Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.N1CCCCC1.C(O)(=O)C>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1/[CH:21]=[C:9](\[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:17])/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)/C(=C/c1ccccc1Cl)C(=O)c1ccccc1O
Yield: 20.1 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (236 mg, 1.0 mmol), 2-chlorobenzaldehyde (113 μL, 1.0 mmol) 15 mL benzene, piperidine (10 μL, 0.1 mmol) and glacial acetic acid (5.6 μL, 0.1 mmol), refluxed for 90 min. Purified via recrystallization from hexanes/CH2Cl2, yielding 72 mg (20%) of a white solid. mp=75-78° C. IR (film) 2979.0; 1720.5; 1630.9; 1156.3 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.80 (bs, 1H); 8.19 (s, 1H); 7.50 (d, J=7.9 Hz, 1H); 7.44 (t, J=7.9 Hz, 1H); 7.36 (d, J=7.9 Hz, 1H); 7.26 (d, J=7.9 Hz, 1H); 7.21 (t, J=7.6 Hz, 1H); 7.08 (t, J=7.06, Hz, 1H); 6.97 (d, J=7.9 Hz, 1H); 6.82 (t, J=7.6 Hz, 1H); 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 200.6, 163.3, 162.8, 139.1, 137.2, 135.0, 134.0, 131.9 (double intensity), 131.3, 130.2, 130.1, 127.2, 120.0, 119.5, 118.5, 83.1, 28.1; LRMS (electrospray): Mass calculated for C20H19ClO4 [M]+, 358.09. Found [M+23]+, 381.5.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[NH:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:23]3[CH:24]=[C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][C:22]=3[O:21][CH2:20][C:19]3[CH:18]=[CH:17][S:16][C:15]2=3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[O:7]=[C:5]([CH3:6])[CH2:4][CH2:3][CH2:2][N:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:23]3[CH:24]=[C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][C:22]=3[O:21][CH2:20][C:19]3[CH:18]=[CH:17][S:16][C:15]2=3)[CH2:10][CH2:9]1
Reactant: COC(=O)Cc1ccc2c(c1)C(=C1CCNCC1)c1sccc1CO2
Reactant: CC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc2c(c1)C(=C1CCN(CCCC(C)=O)CC1)c1sccc1CO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
5-Chloro-2-pentanone (2.4 mL, 20.9 mmol) was added to a DMF (50 mL) solution of methyl (4-piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl)acetate (2.50 g, 7.0 mmol), anhydrous potassium carbonate (2.15 g, 15.6 mmol), and potassium iodide (1.41 g, 8.5 mmol), and the mixture was stirred overnight at 80° C. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvents were then distilled off under a reduced pressure. The residue was purified by column chromatography (chloroform:methanol=19:1), to give 2.40 g (78%) of the captioned compound in the form of an oily product.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]1[N:11](CC(O)=O)[CH:12]=[CH:13][CH:14]=1.F[P-](F)(F)(F)(F)F.N1([O:35]C(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1(N)CC1.C([N:50]([CH:53]([CH3:55])[CH3:54])[CH2:51][CH3:52])(C)C>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]1[N:11]([N:50]([CH:53]2[CH2:54][CH2:55]2)[CH2:51][CH:52]=[O:35])[CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)Cn1cccc1-c1cc2cccnc2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=CCN(C1CC1)n1cccc1-c1cc2cccnc2[nH]1
Reaction time: 1 h

Procedure:
A mixture of [2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-pyrrol-1-yl]-acetic acid [10 mg, Example 54] and 2-(1H-benzotriazole-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (15.7 mg) in dry dimethylformamide (0.2 mL) was agitated for 1 hour then treated with cyclopropylamine (5.68 μL) and diisopropylethylamine (7.16 μL) in dry dimethylformamide (0.226 mL). After agitating for a further 15 hours the crude mixture was subjected to LC-MS triggered purification affording the title compound. LC-MS: METHOD C: RT=2.44 minutes, 281[M+H]+ and 224 (fragment corresponding to the breaking of the amide bond).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:16]([C:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl.CCO>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[C:38]1([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 2.5 mmol) (as prepared in the previous step) in 10 mL of DCM and 0.3 mL EtOH was added 3 mL of TFA and the solution stirred for 3 h at 25° C. The reaction was diluted with 5 mL of EtOH and then concentrated. The residue was crystallized from methanol and ethyl ether to give 0.85 g (70%) of the title compound as a white solid. 1H-NMR (400 MHz, CD3OD) δ 8.18 (d, 1H), 8.04 (s, 1H), 7.22 (dd, 1H), 7.12 (d, 1H), 5.76 (m, 1H), 3.54. (m, 2H), 3.16 (m, 2H), 2.92 (m, 1H), 2.30 (m, 4H), 2.10 (m, 2H), 1.75 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H25N5O, 376.2 (M+H), found 376.2.
Reaction SMILES: [C:1]([C:3]1([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[N:2].[NH2:24][OH:25].[C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])#[C:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCO>[CH2:16]([O:15][C:14]([NH:13][C:3]1([C:1]2[NH:24][O:25][C:27]([CH2:26][C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:2]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CC1(NC(=O)OCc2ccccc2)CCC2(CC1)OCCO2
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NO
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(C2(NC(=O)OCc3ccccc3)CCC3(CC2)OCCO3)NO1
Temperature: 70 °C
Reaction time: 48 h
Yield: 81.3 %

Procedure:
A mixture of benzyl 8-cyano-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (37.4 g, 118.33 mmol), hydroxylamine (7.98 mL, 130 mmol, 50 wt % in water) in EtOH (750 mL) was heated at 70° C. for 48 h. The mixture was then cooled to room temperature and treated with diethyl acetylenedicarboxylate (22.73 mL, 142 mmol). After 48 h at room temperature, the reaction mixture was concentrated and the resulting yellow residue was taken up in ethyl acetate (500 mL), washed with water (2×100 mL) followed by brine (100 mL), then dried (Na2SO4), filtered and concentrated to give a yellow oil. Flash chromatography on silica gel (using 5% to 50% ethyl acetate-hexane gradient) afforded the title compound as a yellow oil (50 g, 82% yield). 1H NMR (500 MHz, CDCl3) δ: 7.33-7.37 (m, 5H), 5.80 (s, 1H), 5.07 (s, 2H), 4.84 (d, 1H, J=23.8 Hz), 4.33 (q, 1H, J=7.02 Hz), 4.27 (q, 1H, J=7.22 Hz), 4.09-4.20 (m, 3H), 3.93 (s, 2H), 3.90-3.92 (m, 2H), 2.16-2.23 (m, 4H), 2.03 (s, 1H), 1.62-1.74 (m, 4H), 1.24-1.37 (m, 6H). LCMS (M+H)=336.14.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)CO>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:17][CH:16]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: Nc1ccc(Br)cc1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(Br)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-bromoaniline (9d, 172 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide 10d as pure product. To a solution of 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide (10d, 150 mg, 0.45 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 112 mg, 0.5 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1d (220 mg 80%); mp: 160-162° C.; 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 7.59 (m, 2H), 7.54 (s, 1H), 7.35-7.28 (m, 3H), 7.22 (brs, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.03-6.94 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.64 ppm (d, J=6.0 Hz, 1H); MS (ESI m/z): 555 [M+H]+. Yield: 80%
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:24](O)=[O:25])=[CH:22][NH:23][C:18]3=[N:17][CH:16]=2)=[N:3]1.[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:28]([NH:31][C:24]([C:21]1[C:19]2=[N:20][C:15]([C:4]3[C:5]4[C:10](=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][CH:6]=4)[N:2]([CH3:1])[N:3]=3)=[CH:16][N:17]=[C:18]2[NH:23][CH:22]=1)=[O:25])([CH3:30])([CH3:29])[CH3:27]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(C(F)(F)F)cc21
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
A mixture of 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (190 mg, 0.526 mmol), 2-methylpropan-2-amine (58 mg, 0.789 mmol), EDCI (301 mg, 1.578 mmol), HOBt (213 mg, 1.578 mmol) and DIPEA (204 mg, 1.578 mmol) in dry DMF (5 mL) was stirred for 16 hours at room temperature. Water (5 mL) was added, the formed precipitate was separated by filtration then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 90% acetonitrile/10% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min.) to afford N-tert-butyl-2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (47 mg, 21%) as a yellow solid. LCMS: (M+H)+=417; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.08 (s, 1H), 8.63 (d, 1H, J=8.4 Hz), 8.38 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.49 (d, 1H, J=8.7 Hz), 4.28 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH:12]([O:14][CH2:15][CH2:16]Cl)=[CH2:13].O>CN(C)C(=O)C.C(OCC)(=O)C>[CH:12]([O:14][CH2:15][CH2:16][O:8][C:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:9])=[CH2:13]
Reactant: C=COCCCl
Reactant: O=C(O)Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: C=COCCOC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 500 ml of N,N-dimethylacetamide (DMAc) was dissolved 100 g of thiophene-2-acetic acid, and to the resulting solution was added 31 g of sodium hydroxide, followed by stirring at room temperature for 10 minutes. Then, 112 g of 2-chloroethyl vinyl ether was added thereto and the mixture was stirred at 120° C. for 2 hours. The deposition of salt was observed. To the reaction solution were added water and ethyl acetate, and the mixture was subjected to separation procedure. The organic phase was washed three times with water, dried, concentrated and distilled under a reduced pressure to obtain the desired compound (X-1). The desired compound (X-1) was identified by NMR.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[C:50](Cl)=[O:51]>>[CH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[C:50]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:51]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc4ccccc4c3)CN2C1=O
Yield: 26.1 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 2-naphthoyl chloride (66 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 33 mg (26%) of 18-(2-naphthoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.5% pure (HPLC), MS m/z 721 (M−H)−, HRMS: calcd. 740.3329 and found 740.3321 (M+NH4)+, mp 156-158° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:16]([NH2:18])=[O:17])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C@@H:8]([OH:19])[CH2:7][C:5]=2[CH:6]=1.CN(C1C=CC=CN=1)C.[C:29](OC(=O)C)(=[O:31])[CH3:30].Cl>O.ClCCl.C(N(CC)CC)C>[CH3:30][C:29]([O:19][C@@H:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]([C:16]([NH2:18])=[O:17])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:31]
Reactant: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
To a solution of eslicarbazepine (30 gm), triethylamine (19.7 gm), dimethylaminopyridine (0.15 gm), and dichloromethane (150 mL), acetic anhydride (14.5 mL in 14.5 mL dichloromethane) was added and solution was stirred at about 20-25° C. for about 3 hrs. The resulting solution was cooled to about 10-15° C. To the resulting solution water (90 mL) was added followed by addition of HCl till pH of the resulting solution was 1-2. Organic layer was separated and washed with water. Water was added to organic layer followed by cooling to about 10-15° C. The pH of the resulting solution was adjusted to 9-10 by adding NaOH (10% w/v) solution. Organic layer was separated and solvent was distilled out completely to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]#[N:27])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[N-:29]=[N+:30]=[N-:31].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>>[CH3:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:31][N:30]=[N:29][N:27]=4)=[CH:16][CH:15]=3)[C:6]=2[N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc(C)c2ccc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2n1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Product: Cc1nc(C)c2ccc(=O)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1

