Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH2:36]([O:38][C:39](=[O:45])[C:40](=[N+]=[N-])[CH2:41][CH3:42])[CH3:37].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH:40]([CH2:41][CH3:42])[C:39]([O:38][CH2:36][CH3:37])=[O:45])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[CH:34][N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCOC(=O)C(CC)=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(=O)OCC)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.87 g), rhodium(II) acetate (dimer) (0.0084 g) and toluene (10 mL) was heated to 80° C. under an argon atmosphere, a solution of 2-diazobutyric acid ethyl ester (1.0 g) in toluene (10 mL) was added dropwise, and the mixture was stirred at 80° C. for 30 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 71%).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:11]([CH2:21][N+:22]#[C-:23])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[C-]#N.[Na+]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C@H:1]1[O:10][CH:23]=[N:22][C@@H:21]1[S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccccc1C=O
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccccc1[C@H]1OC=N[C@@H]1S(=O)(=O)c1ccc(C)cc1

Procedure:
In a manner analogous to Preparation 1, 0-anisaldehyde (053 mL, 5.25 mmol), tosylmethylisocyanide (0.98 g, 5.0 mmol) and NaCN (24.5 mg, 0.50 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 332.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([N+:16]([O-])=O)=[CH:4][CH:3]=1.O.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCC1CCOCC1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)nc1NCC1CCOCC1

Procedure:
A solution of Example 7A (1.057 g, 3.89 mmol) in tetrahydrofuran (1 mL) was added to 50% Raney® nickel in water (335.5 mg, 5.72 mmol) in a pressure bottle. The mixture was stirred under 60 psi hydrogen at room temperature for 13 hours. The mixture was filtered through a polypropylene membrane and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[C:10]3([CH2:12][CH2:11]3)[C:9](=O)[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:7]=1
Reactant: COc1ccc(CN2C(=O)C3(CC3)c3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CC3(CC3)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 60 °C
Yield: 62.5 %

Procedure:
To a solution of 2′,4′-dichloro-7′-(4-methoxybenzyl)spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one (14.0 g, 40.0 mmol) in tetrahydrofuran (200 mL) was added 94% Borane-methyl sulfide complex (8.2 mL, 80.0 mmol) dropwise under nitrogen atmosphere. After the addition was over, the reaction mixture was heated to 60° C. overnight. When the reaction was completed, methanol was added to the reaction solution at 0° C., concentrated in vacuum and the residue was purified by silica gel chromatography to afford the product as a white solid (8.4 g, yield 62.4%). 1H NMR (400 MHz, CDCl3) δ ppm 7.20 (d, J=8.6 Hz, 2H), 6.91-6.86 (m, 2H), 4.59 (s, 2H), 3.81 (s, 3H), 3.48 (s, 2H), 1.71 (q, J=4.9 Hz, 2H), 0.82 (q, J=4.9 Hz, 2H).
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[Br:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:38][CH3:39])[CH:34]=2)[CH:29]=1>C(O)C>[C:5]12([C:32]3[CH:31]=[C:30]4[C:35]([CH:36]=[CH:37][C:28]([Br:27])=[CH:29]4)=[CH:34][C:33]=3[O:38][CH3:39])[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCCCCCC
Product: COc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 48 h
Yield: 20.9 %

Procedure:
In a 100 ml flask, under a nitrogen atmosphere, are placed 1 g of 1-acetoxyadamantane and 30 ml of n-heptane, and 0.25 g of concentrated sulfuric acid is introduced. At a temperature of about 20° C., 1.22 g of 2-bromo-6-methoxynaphthalene are poured in slowly and the mixture is left in vigorous agitation for 48 hours. Next, 20 ml of denatured ethanol are introduced and the mixture is evaporated to dryness under reduced pressure. The product is taken up in denatured ethanol and the precipitate is filtered with sintered glass. After drying of the raw product in a vacuum oven for 24 hours at 30° C., one purifies using silica column chromatography. There were obtained 0.4 g of the desired raw product (Melting point: 164°-168° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.O.[OH-].[K+]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnn2c1NCC=C2c1cccc(F)c1
Agent: CC[SiH](CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cnn2c1NCCC2c1cccc(F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a 5.0 g portion of 7-(3-fluorophenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in Ex. 23) in 50 ml of trifluoroacetic acid, stirred under nitrogen and heated to 60° C. was added 7.2 ml of triethylsilane. Heating was continued for 4 hours, then the mixture was stirred at room temperature for 16 hours. The mixture was carefully poured into an ice cooled beaker containing 150 ml of water and 40 g of potassium hydroxide. The precipitate formed was collected, washed with water and dried. The solid was dissolved in dichloromethane and filtered through hydrous magnesium silicate. Evaporation of the filtrate gave a white solid. Recrystallization from isopropyl alcohol gave the desired product, mp 146°-148° C.
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:9](=S)=[S:10]>C(O)C>[OH:1][CH:2]([CH3:8])[CH2:3][N:4]1[CH2:5][CH2:6][NH:7][C:9]1=[S:10]
Reactant: CC(O)CNCCN
Reactant: S=C=S
Solvent: CCO
Product: CC(O)CN1CCNC1=S
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 100 g portion of (N-2-hydroxypropyl)ethylenediamine was dissolved in 500 ml of ethanol, then cooled to -10° C. and 55 ml of carbon disulfide was added. Another 500 ml of ethanol was added, the mixture was stirred 30 minutes and then the precipitate was collected, washed with ether and dried. This solid was heated at 140°-150° C. until hydrogen sulfide evolution ceased and then cooled to room temperature. The solid was dissolved in 500 ml of boiling water, treated with charcoal, clarified and cooled at 4° C. overnight. The solid was collected, washed with water and dried at 60° C. in vacuo, giving 34.1 g of 1-(2-hydroxypropyl)-2-imidazolidinethione mp 101°-102° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH2:31]O)[CH:30]=1)[C:26]#[N:27]>C(#N)C>[Br:20][CH2:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([Cl:22])[CH:30]=1)[C:26]#[N:27]
Reactant: N#Cc1cc(Cl)cc(CO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: N#Cc1cc(Cl)cc(CBr)c1
Reaction time: 0.5 h

Procedure:
(Step 3) Triphenylphosphine (0.94 g) was suspended in acetonitrile (20 ml), bromine (0.19 ml) was added, and the mixture was stirred for 30 min. A solution (10 ml) of 3-chloro-5-(hydroxymethyl)benzonitrile (0.60 g) obtained in Step 2 in acetonitrile was added to the reaction mixture, and the mixture was stirred at 80° C. for 4 hr. The reaction solution was quenched with water, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:2) to give 3-(bromomethyl)-5-chlorobenzonitrile (0.31 g) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]#[C:12][CH3:13]>>[CH2:16]([O:15][C:10]([C:11]1[C:3]([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)=[N:2][O:1][C:12]=1[CH3:13])=[O:14])[CH3:17]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1ccsc1
Product: CCOC(=O)c1c(-c2ccsc2)noc1C
Yield: 91 %

Procedure:
As described for example 69a, N-hydroxy-thiophene-3-carboximidoyl chloride (Organic Letters, 8(17), 3679-3680, 2006, 11.4 g, 69.6 mmol) instead of N-hydroxybenzenecarboximidoyl chloride using ethyl 2-butynoate instead of cyclopropyl-propynoic acid ethyl ester was converted to the title compound (15.0 g, 91%) which was obtained as a dark brown liquid. MS: m/e=238.0 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:8][C:7]=1[CH3:15].[S:16]([Cl:20])(=O)(=[O:18])[OH:17]>>[C:12]([NH:11][C:9]1[S:10][C:6]([C:2]2[O:1][C:5]([S:16]([Cl:20])(=[O:18])=[O:17])=[CH:4][CH:3]=2)=[C:7]([CH3:15])[N:8]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1nc(C)c(-c2ccco2)s1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)o2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To N-(5-(furan-2-yl)-4-methylthiazol-2-yl)acetamide (0.443 g) under an ice-salt bath was added sulfurochloridoic acid (ClSO3H, 5 ml). After 30 min, the reaction was poured into crushed ice (150 g). Extraction with dichloromethane (3×30 ml), drying and concentration gave 5-(2-acetamido-4-methylthiazol-5-yl)furan-2-sulfonyl chloride (0.359 g) that was used directly for next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(Cl)Cl.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>>[NH:12]1[CH2:11][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C2=CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of tert-butyl 4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (332 mg, 1168 μmol) in CH2Cl2 (4.00 mL, 62167 μmol) was added TFA (0.0900 mL, 1168 μmol). The yellow solution was stirred at RT for 3 h. The reaction mixture was dried under reduced pressure providing an off-white crystalline material 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile-TFA (305 mg, 87.6%). MS (ESI, pos. ion) m/z: 185.4 (M+1).
Reaction SMILES: [CH2:1]([NH:16][CH:17]([P:26](=[O:33])([O:30]CC)[O:27]CC)[P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])/[CH:2]=[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])\[CH3:4].[OH-].[Na+:35]>C(O)C>[Na+:35].[Na+:35].[CH2:20]([O:19][P:18]([CH:17]([NH:16][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])\[CH3:4])[P:26](=[O:27])([O-:30])[O-:33])(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(OCC)C(NC/C=C(\C)CC/C=C(\C)CCC=C(C)C)P(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(OCC)C(NC/C=C(\C)CC/C=C(\C)CCC=C(C)C)P(=O)([O-])[O-]
Yield: 31.8 %

