Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)(=[O:17])=[O:16]
Reactant: OC1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCOC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Hydroxytetrahydrofuran (83.3 μL, 1.03 mmol) was dissolved in methylene chloride (anhydrous, 2 mL) and cooled to 0° C. followed by the addition of triethylamine (166 μL, 1.2 mmol) and methanesulfonyl chloride (88 μL, 1.14 mmol). The reaction mixture was stirred for 16 h while gradually warming to ambient temperature. The reaction was quenched with water, diluted with methylene chloride (20 mL), and the resulting layers were separated. The organic layer was washed with water (2×2 mL) and the combined aqueous phases were extracted with methylene chloride (2×3 mL). The combined organic phases were washed with brine (2×2 mL), dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1>C(O)C.C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccncc2)CC1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
1,1-Dimethylethyl 4-(4-pyridinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 1) (11.4 g) was dissolved in ethanol (200 ml) and acetic acid (2.36 ml). Platinum oxide (2 g) was added under a blanket of argon, and the reaction shaken under hydrogen at 50 psi for 18 h. After carefully filtering off the platinum catalyst, the solvent was evaporated and the residue redissolved in ethyl acetate (50 ml) and washed with saturated sodium hydrogen carbonate solution (50 ml). The aqueous phase was extracted into ethyl acetate (2×50 ml) and the combined organics dried (Na2SO4) and evaporated to give the title compound (D2) as white solid (9.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[C:6]([O:12][CH3:13])=[CH:5][N:4]=1.Br[C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>>[Cl:23][C:21]1[CH:22]=[CH:15][C:16]([C:17]#[N:18])=[C:19]([C:7]2[C:6]([O:12][CH3:13])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:20]=1
Reactant: N#Cc1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(OC)cn1
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(OC)cn1

Procedure:
7.87 g (purity 95%, 40.86 mmol) of 2,5-dimethoxypyridin-4-ylboronic acid and 8.85 g (40.86 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 6.23 g (purity 92%, 51% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)c2ncn(CCC(CO)CO)c2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Reaction time: 4 h
Yield: 82 %

Procedure:
The diol 4 (25 g, 9.2 mmol) was dissolved with a mixed solvent of ethyl acetate (200 ml) and ethanol (100 ml) in a 1 L steel autoclave. The palladium charcoal (5 g) and triethylamine (12 g) were added as well. The reaction mixture was kept at 55° C. under hydrogen pressure (0.8 Mpa) for 4 hours. The reaction was regarded as completed when no hydrogen intake was observed. The catalyst was removed by filtration after cooling down. The filtrate was concentrated by distillation under reduced pressure. The residue was dissolved by addition of DCM and water. The separated aqueous layer was extracted with more DCM (30 ml×3). The combined organic solution was dried and distilled to remove solvent. The residue was dissolved with ethyl acetate (80 ml) and kept at room temperature for 4 hours. The product was collected by filtration and dried under vacuum (18 g, yield 82%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.FC1C(F)=C(C#CC2C=CC(N)=CC=2)C(F)=C(F)N=1.[O:25]=[C:26]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]#[C:55][C:56]2[C:61]([F:62])=[C:60]([F:63])[N:59]=[C:58]([F:64])[C:57]=2[F:65])=[CH:50][CH:49]=1)[C@@H:27]([NH:39]C(=O)OC(C)(C)C)[CH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C>N1C=CC=CC=1.Cl>[ClH:3].[ClH:3].[NH2:39][C@@H:27]([CH2:28][CH2:29][CH2:30][NH2:31])[C:26]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]#[C:55][C:56]2[C:61]([F:62])=[C:60]([F:63])[N:59]=[C:58]([F:64])[C:57]=2[F:65])=[CH:50][CH:49]=1)=[O:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Agent: Cl
Agent: Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Solvent: c1ccncc1
Product: NCCC[C@H](N)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
