.2 ml) was added thereto. The mixture was stirred for 30 minutes. The reaction mixture was purified by silica gel column chromatography and crystals obtained were recrystallized from methanol to give 0.49 g of N-(4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(4-methoxyphenyl)urea having a melting point of 268°-269° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:26][N:25]=1>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1

Procedure:
1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.72 g, 9.6 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(4-methoxyphenyl)pyrimidine (1.04 g, 4.78 mmol) were stirred in DMF (20 mL, anhydrous) at 120° C. for 16 h. The resulting mixture was quenched with saturated NH4Cl, extracted with ethyl acetate and dried with MgSO4. The reaction mixture solvent was evaporated and the residue purified by column chromatography (silica gel, ethyl acetate:hexanes=1:2) to yield the product as a white solid.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH:10]=[C:11]([CH3:26])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:25])[CH2:16][O:17][Si:18]([CH3:24])([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])C(OC)=O)(=[O:3])[CH3:2].[I-].[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[CH3:26][C:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:25])[CH2:16][O:17][Si:18]([CH3:24])([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH2:9][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)C(CC=C(C)CCC=C(C)CO[Si](C)(C)C(C)(C)C)C(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)CCC=C(C)CCC=C(C)CO[Si](C)(C)C(C)(C)C
Temperature: 150 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of methyl 2-acetyl-10-(dimethyl t-butylsilyl)oxy-5,9-dimethyl-4,8-decadienate (96 mg, 0.25 mmol) in hexamethylphosphoric triamide (0.5 ml) were added sodium iodide (45 mg, 0.30 mmol) and water (0.01 ml), and the mixture was stirred at 150° C. After two hours, the reaction mixture was allowed to cool to room temperature, and water (2 ml) was added thereto. The product was extracted with ether (5 ml×2). The extract was dried over Na2SO4, and concentrated to give a residue, which was then purified with silica gel column chromatography to obtain 6,10-dimethyl-11-(dimethyl t-butylsilyl)oxy-5,9-undecadien-2-one (57 mg, 70%).
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.[O:17]1[CH2:21][CH2:20][C:19]2[CH:22]=[C:23]([CH:26]=O)[CH:24]=[CH:25][C:18]1=2.CS(O)(=O)=O>CCOCC>[CH:1]1([N:6]2[C:10]3=[N:11][C:26]([C:23]4[CH:24]=[CH:25][C:18]5[O:17][CH2:21][CH2:20][C:19]=5[CH:22]=4)=[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: O=Cc1ccc2c(c1)CCO2
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4c(c3)CCO4)nc(=O)c1-2
Reaction time: 48 h
Yield: 52.3 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9.0 mmol), 2,3-dihydrobenzo[b]furan-5-carboxaldehyde (1.73 g, 11.7 mmol), methanesulfonic acid (0.25 ml) and xylenes (50 ml) was refluxed for 20 hours and then allowed to stand for about 2 days. The reaction mixture was diluted with ether and the product was collected by filtration and dried to afford 1.65 g (52%) of 1-cyclopentyl-3-ethyl-6-(2,3-dihydrobenzo[b]furan-5-yl)pyrazolo[3,4-d]pyrimidin-4-one 1/10 hydrate, m.p. 253°-254° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([CH2:41][N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH:44]([CH2:49][O:50][Si](C(C)C)(C(C)C)C(C)C)[CH2:43]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([CH2:41][N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH:44]([CH2:49][OH:50])[CH2:43]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)C(CO[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)C(CO)C5)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of Intermediate 56f (60.0 mg, 72.0 μmol) and TBAF (1M in THF, 144 μL, 144 μmol) in THF (3 mL) was stirred at RT for 1 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to afford the title compound as an off-white solid (24.9 mg, 51%). LCMS (Method 5): Rt 3.54 min, m/z 678 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.82-2.01 (4H, m), 2.01-2.25 (7H, m), 2.53-2.88 (3H, m), 3.21 (1H, m), 3.54 (1H, m), 3.96-4.11 (2H, m), 4.37 (1H, dt, J 12.5, 5.4), 4.84 (1H, m), 5.47 (1H, m), 6.32 (1H, s), 7.10 (1H, d, J 8.4), 7.22-7.44 (9H, m), 7.72 (1H, d, J 10.3), 8.02 (1H, s), 8.30 (1H, m).
Reaction SMILES: [CH2:1]([N:8]([S:18]([C:21]1[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=1)(=[O:20])=[O:19])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C(#N)C>[CH2:60]([NH:67][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[S:18]([C:21]2[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=2)(=[O:20])=[O:19])[CH:10]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2cccc(C(=O)O)c2)c1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2cccc(C(=O)NCc3ccccc3)c2)c1
Yield: 4.7 %