Procedure:
A solution of tetraethyl (E,E)-farnesylaminomethylenebisphosphonate (2.42 g) in ethanol (25 ml) was added to a solution of sodium hydroxide (0.40 g) in ethanol (25 ml). The mixture was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (5.0 ml). The solution was subjected to ion-exchange chromatography [Amberlite CG-50 (H+ -type)] to obtain (E,E)-farnesylaminomethylenebisphosphonic acid diethyl ester disodium salt (0.75 g, 29%). Colorless powder, mp: 116°-118° C. Elemental Analysis for C20H37NO6P2Na2.5/2H2O: Calcd.: C, 44.45; H, 7.83; N, 2.59 Found: C, 44.08; H, 7.60; N, 2.59
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([CH2:42][CH3:43])=[N:40][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([CH2:42][CH3:43])=[N:40][CH:41]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: CCc1ncc(Br)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: C1COCCO1
Product: CCc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1
Yield: 54.6 %

Procedure:
A mixture of (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman -3-amine (278 mg, 0.61 mmol), 5-bromo-2-ethylpyrimidine (114 mg, 0.61 mmol), dichloro[1,1′bis(di-tert-butylphosphino)ferrocene]palladium(II) (24 mg, 0.04 mmol) and 2M potassium carbonate (0.64 mL, 1.28 mmol) in dioxane (6 mL) was irradiated in a microwave under an atmosphere of argon at 140° C. for 1 h. The reaction mixture was filtered through a pad of celite, which was washed with methanol, and the filtrate was concentrated in vacuo. The crude was partioned between ethyl acetate and water and the organic layer was dried and concentrated in vacuo. Purification by column chromatography, using a gradient of ethyl acetate in heptane gave 145 mg (55%) of the desired compound, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (s, 2 H), 7.23-7.35 (m, 8 H), 7.14-7.22 (m, 3 H), 6.78-6.87 (m, 2 H), 4.29-4.39 (m, 1 H), 4.04 (t, 1 H), 3.59-3.75 (m, 4 H), 3.03-3.14 (m, 1 H), 2.92-3.03 (m, 3 H), 2.52-2.57 (m, 1 H, obscured by DMSO), 1.36 (t, 3 H); MS (ESI) m/z 436[M+H+].
Reaction SMILES: [C:1]([NH:4][C:5]1[N:14]=[CH:13][C:12]2[C:11](SC)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([NH:4][C:5]1[N:14]=[CH:13][C:12]2[C:11]([NH:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CSc1ncnc2cc(NC(C)=O)ncc12
Reactant: NCc1ccccc1
Product: CC(=O)Nc1cc2ncnc(NCc3ccccc3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A mixture of 7-acetylamino-4-methylthiopyrido[4,3-d]pyrimidine (0.40 g, 1.71 mmol) and benzylamine (1.0 mL, 9.15 mmol) is stirred under N2 at 140° C. for 1 h, and the resulting product is chromatographed on silica gel (EtOAc) to give 7-acetylamino-4-benzylaminopyrido[4,3-d]pyrimidine (0.31 g, 62%) as a white solid. 1H NMR (DMSO) δ 10.79 (1H, s), 9.42 (1H, s), 9.23 (1H, t, J=5.8 Hz), 8.49 (1H, s), 8.18 (1H, s), 7.39 (1H, dt, Jd=6.9 Hz, Jt=1.7 Hz), 7.34 (1H, tt, J=7.3, 1.7 Hz), 7.25 (1H, tt, J=7.1, 1.7 Hz), 4.80 (2H, d, J=5.8 Hz), 2.15 (3H, s).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[CH:16][C:15]=2[F:33])=[O:12])[N:7]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][N:39](C(OCC2C=CC=CC=2)=O)[CH2:38][CH2:37]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[CH:16][C:15]=2[F:33])=[O:12])[N:7]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][NH:39][CH2:38][CH2:37]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc5c(c4)CCN(C(=O)OCc4ccccc4)C5)c(F)c3)ccn2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc5c(c4)CCNC5)c(F)c3)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of benzyl 6-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.14 mmol) in methanol/EtOAc (1:1, 10 mL) was added 10% Pd/C. The solution was stirred overnight under H2 (1 atm) at RT. The solution was filtered and concentrated in vacuo to obtain 1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (73 mg, 90% yield) 1H NMR (400 MHz, DMSO-d6) δ9.00 (brs, 1H), 8.02 (m, 1H), 8.35 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.15 (dt, J=2.4, and 8.8, 1H), 7.95 (s, 1H), 7.1-7.3 (m, 3H), 7.99 (m, 1H), 6.65 (m, 1H), 6.36 (d, J=2.8 Hz, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.53 (m, 1H), 3.01 (m, 1H), 2.88 (m, 1H), 2.79 (m, 1H), 2.60 (m, 1H), 1.25 (s, 9H); MS (ESI) m/z: 581.3 (M+H+).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].Cl.CCOCC.[OH-].[Na+]>CCO.O.[Pd]>[NH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: NCCCN1CCC(C2CCCCC2)(C2CCCCC2)CC1
Yield: 60.9 %