L-Boc-Orn(Boc)-OH (0.25 g, 0.75 mmol) was dissolved in 1.5 mL of pyridine. The solution was cooled to −25° C. and phosphorus oxychloride (0.12 g, 0.75 mmol) was added dropwise with vigorous stirring. After stirring for 15 min. at −25° C., 4-((perfluoropyridin-4-yl)ethynyl)aniline, (13a) (0.10 g, 0.38 mmol) in pyridine (1.5 mL) was added slowly. The reaction mixture was stirred for 0.5 h at −25° C. and then at room temperature for 10 h. The reaction mixture was quenched with ice/water and extracted with EtOAc. The organic layer was washed with sat. NaHSO4 three times, dried with Na2SO4 and was concentrated in vacuo. The crude product was subjected to chromatography with MeOH:CH2Cl2=1:80 and the Boc-protected product was obtained in 23% yield. (S)-Di-tert-butyl (5-oxo-5-((4-((perfluoropyridin-4-yl)ethynyl)phenyl)amino)pentane-1,4-diyl)dicarbamate (100 mg, 0.17 mmol) was dissolved in gaseous HCl saturated MeOH (4 mL) at 0° C. and the solution was stirred for 10 hours at room temperature. The precipitated product (40 mg, 51%) was obtained by filtration: 1H-NMR (300 MHz, CD3OD) δ 7.82 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 4.15 (t, J=6.3 Hz, 1H), 3.14 (t, J=8.4 Hz, 2H), 2.02-2.09 (m, 2H), 1.83-1.88 (m, 2H)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:21]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[C:29]#[CH:30])=[CH:23][CH:22]=1>[Cu]I>[C:21]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[C:29]#[C:30][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: Ic1ccc(CCN2CCCC2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(C#Cc1ccc(CCN2CCCC2)cc1)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
25 mL of THF are degassed and combined with 0.25 g (0.83 mmol) of 1-[2-(4-iodophenyl)ethyl]pyrrolidine, 0.81 g (2.49 mmol) of cesium carbonate, 16 mg (0.083 mmol) of copper (I) iodide and 38 mg (0.033 mmol) of tetrakistriphenylphosphine palladium. Then the mixture is again degassed, and 184 mg (0.83 mmol) of propynoic acid-biphenyl-4-ylamide are added. The reaction mixture is stirred for 3 hours at ambient temperature, poured onto water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol/ammonia=10:1:0.1)). Yield: 90 mg (27.5% of theory); melting point: 180-189° C.; C27H26N2O (M=394.52); calc.: molecular ion peak (M+H)+: 395; found: molecular ion peak (M+H)+: 395.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[O:14][C:10]=3[CH:9]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.CC(O)=O.CO>C(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[O:14][C:10]=3[CH:9]=2)=[CH:19][CH:20]=1
Reactant: CSc1nc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2o1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3ccc(Br)cc3N)cc2o1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a stirred solution of 4-bromo-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline (704 mg, 1.79 mmol), HOAc (2.1 mL) and methanol (2.1 mL) in DCM (18 mL) at 0° C. was added zinc dust (1.16 g, 17.9 mmol) portionwise. After stirring for 2 h, the mixture was filtered. The filtrate was washed with aq NaHCO3 and brine. The organic layer was dried over NaSO4, filtered and concentrated under reduced pressure to give 4-bromo-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (469 mg, 71.9%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.72-7.60 (m, 2H), 7.53 (d, J=5.4 Hz, 1H), 6.68 (s, 1H), 6.49 (d, J=1.8 Hz, 1H), 6.23 (d, J=8.1 Hz, 1H), 5.36 (t, 1H), 4.90 (s, 2H), 4.38 (d, J=6.0 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 365 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[ClH:14]>CO.[Pt](=O)=O>[ClH:14].[CH3:7][C:2]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)c1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)C1CCCNC1
Reaction time: 46 h

Procedure:
0.115 g of methyl 2-methyl-2-pyridin-3-ylpropionate (CAS 476429-23-9) is dissolved in an autoclave in 5 ml of methanol. The solution is admixed with 0.35 ml of 1.2M HCl in methanol and 0.012 g of platinum(IV) oxide, and the reaction mixture is hydrogenated at 4 bar and 23° over 46 hours. The catalyst is filtered off through Hyflo and the filtrate is concentrated by evaporation to give the crude title compound which is used directly in the next step.
Reaction SMILES: ClC1C2N(C)O[C@H]3N[C@H](C([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36](=[O:38])[CH3:37])=O)C[C@@]3(O)C=2C=CC=1.C(N(CC)CC)C>CO>[C:36]([O:35][C@@H:20]1[C:21]([CH3:34])=[CH:22][C@H:23]2[C@@:28]([OH:29])([C@@H:27]([CH3:30])[CH2:26][CH2:25][C@H:24]2[C:31]([CH3:33])=[CH2:32])[C@H:19]1[OH:18])(=[O:38])[CH3:37]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Solvent: CCN(CC)CC
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@H](C)[C@]2(O)[C@@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b -hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate, (Preparation 1, 100 g) and triethylamine (10 ml) in methanol (1000 ml) was stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue was crystallised from ethyl acetate/hexane to give a pure sample of the terpene, (1S,2R,4aR,5R,8S,8aS)-1,8a-dihydroxy-5-isopropenyl-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydro-2-naphthalenyl acetate (Preparation 126). The remaining solution was concentrated and purified by flash column chromatography on silica-gel eluting with ethyl acetate:dichloromethane:hexane (2:1:7) to give further terpene moiety (1S,2R,4aR,5R,8S,8aS)-1,8a-dihydroxy-5-isopropenyl-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydro-2-naphthalenyl acetate as a white solid (Preparation 126, 43 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.[NH2:18][C@H:19]([CH2:29][F:30])[C@@H:20]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[OH:21].C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.O.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>[NH2:18][C@H:19]([CH2:29][F:30])[C@@H:20]([C:22]1[CH:23]=[CH:24][C:25]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[CH:26][CH:27]=1)[OH:21]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Temperature: 90 °C
Yield: 35 %

Procedure:
To a solution of commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.5 g, 2.17 mmol) in degassed dimethoxyethane (10 mL) and water (3 mL) is added (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)-propan-1-ol (0.65 g, 2.20 mmol) and Cs2CO3 (2.15 g, 6.6 mmol). Pd(PPh3)4 (0.25 g, 0.21 mmol) is added and the reaction mixture heated to 90° C. for 1.5 hours. Solvent is evaporated in vacuo and the crude material purified by column chromatography on silica gel eluting in methanol/CHCl3 to afford the title compound (206 mg): 1NMR (400 MHz, CDCl3) δ: 3.09-3.18 (m, 1H), 3.48 (s, 1H), 4.24-4.28 (m, 0.5H), 4.36-4.41 (m, 1H), 4.49-4.52 (m, 0.5H), 4.64 (d, J=6.16 Hz, 1H), 7.53 (d, J=8.16 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 7.76 (d, J=8.2, 1 H), 8.0 (dd, J1=8.16 Hz, J2=2.32 Hz, 1H), 8.93 (d, J=1.76 Hz, 1H). m/z (Cl) 272 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: C=O
Product: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
heating 8-chloro-6-phenyl-1-methyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in an inert organic solvent with paraformaldehyde to 100°-140° C. to give 8-chloro-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine; and
Reaction SMILES: S(=O)(=O)(O)O.C([NH2:8])=O.[Cl:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([O:16][CH:17]([C:23](=O)[CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]2[O:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:24])[N:8]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(OC(=O)c1ccc(Cl)cc1)C(C)=O
Reactant: NC=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)nc1C
Temperature: 140 °C
Yield: 55.6 %

Procedure:
19.6 g (0.2 mol) of concentrated sulphuric acid were added dropwise during 10 minutes to 90 g (2 mol) of formamide, the temperature of the solution being held below 10° C. by external cooling, 26.8 g (0.09 mol) of ethyl 2-(4-chlorobenzoyloxy)-3-oxo-butyrate were added and the stirred solution was heated at 140° C. for 2 hours. The cooled suspension was partitioned between 400 ml of water and 300 ml of diethyl ether. The organic phase was washed twice with 200 ml of 1N hydrochloric acid each time and once with 200 ml of water and then filtered to remove suspended solids. The organic phase was dried over magnesium sulphate, filtered and evaporated. The residue was purified by chromatography on silica gel using 20% by volume ethyl acetate in hexane for the elution. After evaporation of the eluate there were obtained 13.3 g (50%) of ethyl 2-(4-chlorophenyl)-4-methyl-5-oxazolecarboxylate of melting point 80°-81° C.
