Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][S:40]([CH2:43][CH3:44])(=[O:42])=[O:41].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][N:39]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[F:32])[S:40]([CH2:43][CH3:44])(=[O:41])=[O:42])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Reactant: CCS(=O)(=O)Nc1ccccc1F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CN(c2ccccc2F)S(=O)(=O)CC)C2CC2)C1=O
Temperature: 70 °C

Procedure:
To a mixture of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A, 70 mg, 0.153 mmol) and N-(2-fluorophenyl)ethanesulfonamide (93 mg, 0.458 mmol) in toluene (1 ml) was added cyanomethylenetri-n-butylphosphorane (0.111 ml, 0.458 mmol) at rt and the mixture was flushed with N2 for about 20 minutes. The reaction was sealed and heated to 70° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (eluent: 0% to 35% EtOAc/hexanes) to provide the title compound as a solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:21]1([C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[N:21]1([C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[NH:29][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccccc1N1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isonicotinoyl chloride hydrochloride (616 mg, 3.46 mmol, commercially available product) and triethylamine (800 μl, 5.73 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-(1-piperidinyl)aniline (203 mg, 1.15 mmol), obtained as described in Referential Example 18-2. The resulting mixture was warmed to room temperature and stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=1/1). Thus, N-[2-(1-piperidinyl)phenyl]isonicotinamide (GIF-0349) (259 mg, 80.0%) was yielded as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl.O>[CH2:32]([O:31][C:29]([NH:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:30])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(N)cccc3c2C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 605.1 %

Procedure:
To a solution of tert-butyl 6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (7 g, 24.3 mmol) in CH2Cl2 (40 mL) at rt was added saturated K2CO3 (30 mL), ethyl chloroformate (2.4 mL, 4.0 mmol) and stirred at 25° C. for 0.5 hour. The solution was diluted with water (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, and concentrated to afford tert-butyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (8.7 g, 100%) as an crude oil. MS [M+H]+360.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7](O)[CH2:6][CH2:5]2.C1C=CC(OP(OC2C=CC=CC=2)([N:21]=[N+:22]=[N-:23])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CCOC(C)=O>[N:21]([C@H:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[N+:22]=[N-:23]
Reactant: O[C@H]1CCc2cc(Br)ccc21
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CCc2cc(Br)ccc21
Temperature: 15 °C
Yield: 83.5 %

Procedure:
A solution of (S)-5-bromo-indan-1-ol (15.0 g, 70.4 mmol) in toluene (150 mL) was cooled in an ice bath under N2 and was treated with diphenylphosphoric azide (DPPA, 22.0 g, 91.5 mmol) in one portion followed by 1,8-diazabicyclo[5,4,0]undec-7-ene (15.0 g, 98.6 mmol). The reaction temperature was kept between 3 and 10° C. during 3 hours of addition and the mixture was warmed to 15° C. over the next hour (TLC indicated no starting material). The mixture was diluted with EtOAc (300 mL) and was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to give a dark oil. The crude product was purified by silica gel column (packed with 1% Et3N in hexanes, hexane eluant) to give (R)-1-azido-5-bromo-indane (14 g, 83%) as an oil which was used directly in the next step.
Reaction SMILES: CO.C([CH:10]([OH:34])[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])C1C=CC=CC=1.CCCCCC>[Pd].CC(OC)(C)C>[CH2:32]([OH:33])[CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:34]
Reactant: OCCOCCOCCOCCOCCOCCOCCOCC(O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: OCCOCCOCCOCCOCCOCCOCCOCCO
Reaction time: 17 h
Yield: 51 %

Procedure:
10% Pd/C (11.2 g) was added to MeOH (50 mL) at −15° C. in hydrogenation bottle under agron. BnO-dPEG8-OH (69.0 g, 0.15 mole) was added to the bottle along with MeOH (150 mL). The bottle was placed on the Parr shaker for 17 h at 50 psi of H2. The reaction was monitored by tlc on silica gel plates, eluting with 10% MeOH/CH2Cl2. The reaction is about 50% complete. The reaction was worked up. The reaction mixture was filter through glass fiber, used MeOH as needed to make a clean transfer. The filtrate was concentrated in vacuo to give an oil. A column was prepared with 600 g of silica gel and hexane. The crude product was placed onto column with hexane and minimum of TBME (100 mL). The column was eluted as follows: (2 L) 20% TBME/hexane; (2 L) 50% TBME/hexane; (4 L) TBME; (2 L) 5% MeOH/TBME; (2 L) 10% MeOH/TBME. Like fractions containing product were combined and concentrated in vacuo to give 28.5 g (51% yield). The product was characterized by nmr.
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C[O:24][C:25]([C@@H:27]1[CH2:29][C@H:28]1[CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[C:41]3[S:42][CH:43]=[CH:44][C:40]=3[O:39][N:38]=2)[CH2:33][CH2:32]1)=O.CN1CCOCC1.[CH2:52]([C@H:54]1[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]1)[CH3:53]>CN(C)C=O>[CH2:52]([C@H:54]1[CH2:59][CH2:58][C@H:57]([NH:60][C:25]([C@@H:27]2[CH2:29][C@H:28]2[CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[C:41]4[S:42][CH:43]=[CH:44][C:40]=4[O:39][N:38]=3)[CH2:33][CH2:32]2)=[O:24])[CH2:56][CH2:55]1)[CH3:53]
Reactant: COC(=O)[C@@H]1C[C@H]1CN1CCC(c2noc3ccsc23)CC1
Reactant: CC[C@H]1CC[C@H](N)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCC(c3noc4ccsc34)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add TOTU (415 mg, 1.06 mmol) to a solution of trans-2-(4-thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-cyclopropanecarboxylic acid methyl ester (Example 22b) (300 mg, 1.0 mmol), in dimethylformamide (approximately 10 mL), and allow the reaction to stir at ambient temperature for 0.5 h. Add N-methylmorpholine (107 mg, 1.26 mmol) and trans-4-ethylcyclohexylamine (254 mg, 2.0 mmol), and stir for 6 h. Add additional equivalents of N-methylmorpholine and TOTU and continue to stir for overnight. I think again I didn't write it down Concentrate the reaction and purify the residue by column chromatography over silica gel (dichloromethane/MeOH, gradient 0→30%) to obtain 270 mg (65%), LC/MS, m/z=416 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[F:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[F:8][C@@H:9]1[C@@H:14]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H](F)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Triethylamine (0.95 mL, 6.8 mmol) was added to a 0° C. solution of (3S,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (500.0 mg, 2.28 mmol) and methanesulfonyl chloride (0.27 mL, 3.4 mmol) in dichloromethane (9 mL), and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL). Additional dichloromethane (10 mL) was added, and the layers were separated. The organic layer was washed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified directly via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford tert-butyl (3S,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (629 mg, 93%) as a colorless oil that solidified to a white solid upon standing. 1H NMR (300 MHz, CDCl3) δ ppm 1.46 (s, 9H), 1.73-1.87 (m, 1H), 2.15-2.25 (m, 1H), 2.97-3.12 (m, 2H), 3.08 (s, 3H), 3.85-3.95 (m, 1H), 4.39-4.46 (m, 1H), 4.55-4.62 (m, 1H), 4.65-4.78 (m, 1H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][N:27]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[N:26]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[N:29]=[CH:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[N:26]=4)=[CH:23][CH:24]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(CC(=O)OC(C)(C)C)n4)cc3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(CC(=O)O)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(3-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)acetate (66 mg, 0.13 mmol) in DCM (1 mL) was added dropwise TFA (1 mL) at 0° C. under N2. The reaction mixture was stirred at ambient temperature overnight. The solvents were evaporated in vacuo. The residue was dissolved in saturated aqueous NaHCO3 solution and washed with Ether. The aqueous layer was acidified by slow addition of 1N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to give (S)-2-(3-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)acetic acid (48 mg, 82%). LCMS (APCI+) m/z 448.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(OCC)(=O)C>C(Cl)Cl>[Cl:32][C:6]1[CH:5]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:41])=[CH:37][CH:38]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:24])[CH3:23])[CH:28]([CH3:29])[CH3:30])[CH2:18][CH2:19]2)[C:10]1=[O:31]
Reactant: C1COCCN1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCOCC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.2 g, 0.32 mmol) in CH2Cl2 (15 mL) with 1,1′-carbonyldiimidazole (0.10 g, 0.65 mmol) and stir for 1 hour at room temperature. Treat the reaction with morpholine (0.06 g, 0.65 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column and flash with 25% to 35% ethyl acetate in hexanes to afford 0.20 g (90%) of the title compound. MS (m/z): 688 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[CH2:28][CH2:29][O:30][CH2:31][CH:32]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:27]3[CH2:32][CH2:31][O:30][CH2:29][CH:28]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example 35(d)) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 314.0 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:29][CH2:30][CH2:31]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:29][CH2:30][CH2:31][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCF
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCF)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (1.45 g, 11.9 mmol), triphenylphosphine (6.87 g, 26.2 mmol) and 2-fluoroethanol (1.68 g, 26.2 mmol) in dry THF (70 ml) at 0° C., was added DIAD (5.29 g, 26.2 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h then allowed to rise to room temperature and stirred for 48 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (5:1 DCM/Hexane) to give the title compound (0.807 g, 40%) as a colourless solid.
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]([N:21]1[CH2:25][CH2:24][CH:23](Cl)[CH2:22]1)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[C:12]1([C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH:23]2[CH2:24][CH2:25][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22]2)[C:10]#[N:11])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)N1CCC(Cl)C1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h

Procedure:
In a 2 liter, three neck, round-bottom flask fitted with pot thermometer, reflux condensor, electric stirrer and dropping funnel was placed 47.5 g. (1.22 mole) of sodium amide followed by 300 ml. of dry toluene. To this was added dropwise at 50° C. 214 g. (1.11 mole) of diphenylacetonitrile in 800 ml. of dry toluene. When addition was complete, the temperature was raised slowly to reflux and maintained for 4 hours. To the refluxing mixture was added at a rapid dropwise rate 164.9 g. (1.11 mole) of 1-isopropyl-3-chloropyrrolidine. The refluxing and stirring was continued for 3 hours, and the mixture was allowed to stand overnight. The toluene solution was washed with 1 liter of water and extracted with about 2 liters of 1 N hydrochloric acid. The aqueous layer was made basic with dilute sodium hydroxide and extracted with several portions of ether. The ethereal solution was dried over sodium sulfate, concentrated, and the residue distilled through an eight inch beaded column. Yield, 216 g. (64%); b.p. 175°-177° C./0.25 mm. The product crystallized on standing and was recrystallized from iso-octane. m.p. 73°-74° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3ccsc3)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-thiophen-3-yl-7-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27]1(=O)[O:32][C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C(O)CO.C(Cl)Cl>O>[OH:32][C:27]1[C:28]2[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[N:1]([C:3]2[CH:8]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=3[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(NN)c3)c2cc1OC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: OCCO
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4nc(O)c5ccccc5c4=O)c3)c2cc1OC
Temperature: 130 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A mixture of 1-(2-hydrazino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (2.0 g), phthalic anhydride (0.92 g) and ethylene glycol (10 ml) is heated with stirring at 130° C. for two hours. The mixture is cooled to room temperature, and thereto are added methylene chloride and water. The methylene chloride layer is separated, washed, dried, concentrated under reduced pressure to remove the solvent, and the residue is crystallized from ethanol to give 1-[2-{4-(hydroxy)-1(2H)-phthalazinon-2-yl}-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (1.68 g, yield; 61%), which is listed in Table 10.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([O:10]C)[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=2)=[CH:6][N:5]=1)[CH3:2].Br.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH2:1]([NH:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A mixture of N-ethyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.29 g, 0.7 mmol) and 48% aq. HBr (0.32 mL, 2.78 mmol) in acetic acid (5 mL) was heated at 90° C. for 6 h. The mixture was cooled to RT, diluted with water (60 mL), made basic with solid NaHCO3, extracted with 1:1 EtOAc/THF (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was stirred with MeCN for 1 h and the resulting solid was collected via filtration to afford 2-(ethylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one as white solid (210 mg, 75%). 1H NMR (400 MHz, DMSO-d6): δ 11.20 (br s, 1H), 8.67 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.24-8.26 (m, 2H), 7.96 (s, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.88 (br s, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.34-3.32 (m, 2H), 2.34 (s, 3H), 1.12 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>>[N:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:10]=1[CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: ClCc1nc2ccccc2[nH]1
Product: O=C1CCN(Cc2nc3ccccc3[nH]2)CC1

Procedure:
1-(2-Benzimidazolyl)methyl4-piperidone is prepared from 4-piperidone and 2-(chloromethyl)benzimidazole essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:12](O)(=[O:16])[C@@H:13]([CH3:15])[OH:14].CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][O:11][C:12](=[O:16])[C@H:13]([OH:14])[CH3:15])[NH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: NC(=NO)c1cccc(Cl)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)ON=C(N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.82 g (22.4 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide and 2.00 g (22.2 mmol) of (R)-lactic acid were dissolved under Ar at 0° C. in DCM (50 mL) and DMF (15 mL). After 5 min 3.4 mL (33.2 mmol) DIC and 3.50 g (25.9 mmol) HOBt were added. After 15 min the mixture was warmed to r.t. and stirred for additional 3 h, followed by filtration and washing with DCM. The filtrate was evaporated in vacuo to near dryness, taken up in EA and washed with aq. NaHCO3, followed by water and finally 2 M aq. citric acid. The EA layer was filtered over a mixture of Na2SO4 and silica. Flash chromatography (Hep/EA=4/1 to 2/1 to 1/2) gave an oil which was triturated with Et2O to yield after drying 4 g (75%) of the title compound. 1H NMR: 7.69 (t, 1 H), 7.55-7.59 (m, 1 H), 7.44-7.49 (m, 1 H), 7.36 (t, 1 H), 5.10 (s, 2 H), 4.50 (q, 1 H), 1.54 (d, 3 H)