Procedure:
A solution of 3-(4,4-diphenylpiperidin-1-yl)propionitrile (1.01 g, 3.48 mmol, 1.00 equiv) in denatured EtOH (50 mL, 5% isopropanol) was stirred at 120-130° C. in the presence of 10% Pd on activated carbon (1.00 g, Aldrich) and hydrogen at 440 psi for 15 hours. The catalyst was filtered out by use of Celite and washed with CH2Cl2 (100 mL) and MeOH (150 mL). After removal of the solvents, the residue was dissolved in CH2Cl2 (10 mL) and treated with HCl in ether (1.0 M, 8.7 mmol, 2.5 equiv). The solvents were removed again and the residue was recrystallized from hot EtOH-ether (1:2). The white solid obtained from filtration of this mixture was taken up in water (40 mL), which was basified to pH 10 by addition of 1 N NaOH and extracted with CH2Cl2 (3×75 mL). The combined organic solutions were dried over MgSO4 and concentrated to afford 650 mg of colorless oil (61%), which was characterized spectroscopically.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:67]=[CH:66][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C:57]5([C:62]([O:64]C)=[O:63])[CH2:61][CH2:60][CH2:59][CH2:58]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:67]=[CH:66][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C:57]5([C:62]([OH:64])=[O:63])[CH2:58][CH2:59][CH2:60][CH2:61]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CCCC1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2(C(=O)O)CCCC2)C3)cc1)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
The compound of example 533 was prepared analogous to compound of example 98 by hydrolysis of compound of example 532.
Reaction SMILES: C([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])C1C=CC=CC=1.FC(F)(F)C(O)=O>CO.[Pd]>[OH:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15]
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Yield: 95.7 %

Procedure:
A solution of 750 mg (1.40 mmol) of the intermediate obtained in Step A in methanol containing 2 drops of trifluoroacetic acid was hydrogenated at room temperature and 40 psi in the presence of 300 mg of 30% palladium on carbon for 3 days. The catalyst was removed by filtration through Celite and the filtrate concentrated under vacuum to give 600 mg (1.34 mmol, 96%) of product. 1H NMR (200 MHz, CD3OD): 1.22 (d,7 Hz,3H), 1.37 (s,3H), 1.39 (s,3H), 2.14 (m,1H), 2.3-3.0 (m,6H), 3.09 (dd;2,11 Hz;1H), 3.93 (m,1H), 4.38 (dd;8,12 Hz;1H), 7.05 (d,8 Hz,1H), 7.10-7.35 (m,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][CH2:13][P:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[O:15][CH:16]([CH3:18])[CH3:17]>>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:12][CH2:13][P:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)OP(=O)(CN)c1ccccc1
Product: CC(C)OP(=O)(CN=Cc1ccccc1[N+](=O)[O-])c1ccccc1
Yield: 100 %

Procedure:
Starting from 0.1 mol o-nitrobenzaldehyde and 0.1 mol isopropyl aminomethyl-phenylphosphinate, 0.1 mol (100%) of the desired imine is obtained (by following the procedure described in Example 1) in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11]CC2C=CC(OC)=CC=2)[S:4][C:3]=1[C:21]([NH2:23])=[O:22].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][NH:6][C:5]=2[S:4][C:3]=1[C:21]([NH2:23])=[O:22]
Reactant: COc1ccc(COc2ccnc3sc(C(N)=O)c(N)c23)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1sc2[nH]ccc(=O)c2c1N

Procedure:
A solution of 2.43 g 3-amino-4-(4-methoxy-benzyloxy)-thieno[2,3-b]pyridine-2-carboxylic acid amide (Example 18) was stirred 6 h in 20 mL trifluoroacetic acid with a drying tube. The reaction was concentrated in vacuo and then co-evaporated 3 times with toluene and 2 times with CH2Cl2 to give a yellow resin. This was triturated in EtOAc and filtered to give 1.88 g 3-amino-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-2-carboxylic acid amide trifluoroacetic acid salt as a yellow solid.