Reaction SMILES: C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[C:38]3[N:39]([CH2:42][C@H:43]4[CH2:48][CH2:47][C@H:46]([CH3:49])[CH2:45][CH2:44]4)[CH:40]=[N:41][C:37]=3[CH:36]=[C:35]([C:50]#[N:51])[N:34]=2)[CH:30]=[N:31][CH:32]=1.Br[C:53]1[CH:58]=[C:57]([CH:59]([CH3:61])[CH3:60])[CH:56]=[CH:55][N:54]=1.[F-].[Cs+].C(O)(=O)C(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[C:38]3[N:39]([CH2:42][C@H:43]4[CH2:48][CH2:47][C@H:46]([CH3:49])[CH2:45][CH2:44]4)[C:40]([C:53]4[CH:58]=[C:57]([CH:59]([CH3:61])[CH3:60])[CH:56]=[CH:55][N:54]=4)=[N:41][C:37]=3[CH:36]=[C:35]([C:50]#[N:51])[N:34]=2)[CH:30]=[N:31][CH:32]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC(C)c1ccnc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: C1COCCO1
Product: CC(C)c1ccnc(-c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)c1
Temperature: 50 °C

Procedure:
A vial equipped with a stir bar was charged with di(1-adamantyl)-n-butylphosphine (cataCXium A, Strem) (143.2 mg, 0.40 mmol) and palladium acetate (45 mg, 0.20 mmol). Dioxane (2.5 mL) was added, and the mixture was degassed with N2. The vial was then sealed and heated at 50° C. for 30 minutes. The catalyst slurry was then cooled back to room temperature, and 1.5 mL of this catalyst slurry was added via syringe to a second vial equipped with a stir bar and containing 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, Step 2;100 mg, 0.273 mmol), 2-bromo-4-isopropylpyridine (109 mg, 0.547 mmol; purchased from Combiphos), cesium fluoride (125 mg, 0.82 mmol), and pivalic acid (36.3 mg, 0.355 mmol). The reaction was degassed with N2 for 2 minutes, and then the vial was sealed and heated at 110° C. for 20 hours. The reaction was then cooled to room temperature, diluted with hexanes (2 mL) and CH2Cl2 (2 mL), and loaded directly onto a silica gel column. Purification with 0 to 75% EtOAc/hexanes afforded 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[4-(propan-2-yl)pyridin-2-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C28H29ClN6 [M+H]+=485. found=485.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]5([C:27]([N:29]6[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]6)=O)[CH2:26][CH2:25]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C:24]5([CH2:27][N:29]6[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]6)[CH2:25][CH2:26]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)N5CCN(C)CC5)CC4)cc2OCC3)n(C(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(CN5CCN(C)CC5)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
To an ice-cooled solution of {1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropyl}-(4-methylpiperazin-1-yl)methanone from Example 50 (90 mg, 0.18 mmol) in THF (5 mL) was added LiAlH4 (1.0M in THF, 0.18 mL) and the mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched by addition of 1N NaOH and then was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 0-60% 0.1% HCO2H in acetonitrile/water) affording 259 (41 mg, 48%). LCMS: RT 2.73 min [M+H]+ 478.1. 1H NMR (DMSO, 400 MHz): δ 8.30 (1H, d, J=8.96 Hz), 8.18 (1H, s), 7.82 (1H, s), 6.82 (1H, dd, J=8.97, 2.49 Hz), 6.63 (1H, d, J=2.47 Hz), 5.89-5.76 (1H, m), 4.48 (4H, s), 2.69 (2H, s), 2.52-2.41 (3H, m), 2.38-2.21 (7H, s), 2.15 (3H, s), 1.45 (6H, d, J=6.60 Hz), 0.96-0.84 (4H, m)
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[C:18](=[O:19])[NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:20])#[N:2].N[CH2:22]CNCCCNCCN>>[C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[C:7](=[O:20])[NH:8][CH2:9][CH2:10][NH:11][CH2:22][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]1=[O:19])#[N:2]
Reactant: N#CCCCC1C(=O)NCCNCCNCCNC1=O
Reactant: NCCNCCCNCCN
Product: N#CCCCC1C(=O)NCCNCCCNCCNC1=O
Yield: 30 %

Procedure:
The procedure of (2) of Example 1 was repeated with the exception that N,N'-bis(2-aminoethyl)-1,3-propylenediamine was used in place of triethylenetetramine. Thus, 3-(3-cyanopropyl)-2,4-dioxo-1,5,8,12-tetraaza-cyclotetradecane (C-substituted cyclic diamide) was obtained in a yield of 30%.
