Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>ClCCl>[P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([F:31])([F:32])[C:21]([F:29])([F:30])[C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(CCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 15.23 g of 1-(diethylphosphono)-11-(nonafluorobutyl)undecane in 40 mL of dichloromethane was added 11.50 g of bromotrimethylsilane. After 24 hr at room temperature, the solution was concentrated to a pale yellowish liquid, and the intermediate silylphosphonate ester was dissolved in 200 mL of methanol. The resultant solution was stirred at room temperature for 30 min and concentrated to a white solid. Dissolution in methanol and concentration were repeated two times, and two recrystallizations of the crude product from heptane gave 10.85 g of 1-phosphono-11-(nonafluorobutyl)undecane (CF3(CF2)3(CH2)11PO3H2) as colorless plates, m.p. 93-96° C.
Reaction SMILES: [CH3:1]/[C:2](/N)=[CH:3]\[C:4]#[N:5].Cl.[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][NH2:16])[CH:12]=[CH:13][CH:14]=1>Cl.O>[Cl:8][C:9]1[CH:10]=[C:11]([N:15]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:1])=[N:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: NNc1cccc(Cl)c1
Reactant: C/C(N)=C\C#N
Agent: Cl
Solvent: O
Product: Cc1cc(N)n(-c2cccc(Cl)c2)n1
Yield: 20.1 %

Procedure:
(see, e.g., Ganesan, A., et al., Journal of Organic Chemistry 1993, 58, 6155-6157). A solution of 3-aminocrotonitrile (mixture of cis and trans) (1.50 g, 17.5 mmol) and 3-chlorophenylhydrazine hydrochloride (3.0 g, 16.2 mmol) in 25 mL of 1N HCl was heated to reflux for 3 h under nitrogen. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was recrystallized from hot iPrOH to give the title compound (677 mg, 20%) as a beige fluffy solid. 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.28 (d, J=9.5 Hz, 1H), 5.46 (s, 1H), 2.22 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 149.95, 145.30, 139.87, 135.05, 130.32, 126.86, 123.67, 121.28, 91.41, 13.89.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:15](=O)[CH3:16])[CH2:13][CH3:14])[CH:6]=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])[CH:6]=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CCN(C(C)=O)c1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Solvent: C1CCOC1
Product: CCN(CC)c1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
570 mg of 6-chloro-2-(N-acetyl-N-ethylamino)-4-(4-nitrophenyl)quinoline were suspended in 11.4 ml of THF and, under argon, added in portions to 3.1 ml of borane-THF complex. The temperature rose to 30° C. After stirring at room temperature for 3 hours, the solvent was removed by distillation and the residue was mixed with 50 ml of ethanol and 20 ml of concentrated HCl and heated on a water bath, cooled and distilled to remove the water. The residue was mixed with water, made alkaline with 2N NaOH, extracted with ethyl acetate and washed with water. The product was purified by MPLC chromatography using an MPRC cartridge with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution. A yellow solid product was isolated.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:21]=O)[C:15]=2[CH:14]=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1.[C-]#N.[Li+].[C:31](P(=O)(OCC)OCC)#[N:32].CC(O)(C)C.[I-].[Sm+2].[I-]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([CH2:21][C:31]#[N:32])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(C=O)cccc21
Reactant: CCOP(=O)(C#N)OCC
Agent: [C-]#N
Agent: [I-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(CC#N)cccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 44.4 %

Procedure:
Add 1-[3-(tert-Butyldimethylsilyloxy)propyl]-1H-indole-4-carboxaldehyde (2.34 g, 14.4 mmol) and lithium cyanide tetrahydrofuran complex (LiCN*1.5 THF, 204 mg, 1.44 mmol) to tetrahydrofuran (40 mL) under nitrogen. Add dropwise neat diethyl cyanophosphonate (2.8 mL, 18.4 mmol) to the stirring reaction mixture. Stir at room temp under nitrogen for 60 hours. Add 2-methyl-2-propanol (1.4 mL, 14.6 mmol). Add the reaction mixture via cannula to a stirred 0.1 molar solution of samarium(II) iodide in tetrahydrofuran (360 mL, 36.0 mmol) at 25° C. under nitrogen. If the resulting reaction mixture is not deep blue add additional samarium(II) iodide solution until deep blue color persists. Stir the reaction at 25° C. for 1 hour. Concentrate under reduced pressure, dilute with ethyl acetate, diethyl ether (1:1), wash with aqueous 0.1 molar hydrochloric acid, and aqueous saturated sodium chloride. Dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from neat hexane to 25% ethyl acetate in hexane to obtain 2.1 g (84%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-dd) 7.43 (d, J=8 Hz, 1H), 7.38 (m, 1H), 7.14 (m, 1H), 7.0 (d, J=8 Hz, 1H), 6.54 (m, 1H), 4.23 (t, J=7, 2H), 4.18 (s, 3H), 3.5 (t, J=7 z, 2H), 1.9 (m, 2H), 0.85 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [C:1]([CH:4]1[O:10][CH:9]2[CH:6]([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:24])[CH3:23])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[N:5]1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(O)=[O:2].C(Cl)(=O)[C:35]([Cl:37])=O.[N+](=CC(C1OC2C(C(=O)N2C(=C(C)C)C(OCC2C=CC=CC=2)=O)N1C(=O)C1C=CC=CC=1)=O)=[N-].Cl>C1C=CC=CC=1.CN(C)C=O.CCOCC>[Cl:37][CH2:35][C:1]([CH:4]1[O:10][CH:9]2[CH:6]([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:23])[CH3:24])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[N:5]1[C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)O)N2C(=O)c1ccccc1
Agent: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)C=[N+]=[N-])N2C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)CCl)N2C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 5.8 g of benzyl α-(3ξ-carboxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 70 ml of benzene and 0.14 ml of N,N-dimethylformamide is added 1.33 ml of oxalyl chloride at room temperature under nitrogen atmosphere, and the mixture allowed to stand for 30 minutes, and concentrated to 1/2 volume. The resulting solution of benzyl α-(3ξ-chlorocarbonyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is mixed under ice-cooling with an ether solution of diazomethane prepared from 4 g of N-nitrosomethylurea. The resulting solution of benzyl α-(3ξ-diazoacetyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is mixed with 2.1 ml of ether containing 0.47 g of hydrogen chloride at 0° C., and after 2 hours, evaporated to yield 6.3 g of benzyl α-(3ξ-chloroacetyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as an yellow-brown oil.
Reaction SMILES: OC[C@@H](N)CC(C)C.COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:34])[C:30]=1[N+:31]([O-:33])=[O:32])[NH2:27].[CH3:35][C:36]1[CH:37]=[C:38]([N:46]=[C:47]=[S:48])[CH:39]=C(C)[C:41]=1[N+]([O-])=O>>[CH3:34][C:29]1[CH:28]=[C:26]([N:27]=[C:47]2[NH:46][C@@H:38]([CH2:37][CH:36]([CH3:41])[CH3:35])[CH2:39][S:48]2)[CH:25]=[C:24]([CH3:23])[C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1cc(N)cc(C)c1[N+](=O)[O-]
Reactant: Cc1cc(N=C=S)cc(C)c1[N+](=O)[O-]
Agent: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(N=C2N[C@@H](CC(C)C)CS2)cc(C)c1[N+](=O)[O-]

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 3,5-Dimethyl-4-nitroaniline was converted to 3,5-Dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 3,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:12]=2[F:26])[CH:7]=[CH:6][N:5]=1)(=O)N.C[N:28](C=O)C>>[NH2:28][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:12]=2[F:26])[CH:7]=[CH:6][N:5]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Reactant: CN(C)C=O
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Yield: 86 %

Procedure:
Prepared in a manner similar to that which is described in Step A of Example 91. Ethyl 3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (900 mg, 2.5 mmol) in DMF (10.0 mL) was converted to ethyl 3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (710 mg, 86% yield). MS(ESI+) m/z 334.26 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.S(Cl)(Cl)=O.[NH3:19]>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:19])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CSc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: N
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(N)=O)c([N+](=O)[O-])c1

Procedure:
A stirred solution of 4-methylthio-2-nitrobenzoic acid (4.56 g) and thionyl chloride (2.77 g) in benzene (65 ml) was heated under reflux for 1.5 hours. Aqueous ammonia (10 ml) was added dropwise to the stirred cooled (5° C.) reaction mixture, which was then stirred with cooling for 45 minutes. Benzene was removed under reduced pressure and the residual solid was washed with water and recrystallized to yield 4-methylthio-2-nitrobenzamide, (2.35 g), m.p. 176°-8° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13]>O>[N:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[N:11][C:12]=1[OH:13]
Reactant: NC(N)=O
Reactant: COC(=O)c1sccc1N
Solvent: O
Product: Oc1nc(O)c2sccc2n1
Temperature: 180 °C

Procedure:
A solid mixture of methyl 3-aminothiophene-2-carboxylate (40.0 g, 254 mmol) and urea (99.4 g, 163 mmol) was stirred and heated to 180° C. for 5 h. The now semi-fluid mixture was cooled to 75-80° C. before water (800 ml) was added. After stirring at room temperature for 2 h the formed precipitate was filtered off, washed with further water and dried at 40° C. i. vac. Thieno[3,2-d]pyrimidine-2,4-diol was obtained as cream-coloured powder (37.15 g, 87% yield) of >95% purity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[C:18](N)(=O)[CH2:19][CH2:20]C.B(Br)(Br)Br>ClCCl>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH:19]=[CH2:18]
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Reactant: CCCC(N)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 75 %

Procedure:
(trans)-N-[[2-(3-Hydroxyphenyl)cyclopropyl]methyl] butanamide: To a stirred solution of (trans)-N-[f2-(3-methoxyphenyl)cyclopropyl]methyl]butanamide (3.50 g, 14.2 mmol) in dichloromethane (50 mL) at -78° C. was added BBr3 (28.4 mL, 1N in CH2Cl2, 28.4 mmol) dropwise. After addition was complete, the cooling bath was removed and stirring was continued for 18 h. The solution was poured over ice/H2O (100 mL) and extracted with 2.5N NaOH. The basic extracts were combined, washed with dichloromethane, and acidified (conc. HCl). The acidic solution was extracted with dichloromethane, the organics were combined, washed with brine, dried (MgSO4), and concentrated to afford 2.49 g (75%) of the title compound: 1H NMR (300 MHz, DMSO-d6)δ0.72-0.84 (m, 5H), 1.09-1.15 (m, 1H), 1.42-1.54 (m, 2H), 1.63-1.69 (m, 1H), 2.02 (t, J=5.0 Hz, 2H), 2.99-3.11 (m, 2H), 6.39-6.50 (m, 3H), 6.98 (t, J=7.8 Hz, 1H), 7.91 (s, 1H), 9.19 (br s, 1H); IR (NaCl Film) 3300, 2964, 1642, 1585, 1542, 1466 cm-1 ; MS (isobutane--DCI) m/e 233; Analysis calc'd for C14H19NO2.0.1 H2O: C, 71.52; H, 8.23; N, 5.96; found: C, 71.53; H, 8.32; N, 5.92.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]([CH3:31])=[CH:29][S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[C:30]([CH3:31])=[CH:29][S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: N#Cc1ncc(CO)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ncc(C=O)cc1Cl
Temperature: 40 °C
Yield: 59.3 %

Procedure:
CrO2 (Magtrieve) (335 mg, 3.99 mmol) was added to a solution of 3-chloro-5-(hydroxymethyl)-2-pyridinecarbonitrile (33.6 mg, 0.199 mmol) in DCM (2.5 ml) and the mixture was stirred at 40° C. TLC (5% MeOH in DCM) after 3 h showed some starting material. It was heated at 40° C. overnight and full conversion was observed by TLC. The solids were filtered off and the solvent evaporated, yielding 3-chloro-5-formyl-2-pyridinecarbonitrile (19.7 mg, 0.118 mmol, 59% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:14]=[C:13](I)[CH:12]=[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:5]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[N:26]=1.O>O1CCCC1.C(#N)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:14]=[C:13]([C:31]2[CH:32]=[C:33]3[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][CH3:17])=[N:26][N:27]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:48])([CH3:50])[CH3:49])[C:28]3=[N:29][CH:30]=2)[CH:12]=[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:5]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1cc(I)cc(C(=O)N(C)C)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)N(C)C)cc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)c1
Yield: 69 %

Procedure:
In a personal chemistry microwave vial 5-Iodo-N,N-dimethyl-isophthalamic acid methyl ester (0.75 g, 2.25 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.08 g, 2.25 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium carbonate (20 ml) was degassed with nitrogen and 1,1′-bis(diphenylphosphino) ferrocenepalladium(II)-dichloride dichloromethane adduct (0.184 g, 0.23 mmol) was added and the vial sealed. This reaction mixture was irradiated in a microwave vial to 100° C. for 30 minutes. 100 ml water was added and this mixture was extracted with ethyl acetate (3×) the combined organic layers were dried over Magnesium Sulfate and purified by silica gel chromatography to yield 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-isophthalamic acid methyl ester as a white solid (0.87 g, 69% yield). MS: m/z 583.7 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:17]1[CH2:18][CH:13]3[CH2:19][CH:16]1[CH2:15][N:14]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:7][N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1nncc2cc(Br)ccc12
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.245 g, 1 mmol), (s,s) tert-butyl 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (0.22 g, 1.1 mmol) and potassium carbonate (0.14 g, 1 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After about 20 min., all starting material was converted to product (M+1=405, 407). The mixture was concentrated under vacuum, and purified via flash chromatography (silica gel) eluting with 1:1 hexane/ethyl acetate to give (0.18 g) tert-butyl 5-(6-bromophthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate as a yellow solid. Found MS (ES+): 405, 407(M+H)+.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>O1CCCC1>[C:1]1([N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:12]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCNc1ccccc1
Solvent: C1CCOC1
Product: O=C1NCCCN1c1ccccc1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
2.5 g (16.5 mM) of N1 -phenylpropane-1,3-diamine are dissolved in 56.5 ml of anhydrous tetrahydrofuran. A mixture of 3.8 g (23.3 mM) of carbonyldiimidazole in 115 ml of anhydrous tetrahydrofuran is poured into the solution, and the mixture is left at room temperature overnight. The mixture is concentrated, taken up in ethyl acetate, washed with normal HCl and dried over MgSO4 to yield 2 g of a white solid that melts at 210°-211° C. and corresponds to the expected product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH3:8].[CH3:25][C:26]1[C:27]([CH:32]=O)=[N:28][CH:29]=[CH:30][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:25][C:26]1[C:27]([CH2:32][N:9]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@@H](NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCN1C(=O)c2ccccc2C1=O)C(C)c1ccccn1

Procedure:
Using General Procedure B, reaction of (R)-2-[4-(1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dion and 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave 2-{4-[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-butyl}-isoindole-1,3-dione. 1H NMR (CDCl3) δ 1.21-1.32 (m, 2H), 1.38-1.47 (m, 5H), 2.25 (s, 3H), 2.35-2.54 (m, 1H), 2.54-2.60 (m, 1H), 3.48 (t, 2H, J=7.5 Hz), 3.79 (s, 2H), 3.94-4.00 (m, 1H), 6.97-6.99 (m, 1H), 7.05-7.10 (m, 1H), 7.29-7.36 (m, 2H), 7.56-7.57 (m, 1H), 7.66-7.69 (m, 2H), 7.78-7.81 (m, 2H), 8.27 (d, 1H, J=3.5 Hz), 8.49 (d, 1H, J=3.5 Hz). Deprotection with H2NNH2.H2O following General Procedure E gave N1-(3-methyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-butane-1,4-diamine as a beige oil. 1H NMR (CDCl3) δ 1.03 (s, 1H), 1.20-1.26 (m, 2H), 1.31-1.37 (m, 2H), 1.49 (d, 3H, J=6.0 Hz), 2.31 (s, 3H), 2.39-2.56 (m, 4H), 3.83 (s, 2H), 3.97-4.04 (m, 1H), 7.07-7.09 (m, 2H), 7.39 (d, 2H, J=9.0 Hz), 7.61-7.62 (m, 1H), 8.34-8.36 (m, 1H), 8.53-8.55 (m, 1H). Conversion to the HBr salt using General Procedure D gave COMPOUND 243 as a white solid. 1H NMR (D2O) 1.47-1.49 (m, 4H), 1.59 (d, 3H, 6.6 Hz), 2.45 (s, 3H), 2.60-2.66 (m, 1H), 2.70-2.77 (m, 1H), 2.85-2.86 (m, 2H), 4.30 (s, 2H), 4.57-4.60 (m, 2H), 7.81-7.85 (m, 1H), 7.99 (t, 1H, J=6.6 Hz), 8.13 (d, 1H, J=9.0 Hz), 8.32 (d, 1H, J=7.2 Hz), 8.56-8.58 (m, 2H), 8.77 (d, 1H, J=5.1 Hz). 13C NMR (D2O) δ 15.00, 17.00, 23.97, 25.01, 39.52, 51.06, 52.70, 59.88, 125.85, 126.82, 126.88, 137.10, 138.28, 142.11, 148.19, 148.25, 152.29, 156.10. ES-MS m/z 299 (M+H). Anal. Calcd. for C18H26N4.3.4HBr.0.3C4H10O.2.3H2O: C, 36.19; H, 5.85; N, 8.79; Br, 42.64. Found: C, 36.11; H, 5.54; N, 8.75; Br, 42.65.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)[NH2:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:24]2)=[CH:26][CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(NN)cc1
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CCCC1)C2=O
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CCCC2)cc1

Procedure:
The title compound was prepared from methyl 3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate; Preparation 31 (286 mg, 1.0 mmol) and 4-hydrazinylbenzonitrile hydrochloride (Aldrich; 254 mg, 1.5 mmol) according to Method B and Method C. 2-(4-Cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid was obtained (yellow solid, 142 mg, 0.367 mmol, 37% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br. s., 1H), 7.93 (d, J=7.8 Hz, 1H), 7.53-7.66 (m, 3H), 7.46 (s, 1H), 7.27 (d, J=9.0 Hz, 2H), 4.90 (dd, J=9.4, 7.0 Hz, 1H), 4.77 (dd, J=10.4, 5.7 Hz, 1H), 4.30 (dd, J=12.7, 10.7 Hz, 1H), 3.98 (ddd, J=12.9, 9.8, 5.9 Hz, 1H), 2.02-2.16 (m, 1H), 1.56-1.67 (m, 1H), 1.43-1.55 (m, 3H), 1.29-1.43 (m, 2H), 1.13-1.29 (m, 2H). ES-MS m/z 388 (M+H).