Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([S:13]([OH:16])(=O)=[O:14])=[CH:10]2)=[CH:5][CH:4]=1.[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>P(Cl)(Cl)(Cl)=O.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([S:13]([Cl:19])(=[O:16])=[O:14])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(S(=O)(=O)O)cc2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Temperature: 60 °C

Procedure:
To a suspension of 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (15 g, 60.9 mmol) in H2O/ethanol (150 mL, 2:1) is added solid NaOH (2.68 g, 67 mmol) at room temperature. The mixture is stirred until a homogenous solution forms and dimethyl sulfate (6.34 mL, 67 mmol) is then added. A precipitate slowly forms and the mixture is stirred over a period of 16 hours. The crude mixture is concentrated in vacuo and the residue is stirred in absolute EtOH (100 mL) as a slurry for 2 hours. The precipitate is filtered and dried. The solid is heated at reflux in 95% EtOH (100 mL) for 2 h, allowed to cool to room temperature, filtered and dried to give 12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (12.6 g, 48.6 mmol) in phosphorous oxychloride (20 mL) and phosphorous pentachloride (13.2 g, 63.2 mmol) is heated slowly to 60° C. until a homogenous solution forms and then is heated at 120° C. for 4 hours. The resulting mixture is cooled in an ice bath and a mixture of ice/ice water is added slowly with stirring. The mixture is diluted with water and extracted with CHCl3 (2×100 mL). The combined organic layers are washed successively with water, saturated NaHCO3 solution and saturated NaCl. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give 10 g of a crude oil. The crude product is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a white crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)c(C)c(-c2ccccc2)n3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 119.5 %

Procedure:
To a solution of 1-benzyl-5-bromo-3-methyl-2-phenyl-1H-indole (1.907 g, 5.068 mmol) in dioxane (51 ml) was added aqueous 2M K2CO3 (5.1 ml) followed by 4-methoxyphenylboronic acid (0.924 g, 6.082 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.083 g, 0.101 mmol). The mixture was stirred at RT for 0.75 hours, then warmed to ˜90° C. After heating for 18 hours, the reaction mixture was cooled and concentrated. The residue was partitioned between EtOAc (120 ml) and 1N HCl (30 ml). The layers were shaken, separated, and the organic layer washed with 1N HCl (2×20 ml) and brine (2×20 ml), dried over Na2SO4, filtered, concentrated, and dried to give a black residue (2.444 g). The residue was purified by flash column chromatography (silica), eluting with hexane, 0.5% and 1% EOAc/hexane, to give the product (1.223 g, 3.031 mmol, 60%) as an off-white solid, mp 117-122° C. 1H NMR (DMSO-d6) δ 2.26 (s, 3H), 3.79 (s, 3H), 5.32 (s, 2H), 6.85 (d, J=7.3 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 7.15 (t, J=7.0 Hz, 1H), 7.20 (t, J=6.7 Hz, 2H), 7.35-7.44 (m, 5H), 7.49 (t, J=7.0 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.75 (s, 1H); [ESI(+)], m/z 404 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=CC=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3][CH2:6]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC1CCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCC1
Yield: 69.1 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclobutylamine (0.084 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 83.9 mg (0.30 mmol, 69.1% yield) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16](=O)[NH:17][N:18]=1>CN(C)C=O>[Cl:3][C:16]1[N:17]=[N:18][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[OH:6])=[CH:14][CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccccc2O)n[nH]1
Solvent: CN(C)C=O
Product: Oc1ccccc1-c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96 %