Procedure:
3-[Benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzoic acid (50 mg, 1.3 mmol), HATU (77 mg, 0.2 mmol), diisopropylethylamine (74 μL, 0.4 mmol) and benzylamine (22 μL, 0.2 mmol) were heated in dry acetonitrile under nitrogen at 60° C. for 18 hrs. After cooling, solvent was removed in vacuo and the residue purified by preparative TLC (100% ethyl acetate), to afford the title compound as a colourless oil (4.3 mg). HPLC retention time 5.46 min. Mass spectrum (ES+) m/z 462 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]1=[O:21].Cl.N.CS(C)=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:26])[CH:6]2[CH2:12][CH2:13][N:14]1[C:15](=[O:21])[CH2:16][CH2:17][CH2:18][C:19]1=[O:20]
Reactant: COc1ccc2[nH]cc(CCN3C(=O)CCCC3=O)c2c1
Reactant: CS(C)=O
Agent: Cl
Agent: N
Product: COc1ccc2c(c1)C(CCN1C(=O)CCCC1=O)C(=O)N2

Procedure:
145 mg of N-[2-(5-methoxyindol-3-yl)ethyl]glutarimide are dissolved in DMSO (30 μl) in a round-bottomed flask and concentrated HCl (72 μl) is added with stirring. The mixture is stirred overnight at room temperature. The crude product is neutralized with NH3 and then extracted with EtOAc. After separation on a silica plate, N-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]-glutarimide is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[N:12][CH:11]=2)=[N:7][CH:6]=1)=O.[NH4+:32].[OH-].[NH4+].[Cl-]>CO>[N:26]1([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:13]3[C:14]4[N:15]([CH:16]=[CH:17][N:18]=4)[C:10]([C:8]4[S:9][C:5]([C:3]([NH2:32])=[O:2])=[CH:6][N:7]=4)=[CH:11][N:12]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1cnc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)s1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cnc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)s1
Yield: 6 %

Procedure:
A solution of 2-[8-(4-morpholin-4-yl-phenylamino)-imidazo[1,2-a]pyrazin-5-yl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.21 mmol), 35% NH4OH (2.5 mL), and NH4Cl (0.2 g), in MeOH (12 mL) is heated at 85° C. in a stem tube for 48 hours. The mixture is concentrated in vacuo and purified by silica gel column chromatography eluting with 99:1 and 97:3 DCM:NH3 (7M in MeOH). Trituration with diethyl ether-MeOH gives the title compound (4.9 mg, 6%). LCMS: Rt 2.52 min (90%), m/z (ES+) 422 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.13 (4H, m), 3.79 (4H, m), 7.00 (2H, d), 7.75 (1H, br s), 7.81 (1H, s), 7.91 (2H, d), 8.25 (1H, s), 8.28 (1H, br s), 8.55 (1H, s), 9.08 (1H, s), 10.05 (1H, s).
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:11]=1>C(#N)C>[OH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:11]=1
Reactant: COc1ccnc(Nc2ccc(C#N)cc2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: N#Cc1ccc(Nc2nccc(O)n2)cc1
Temperature: 155 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Pyridine hydrochloride (23 gm) was added to 4-(4-methoxypyrimidin-2-ylamino)benzonitrile (15 gm) and then heated to 150 to 160° C. for 3 hours. The mixture was then cooled to room temperature, then transferred in to ice water and stirred for 1 hour. The resulting precipitate was filtered and washed with water. The solid thus obtained was slurried in acetonitrile at 0 to 5° C. for 1 hour and filtered. The solid obtained was dried to give 12.3 gm of 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile.