Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[F:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:26]([F:32])[CH:27]=1
Reactant: CSCc1cc(F)cc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3F)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
190 mg (2.91 mmol) of potassium cyanide and 8.9 mg (0.07 mmol) of 4-N,N-dimethylaminopyridine were added to 670 mg (1.46 mmol) of the compound from Example 56A in 40 ml of DMSO. The mixture was stirred at 80° C. for 2 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 522 mg (92% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][C:26](F)=[C:25]([Br:30])[CH:24]=3)=O)=[C:19]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:33][CH:32]=3)[S:18][C:17]=2[CH:45]=1.[OH2:46].CN([CH:50]=[O:51])C>>[OH2:3].[C:50]([OH:51])(=[O:12])[C:4]([OH:3])=[O:46].[C:50]([OH:51])(=[O:3])[C:11]([OH:12])=[O:46].[Br:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:21][C:20]1[C:16]2[CH:15]=[CH:14][C:13]([OH:12])=[CH:45][C:17]=2[S:18][C:19]=1[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44]2)=[CH:35][CH:36]=1
Reactant: OCCN1CCCC1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(C(=O)c3ccc(F)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)O
Product: Oc1ccc2c(Cc3ccc(OCCN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Sodium hydride (95 mg of a 60% suspension in mineral oil; 2.4 mmol) was suspended in 2 mL of DMF in a flame-dried, argon-filled flask and stirred for about 5 min. 1-(2-Hydroxyethyl)pyrrolidine (0.23 mL; 2.0 mmol) was added and the mixture was stirred for 15 min. 3-Bromo-4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone in 3 mL of DMF was then added. The mixture was stirred for 4 h at room temperature, then poured into water (25 mL), and extracted with EtOAc (4×25 mL). The combined organics were washed with brine and dried over magnesium sulfate. The title compound (135 mg; 10% yield) was isolated by flash chromatography on silica gel eluting with a gradient of EtOAc(100-90%)/Et3N(0-5%)/MeOH(0-5%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][C:31]([C:34]#[N:35])=[CH:32][N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(C(C)C)C(C)C.[CH3:45][S:46]([CH2:49][CH2:50]OS(C)(=O)=O)(=[O:48])=[O:47]>C(Cl)Cl>[C:8]1([C:14]2[N:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:50][CH2:49][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][C:31]([C:34]#[N:35])=[CH:32][N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Reactant: N#Cc1cnc(C(=O)Nc2ccc(C3CCNCC3)nc2C2=CCCCC2)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)CCN1CCC(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)n2)CC1
Reaction time: 8 h
Yield: 42 %

Procedure:
To a slurry of 5-cyano-1H-imidazole-2-carboxylic acid (6-cyclohex-1-enyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-amide trifluoroacetic acid salt (57 mg, 0.11 mmol) in 5 mL of DCM was added DIEA (50.4 μL, 0.290 mmol) followed by 30.5 mg (0.150 mmol) of methanesulfonic acid 2-methanesulfonyl-ethyl ester (as prepared in Example 40, step(a)). The reaction was allowed to stir overnight, diluted with 20 mL of DCM, washed with satd aq NaHCO3 (1×20 mL) and dried over Na2SO4. Purification by preparative TLC (silica gel, 40% EtOAc-hexanes) afforded 22.3 mg (40%) of the title compound as a white solid. 1H-NMR (DMSO; 400 MHz): δ 10.02 (s, 1H), 8.24 (s, 1H), 8.11 (d, 1H, J=8.4 Hz), 7.18 (d, 1H, J=8.4 Hz), 5.96 (s, 1H), 3.04 (s, 3H), 3.02-2.99 (m, 3H), 2.73 (t, 2H, J=2.7 Hz), 2.39-2.37 (m, 2H), 2.11-2.05 (m, 4H), 1.85-1.64 (m, 10H). Mass Spectrum (ESI, m/z): Calcd. for C24H31N6O3S, 483.2 (M+H), found 483.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[N:5][C:4]=1[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(N(C(C)C)CC)(C)C>C(#N)C.Cl.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[N:6]=[N:5][C:4]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([C:21]([F:20])([F:30])[F:31])[CH:23]=2)[CH2:16][CH2:15]1
Reactant: COc1cc(C(F)(F)F)nnc1NC1CCNCC1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)nnc1NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.6 %

Procedure:
