Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:16])[CH:8]=2)[N:3]=1.[C:17]([C@@H:21]1[CH2:26][CH2:25][C@H:24](O)[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18].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>C1(C)C=CC=CC=1.C1COCC1>[C:17]([C@H:21]1[CH2:26][CH2:25][C@H:24]([O:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[C:12]([F:13])([F:15])[F:14])[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cc(C(F)(F)F)c2cc(O)ccc2n1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(F)(F)F)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Methyl-4-trifluoromethyl-quinolin-6-ol (0.771 g, 0.00339 mol, cis-4-tert-Butyl-cyclohexanol (0.8570 g, 0.005484 mol) and Triphenylphosphine (1.423 g, 0.005425 mol) were placed in a flask, and dissolved in Toluene (25 mL). For the Mitsunobu reaction of certain analogs, THF was substituted for toluene as solvent. Diisopropyl azodicarboxylate (1.137 mL, 0.005430 mol) was then added dropwise. After 3 d stirring at RT, the reaction was evaporated to dryness. The residue was purified by silica gel chromatography using 0-30% ethyl acetate in hexanes as eluent (Rf=0.38 in 3:1 hexanes/ethyl acetate). Isolated was 0.739 g of product (60%). ESI-MS (M+H+): 366.20.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1)[CH:8]=[C:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[Cl-:22].[CH3:23][N+:24](=[CH2:26])[CH3:25]>C(#N)C>[ClH:22].[C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1)[CH:8]=[C:9]1[CH2:13][CH2:12][CH:11]([CH2:23][N:24]([CH3:26])[CH3:25])[C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=[N+](C)C
Reactant: [Cl-]
Reactant: CC(C)(C)c1cc(C=C2CCCC2=O)cc(C(C)(C)C)c1
Solvent: CC#N
Product: CN(C)CC1CCC(=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1=O
Product: Cl
Yield: 87.3 %

Procedure:
0.03 mol of 2-(3,5-di(t-butyl)-benzylidene)cyclopentanone was dissolved in 30 mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product which was then suction filtered, dried and recrystallized in acetonitrile/chloroform to yield 2-(3,5-di(t-butyl)-benzylidene)-5-dimethylaminomethyl-cyclopentanone hydrochloride with a yield of 87.3%.
Reaction SMILES: [N+]([O-])([O-])=O.[K+].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8].[C:12]([OH:15])(=[O:14])C>[Mo]>[C:12]([OH:15])(=[O:14])/[CH:8]=[CH:7]\[C:6]([OH:11])=[O:10].[C:6]([OH:11])(=[O:10])/[C:7](=[CH:9]\[C:12]([OH:15])=[O:14])/[CH3:8]
Reactant: CC(=O)O
Reactant: C=C(C)C(=O)O
Agent: [Mo]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: C/C(=C/C(=O)O)C(=O)O
Product: O=C(O)/C=C\C(=O)O

Procedure:
A catalyst is prepared using the general method of preparation described in Example 3, but without the addition of potassium nitrate and with a larger amount of molybdenum. The resulting catalyst corresponds to the formula W6Mo6.4 P1As0.2 Cu0.25 Ox. Under the test conditions of Example 3 and at a bath temperature of 306° C., the conversion is 67.2 mole %, and the selectivities with respect to methacrylic acid and acetic acid are 81.7 mole % and 5.1 mole % respectively. Maleic acid and citraconic acid are formed in a total amount of 1.8%.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10].[Cl-].[NH4+]>O1CCCC1.CCOCC>[Cl:5][C:6]1[CH:7]=[C:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)([OH:10])[CH2:2][CH3:3])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1cccc(Cl)c1
Reactant: CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
To a Grignard reactant prepared from 7.2 g. of magnesium turnings and 32.6 g. of ethyl bromide in 120 ml. of dry ether a solution of 24 g. of 3-chloro-4'-benzyloxy-benzophenone in 120 ml. of tetrahydrofurane is added dropwise, with stirring at 0° to 5° C. The reaction mixture is then slightly boiled for 30 minutes, and the Grignard complex is decomposed with a saturated aqueous solution of ammonium chloride under cooling. The aqueous phase is extracted with ether, the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. Crystallization of the residue from a mixture of ethyl acetate and n-hexane yields 16.2 g. of the named compound, melting at 52°-53° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])=[O:22])[N:9]=1
Reactant: NC(CO)CO
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NC(CO)CO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.0 g of 2-amino-1,3-propanediol are boiled under reflux for 3 h in 8 ml of ethanol. The crystals precipitating on cooling are recrystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazol-1-yl]-N-(2-hydroxy-1-hydroxymethylethyl)acetamide remains as colorless less crystals of m.p. 212-214° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:25])C>C(O)(=O)C>[C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:25])=[O:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCOc1cc(-c2ccccc2)nc2ccccc12
Reactant: CCO
Solvent: CC(=O)O
Product: O=C(O)CCCOc1cc(-c2ccccc2)nc2ccccc12
Reaction time: 1 h