Procedure:
Using the same procedure as described in Step 3 of Example 8, heat a mixture of 2,4-dimethyl-8-[[2'-cyano[1,1-biphenyl]-4-yl]methyl]-7H-pyrido[2,3-d]pyrimidin-7-one, NaN3, and tri-n-butyltin chloride in xylenes under reflux for 48 h. Cool the mixture and add 1N HCl (2 mL). Add CHCl3 and water, and dry (MgSO4) and concentrate the organic phase. Recrystallization from EtOAc gives the product.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH:13][C:14]#[N:15])=[CH:5][CH:4]=[C:3]3[CH2:2]1.[ClH:16].[Cl:17][C:18]1[C:24]([Cl:25])=[C:23]([Cl:26])[CH:22]=[CH:21][C:19]=1[NH2:20]>ClC1C=CC=CC=1>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH:13][C:14]([NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:26])=[C:24]([Cl:25])[C:18]=2[Cl:17])=[NH:15])=[CH:5][CH:4]=[C:3]3[CH2:2]1.[ClH:16]
Reactant: Nc1ccc(Cl)c(Cl)c1Cl
Reactant: N#CNc1ccc2c3c(cccc13)CC2
Agent: Cl
Solvent: Clc1ccccc1
Product: N=C(Nc1ccc(Cl)c(Cl)c1Cl)Nc1ccc2c3c(cccc13)CC2
Temperature: 20 °C
Reaction time: 24 h
Yield: 72.2 %

Procedure:
A mixture of 5-acenaphthyl cyanamide (0.194 g, 1 mmol) and 2,3,4-trichloroaniline hydrochloride (0.221 g, 0.95 mmol; prepared from 2,3,4-trichloroaniline and 1. ON HCl-ether) were heated at reflux in 5 mL of chlorobenzene. Shortly after reflux temperature was reached all the solids had dissolved to give a clear solution. After a total of 2 hour reflux, the mixture was cooled to 20° C. and allowed to stand for 24 hours. The solid was collected by filtration and washed with excess of methylene chloride and dried in vacuo at 40° C. to give product (0.293 g, 68%) as an off white solid, mp: 208°-10° C.; 1H NMR (CD3OD): δ 7.70-7.58 (m, 3H, Ar--H), 7.48 (d, 2H, J=7.5Hz, Ar--H), 3.47-3.41 (m, 4H, 2×CH2); HRMS 389.0220 (389.0253 calcd. for C19H14N3Cl3); Anal Calcd. for C19H15N3CI4 (427.15): C, 53.42; H, 3.54; N, 9.84; Cl, 33.2; Found: C, 53.25: H, 3.57; N, 9.67; Cl, 33.75.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(C(C)C)CC)(C)C.[CH:19]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][N:34]=[C:33]3[SH:41])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[C:36]([C:37]([F:38])([F:40])[F:39])=[N:35][N:34]=[C:33]3[S:41][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: FC(F)(F)c1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Sc1nnc(C(F)(F)F)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 60 °C
Yield: 37.3 %