A mixture of (4-methoxy-6-trifluoromethyl-pyridazin-3-yl)-piperidin-4-yl-amine (D8) (0.10 g, 0.36 mmol), 3-trifluoromethyl-benzyl bromide (0.060 ml, 0.29 mmol) and diisopropylethylamine (0.138 ml, 0.79 mmol) in acetonitrile (2 ml) was stirred at room temperature for 16 h. After this period, the solvent was evaporated in vacuo and the crude product purified by short open column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The product thus obtained was dissolved in a solution 2M of hydrochloric acid in diethyl ether to yield the corresponding hydrochloride salt E4 (0.138 g, 88%) as a solid. C19H20F6N4O.HCl free base requires 434; Found 435 (MH+). Rt (Method 1): 4.73 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][CH:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: OCCC1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(CCO)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 4-(2′-hydroxyethyl)piperidine. A yellow solid 108 was obtained (0.0308 g, 64%). 1H-NMR (CDCl3, 400 MHz) δ 1.34-1.43 (m, 2H), 1.58 (q, J=6.6 Hz, 2H), 1.84-1.93 (m, 1H), 1.96-2.02 (m, 2H), 3.21-3.29 (m, 2H), 3.74 (t, J=6.2 Hz, 2H), 3.83 (s, 3H), 4.33-4.39 (m, 2H), 6.91 (d, J=6.6 Hz, 1H), 6.96 (s, 1H), 7.00-7.07 (m, 3H), 7.45-7.52 (m, 3H), 7.84 (s, 1H), 8.24 (d, J=6.6 Hz, 1H); MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH3:43][N:44]([CH2:46][CH2:47][CH2:48][NH2:49])[CH3:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:49][CH2:48][CH2:47][CH2:46][N:44]([CH3:45])[CH3:43])=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and dimethylaminopropylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>C(Cl)Cl.COC1C=CC(O)=CC=1>[C:14]([O:5][CH:3]([C:2](=[O:1])[CH3:6])[CH3:4])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(=O)C(C)O
Agent: COc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC(C)C(C)=O
Temperature: 5 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
In a 2 L four-necked flask subjected replacement with nitrogen, 150 g of 3-hydroxy-2-butanone (made by Tokyo Chemical Industry Co., Ltd., purity: 95.0% or more) was put, and dissolved in 750 g of methylene chloride, and a stirrer, a thermometer and a Dimroth cooling tube were connected thereto. After the solution was stirred and cooled to about 5° C., 190 g of triethylamine and 80 mg of p-methoxyphenol were added thereto. While the solution was cooled to about 5° C. under stirring, 178 g of methacryloyl chloride was slowly added dropwise thereto over 4 hours, and further stirred for 30 minutes after completion of the dropwise addition to allow a reaction. The resulting reaction mixture was washed with 1 N-hydrochloric acid, a 10% sodium carbonate aqueous solution and saturated brine at room temperature, dried over anhydrous magnesium sulfate and separated by filtration to obtain a reaction crude liquid. The solvent of the reaction crude liquid was distilled off using an evaporator, 80 mg of p-methoxyphenol was added thereto and the resulting solution was distilled under reduced pressure to give 141 g of 3-oxobutane-2-yl methacrylate of 96.5% GC purity (yield: 53.1% based on 3-hydroxy-2-butanone).
Reaction SMILES: [Br:1][C:2]1[C:6]([S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[NH:4][C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].ClC1C=C(C=CC=1)C(OO)=[O:31].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:6]([S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:5]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[NH:4][C:3]=1[S:21]([C:22]([F:25])([F:24])[F:23])=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(c1c(-c2ccc(Cl)cc2)[nH]c(SC(F)(F)F)c1Br)C(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=S(c1[nH]c(-c2ccc(Cl)cc2)c(S(=O)(=O)C(F)(F)F)c1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A solution of 3-bromo-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]-2-[(trifluoromethyl)thio]pyrrole (0.4 g, 0.00082 mol) in chloroform (5 mL) is cooled with an ice bath, treated with a solution of 3-chloroperoxybenzoic acid (0.24 g, 60%, 0.00082 mol) in chloroform (10 mL), stirred for two hours, warmed to room temperature and stirred overnight. The reaction mixture is treated with saturated sodium metabisulfite solution, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. The residue is placed on a prep plate and eluted with a 1:2 ethyl acetate/hexanes solution to give the title product as a white solid (0.25 g, mp 120°-170° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: C1=COCCC1