Procedure:
A solution of 4-[(2-phenyl-4-quinolyl)oxy]butanol (2.20 g) in glacial acetic acid (10 cc) is added slowly to a solution, cooled to 5° C., of chromic anhydride (2.25 g) in 90% strength acetic acid (5 cc). The temperature is allowed to rise to approximately 20° C., and the mixture is then stirred for one hour at this temperature. Ethanol (50 cc) is then added, the solvents are evaporated off under reduced pressure, the residue is taken up with water (100 cc) and the insoluble material is drained and washed several times with water. This insoluble material is taken up with normal sodium hydroxide solution (15 cc) and heated under reflux for two hours. The insoluble material is removed by filtration and the filtrate acidified by adding glacial acetic acid. The precipitate obtained is drained. 4-[(2-Phenyl-4-quinolyl)oxy]butanoic acid (0.740 g), m.p. 264° C., is obtained.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[N:18]#CN>ClCCl>[NH2:18][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#CN
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: Nc1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.7 %

Procedure:
To a cooled solution of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (2.00 g, 8.08 mmole) in 25 mL dichloromethane, cyanamide (0.728 g, 16.2 mmole) was added in one portion and the mixture was stirred for 48 h at room temperature. The resulting precipitate was filtered, slurried in methanol and subsequently washed with dichloromethane to give 1.01 g (66%) of 3-amino-1,2,4-thiadiazolo[4,5-a]benzimidazole as colourless crystals: mp 255-256° C.; 1H NMR (DMSO-d6)δ 8.23 (d, 1H), 7.71 (d, 1H), 7.43 (t, 1H), 7.54 (s, 2H), 7.32 (t, 1H) ppm; IR (KBr)ν 3302, 3151, 1661, 1577, 1487, 1473, 1251, 1207, 810 cm-1 ; HRMS calcd for C8H6N4S 190.0313, found 190.0293. Anal. Calcd for C8H6N4S: C, 50.51;H. 3.18; N. 29.45. Found: C, 50.26;H, 3.26; N, 29.38.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>O1CCCC1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd]>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Br)c2C1=O
Reactant: C[Sn](C)(C)c1ccccn1
Agent: [Pd]
Agent: [CH2-]c1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1Cc2cccc(-c3ccccn3)c2C1=O
Yield: 90 %

Procedure:
16.9 g (75 mmol) of (2) and 20 g (90 mmol) of 2-trimethylstannylpyridine were placed in 165 ml of tetrahydrofuran in the reaction vessel, the mixture was degassed a number of times and saturated with argon. 350 mg (0.37 mmol) of trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) were added and the reaction mixture was refluxed for 24 hours. After addition of 200 ml of water, the mixture was extracted 4 times with 150 ml each time of diethyl ether, the ether phase was washed with 100 ml of water and 100 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent and drying for 24 hours at 0.1 mbar at 60° C. (removal of the trimethylstannyl bromide) gave 15.07 g of (24) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]=O)[CH:6]=[CH:5]2.[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].[F-].C([NH+](CCCC)CCCC)CCC.Cl.CN(C=[O:42])C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:42])([CH3:13])[C:16]([F:18])([F:17])[F:15])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CCc1ccc2cc(Br)ccc2n1
Reactant: CN(C)C=O
Agent: CCCC[NH+](CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: CC(O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A DMF (5 ml) solution of the 6-bromoquinoline-ethanone (129 mg, 0.52 mmol), (trifluoromethyl)trimethylsilane (220 mg, 1.55 mmol) and tributylammonium fluoride (13.5 mg, 0.052 mmol) was stirred at 100° C. for 2 hours. Then the mixture was cooled to room temperature and added 1M-hydrochloride aqueous solution (2 ml). After 4 hours, the mixture was quenched with saturated sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate and dried over sodium sulfate. Then, filtration, evaporation, purification through silica gel column chromatography eluting with hexane/ethyl acetate (4:1) furnished the title compound (175 mg, quant.) as a white solid. 1H NMR (300 MHz, CDCl3) ppm 1.81 (3H, s), 6.51 (1H, s), 7.64 (1H, d, J=8.1 Hz), 7.66-7.89 (1H, m), 8.00-8.12 (2H, m), 8.21 (1H, d, J=8.8 Hz). MS (ESI): m/z 320, 322 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)O
Reactant: COc1cccc(S)c1
Solvent: CCOCC
Product: COc1cccc(SCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 113.8 h
Yield: 36.4 %

Procedure:
3-Methoxythiophenol (5.70 g, 41 mmol) was placed in a flask with acrylic acid (2.36 g, 33 mmol) and stirred at room temperature for 113.8 hours. The reaction mixture was dissolved in ether and extracted with 10% Na2CO3. The aqueous layer was acidified with concentrated HCl, extracted with ether, dried over MgSO4, and concentrated in vacuo to give the 3-(3-methoxyphenylthio)propanoic acid (2.55 g , 37%) as a white solid: mp 39°-42° C.; 1H NMR (CDCl3) 300 MHz 7.21 (m, 1H) 6.91 (m, 2H) 6.77 (d, J=8.3 Hz, 1H) 3.79 (s, 3H) 3.16 (t, J=7.5 Hz, 2H) 2.68 (t, J=7.3 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].O.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[CH2:12][CH2:11][CH:10]=[CH2:9])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 176.4 %

Procedure:
A solution of tert-butyl-4-[methoxy(methyl)-carbamoyl]-piperidine-1-carboxylate (5.04 g, 18.53 mmol), in tetrahydrofuran (50 mL) maintained under an atmosphere of nitrogen was cooled to 0° C. To this cold solution was added a THF solution of 4-butenylmagnesiun bromide (0.5 M in THF, 45 mL, 22.5 mmol) in a dropwise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave tert-butyl-4-pent-4-enoylpiperidine-1-carboxylate as a colorless oil (4.37 g, 88%); 1H NMR (CDCl3, 300 MHz) δ 5.79 (m, 1H), 4.98 (m, 2H), 4.10 (m, 2H), 2.76 (t, J=11.5 Hz, 2H), 2.54 (m, 2H), 2.46 (tt, J1=11.5 Hz, J2=3.5 Hz, 1H), 2.32 (m, 2H), 1.78 (m, 2H), 1.48-1.58 (m, 2H) and 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:30][CH3:31]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([CH2:30][CH3:31])[N:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(CC)n1
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a solution of 10.0 g (0.028 mole) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate [prepared in Example 2] in 75 mL of N,N-dimethylformamide was added 1.2 g of 60% sodium hydride (0.03 mole) in mineral oil was added. After stirring for 0.5 hour, the sodium hydride had dissolved and 8.5 g (0.056 mole) of iodoethane was added. The solution was stirred at room temperature for 16 hours, diluted to 400 mL with water and extracted with CH2Cl2. The extracts were dried and concentrated in vacuo. The residue was triturated with hexane to remove mineral oil. The residue was absorbed onto silica gel by dissolving in CH2Cl2 and adding dry silica gel, then concentrating in vacuo to a dry powder. This material was transferred to the top of a silica gel column and eluted with 10% (v/v) ethyl acetate in hexane to give 4.9 g (45.5%) of the title compound; m.p.= 113-114.5° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1.OCC1N2C=NC=C2SC=1.Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].C(=O)([O-])O.[Na+]>O.ClCCl>[CH2:26]([O:25][C:23]([N:2]([CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1)[CH3:1])=[O:24])[CH:27]=[CH2:28]
Reactant: CNCc1csc2cncn12
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: OCc1csc2cncn12
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N(C)Cc1csc2cncn12
Reaction time: 0.5 h

Procedure:
To 207 mg of a mixture of 3-(N-methylamino)methylimidazo[5,1-b]thiazole and 3-hydroxymethylimidazo[5,1-b]thiazole in a ratio of about 1:1, 10 ml of dichloromethane and 3 ml of water were added, and then 0.092 ml of allyl chloroformate was added thereto under ice-cooling. The mixture was stirred for 30 minutes under ice-cooling, while the aqueous layer was adjusted to pH 8.5 by adding a sodium hydrogencarbonate solution. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 73.6 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH2:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:12]#[CH:13].CCN(CC)CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CC#N>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:12][CH2:11][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: C#CCNS(C)(=O)=O
Reactant: COC(=O)c1ccc(Br)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid methyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09 g, 8.2 mmol), Et3N (1.7 mL, 12.1 mmol), and CH3CN (30 mL) was added Pd(PPh3)4 (462 mg, 0.4 mmol) followed by CuI (76 mg, 0.4 mmol). The reaction was heated at reflux for 24 h and was cooled to room temperature. The volatiles were removed in vacuo and the residue was purified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc in hexanes) to yield 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester as a pale yellow solid (1.1 g). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H), 3.10 (s, 3H); MS 274 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:59]=[CH:58][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][C@H:45]3[F:57])=[N:26]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH:41][C:14]([C:10]5[C:9](=[O:17])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH:13]=[CH:12][N:11]=5)=[O:16])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[CH2:46][C@H:45]3[F:57])=[N:26]2)=[CH:58][CH:59]=1
Reactant: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1

Procedure:
Prepared from 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (190 mg, 0.811 mmol, prepared according to the procedure for Example 125, Step E) and ±(3R*,4S*)-tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (157 mg, 0.270 mmol, obtained from Example 145, Step A) according to the procedure described for Example 145, Step B. Yield: 138 mg (51%).
Reaction SMILES: [CH2:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CCOCC.N.[Li]>O1CCCC1.C(O)C>[CH2:1]1[CH:13]2[CH:5]([C:6]3[CH2:7][CH:8]=[CH:9][CH2:10][C:11]=3[CH2:12]2)[CH2:4][CH2:3][CH:2]1[N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: c1ccc2c(c1)CC1=C2CCC(N2CCCC2)C1
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: C1=CCC2=C(C1)CC1CC(N3CCCC3)CCC21
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
A solution of 20.1 g (0.084 moles) of 1-(1,2,3,4-tetrahydrofluoren-2-yl)pyrrolidine, prepared as per Example 7, in 400 ml of tetrahydrofuran and 100 ml of ether is added to 2.5 l of liquid ammonia. 12.25 g (1.72 g-atoms) of lithium ribbon is added over 25 min and the mixture stirred for 15 minutes. 160 ml of ethanol is added over 2.5 hr., the ammonia evaporated and the residue added to 1 liter of cold water. The layers are separated and the aqueous layer is extracted with ether (2 × 300 ml). The combined ether layers are washed, dried and evaporated in vacuo to give 20.2 g of oil of the above title.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:30]=3)[CH:19]=[CH:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][CH:22]=3>C(O)C.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:30]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][CH:22]=3.[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4]
Reactant: Clc1cnc2nc1Nc1cccc(c1)C=Cc1cccc(c1)N2
Agent: [Pd]
Agent: Clc1cnc2nc1Nc1cccc(c1)/C=C\c1cccc(c1)N2
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Clc1cnc2nc1Nc1cccc(c1)CCc1cccc(c1)N2
Product: O=C([O-])C(F)(F)F
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of (14Z)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,14,16,18-decaene trifluoroacetate (21 mg, 0.045 mmol) in ethanol (1 mL) was added 5% palladium on carbon (5 mg) and the mixture was purged and degassed with hydrogen three times. The mixture was stirred for 1 hour with balloon pressure of hydrogen. Filtration through celite and purification by preparative LCMS (pH 2) gave the desired product as a trifluoroacetate salt (1.7 mg, 30%). LCMS for C18H16ClN4 (M+H)+: m/z=323.1. 1H NMR (400 MHz, CD3OD): δ 7.75 (m, 2H), 7.30 (m, 1H), 7.22 (m, 1H), 7.12 (m, 1H), 7.03 (m, 2H), 6.90 (m, 1H), 3.00 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH2:20])=[O:19])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](C(C)C)[C:6]=2[N:17]=1.I[CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24].BrC(C)C>C(O)=O>[C:28]([O:27][C:26](=[O:32])[NH:25][C@@H:23]([CH3:22])[CH2:24][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:4]=[C:3]([C:18]([NH2:20])=[O:19])[C:2]([NH2:1])=[N:17][C:6]1=2)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: C[C@@H](CI)NC(=O)OC(C)(C)C
Solvent: O=CO
Solvent: CC(C)Br
Product: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)OC(C)(C)C

Procedure:
tert-butyl{(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xvi-b) was prepared following the procedure detailed in the synthesis of 13 substituting tert-butyl [(1S)-2-iodo-1-methylethyl]carbamate for 2-bromopropane. HCOOH Standard Conditions. M+H=384. 1H NMR (300 MHz, d6-DMSO): δ 8.71 (s, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.57-7.49 (br s, 2H), 7.31 (dd, J=7.9, 7.3 Hz, 1H), 7.16 (dd, J=7.9, 7.3 Hz, 1H), 6.90 (br d, 1H), 4.27 (dd, J=6.1, 13.4 Hz, 1H), 4.14-3.95 (m, 2H), 1.18 (s, 9H), 1.05 (d, J=6.1 Hz, 3