Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[C:7]([CH:9]([C:36](OCC)=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=1)#[N:8]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[NH2:5][C:4]1[NH:6][C:36](=[O:37])[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:15]2[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[C:7]([NH2:8])[N:3]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1ccc(N(CCCCC(C#N)C(=O)OCC)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N(CCCCc2c(N)nc(N)[nH]c2=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.377 g (0.0164 mol) of sodium in 8 mL of absolute ethanol under nitrogen was added 1.04 g (0.0109 mol) of guanidine hydrochloride and 1 mL of rinse absolute ethanol. The mixture was stirred for 30 min, and to it was added a solution of 2.73 g (0.00546 mol) of ethyl 4-[(5-cyano-6-ethoxy-6-oxohexyl)tosylamino]benzoate.0.15 ethyl acetate in 6 mL of absolute ethanol and then 7 mL of rinse absolute ethanol. The mixture was refluxed for 4 h and was allowed to cool to room temperature and stand under nitrogen overnight. The reaction mixture was filtered by suction, and the filtrate was neutralized with 0.984 g (0.0164 mol) of glacial acetic acid. The solution was concentrated under vacuum at 30° C. to a solid that was washed well with 50 mL of water, collected by suction filtration, washed again with 25, 25, and 10 mL of water, and dried under vacuum at 60° C.; yield, 2.76 g. Fourier transform NMR (Me2SOd6) and chemical ionization mass spectroscopy indicated a mixture of product and uncyclized intermediates. A 2.41 g sample of solid was added to a solution of 3.16 g (0.137 mol) of sodium in 138 mL of absolute ethanol under nitrogen. The mixture was heated to reflux, and the resulting solution was refluxed for 3 h 15 min. The slightly cloudy solution was allowed to cool to room temperature, and the resulting mixture was allowed to stand under nitrogen overnight. The mixture was heated briefly back to reflux, and the resulting slightly cloudy, hot solution was neutralized with 8.30 g (0.138 mol) of glacial acetic acid. The thick mixture was concentrated under vacuum at 35° C. to a white solid to which was added 50 mL of water. Then to the stirred mixture was added approximately 5-8 mL of concentrated hydrochloric acid. The mixture with a pH of 5.5 was filtered by suction, and collected solid was washed with 15 and 20 mL of water and dried under vacuum overnight at room temperature in a desiccator; yield, 1.98 g (84%): NMR (Me2SOd6) δ 1.2-1.4 (m, 4H), 2.06 (t, 2H), 2.37 (s, 3H), 3.54 (t, 2H), 5.58 (br s, 2H), 5.89 (br s, 2H), 7.14 (d, 2H), 7.3-7.5 (AA'BB', 4H), 7.86 (d, 2H), 9.75 (br), 0.13 mol of acetic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C@H:25]1[CH2:28][C@H:27]([NH2:29])[CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C@H:25]1[CH2:26][C@H:27]([NH:29][C:10](=[O:12])[C:9]([C:8]2[C:3]([Cl:2])=[N:4][CH:5]=[CH:6][CH:7]=2)([CH3:14])[CH3:13])[CH2:28]1
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: CC(C)(C(=O)O)c1cccnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Intermediate 25 (216 mg, 1.083 mmol), intermediate 11 (198 mg, 0.903 mmol), HBTU (376 mg, 0.993 mmol) and triethylamine (377 μl, 2.71 mmol) were dissolved in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with saturated ammonium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give the crude material as a tan solid. The crude material was absorbed onto a plug of silica gel and purified by silica chromatography (hexane to ethyl acetate gradient) to provide N-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-2-(2-chloropyridin-3-yl)-2-methylpropanamide (220 mg, 0.549 mmol, 60.8% yield) as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([Cl:23])=[O:14])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(CCC(=O)O)ccc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(CCC(=O)Cl)ccc1F
Reaction time: 2 h
Yield: 100 %

Procedure:
3-(3-Cyano-4-fluorophenyl)-propionic acid (Int. A7) was dissolved in dichloromethane (30 ml) containing 0.1 ml DMF and oxalyl chloride (0.79 g, 6.2 mmol) added dropwise over 5 min. The reaction mixture was stirred for 2 h then concentrated in vacuo to yield the title compound as an oil (1.3 g, 100%). 1H-NMR (CDCl3) δ 3.02 (2H, t), 3.21 (2H, t), 7.13 (1H, t), 7.45 (2H, m).
Reaction SMILES: [C:1]12([CH3:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH2:10].C12(C)C(C)(C)C(CC1)CC2N.CS(O)(=O)=O>>[C@:1]12([CH3:11])[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH2:10]
Reactant: CC1(C)C2CCC1(C)C(N)C2
Agent: CS(=O)(=O)O
Product: CC1(C)C2CC[C@@]1(C)C(N)C2

