Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([NH-])(C)C.[Li+].[I:23]I.CCOC(C)=O>C1COCC1>[I:23][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=1
Reactant: CCOC(=O)c1ncoc1-c1ccccc1
Reactant: II
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(I)oc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of ethyl 5-phenyl-1,3-oxazole-4-carboxylate (Example 20, 0.921 mmol, 1 eq.) in THF (7 mL) at −78° C. was added a solution of lithium (trimethylsilyl) amide in THF (1 M in THF, 1.11 mmol, 1.2 eq.) dropwise by syringe. The resulting solution was stirred at −78° C. for 1 hour at which time a solution of iodine (1.38 mmol, 1.5 eq. in 2 mL THF) was added dropwise by a syringe. The reaction mixture was allowed to warm to rt and stirred at this temperature for 1.5 hours. The resulting solution was poured onto 10% aqueous NaS2O3 (15 mL) and extracted with EtOAc. The organic extracts were washed with brine, dried over anhyd. sodium sulfate, concentrated in vacuo, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=9:1). The product was obtained as a pale yellow solid in 82% yield. MH+=344.0, Rf=0.31 (hexanes:EtOAc=6:1), retention time (LC-MS)=3.01 min.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][CH:8]([C:16]([O:18]C)=[O:17])[CH2:9][N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][CH:8]([C:16]([OH:18])=[O:17])[CH2:9][N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)N1CC(C(=O)OC)Oc2ccc(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CC(C(=O)O)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a solution of 4-ethyl 2-methyl 6-cyano-2H-benzo[b][1,4]oxazine-2,4(3H)-dicarboxylate (665 mg, 2.29 mmol) in ethanol (12.5 mL) was added NaOH (2.3 mL of 1 M, 2.30 mmol). The mixture was stirred at room temperature for 10 min. A solution of 1 N HCl was slowly added until the pH was acidic. After removing the ethanol, the aqueous layer was extracted with dichloromethane (3×20 mL), dried over Na2SO4 and concentrated in vacuo to provide 6-cyano-4-ethoxycarbonyl-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (590 mg, 2.14 mmol). 1H NMR (400.0 MHz; DMSO-d6) δ 13.57 (s, 1H), 8.12 (s, 1H), 7.50 (dd, J=2.0, 8.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 5.20 (s, 1H), 4.44-4.40 (m, 1H), 4.20 (dd, J=7.2, 8.0 Hz, 2H), 3.72 (dd, J=3.3, 14.0 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:19]C(=O)[NH:17][CH:16]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:17][CH:16]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[CH:23]=1)[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[OH:19]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(OCc3ccccc3)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
To a solution of (4RS,5SR)-5-[4-(benzyloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (2.50 g, 5.26 mmol) in ethanol (30 ml) was added 8N aqueous sodium hydroxide solution (2 ml, 16 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solution was concentrated and diluted with water (100 ml). The mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (2.4 g, 100%)
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([CH:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)[CH2:3]1>C(O)C.[OH-].[Pd+2].[OH-].[C]>[CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:3]1
Reactant: CC1CN(C2CCN(Cc3ccccc3)CC2)CCN1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CN(C2CCNCC2)CCN1C
Yield: 57.2 %

Procedure:
To a solution of 4-(3,4-dimethyl-1-piperazinyl)-1-benzylpiperidine (4.2 g) in ethanol (50 ml) is added 20% palladium hydroxide-carbon (0.4 g), and the mixture is subjected to catalytic hydrogenation at 50° C. under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is evaporated to give 4-(3,4-dimethyl-1-piperazinyl)piperidine (1.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]#[CH:33])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][C:32]#[CH:33])[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: C#CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C#CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)=O
Yield: 53 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(prop-2-yn-1-ylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 2.03 (s, 3H), 3.27 (s, 1H), 3.93-4.04 (m, 2H), 4.24-4.32 (m, 2H), 4.43 (t, 1H), 4.56-4.63 (m, 1H), 5.31 (s, 2H), 7.13 (d, 1H), 7.25 (d, 1H), 7.34 (d, 1H), 7.35-7.41 (m, 1H), 7.52-7.63 (m, 2H), 7.70-7.79 (m, 1H), 7.86-7.93 (m, 2H), 8.44 (s, 1H), 8.61 (d, 1H), 9.69 (s, 1H); Mass spectrum MH+ 502.
Reaction SMILES: Cl[CH:2]1[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1.C(N(CC)CC)C.NC1N=CN=C([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)C=1>C(O)CCC>[O:6]=[S:4]1(=[O:7])[CH2:5][CH:2]([N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ncn2)CC1
Reactant: O=S1(=O)CC(Cl)C1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C2CS(=O)(=O)C2)CC1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
3-Chlorothietane 1,1-dioxide 50-1 (0.50 g, 3.56 mmol) was dissolved in n-butanol (4 mL) then triethylamine (1.08 g, 10.67 mmol) was added followed by tert-butyl piperazine-1-carboxylate 12-1 (0.66 g, 3.56 mmol). This was then stirred at 150° C. for 5 hours. Upon cooling the solid was filtered off, washed with n-butanol, ethyl ether and then purified on a silica column to afford 50-2. 1H-NMR (CDCl3): 4.10(complex, 4H); 3.46(t, 4H); 3.19(m, 1H); 2.36(t, 4H); 1.46(s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH:17]=3)[C:12](=[O:27])[N:11]([O:28]CC3C=CC=CC=3)[C:10]2=[O:36])[CH:6]=[CH:7][CH:8]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[CH:17]=3)[C:12](=[O:27])[N:11]([OH:28])[C:10]2=[O:36])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCN(C)CC4)cc32)c1
Agent: [Pd]
Product: COc1cccc(-n2c(=O)n(O)c(=O)c3cc(F)c(N4CCN(C)CC4)cc32)c1
Yield: 83.2 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.04 g) with 1-(3-methoxyphenyl)-6-fluoro-3-benzyloxy-7-(4-methylpiperazin-1-yl)-1H-quinazoline-2,4-dione (Example U-1, 0.12 g, 0.24 mmol) afforded 0.08 g of the title compound as a solid, mp 158-160° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[NH:17])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -30 °C

Procedure:
4,4′-difluorobenzophenone (25 g) was dissolved in anhydrous toluene (800 mL), and the solution was cooled at −30° C. Titanium tetrachloride (21.4 mL) was dropwise added to the solution under nitrogen, and ammonia gas was passed through the mixture for about 20 minutes. Then the mixture was warmed up to room temperature and stirred over night. Saturated potassium carbonate aqueous solution (400 mL) was added to the reaction mixture, and the mixture was stirred for an additional 1 hour. The organic layer was separated and washed with water and saturated saline once respectively. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo to give crude product of 1,1-bis(4-fluorophenyl)methanimine (31.7 g). The crude product was dissolved in anhydrous toluene (80 mL), and trimethylsilylcyanide (171.86 mL) and zinc iodide (1.83 g) were added to the solution. Then the mixture was stirred at room temperature over night. The reaction mixture was washed with saturated sodium hydrogen carbonate aqueous solution and saturated saline in this order, and dried over anhydrous sodium sulfate. Then solvent was evaporated in vacuo to obtained crude product of 2-amino-2,2-bis(4-fluorophenyl)acetonitrile (30.84 g). The crude product was dissolved in anhydrous toluene (100 mL), and then 1M diisobutylaluminum hydride—toluene solution (500 mL) was dropwise added to the solution at −78° C. Then temperature of the mixture was raised by standing to room temperature, and the mixture was stirred over night. Sodium sulfate decahydrate was added to the reaction mixture, and the resultant mixture was stirred for one hour. Moreover, anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was stirred for one hour. Then insolubles were removed by filtration. The filtrate was concentrated in vacuo, and then the obtained residue was purified by silica gel column chromatography (C-300; 100% ethyl acetate→100% methanol) to give the title compound (8.55 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][C@@H:11]1[CH3:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Cl)[N:20]=1>CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[N:20]=2)[CH2:12][C@@H:11]1[CH3:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1cccc(Cl)n1
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H]1C[C@@H](Oc2cccc(Cl)n2)CCN1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Add sodium hydride (95%, 0.318 g) to a solution of 4-hydroxy-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 3, 2.465 g) in DMSO (100 mL) and heat in an oil bath at 65° C. After 30 min., add 2,6-dichloropyridine (1.864 g) and beat at 100° C. After 4 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with ethyl acetate-hexane (1:39) to give the title compound (3.26 g). 1H NMR (CDCl3): 7.50 (t, 1H), 6.87 (d, 1H), 6.61 (d, 1H), 5.38 (m, 1H), 4.35 (m, 1H), 3.89 (m, 1H), 3.22 (m, 1H), 1.93 (m, 3H), 1.75 (m, 1H), 1.46 (s, 9H), 1.26 (d, 3H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15](=[N:23][OH:24])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].N.C(#N)C>O1CCCC1>[NH2:29][C:27]([O:24]/[N:23]=[C:15](/[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)\[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:28]
Reactant: COc1ccc(C(Cc2ccccc2)=NO)cc1OC1CCCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(/C(Cc2ccccc2)=N/OC(N)=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a magnetically-stirred solution of 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl ethanone oxime (4.51 mmol, 1.48 g) in dry tetrahydrofuran (45 mL) at 0° C. is added trichloroacetyl isocyanate (5.00 mmol, 0.943 mg; 0.596 mL) dropwise over 2 minutes and the resulting solution is allowed to stir as the temperature rises slowly from 0° C. to room temperature overnight. The reaction mixture is then cooled to 0° C. and saturated NH3 /acetonitrile solution (25 mL; prepared by bubbling gaseous ammonia through CH3CN at room temperature for 1 hour) is added dropwise to the reaction mixture. The solution is allowed to stir as it warms slowly from 0° C. to room temperature. After 1.5 hours, the tetrahydrofuran is removed in vacuo and the residue is partitioned between methylene chloride (200 mL) and water (200 mL). The aqueous phase is extracted with ethyl acetate (200 mL) and the combined organics are washed with water (200 mL), dried (Na2SO4), and concentrated in vacuo to afford a mixture of product and oxime (~1:1). The residue is purified via flash chromatography (SiO2 : 1) 2% ethyl acetate/methylene chloride, 2) 5% ethyl acetate/methylene chloride, 3) 7% ethyl acetate/methylene chloride) to give a white solid which is triturated with ether/hexane and dried in vacuo at 50° C. to afford analytically-pure title compound (1.22 mmol, 0.450 g; 27%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1>C(O)C>[NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1
Reactant: CCCc1nc(N)sc1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCCc1nc(N)sc1Cc1ccc(N)cc1
Yield: 59.1 %

Procedure:
4.0 g of 2-amino-5-(4-nitrobenzyl)-4-propylthiazole (13 mmol) in 100 ml of ethanol are hydrogenated according to Example 25. 1.9 g of 2-amino-5-(4-aminobenzyl)-4-propylthiazole are obtained in the form of a brown oil.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[NH2:28][C:29]1[N:34]2[N:35]=[CH:36][C:37]([C:38]3[CH:39]=[N:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:42][CH:43]=3)=[C:33]2[N:32]=[C:31]([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[C:30]=1[C:56](=[O:59])[CH2:57][OH:58].C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:28][C:29]1[N:34]2[N:35]=[CH:36][C:37]([C:38]3[CH:39]=[N:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:42][CH:43]=3)=[C:33]2[N:32]=[C:31]([CH:50]2[CH2:55][CH2:54][N:53]([C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH2:52][CH2:51]2)[C:30]=1[C:56](=[O:59])[CH2:57][OH:58]
Reactant: Nc1c(C(=O)CO)c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-2-hydroxypropanoic acid (13.8 mg, 0.16 mmol), EDCI (46 mg, 0.24 mmol), and 1-hydroxybenzotriazole (16.22 mg, 0.12 mmol) in DMF (2 ml) was stirred at room temperature for 10 min. To this 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyethanone (58.77 mg, 0.12 mmol) was added followed by N,N-diisopropylethylamine (0.1 ml, 0.6 mmol). It was stirred further for 20 min at room temperature at which time LC/MS analysis confirmed full consumption of starting material. This crude compound was submitted to the analytical group for purification to afford the desired (R)-1-(4-(7-amino-6-(2-hydroxyacetyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)-2-hydroxypropan-1-one. LCMS: 3.27 mins, m/z=501.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: C1CCNCC1
Reactant: CSc1nc(Cc2cccc(F)c2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCCCC2)nc(Cc2cccc(F)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.36 mmol) of 2-(3-fluorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 309 mg (3.63 mmol) of piperidine to give 40 mg (35% of theory) of the title compound.
Reaction SMILES: S1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].O[O:31][S:32]([O-:34])=O.[K+].C(=O)(O)[O-].[Na+]>C(#N)C>[O:31]=[S:32]1(=[O:34])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCSCC1
Reactant: O=S([O-])OO
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: O=C1CCS(=O)(=O)CC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of tetrahydrothiopyran-4-one (400 mg, 3.45 mmol) in acetonitrile (5 ml) was added aqueous Na2EDTA (3 ml, 0.0004 M). A mixture of oxone (6.30 g, 10.30 mmol) and sodium bicarbonate (2.70, 32 mmol) was added in small portions to the above solution over a period of 20 min. The slurry was stirred for another 1 h before being quenched with methylene chloride. The organic solvent was decanted and the solid residue was triturated with ethyl acetate (3×25 ml). The combined organic layers were dried over sodium sulfate and concentrated to give the desired ketone (0.37 g, 73%) as a colorless solid. mp 170-172° C. (lit. 168-170° C.); 1H NMR (500 MHz, CDCl3) 2.99 (t, J=6.8 Hz, 4H), 3.39 (t, J=6.8 Hz, 4H). Ref: Yang, D.; Yip, Y.-C.; Jiao, G.-S.; Wong, M.-K. Design of Efficient Ketone Catalysts for Epoxidation by Using the Field Effect. J. Org. Chem, 1998, 63, 8952-8956.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[S:26][C:25]([NH:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[N:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[S:26][C:25]([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3cnc(NCC4CC4)s3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2c(c1CSc1cnc(NCC3CC3)s1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.113 g, 0.237 mmol) in anhydrous DCM (4.9 mL) at room temperature add trifluoroacetic acid (4.9 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, load the solution on to an Analogix® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 90:10 DCM/2M ammonia in methanol over 30 min; 90:10 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.075 g, 83%). MS (ES+) m/z: 380.1 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.[H][H]>[Ni].O1CCCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CCOC(=O)N1CCC(CCC=O)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(CCCO)CC1
Yield: 98.3 %

Procedure:
A mixture of 36 parts of ethyl 4-(3-oxopropyl)-1-piperidinecarboxylate and 450 parts of tetrahydrofuran was hydrogenated at normal pressure and at 20° C. with 2 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 260 parts of dichloromethane. The organic layer was washed with 100 parts of a diluted hydrochloric acid solution, dried, filtered and evaporated, yielding 36 parts (98.3%) of ethyl 4-(3-hydroxypropyl) -1-piperidinecarboxylate as a residue (int. 47).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].Cl.[NH2:28][CH2:29][C:30]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[OH:35][C:30]1([CH2:29][NH:28][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NCC1(O)CCCC1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Product: N#Cc1ccc2c(c1)cc(C(=O)NCC1(O)CCCC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 1-aminomethyl-cyclopentanol hydrochloride in a manner similar to that described in Example 11.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH3:13][O:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:2]=[CH:3]2)=[O:11]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1ccc2cc(C(=O)OC)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl indole-5-carboxylate (0.875 g, 5.0 mmol) was added to a suspension of sodium hydride (60% in oil, 0.22 g, 5.5 mmol) in N,N-dimethylformamide (15 mL) at 0° C. The resultant solution was stirred at room temperature for 30 min. Bromopentane (0.706 mL, 5.69 mmol) was added to the solution, and stirring was continued for 4 hours. The solution was poured into ice water (100 mL), and the product was extracted into dichloromethane. The organic solution was washed several times with water and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash silica gel chromatography using 5% ethyl acetate in hexane as the eluant, to give the product, 0.975 g (79%), as an oil. MS: m/z 280 (MH+). 1H NMR (CDCl3): 0.87 (t, 3 H), 1.22-1.40 (m, 4 H), 1.77-1.87 (m, 2 H), 3.92 (s, 3 H), 4.11 (t, 2 H), 6.58 (d, 1 H), 7.14 (d, 1 H), 7.32 (d, 1 H), 7.90 (d of d, 1 H) and 8.40 (d, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH:36]1[CH2:37][CH2:38][N:39]([C:24]([C:13]2[CH:12]=[N:11][C:10]3[N:9]([N:8]=[CH:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]=2[NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[F:23])=[O:25])[CH2:40][CH2:41]1
Reactant: Fc1ccc(C2CCNCC2)c(F)c1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4F)CC3)cnc12
Yield: 47.3 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (160 mg, 0.46 mmol) obtained in Example 90, step 2 and 4-(2,4-difluorophenyl)piperidine hydrochloride (WO2007/018998, 160 mg, 0.69 mmol), the title compound (117 mg, 47%) was obtained.