Reactant: COC(=O)CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Pyridinium p-toluenesulfonate (7.65 g, 30.45 mmol) was added to a clear solution of methyl 3-hydroxypropanoate (63.4 g, 609.00 mmol) and 3,4-dihydro-2H-pyran (78 mL, 852.60 mmol) in dichloromethane (650 mL) at room temperature under nitrogen to give a cloudy solution. This was allowed to stir at room temperature overnight. The reaction mixture was washed with water (250 mL) and brine (250 mL) before drying (MgSO4) and evaporating to an oil. This crude product was purified by flash silica chromatography, elution gradient 15 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford methyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (67.7 g, 59.0%) as a colourless oil: 1H NMR Spectrum: (CDCl3) 1.47 (4H, dddd), 1.55-1.84 (2H, m), 2.55 (2H, t), 3.33-3.53 (1H, m), 3.53-3.7 (4H, m), 3.78 (1H, ddd), 3.93 (1H, dt), 4.42-4.72 (1H, m); Mass Spectrum [MH]+=189.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccccc1F)C=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
2-Fluorobenzaldehyde (1t, 0.5 ml, 4.7 mmol) and acetone (19, 0.18 ml, 2.4 mmol) were combined in ethanol (20 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.29 g, 7.3 mmol) and water (15 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was filtered and chromatographed on silica gel with ethyl acetate/hexane to give a solid. The crude solid was recrystallized from ethanol to afford 0.27 g (41%) of yellow crystals: mp 68-72° C. [expected mp 68-70° C.]; 1H NMR: δ 7.13 (m, 6H), 7.36 (m, 2H), 7.61 (dt, 2H, J=7.6 Hz, 1.4 Hz), 7.84 (d, 2H, J=16.3 Hz); 13C NMR: δ 116.2, 122.8, 124.4, 127.6, 129.3, 131.8, 135.9, 161.5, 188.7.
Reaction SMILES: C(OC(OCC)C[NH:6][C:7]1[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=3)[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1)C.[CH:37]([SH:40])([SH:39])[CH3:38].[C:41]1(C)C=CC=C[CH:42]=1>>[CH3:33][N:31]([CH3:32])[CH2:30][CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:14]2[NH:13][C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:38][CH:37]4[S:40][CH2:42][CH2:41][S:39]4)[C:8]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccccc1
Reactant: CC(S)S
Reactant: CCOC(CNc1ncnc2[nH]c(-c3ccc(OCCN(C)C)cc3)c(-c3ccccc3)c12)OCC
Product: CN(C)CCOc1ccc(-c2[nH]c3ncnc(NCC4SCCS4)c3c2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
(2,2-Diethoxyethyl)-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine (Example 33, Step C; 50 mg, 0.12 mmol) was combined with 12 μl ethanedithiol in 5 ml toluene, then the mixture was heated to reflux for 4 h. After that time the mixture was cooled to rt, concentrated and purified by chromatography on silica gel (CH2Cl2:MeOH=95:5) to give the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 2.21 (s, 6H), 2.61 (t, 2H, J=5.73 Hz), 3.16-3.05 (m, 4H), 3.61 (t, 2H, J=6.07 Hz), 4.03 (t, 2H, J=5.77 Hz), 4.68 (t, 1H, J=6.29 Hz), 5.23 (t, 1H, J=5.86 Hz), 6.86 (d, 2H, J=8.84 Hz), 7.25 (d, 2H, J=8.80 Hz), 8.14-7.38 (m, 5H), 8.21 (s, 1H), 12.12 (s, 1H). Mass Spectrum (ESI) m/e=492 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:23])[C:11]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[C:4]2[N:3]=1.[OH-].[NH4+:25].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCOCC1.C(O)C>[CH3:23][C:10]1[C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[C:4]2[N:3]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:7]=[C:6]([NH2:25])[N:5]2[N:9]=1
Reactant: C1COCCN1
Reactant: [NH4+]
Reactant: Cc1nn2c(Cl)cc(Cl)nc2c1Cc1cccc2ccccc12
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nn2c(N)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the solution of 5,7-dichloro-2-methyl-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine (0.05 g, 0.146 mmol) in 1,4-Dioxane (5 mL) was added ammonium hydroxide (0.508 mL, 3.65 mmol). The reaction was stirred at rt for 3 days. The reaction was concentrated to give the solid. To the mixture of the solid in Ethanol (1 mL) was added morpholine (0.382 mL, 4.38 mmol). The mixture was subjected to MW irradiation at 150° C. for 6 h. The reaction mixture was concentrated. The crude was purified by reversed phase HPLC (20˜50% CH3CN (0.1% TFA)/Water (0.1% TFA)). The