Reaction SMILES: Cl.[CH:2]12[N:10]([CH2:11][C@@H:12]([C:14]3[CH:23]=[CH:22][C:17]4[C:18](=[O:21])[O:19][CH2:20][C:16]=4[C:15]=3[CH3:24])[OH:13])[CH:7]([CH2:8][CH2:9]1)[CH:6]1[NH:25][CH:3]2[CH2:4][CH2:5]1.[CH3:26][C:27]1[N:34]=[C:33]([CH:35]2[CH2:37][O:36]2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>>[OH:36][CH:35]([C:33]1[N:34]=[C:27]([CH3:26])[C:28]([C:29]#[N:30])=[CH:31][CH:32]=1)[CH2:37][N:25]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH:2]1[N:10]([CH2:11][C@H:12]([OH:13])[C:14]3[CH:23]=[CH:22][C:17]4[C:18](=[O:21])[O:19][CH2:20][C:16]=4[C:15]=3[CH3:24])[CH:7]2[CH2:8][CH2:9]1
Reactant: Cc1nc(C2CO2)ccc1C#N
Reactant: Cc1c([C@@H](O)CN2C3CCC2C2CCC3N2)ccc2c1COC2=O
Agent: Cl
Product: Cc1nc(C(O)CN2C3CCC2C2CCC3N2C[C@H](O)c2ccc3c(c2C)COC3=O)ccc1C#N

Procedure:
6-(1-Hydroxy-2-{10-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-9,10-diazatricyclo[4.2.1.12,5]dec-9-yl}ethyl)-2-methylpyridine-3-carbonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(1R)-2-(9,10-diazatricyclo[4.2.1.12,5]dec-9-yl)-1 hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one hydrochloride (INTERMEDIATE 9) and 2-methyl-6-(oxiran-2-yl)nicotinonitrile (PCT Published Application WO 2010/129379).
Reaction SMILES: [CH3:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([CH2:6][OH:7])=[C:4]([F:12])[C:3]=1[F:13].[C:14]([C:16]([CH3:26])=[CH:17][C@@H:18]1[C@@H:20]([C:21](O)=[O:22])[C:19]1([CH3:25])[CH3:24])#[N:15]>CN(C)C1C=CN=CC=1.ClCCl>[C:14]([C:16]([CH3:26])=[CH:17][C@@H:18]1[C@@H:20]([C:21]([O:7][CH2:6][C:5]2[C:4]([F:12])=[C:3]([F:13])[C:2]([CH3:1])=[C:9]([F:10])[C:8]=2[F:11])=[O:22])[C:19]1([CH3:25])[CH3:24])#[N:15]
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C#N)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
Under a nitrogen atmosphere, 0.59 g of N,N-dicyclohexyl carbodiimide was added to a mixture of 0.55 g of 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol, 0.51 g of (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid, 0.10 g of 4-dimethylaminopyridine and 7 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.72 g of 4-methyl-2,3,5,6-tetrafluorobenzyl(1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate represented by the following formula: