Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:22]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:23]([CH2:25][CH2:26][C:27]([NH:29][CH2:30][CH2:31][NH:32][C:33](=[S:50])[NH:34][CH2:35][CH2:36][NH:37][C:38](=[S:49])[NH:39][CH2:40][CH2:41][NH:42][C:43](=[S:48])[NH:44][CH2:45][CH2:46][NH2:47])=[O:28])=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:65][N:66]=[C:67]=[S:68]>C(Cl)Cl>[CH2:51]([N:22]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:23]([CH2:25][CH2:26][C:27]([NH:29][CH2:30][CH2:31][NH:32][C:33](=[S:50])[NH:34][CH2:35][CH2:36][NH:37][C:38](=[S:49])[NH:39][CH2:40][CH2:41][NH:42][C:43](=[S:48])[NH:44][CH2:45][CH2:46][NH:47][C:67](=[S:68])[NH:66][CH3:65])=[O:28])=[O:24])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]
Reactant: CN=C=S
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCC(=O)NCCNC(=S)NCCNC(=S)NCCNC(=S)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCC(=O)NCCNC(=S)NCCNC(=S)NCCNC(=S)NCCNC(=S)NC
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Triethylamine (1.38 mmol, 0.19 ml) was directly added to the amine (14) (0.23 mmol, 0.224 g) obtained in the preceding stage and the reaction mixture was kept under stirring for 15 minutes. Then, CH2Cl2 (2.3 ml) and methylisothiocyanate (0.46 mmol, 0.034 g) were added and the reaction mixture was left at room temperature under stirring for 12 hours. The mixture was then evaporated and purified by flash chromatography (100% ethyl acetate followed by ethyl acetate/methanol 95:5). 109 mg of DT-4TU were thus obtained (yield: 51%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:12]([N:11]1[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=[C:6]1[C@H:2]([NH:1][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([CH3:29])=[CH:31][CH:32]=1)[CH:3]([CH3:4])[CH3:5])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1nc([C@H](N)C(C)C)n(Cc2ccccc2)c(=O)c1C
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.9 %

Procedure:
To 2-((R)-1-amino-2-methyl-propyl)-3-benzyl-5,6-dimethyl-3H-pyrimidin-4-one (50 mg, 0.175 mMol) and triethylamine (49 μL, 0.350 mMol) in CH2Cl2 was add 4-methyl-benzoyl chloride (21 μL, 0.157 mMol) was added. The reaction was stirred at RT for 48 h, quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and evaprated to give the title compound (50 mg, 72%) as colorless oil. MS (ES) m/e 404.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1.O=S(Cl)[Cl:23]>C(Cl)Cl>[Cl:23][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CO
Solvent: ClCCl
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl

Procedure:
0.300 g (1.059 mmol) of the above prepared [2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol was dissolved in 5.3 ml of CH2Cl2 and treated dropwise at 0° C. with 0.15 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate and evaporation of the solvents generated 0.315 g of pure title compound as light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1.C(=O)([O-])[O-]>CCOCC>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:13][C:10]2[CH:11]=[CH:12][C:3]3[N:2]([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:9]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCCCc2cc(N)ccc21
Agent: O=C([O-])[O-]
Solvent: CCOCC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCCN3C)ncc1Cl
Reaction time: 0.5 h

Procedure:
Following the procedure of Example 101b, 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (33 mgs, 0.19 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (1.2 eq) were reacted except that following completion of the reaction a precipitate ensued. This mixture was diluted with ether and filtered. The resulting solid was treated with MP-carbonate (3 eq), stirred for 30 min, filtered and concentrated to give 2-[5-Chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a off-white/yellow solid (39.01 mgs). MP=170-172° C. 1H-NMR (CDCl3) δ 11.06 (s, 1H), 8.70 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.30-7.27 (m, 2H), 7.07 (t, J=7.6 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.81 (s, 2H), 6.20 (br s, 1H), 3.05 (d, J=4.8 Hz, 3H), 2.83 (s, 5H), 2.77-2.73 (m, 2H), 1.84-1.75 (m, 2H), 1.64-1.55 (m, 2H); LC/MS (ESI+): 437.30 (M+H).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[CH2:12]([N:19]=[N+:20]=[N-:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:1].[CH2:12]([N:19]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 45.8 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.073 g, 0.423 mmol) was reacted with benzyl azide (0.068 g, 0.509 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.059 g, 46%) as a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.83 (d, 1H), δ 7.37-7.24 (m, 5H), δ 6.44 (d, 1H), δ 5.54 (d, 2H), δ 2.96 (m, 2H), δ 2.83 (m, 2H) ppm; 13C (75 MHz, CD3OD) δ 163.7, 147.3, 146.4, 135.7, 128.8, 128.4, 127.9, 127.8, 126.5, 122.6, 109.1, 53.7, 24.1, 23.9 ppm; HRMS (ESI) calcd for C14H16N6 (M+) 269.1515. found 269.1513.
Reaction SMILES: Cl.[CH3:2][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][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH3:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]cc(CCNC(=O)c3ccc(Cc4cccc(F)c4)cc3)c2c1
Yield: 41.9 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(5-methyl-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with 2-(5-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.060 g; 0.284 mmol), 4-(3-fluorobenzyl)benzoic acid (0.079 g; 0.341 mmol), HATU (0.141 g; 0.370 mmol) and N,N-diisopropylethylamine 0.123 mL; 0.711 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.046 g (42%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[O:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 31.6 %

Procedure:
Step 1 A solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.00 g, 6.32 mmol), phenol (0.714 g, 7.59 mmol) and triphenylphosphine (1.824 g, 6.95 mmol) in DCM (21.07 mL) was treated with diisopropyl azodicarboxylate (1.48 mL, 7.59 mmol) and the mixture was stirred at rt for 5 days. The mixture was concentrated and the residue was purified by column chromatography, eluting with a gradient from hexane to 80:20 hexane-EtOAc). The crude product was dissolved in EtOAc and the solution was washed twice with 1 M aqueous sodium hydroxide and brine, dried and concentrated to provide 8-phenoxy-1,4-dioxaspiro[4.5]decane as a colorless liquid (0.468 g, 32%). 1H NMR (500 MHz, chloroform-d) δ 7.16-7.24 (2H, m), 6.81-6.89 (3H, m), 4.30-4.38 (1H, m), 3.85-3.93 (4H, m), 1.80-1.90 (6H, m), 1.50-1.59 (2H, m).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C:7]1[N+:8]([O-])=[C:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
POCl3 (2.23 mL, 24.3 mmol) was added dropwise to a stirred solution of N-oxide 1 (5.0 g, 20.2 mmol) in dry DCM (100 mL) and the mixture stirred at 40° C. for 16 h. The solution was poured into a slurry of ice/1 M NaOH solution (100 mL) and the mixture stirred for 10 min. The mixture was extracted with DCM (3×50 mL), the combined organic extract dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 20% EtOAc/pet. ether, to give benzoate 2 (4.12 g, 77%) as a white powder: mp (EtOAc) 127-128° C.; 1H NMR (CDCl3) δ 8.06-8.12 (m, 4 H, H-2, H-3, H-5, H-6), 4.56 (s, 2 H, CH2Cl), 3.94 (s, 3 H, OCH3), 2.45 (s, 3 H, CH3); MS m/z 266.6 (MH+, 100%). Anal. calcd for C13H12C1NO3: C, 58.77; H, 4.55; N, 5.27. Found: C, 58.82; H, 4.43; N, 5.18%.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[CH:22][CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-n2cncn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,4-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36]1[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=1>CS(C)=O.C(OCC)(=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36]1[CH2:37][CH2:38][N:39]([CH2:12][CH:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)[CH2:40][CH:41]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]ccc4c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6[nH]ccc6c5O4)CC3)c2c1

Procedure:
A solution of 0.30 g (0.84 mmole) of (2R)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl 4-methylbenzenesulfonate and 0.40 g (1.8 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 30 mL of DMSO was heated at 65° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-1.5% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.10 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 112° C., with one-quarter mole of ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[H-].[Na+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:20][CH:19]([N:10]1[C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[CH:8]=[CH:9]1)[CH3:21]
Reactant: COC(=O)c1ccc(OC)c2[nH]ccc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a cooled (ice/water bath) solution of methyl 7-(methyloxy)-1H-indole-4-carboxylate (350 mg, 1.706 mmol) in DMF (20 mL) was added sodium hydride (56.0 mg, 2.217 mmol). After 10 minutes added 2-iodopropane (0.188 mL, 1.876 mmol). The reaction was stirred at RT for 1 h, followed by heating at 50° C. for 2 h. The reaction was then cooled in an ice water bath and more sodium hydride (56.0 mg, 2.217 mmol) and 2-iodopropane (0.188 mL, 1.876 mmol) were added. The reaction was heated at 50° C. for 3 h, at which time it was concentrated. The residue was dissolved in DCM and washed with water and brine, dried over MgSO4, filtered and concentrated to give 400 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (d, 6H), 3.95 (s, 3H), 4.01 (s, 3H), 5.46 (dt, J=13.39, 6.69 Hz, 1H), 6.66 (d, J=8.34 Hz, 1H), 7.15 (d, J=3.03 Hz, 1H), 7.34 (d, J=3.28 Hz, 1H), 7.87 (d, J=8.34 Hz, 1H). MS(ES) [M+H]+ 248.2.
Reaction SMILES: [C-]#N.[Na+].BrC[C:6]1[CH:21]=[CH:20][C:9]2[C:10](=[O:19])[C:11]3[CH:18]=[CH:17]C=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1.[CH3:22][C:23]([CH3:27])(O)[C:24]#[N:25]>CCOCC>[CH:15]1[C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[CH:6][CH:21]=[CH:20][C:9]=3[C:10](=[O:19])[C:11]=2[CH:18]=[CH:17][C:22]=1[CH:23]([CH3:27])[C:24]#[N:25]
Reactant: CC(C)(O)C#N
Reactant: O=c1c2ccccc2ccc2cc(CBr)ccc12
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Product: CC(C#N)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
12.0 Gm. of sodium cyanide and 6.0 gm. of 2-bromomethyl-5H-dibenzo[a,d]cyclohepten-5-one are stirred at 100° C. for 40 minutes in 150 ml. of acetone cyanohydrin. The mixture is cooled and poured into ether. The ethereal layer is washed with water, dried and evaporated. The residue is chromatographed on 350 gm. of silica gel, eluting with hexane/ethyl acetate (3:2) to obtain 8.8 gm., 78%, of 5H-dibenzo[a,d]cyclohepten-5-on-2-yl acetonitrile which is recrystallized from ethyl acetate/hexane, m.p. 119°-121°- C. Use of 2-(α-bromoethyl)-5H-dibenzo[a,d]cyclohepten-5-one gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionitrile, m.p. 108°-109° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH:5]=[N:4][CH:3]=1.B([C:27]1[CH:38]=[CH:37][C:30]([CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=[CH:29][CH:28]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:33][CH:32]([CH2:31][C:30]1[CH:37]=[CH:38][C:27]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)[N:7]=2)=[CH:28][CH:29]=1)[C:34]([OH:36])=[O:35]
Reactant: COc1ccc(CNc2cncc(Cl)n2)cc1OC1CCCC1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CNc2cncc(-c3ccc(CC(N)C(=O)O)cc3)n2)cc1OC1CCCC1
Temperature: 150 °C
Yield: 7.9 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50 mg, 0.15 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to the solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 5.5 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}-propionic acid, yield 6%. 1H-NMR (400 MHz, DMSO-d6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08(m, 2H), 3.65(s, 3H), 4.0(m, 1H), 4.45(d, 2H), 4.65(m, 1H), 6.90(s, 2H), 6.95(s, 1H), 7.32(d, 2H), 7.60(t, 1H), 7.90(s, 1H), 7.95(d, 2H), 8.25(s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:27]1([C:33]2[CH:37]=[C:36]([CH2:38][NH2:39])[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)CCC>[Cl:17][C:4]1[N:3]=[C:2]([NH:39][CH2:38][C:36]2[O:35][N:34]=[C:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:37]=2)[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=1
Reactant: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Reactant: NCc1cc(-c2ccccc2)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2cc(-c3ccccc3)no2)n1
Temperature: 90 °C
Reaction time: 30 h
Yield: 60.9 %

Procedure:
To a solution of 2,6-dichloropyrimidin-4-yl-(5-cyclopropyl-1H-pyrazol-3-yl)-amine (19.3 g, 71.7 mmol) in 1-butanol (200 mL) was added diisopropylethylamine (23.7 mL, 143 mmol) and 3-phenylisoxazol-5-ylmethylamine (15.0 g, 86.1 mmol). The mixture was stirred at 90° C. for 30 h, then concentrated on a rotary evaporator. The residue was taken up in 100 mL of methanol and boiled until the volume reached around 50 mL. The solution was allowed to cool to room temperature and then placed in the refrigerator overnight. The solid that formed was collected by filtration, while the filtrate was dissolved in dichloromethane and sonicated. The solid that formed was collected and combined with the first recrystallized crop to give the desired product (17.8 g, 61%) as a white solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([CH3:24])[C:11]=2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])[C:6](=[O:8])[CH:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C.C(OCC)(=O)C.Cl>[CH3:24][C:10]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])=[C:4]2[N:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=1
Reactant: C1COCCN1
Reactant: Cc1nn2c(=O)cc(Cl)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nn2c(O)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C

Procedure:
To a solution of 5-chloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-7(4H)-one (55 mg, 0.155 mmol) in ethanol (1.5 mL) was added morpholine (40.4 mg, 0.464 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 145° C. for 3 hour. The reaction mixture was then diluted with ethyl acetate (15 mL) and 5% HCl solution (3 mL). Two layers were separated. Organic layer was dried, concentrated and purified with silica gel column (methanol/DCM, 0-10%). The titled compound was obtained. (37 mg, 59%); LC/MS: MS (ES+) m/e 407 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 3H) 2.45 (s, 3H) 3.31 (d, J=4.80 Hz, 3H) 3.29 (br. s., 1H) 3.69 (br. s., 1H) 3.67 (d, J=5.05 Hz, 3H) 3.96 (s, 2H) 5.07 (s, 1H) 7.15 (br. s., 1H) 7.25-7.32 (m, 1H) 7.54 (d, J=7.83 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([N:14]=[C:24]=[O:26])=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)COC(=O)c1ccc(N=C=O)cc1
Temperature: 75 °C

Procedure:
To a mixture of 4-amino-benzoic acid methoxycarbonylmethyl ester 6 (10 grams, 47.84 mmol) and triethylamine (9.68 grams, 95.67 mmol) in toluene (150 mL) under nitrogen atmosphere at 0° C. is added triphosgene (5.195 grams, 17.50 mmol) in one lot. Later the reaction mixture is heated to 75° C. over a period of one hour and maintained at this temperature for 20 hours. The reaction mixture is cooled to room temperature. The solids are filtered off, and the toluene is distilled under vacuum to give crude 11, which can be purified by a suitable method.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].C(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>O>[Cl:13][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: ClC(Cl)Cl
Reactant: [O-][n+]1ccc2ccccc2c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ccccc12
Reaction time: 3 h
Yield: 44.9 %

Procedure:
69.3 g (448 mmol) of isoquinoline N-oxide (made by Tokyo Kasei) and 225 ml of chloroform were placed and dissolved in a 1 liter-three-necked flask, and under stirring and cooling with ice, 219.6 g (1432 mmol) of phosphorus oxychloride was gradually added dropwise thereto while the internal temperature was held at 15-20° C. Thereafter, the temperature was raised, and reflux under stirring was performed for 3 hours. The reaction product was cooled by standing to room temperature and poured into iced water. After extraction with ethyl acetate, the organic layer washed with water until neutrality, and the solvent was removed under a reduced pressure to provide a dry solid, which was then purified by silica gel column chromatography (eluent: chloroform/hexane=5/1) to obtain 35-5 g (yield: 44.9%) of 1-chloroisoquinoline white crystal.
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:4]=[CH:5][C:6](N)=[N:7][C:8]=1[CH3:9].N([O-])=O.[Na+]>O>[Cl:1][C:6]1[N:7]=[C:8]([CH3:9])[C:3]([I:2])=[CH:4][CH:5]=1
Reactant: Cl
Reactant: Cc1nc(N)ccc1I
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a stirred solution of concentrated hydrochloride acid (233 mL) at 0° C. was added 5-iodo-6-methyl-pyridin-2-ylamine (25 g, 107 mmol, 1 eq) followed by addition of pre-dissolved sodium nitrite (29.5 g, 427 mmol, 4 eq) in water (150 mL) in drop wise manner over period of 30 minutes. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was cooled to 0° C., and pH was adjusted to 12 by saturated aqueous sodium hydroxide solution, extracted with DCM (3×200 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown oil (20 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 4% ethyl acetate in hexane to get title compound as brown oil (8 g, 30%). 1H NMR (400 MHz, CDCl3) δ: 2.69 (s, 3H), 6.88 (d, J=8.04 Hz, 1H), 7.95 (d, J=8.24 Hz, 1H). LC-MS (m/z): 254.0 (M+H).