fractions from purification were concentrated. NaHCO3 solution (3 mL) was added in and extracted with EtOAc (20 mL). The organic phase was washed with Brine (5 mL), dried (MgSO4) and concentrated to give the product as solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 3.46-3.52 (t, J=5.24 Hz, 4H) 3.65-3.74 (t, J=4.52 Hz, 3H) 4.28 (s, 2H) 5.49 (s, 1H) 7.07 (br. s., 2H) 7.31 (m, 1H) 7.37-7.43 (m, 1H) 7.45-7.52 (m, 2H) 7.75 (d, J=8.34 Hz, 1H) 7.85-7.93 (m, 1H) 8.54 (m, 1H); LC/MS: MS (ES+) m/e 374.0 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:19]=[CH:18][C:17]2[NH:16][C:15]3[CH:14]=[C:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[C:12]4[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:11]=4[C:10]=3[C:9]=2[CH:8]=1)(=O)=O.[CH2:34]([Sn](CC)(CC)CC)[CH3:35].[SnH4]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:13]1[C:12]2[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:11]=2[C:10]2[C:9]3[CH:8]=[C:7]([CH:34]=[CH2:35])[CH:19]=[CH:18][C:17]=3[NH:16][C:15]=2[CH:14]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1[nH]c3ccc(OS(=O)(=O)C(F)(F)F)cc3c21
Reactant: CC[Sn](CC)(CC)CC
Agent: [SnH4]
Product: C=Cc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O

Procedure:
Compound (616) was prepared from (615) prepared as described in example 479 (using the procedure described in example 309, with tetraethyl tin as the stannane to give a yellow oil. 1H NMR δ [(CD3)2SO] 11.71 (s, 1H), 11.48 (br, 1H), 8.23 (s, 1H), 8.78, (s, 1H), 7.99 (s, 1H), 7.62–7.43 (m, 5H), 7.2–7.1 (m, 1H), 6.10 (d, J=17.6 Hz, 1H), 5.46 (d, J=11.3 Hz, 1H). EIMS found: M+=372.0661. C22H13ClN2O2 requires 372.0666.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(OC)c2)cc1
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (146 mg, 0.47 mmol), 4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (178 mg, 0.47 mmol) and N,N-dimethylaminopyridine (57.4 mg, 0.47 mmol) in DMF (10 ml) was added EDC.HCl (99.0 mg, 0.52 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (288 mg, 91%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ2.00-2.20 (m, 3 H), 2.34-2.43 (m, 1 H), 3.35 (s, 2 H), 3.72 (s, 3 H), 3.89 (s, 3 H), 4.38-4.49 (m, 2 H), 4.62 (brs, 1 H), 4.94 (t, J=7.2 Hz, 1 H), 6.54 (d, J=8.4 Hz, 1 H), 6.67 (s, 1 H), 6.91-7.05 (m, 4 H), 7.28-7.42 (series of m, 7 H), 7.51 (d, J=8.0 Hz, 2 H), 7.87 (d, J=8.4 Hz, 1 H), 7.99 (d, J=8.8 Hz, 2 H), 8.14 (d, J=8.4 Hz, 2H); MS (ESI) m/z, 672 (M+), 674 (M++2).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:22]([CH:24]([C:32]#[N:33])[C:25]([CH3:31])([CH3:30])[C:26](OC)=[O:27])#[N:23].CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[NH2:23][C:22]1[C:24]2[C:25]([CH3:31])([CH3:30])[C:26](=[O:27])[NH:33][C:32]=2[N:17]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][C:11]([CH3:14])=[N:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)[N:16]=1
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1

Procedure:
200 mg (0.70 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were admixed with 3 ml of tert-butanol, 146 mg (0.70 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 1.5 ml of tert-butanol and 94 mg (0.84 mmol) of potassium tert-butoxide, and the mixture was heated under reflux for 48 h. Water was added and the precipitate was filtered off. The filtrate was extracted with dichloromethane, and the organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was stirred with water/ethanol. The solid was filtered off and dried under high vacuum. 102 mg (34% of theory) of the target compound were obtained.
Reaction SMILES: [CH:1]1([C@H:4]([NH:10][C:11]2[CH2:15][S:14][C:13](=[O:16])[N:12]=2)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[CH2:3][CH2:2]1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:15]2/[C:11]([NH:10][C@@H:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])=[N:12][C:13](=[O:16])[S:14]/2)[CH2:24][CH2:23]1
Reactant: CN(C)C(=O)[C@@H](NC1=NC(=O)SC1)C1CC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C1CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of (2S)-2-cyclopropyl-N,N-dimethyl-2-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]ethanamide (796 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (479 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1111 mg).