Procedure:
Dimethylformamide (85 ml.) was cooled to 5° and phosphorus oxychloride (115 ml.) was added slowly to maintain a solution temperature below 60°. 6-(2-Hydroxyphenyl)-3(2H)-pyridazinone (30 g., 0.16 m.) was added rapidly in several portions. The reaction mixture was heated to 85° and held at this temperature for 4.5 hours with stirring. The mixture was then cooled to 35° and poured into 1 liter of ice cold water keeping the quenched solution below 35°. The resulting precipitate was filtered off, washed with water and dried to give 30.8 g. (96% yield) of crude 3-chloro-6-(2-hydroxyphenyl)pyridazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH:19]1([C:22]#[CH:23])[CH2:21][CH2:20]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C(NC(C)C)(C)C.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.[Cu]I>[CH:19]1([C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCc1cccc(C#CC2CC2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a degassed solution of tert-butyl 3-(3-bromophenyl)propylcarbamate (57) (1.0 g, 3.1 mmol) and cyclopropyl acetylene (2.9 mL, 3.4 mmol, 70% soln in toluene) in diisopropylamine (4 mL) was added PdCl2(PPh3)2 (0.120 g, 0.17 mmol), tri-o-tolylphosphine (0.048 g, 0.16 mmol) and CuI (0.026 g, 0.16 mmol). The resulting mixture was degassed and stirred under nitrogen at 90° C. for overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography (10-40% ethyl acetate-hexane gradient) gave tert-butyl 3-(3-(cyclopropylethynyl)phenyl)propylcarbamate. Yield (0.756 g, 79%). This alkyne was used for deprotection without futher purification.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].B>O1CCCC1>[CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: B
Solvent: C1CCOC1
Product: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 90 %

Procedure:
For instance, as depicted in FIG. 4, a solution of 60 mg wortmannin (0.14 mmol from Aldrich) in 12 mL tetrahydrofuran (THF) is cooled in a 0° C. ice bath under nitrogen. 1M borane in THF solution (134 μL, 0.14 mmol from Aldrich) is added and the reaction mixture is stirred at 0° C. for 3.5 hours. The reaction is quenched with 1 mL water. After warming to room temperature, the reaction mixture is diluted with water and extracted with ethyl acetate. After work up, about 60 mg (90% pure 17-hydroxy-wortmannin by HPLC) solid is obtained. This solid (about 0.126 mmol 17-hydroxy-wortmannin) is dissolved in 15 mL methylene chloride, reacted with iodoacetic acid (24 mg, 0.13 mmol), dicyclohexylcarbodiimide (DCC) (27 mg, 0.13 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (0.1 mg as catalyst). The reaction mixture is kept at room temperature for 1 hour. After work up, about 75 mg crude product (yellow solid) is obtained. Pure 17-dihydro-17-(1-iodoacetyl)-wortmannin is isolated by preparative HPLC. A total of 54 mg of white solid is obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:16]1[C:17]2[CH:26]=[CH:25][N:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])[C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=1>CN(C=O)C.O>[C:28]1([CH3:35])[CH:29]=[C:30]([CH3:34])[CH:31]=[C:32]([CH3:33])[C:27]=1[N:24]1[C:18]2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=[C:16]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)[C:17]=2[CH:26]=[CH:25]1
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-n2ccc3c(OCc4ccc(C(F)(F)F)cc4)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of 4-(trifluoromethyl)benzyl alcohol (0.062 ml, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (45.3 mg, 0.15 mmol). The mixture was stirred at 60° C. for 1 hour, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 16 mg (24%) of the title compound as crystals.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16]([OH:18])=O)=[C:4]2[CH:3]=[CH:2]1.[N:19]([CH2:22][C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:24])=[N+:20]=[N-:21].CCN(C(C)C)C(C)C.O>CN(C=O)C>[N:19]([CH2:22][C@@H:23]([NH:24][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)=[O:18])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NC[C@@H](N)c1ccccc1
Reactant: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC[C@@H](NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)thiophene-2-carboxylic acid (130.00 mg; 0.50 mmol; 1.00 eq.), (1S)-2-azido-1-phenylethanamine (129.67 mg; 0.55 mmol; 1.10 eq.), n,n-diisopropylethylamine (0.33 ml; 2.01 mmol; 4.00 eq.) in DMF (2.00 ml), O-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluoro-phosphate (209.70 mg; 0.55 mmol; 1.10 eq.) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water. The solid was too tiny to be filtered. The aqueous mixture was extracted with ethyl acetate to afford the title compound in 79% yield. LCMS: m/e 404 (M+H). 1H NMR (DMSO-d6): ppm 11.56 (1H, br, s.), 10.25 (1H, s.), 8.72 (1H, d, J=8.44 Hz), 8.02 (1H, d, J=5.48 Hz), 7.85 (1H, d, J=5.52 Hz), 7.50 (1H, d, J=5.48 Hz), 7.42-7.44 (1H, m), 7.26-7.35 (4H, m), 6.81 (1H, d, J=5.16 Hz), 6.40 (1H, dd, J=3.28, 1.84 Hz), 5.27-5.32 (1H, m), 3.79 (1H, dd, J=12.84, 9.52 Hz), 3.60 (1H, dd, J=12.48, 4.76 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:59][C:57]1[S:56][C:46]2[C:47]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=2[N:58]=1)=[O:7]
Reactant: O=C(O)c1cccc(F)c1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3cccc(F)c3)nc12

Procedure:
From 3-fluorobenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: B.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=O)=[CH:3]1>O1CCCC1.CCOCC>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH:17]2[CH2:16][CH2:15][N:14]([CH2:12][CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:2][CH:3]=3)[CH2:19][CH2:18]2)=[CH:26][CH:25]=1
Reactant: O=C(C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1)c1c[nH]c2ccccc12
Agent: B
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1ccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
60 ml. of a 1M solution of boron trihydride in tetrahydrofuran are added dropwise to a stirred solution of 7.0 g of 1-(indol-3-ylglyoxyloyl)-4-(p-chlorophenoxy)piperidine in 135 ml. of tetrahydrofuran under nitrogen. The solution is stirred at ambient temperature for 18 hours and the tetrahydrofuran is removed under reduced pressure to give a white boron complex. The complex is destroyed by refluxing in 135 ml. of methanol with a few drops of glacial acetic acid. After cooling, the methanol is removed under reduced pressure to give a yellow oil. The oil is dissolved in ether, the ether is washed with water, dried and removed under reduced pressure to give a yellow oil. After standing under vacuum for a week, the oil crystallizes to a yellow solid. The solid is recrystallized from toluene and then from an ethanol and water mixture to give white crystals of 3-{2-[4-(p-chlorophenoxy)piperidyl]ethyl}indole, m.p. 132°-133° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[C:14]3[N:15]([C:23](=[O:26])[NH:24][N:25]=3)[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:18]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>O1CCOCC1>[C:19]([C:17]1[N:18]=[C:13]([NH:12][CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)[C:14]2[N:15]([C:23](=[O:26])[NH:24][N:25]=2)[CH:16]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)N1CCC(Nc2nc(C(C)(C)C)cn3c(=O)[nH]nc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1cn2c(=O)[nH]nc2c(NC2CCNCC2)n1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A solution of 45 mg of 4-(6-tert-butyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8-ylamino)-piperidine-1-carboxylic acid ethyl ester in dioxane (10 mL) was treated with 6N KOH (1.0 mL) and the mixture was heated to reflux. After eight h, the reaction mixture was concentrated and the residue was dissolved in 48% HBr and heated at 80° C. After 14 h, the reaction mixture was concentrated to afford the title compound as a tan solid. MS (M+H+)=290.3.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O.[Al].[Cl-].[Cl-].[Cl-].[Al+3]>C1C=CC=CC=1.CCOC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]([C:9]2[CH:10]=[CH:11][CH:15]=[CH:16][CH:17]=2)=[O:14])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(C(=O)O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1cccc(C(=O)c2ccccc2)c1
Temperature: 10 °C
Reaction time: 0.83 h

Procedure:
To the mixture of phosphorus pentachloride (3763 g, 18.1 mol) in 7500 mL of benzene, 3-methoxy benzoic acid (2500 g, 16.4 mol) was added in portions. The mixture was stirred for 50 minutes until it became homogenous. The formation of the acid chloride was controlled by TLC. After completion, the mixture was cooled down to 10° C., reactor was covered with aluminum foil and aluminium trichloride (4820 g, 36.1 mol) was added in portions (internal temperature was held up to 30° C. maximum). Stirring was continued for 18 hours at RT. The reaction was monitored by TLC (AcOEt:hex 1:9). After completion, the reaction mixture was poured into ice and was diluted with AcOEt (7 L). Then organic layer was separated and the aqueous layer was extracted with AcOEt (2×10 L, 1×6 L). Combined organic layers were washed with water (5×3 L) to pH-6-7, saturated aqueous sodium hydrogen carbonate solution (15 L), dried (sodium sulfate), filtered and the solvent evaporated at reduced pressure to give a crude oil. The product was purified by vacuum distillation (130-139° C., 2 mbar) to obtain title compound as a (2637 g 76%) of pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:44])([F:43])[CH2:38][C:39]([NH:41][NH2:42])=O>CC1C=CC(C)=CC=1>[C:29]1([C:19]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)=[N:28][C:22]3[O:23][CH2:24][C:25]4[N:26]([C:39]([CH2:38][C:37]([F:44])([F:43])[F:36])=[N:41][N:42]=4)[C:21]=3[CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NNC(=O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3CC(F)(F)F)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 12.8 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (250 mg, 0.513 mmol) and 3,3,3-trifluoropropanehydrazide (145 mg, 1.205 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (38 mg, 13%). LCMS (Method D): RT=1.499 min, M+1=578. 1H NMR (500 MHz, CDCl3): 7.84 (1H, s), 7.36-7.32 (5H, m), 7.31-7.28 (2H, m), 7.23-7.18 (2H, m), 5.60 (2H, s), 4.12 (2H, q), 2.52-2.42 (4H, m), 2.12-2.01 (1H, m), 1.87-1.78 (1H, m), 1.44-1.26 (9H, bs).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:23][CH2:24][C:25]#[N:26])[CH2:19][CH2:20][C:21]#[N:22])=[CH:13][CH:12]=1)[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:6][CH2:7][CH2:8][NH2:9])=[CH:16][CH:15]=1)[CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)Cc1ccc(CN(CCC#N)CCC#N)cc1
Solvent: C1COCCO1
Product: NCCCN(CCCN)Cc1ccc(CN(CCCN)CCCN)cc1
Yield: 96 %

Procedure:
6.97 g of 1,4-bis(N,N-bis(2-cyanoethyl)aminomethyl)benzene, 0.70 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 7.00 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:40]4[CH2:39][CH2:38][C:37]5[C:42](=[CH:43][CH:44]=[CH:45][C:36]=5[F:35])[CH2:41]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc2c1CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)cccc5C4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (170 mg, 0.358 mmol), 5-fluoro-1,2,3,4-tetrahydroisoquinoline (114 mg, 0.716 mmol), cupric acetate (65.7 mg, 0.358 mmol), pyridine (59 μL, 0.72 mmol), 4 Å molecular sieves (95 mg, 264 mg/mmol SM), and DCM (9 mL, 100 mmol) was stirred at rt under an atmosphere of air for 5 d. The mixture was diluted with DCM (50 ml), washed with EDTA solution (2%, 3×50 ml), water (3×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark black oil that was purified by MDPS to give the title compound as a brown oil. 1H NMR (400 MHz, CDCl3): δ=1.48 (s, 9H), 1.87-1.99 (m, 2H), 2.12-2.19 (m, 2H), 2.84-2.98 (m, 2H), 3.00 (t, J=5.6 Hz, 2H), 3.34 (t, J=6.0 Hz, 2H), 4.17 (s, 2H), 4.22-4.36 (m, 3H), 6.90 (d, J=7.2 Hz, 1H), 6.98 (t, J=8.4 Hz, 1H), 7.18-7.24 (m, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.65 (s, 1H), 7.67 (d, J=1.6 Hz, 1H). MS(ES+): m/z=494.38 (100) [MH+]. HPLC: tR=2.84 min (ZQ2, polar—5 min).