Procedure:
Ethyl 2-bromo-2-methylpropanoate (894, 0.596 mmol) and diisopropylethylamine (0.31 mL, 1.789 mmol) were added to a solution of 4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.596 mmol) in DMF (1.2 mL) and the mixture heated at 60° C. for 20 hours. The mixture was concentrated, acidified with HCl (1M aqueous, 2 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts were dried over sodium sulfate, concentrated and purified by column chromatography (0-25% EtOAc/hexanes) to provide ethyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a clear oil (0.1 g, 37%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.S(Cl)([Cl:12])=O.[CH2:14](O)[CH3:15]>>[ClH:12].[CH2:14]([O:8][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][NH2+:1][CH2:2]1)=[O:9])[CH3:15]
Reactant: O=C(O)C1CCCNC1
Reactant: O=S(Cl)Cl
Reactant: CCO
Product: CCOC(=O)C1CCC[NH2+]C1
Product: Cl

Procedure:
To a solution of piperidine-3-carboxylic acid (10.7 g, 83 mmol) in ethanol (40 mL) was added thionyl chloride (22.5 mL) at 0° C. dropwise, the reaction mixture was refluxed overnight. Then the mixture was evaporated at reduced pressure to give 3-(ethoxycarbonyl)piperidinium hydrochloride. (13 g, Y: 100%). LC-MS (ESI) (m/z): 158 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](C23NCCN2C(=O)C2C3=CC=CC=2)=[CH:4][CH:3]=1.F[C:22]1[CH:30]=[CH:29][C:25](C(Cl)=O)=[CH:24][CH:23]=1.C1(O)C=CC=CC=1.ClCC#N.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:22]1([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:30]=[CH:29][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C1c2ccccc2C2(c3ccc(O)cc3)NCCN12
Agent: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: c1ccc(Oc2ccccc2)cc1

Procedure:
Compound 239 was prepared from 9b-(4-hydroxyphenyl)-1,2,3,9b-tetrahydroimidazo[2,1-a]isoindol-5-one using Method L. The tetrahydroimidazoisoindolone was bis-acylated with 4-fluorobenzoyl chloride according to Method H and the resulting phenolic ester function was converted to a phenol by basic hydrolysis. The product was then treated with chloroacetonitrile and K2CO3 in acetone and heated to reflux for 30 h to yield phenyl ether compound 239.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[CH:21](I)([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:22][CH:21]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)[CH3:23]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 50 °C

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (3 g), isopropyl iodide (3.2 ml) and K2CO3 (2.94 g) were combined in acetonitrile (70 ml) and the reaction mixture heated at 50° C. overnight. The reaction was allowed to cool to room temperature, filtered and evaporated. The residue was dissolved in diethylether (50 ml) and washed successively with water (50 ml), saturated sodium thiosulphate solution (50 ml), saturated brine (50 ml) and dried (Na2SO4). The solvent was evaporated to give the title compound (D3) as a pale yellow oil (3.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([CH:9]([CH2:25][CH2:26][CH:27]=O)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8].[CH3:35]CN(C(C)C)C(C)C.Cl.N1[C:49]2[NH:50][CH2:51][CH2:52][NH:53][C:48]=2[N:47]=[N:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([CH:9]([CH2:25][CH2:26][CH2:27][N:50]1[CH2:51][CH2:52][N:53]2[CH:35]=[N:46][N:47]=[C:48]2[CH2:49]1)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)C(CCC=O)COC(=O)Nc1cc2ccccc2cn1
Reactant: C1CNc2[nH]nnc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)C(CCCN1CCn2cnnc2C1)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.6 %

Procedure:
To a solution of isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-oxo-pentyl ester (75 mg crude mixture, 0.15 mmol) in anhydrous DCE (2 mL) and DIEA (56 uL, 0.32 mmol) was added the triazolopiperazine HCl salt (27 mg, 0.17 mmol) at RT. After 5 min of stirring at RT, sodium triacetoxyborohydride (98 mg, 0.45 mmol) was added in one portion. The slurry was stirred for 16 h at RT, the diluted in CH2Cl2 and washed with saturated aq. NaHCO3 and brine. After drying the solution over Na2SO4, the reaction mixture was concentrated and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-(5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-pentyl ester (30 mg, 30%) LRMS (M+H+) m/z 595.2.