Procedure:
Bornylamine (X) was recycled by first adjusting the pH of the aqueous solution of bornylamine-methane sulfonic acid (XM), obtained from the previous step, to 10-13, and then extracting the free amine into MTBE. After removal of solvent, 4.308 g of (R)-bornylamine (X) was obtained (>97% pure by 1H NMR, 92.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[N:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31][CH2:30]3)[C:21]2=[O:37])[CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC([O-])(C)C.[Na+].O>COCCOC.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[N:20]3[C:21](=[O:37])[C:22]4[C:27]([C@H:28]3[CH2:14][CH2:13][CH2:12]2)=[C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH2:34]2)[CH:25]=[CH:24][CH:23]=4)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN1CCN(c2cccc3c2CN(C(CCCOS(C)(=O)=O)c2ccc(OC)c(OC)c2)C3=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCN1CCN(c2cccc3c2[C@H]2CCC[C@H](c4ccc(OC)c(OC)c4)N2C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 4-(3,4-dimethoxy-phenyl)-4-[4-(4-ethyl-piperazin-1-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyl ester (112 mg, 0.211 mmol) was dissolved in DME (0.80 mL), and a 4 M solution of NaOtBu in THF (0.5 mL) was added. The resulting mixture was stirred at 60° C. for 1 hour and then allowed to cool to room temperature. The resulting mixture was then poured into water (10 mL) and extracted with EtOAc (2 times, 15 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuum to yield a residue. The residue was purified using prep-HPLC 5-90 gradient water (0.2% TFA buffer)/acetonitrile (0.15% TFA buffer) to yield the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+].CO>O.C(OCC)(=O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH3:24])[N:13]=[CH:12][C:11]([C:25]#[N:26])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Yield: 75.9 %

Procedure:
A mixture of 4.88 g (13 mmol) of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-nitro-quinoline-3-carbonitrile, 5.2 g (97.5 mmol) of ammonium chloride, and 3.3 g (58.5 mmol) iron was stirred at reflux in 60 ml of water and 60 ml of methanol for 4.5 hours. The mixture was diluted with 500 ml of hot ethyl acetate and the hot mixture was filtered. The filtration was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with mixture of ethyl acetate and methanol to give 3.38 g of yellow solid: mass spectrum (electrospray, m/e): M+H 343.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH2:34])=[CH:23][CH:22]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl[C:40]([O:42][CH3:43])=[O:41]>C(N(CC)CC)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH:34][C:40]([O:42][CH3:43])=[O:41])=[CH:25][CH:26]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 31 mg (0.066 mmol) of the intermediate obtained in Step C in I mL of methylene chloride at room temperature was treated with 1 drop of triethylamine followed by 5 μL (6 mg, 0.067 mmol, 1 eq.) of methyl chloroformate. The mixture was stirred at room temperature for 1 hour then diluted into 10 mL of ethyl acetate and washed with 5% aqueous citric acid and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with 5% methanol in ethyl acetate, to give 33 mg (0.062 mmol, 95%) of the product as a colorless glass. 1H NMR (400 MHz, CDCl3): δ 1.38 (s, 9H), 1.91 (m, 1H), 2.43-2.60 (m, 3H), 3.62 (s, 3H), 4.26 (m, 3H), 4.68 (br t, 1H), 4.93 (d, 15 Hz, 1H), 5.18 (d, 15 Hz, 1H), 5.45 (br d, 7 Hz, 1H), 7.13-7.35 (m, 11H), 7.41 (d, 8 Hz, 1H). FAB-MS: calculated for C31H35N3O5 529; found 530 (M+H, 25%), 430 (M-BOC, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[N:38]1[CH:39]=[CH:40][C:35]([C:34]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]3[O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:5][CH:4]=2)=[O:41])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)c3ccncc3)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 20.9 %

Procedure:
A solution of 60 mg (0.13 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine--carboxylate, 16 mg (0.13 mmol) of isonicotinic acid, 34 mg (0.26 mmol) of ethyidiisopropylamine and 58 mg (0.13 mmol) of benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) in 5 ml of acetonitrile was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was evaporated under reduced pressure and the residue, without further working-up, was chromatographed on silica gel using a 3:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 15 mg (21% of theory) of (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzyl pyridine-4-carboxylate as a colourless solid; MS: 552 (M)+.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][C:9]#[N:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.I([O-])(=O)(=O)=O.[Na+].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CC(C)=O.O.C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:28][CH2:2][CH2:6][CH2:7][CH2:8][C:9]#[N:10]
Reactant: Nc1ccccn1
Reactant: N#CCCCC1OCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: N#CCCCCNc1ccccn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
4-(1,3-Dioxolan-2-yl)butanenitrile (6.26 g; 0.0443 moles) was dissolved in a mixture of acetone (50 mL) and water (50 mL) under nitrogen. p-Toluene-sulfonic acid (843 mg; 0.00443 moles) was added followed by sodium periodate (9.67 g; 0.0452 moles) and the mixture was heated at 40° C. for 32 hours with magnetic stirring. The mixture was filtered, washing the filter cake with ethyl acetate (100 mL). The filtrate was mixed with aqueous sodium bicarbonate solution (50 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate and filtered. Removal of solvent under vacuum gave the crude product (5-oxopentanenitrile). This material was dissolved in methylene chloride (150 mL). 2-Aminopyridine (4.17 g; 0.0443 moles) was added and the reaction mixture was magnetically stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (14.1 g; 0.0665 moles) was added and the reaction mixture was stirred for 4 hours. The reaction mixture was added to aqueous sodium bicarbonate solution (50 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (4×50 mL). The combined organic phases were dried over sodium sulfate and filtered. Removal of solvent under vacuum gave crude product which was purified by chromatography on silica gel, eluting with methylene chloride followed by methylene chloride/acetone (10:1). Removal of solvent under vacuum gave the product, 5-(pyridin-2-ylamino)pentane-nitrile, as an off white solid (4.30 g; 55%). 1H NMR (CDCl3) δ 8.05-8.10 (1H, m), 7.38-7.43 (1H, m), 6.55-6.60 (1H, m), 6.38 (1H, d, J=8.5 Hz), 4.38-4.58 (1H, br), 3.30-3.40 (2H, m), 2.35-2.45 (2H, m), 1.70-1.85 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=[N:31][CH2:32][CH2:33][CH2:34][N:35](C)C.Cl.C1C=CC2N(O)N=NC=2C=1.NCCC#N>C1COCC1>[Cl:26][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:10]([NH:35][CH2:34][CH2:33][C:32]#[N:31])=[O:11])=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Agent: Cl
Agent: N#CCCN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)NCCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(3′-chlorobiphenyl-4-yl)propanoic acid (1 g, 2.66 mmol) in THF (30 ml) at room temperature was added EDC.HCl (1.020 g, 5.32 mmol) and HOBT (0.815 g, 5.32 mmol). The reaction was stirred at room temperature for 10 minutes then was added 3-aminopropionitrile (0.389 ml, 5.32 mmol) and TEA (0.742 ml, 5.32 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 2 to 4% EtOH/DCM) and gave the title compound: 1.1 g (yield: 97%). LCMS (condition B): 428.2 (M+1); retention time=1.20 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14].CC(C)([O-])C.[K+].C(OCC)(=O)C>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: Oc1cccc(F)c1
Reactant: N#Cc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2cccc(F)c2)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
To a solution of 3-fluoro-phenol (500 mg, 4.46 mmol) and 3-fluoro-benzonitrile (540 mg, 4.46 mmol) in dimethylsulfoxide (1.0 mL) was added potassium tert-butoxide (500 mg, 4.46 mmol), and the solution was stirred at 140° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), and 3-(3-fluoro-phenoxy)-benzonitrile (313 mg, 33%) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.[CH3:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC>[Cu]I>[CH3:15][C:12]([CH3:13])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:26]([CH3:25])[C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CNC(=O)c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Product: CN(C(=O)c1ccccc1)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Temperature: 110 °C
Yield: 29.2 %

Procedure:
A mixture of 1-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.25 g, 0.61 mmol), N-Methyl-benzamide (0.243 g, 1.8 mmol), K2CO3 (0.185 g, 1.34 mmol), CuI (0.0175 g, 0.092 mmol) and N,N′-Dimethyl-ethane-1,2-diamine (0.02 mL, 0.184 mmol) in tolene was heated under an argon atmosphere in a microwave oven at 110° C. overnight. After cooling to room temperature, the reaction mixture was purified by flash column chromatography on silica gel with EtOAc in hexane (10% to 40% gradient over 30 min) to give the desired product (60 mg, 21% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 8.43 (s, 1H), 8.04 (s, 1H), 7.45-7.24 (m, 5H), 5.65 (s, 2H), 3.74 (s, 3H), 3.62-3.59 (m, 2H), 1.51 (s, 9H), 0.99-0.94 (m, 2H), 0 (s, 9H); MS [M+H]+: 467. Step 2: The general procedures as described in these Examples were followed. 1H NMR (CDCl3): δ 9.50 (s, 1H), 8.35 (s, 1H), 8.00 (s, 1H), 7.39-7.21 (m, 5H), 3.69 (s, 3H), 1.45 (s, 9H); MS [M+H]+: 337.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][NH:17][C:18](=[O:30])[CH2:19][O:20][C:21]1[C:26]([CH3:27])=[N:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=1>CN(C)C=O>[C:1]1([S:7][CH2:15][CH2:16][NH:17][C:18](=[O:30])[CH2:19][O:20][C:21]2[C:26]([CH3:27])=[N:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: Cc1nc(C)c(OCC(=O)NCCBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C)c(OCC(=O)NCCSc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
Thiophenol (0.60 g, 5.4 mM) and potassium carbonate (0.75 g, 5.4 mM) were added to compound 648 (0.91 g, 3.0 mM) dissolved in dimethylformamide (10 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was further extracted with chloroform. The combined organic layer was chromatographed by eluting successively with benzene and benzene-ethyl acetate (10:1) to obtain the product (0.35 g, yield: 35.2%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A suspension of 5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced as in Example 1A (210 mg, 0.86 mmol), ethylisocyanate (600 mg, 8.6 mmol), and dibutyltin diacetate (2 drops) in a mixture of toluene and THF (1:1, 10 mL) was heated at 110° C. with stirring in a sealed tube for 5 h. The homogeneous reaction mixture was cooled to RT. The solvent was removed under reduced pressure and the resulting solid was triturated with chloroform (10 mL) and hexanes (250 mL). The solid was filtered, washed with hexanes, and dried to obtain 1-(5-Chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea LCMS (APCI+) 317.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16]N1C(=O)CCC1.C[Mg]Cl.C[Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH3:16])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CN1CCCC1=O
Agent: C[Mg]Br
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 150.5 %

Procedure:
To a solution of 5,6-dichloronicotinic acid tert.-butyl ester (3.37 g, 13.6 mmol), Fe(acac)3 (719 mg, 2.04 mmol) and NMP (1.95 mL, 20 mmol) in THF (300 mL), a solution of methylmagnesium chloride in THF (3M, 5.4 mL, 16.3 mmol) is slowly added at −78° C. The brown solution turns turbid and black. Stirring is continued for 1 h at −75° C. before it is warmed to 0° C. The reaction is incomplete and the mixture is cooled again at −70° C. A further batch of methylmagnesium bromide in THF (3M, 5.4 mL, 16.3 mmol) is slowly added at −70° C. The dark green mixture is slowly warmed to −20° C. and carefully quenched with 0.7N aq. HCl (150 mL). The mixture is extracted with ether (5×60 mL). The combined org. extracts are dried over Na2SO4, filtered and evaporated to give crude 5-chloro-6-methyl-nicotinic acid tert.-butyl ester as a yellow oil (4.66 g); LC-MS: tR=1.03 min, [M+1]+=228.22.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([CH3:31])[CH:22]=1)=[O:19].C([O-])(O)=O.[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([CH3:31])[CH:22]=2)=[O:19])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(NC(=O)OC(C)(C)C)C2)c2ccccc2n1
Temperature: 70 °C
Reaction time: 144 h

Procedure:
A mixture of pyrrolidin-3-yl-carbamic acid tert-butyl ester (10 mmol), 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (10 mmol), NaHCO3 (20 mmol), Nal (0.5 mmol), and THF (70 mL) is stirred in a sealed vessel at 70° C. for 6 d. The reaction mixture is filtered, evaporated to dryness, and the residue is purified by preparative HPLC to provide the title compound.