Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].[O-:18][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(N[C@@H]1CCCc2ccccc21)C(F)(F)F
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
To a cooled solution of 1 g (4.1 mmol) of (R)-2,2,2-trifluoro-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acetamide in acetone (30 mL) at 0° C., was added a solution of 2.03 g (8.2 mmol) MgSO4.7H2O in 15 mL of water. After 5 min of stirring, 1.95 g (12.3 mmol) of KMnO4 was added in small portions over 1 hr. The mixture was then stirred overnight, slowly warming to room temp. The mixture was filtered. The filtrate was treated with saturated sodium metabisulfite and filtered. The filtrate was extracted with DCM several times. The combined organic extracts were washed with distilled water and brine, dried over MgSO4 and concentrated in vacuo to afford 0.96 g (91%) of the title compound, whose purity was good enough to use crude.
Reaction SMILES: COC(=O)[C@H:4]([N:7]([C:17](=[O:28])[C@@H:18]([NH:20][C:21](OC(C)(C)C)=[O:22])[CH3:19])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:5][CH3:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:5]([C@H:4]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:17](=[O:28])[C@H:18]([CH3:19])[NH:20][C:21]1=[O:22])[CH3:6]
Reactant: CC[C@H](C(=O)OC)N(Cc1ccc(OC)cc1)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N[C@@H](C)C(=O)N1Cc1ccc(OC)cc1
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of 7.60 g of (R)-2-[((S)-2-tert-Butoxycarbonylamino-propionyl)-(4-methoxy-benzyl)-amino]-butyric acid methyl ester in 116 ml DCM were added 116 ml of TFA at 0° C. during 1 h. After 2 h at 0° C. the reaction mixture was allowed to come to r.t. and stirred for another 1.5 h. The reaction mixture was then concentrated in vacuo, dissolved in EtOAc, and 120 ml of 1M aqueous NaHCO3-solution were added. After stirring for 1 h, the layers were separated. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 5.34 g (100%) of the title compound, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10].C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22]Cl.Cl>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:20][O:21][CH3:22])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Reactant: COCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCOCc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
9.10 g of (4-bromo-3-methylphenyl)methanol was dissolved in 91 mL of methylene chloride and cooled to 5° C., to which 19.7 mL of N-ethyldiisopropylamine and 6.9 mL of chloromethyl methyl ether were successively added dropwise at 5 to 10° C., and then this mixture was stirred for 2.5 hours at room temperature. Water was added to the reaction mixture and adjusted to pH 7 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to yield 10.44 g of 1-bromo-4-[(methoxymethoxy)methyl]-2-methylbenzene as yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]#N)[CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12].C(O)(C(F)(F)F)=[O:25].CC#N>CCOCC.C(Cl)Cl>[CH2:9]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[O:25])[CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCN1CCN(CCCC#N)CC1
Reactant: Cc1ccccc1I
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCN1CCN(CCCC(=O)c2ccccc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10 mL oven-dried flask charged with Mg turnings (100 mg, 4.0 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of 2-iodotoluene (0.66 g, 3.0 mmol) in Et2O (3 mL) and the reaction mixture was allowed to reflux for 1 hours. A suspension of compound 16 (0.43 g, 2.0 mmol) in CH2Cl2 (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (6 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (8 mL, 2 M). Addition of THF (15 mL) was followed by extraction with CH2Cl2 (3×20 mL), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.50 g of crude 17. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN+0.1%TFA] to produce an analytical pure sample of compound 17. LC-MS [M+H]+ 302 (cald. 302.5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Br:18]>C1C=CC=CC=1>[Cl-:8].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Br:18]
Reactant: Nc1ccccn1
Reactant: ClCSc1ccc(Cl)cc1Br
Solvent: c1ccccc1
Product: Nc1cccc[n+]1CSc1ccc(Cl)cc1Br
Product: [Cl-]
Yield: 85.9 %

Procedure:
To a solution of 18.8 g of 2-aminopyridine in 180 ml of benzene is added 54.6 g of the product from example 30, and the mixture stirred and heated under reflux for about twelve hours. The cooled mixture is filtered to give about 62.8 g of the named compound, mp about 240°-242°.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].[CH3:32][C:33]1[C:37]([NH2:38])=[C:36]([CH3:39])[NH:35][N:34]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:38][C:37]2[C:33]([CH3:32])=[N:34][NH:35][C:36]=2[CH3:39])=[O:20])[CH:8]=1)=[O:5]
Reactant: Cc1n[nH]c(C)c1N
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]c(C)c1NC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 110 mg, 0.24 mmol), 3,5-dimethyl-1H-pyrazol-4-amine (30 mg, 0.27 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DMF (1.5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (101 mg, 0.26 mmol) and the reaction was stirred for 2 hours at room temperature. The reaction was concentrated in vacuo and the residue purified using Preparative HPLC to afford the title compound (65 mg, 49%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][NH2:7].C1C2C(=CC=CC=2)C=C[C:13]=1[N:22](C)N.[O:25](CCNN)[C:26]1[CH:31]=[CH:30]C=CC=1>C(O)C>[NH2:22][C:13]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[CH:2][CH:3]=2)[C:26](=[O:25])[C:31]=1[CH3:30]
Reactant: NNCc1ccc(Cl)c(Cl)c1
Reactant: NNCCOc1ccccc1
Reactant: CN(N)c1ccc2ccccc2c1
Solvent: CCO
Product: Cc1c(N)[nH]n(Cc2ccc(Cl)cc2)c1=O

Procedure:
The compounds shown in the table which follows were prepared analogously to the procedure described in Example 17:No. Structural formula Recrystallization Yield, % Melting point from of theory °C__________________________________________________________________________18 Ethanol 54 147 From: 3,4-di-chlorobenzylhydrazine + (y)*19 Ethanol 43 120 From: 2-naphthyl-methylhydrazine + (y)*20 Ethanol 40 126 From: phenoxyethylhydrazine + (y)*__________________________________________________________________________ (y)* = β-amino-β-ethoxy-methacrylic acid ether ester?
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1Cl)CCC.[CH2:15]([Mg]Cl)[CH3:16].[O:19]1CCCC1>C(OCC)C.[Cl-].[Mn+2].[Cl-]>[CH2:15]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[CH:6]=[O:19])[CH3:16]
Reactant: CCCC/N=C/c1c(C)cccc1Cl
Reactant: C1CCOC1
Reactant: CC[Mg]Cl
Agent: [Mn+2]
Agent: [Cl-]
Solvent: CCOCC
Product: CCc1cccc(C)c1C=O
Temperature: 7.5 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
This compound was prepared using methodology described in Synthesis 1999, 2138-2144. To a solution of 3.20 g (15.3 mmol) butyl-[1-(2-chloro-6-methyl-phenyl)-meth-(E)-ylidene]-amine in 30 ml tetrahydrofuran at 0° C. was added 0.19 g (1.53 mmol) manganese(II) chloride. 15.3 ml (30.5 mmol) of a 2 M solution of ethylmagnesium chloride in diethyl ether was then added dropwise while the temperature of the reaction mixture was maintained at 5-10° C. After the addition was complete, the reaction mixture was stirred for a further 90 minutes, during which time the temperature rose to 50° C. (exotherm). The reaction mixture was then quenched by dropwise addition of water before being diluted with ethyl acetate. The mixture was then washed sequentially with water and with saturated brine. The phases were separated and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 1.88 g (83%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.26 (3H, t, CH3), 2.60 (3H, s, CH3), 2.98 (2H, q, CH2), 7.09 (1H, d, ArH), 7.12 (1H, d, ArH), 7.35 (1H, dd, ArH), 10.6 (1H, s, CHO).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:13][CH:12]3[CH2:14][CH:9]([CH2:10][N:11]3C(OC(C)(C)C)=O)[CH:8]=2)[CH:2]=1.N1C=CC=C(C2CC3CC(C=2)N(C(OC(C)(C)C)=O)C3)C=1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:13][CH:12]3[CH2:14][CH:9]([CH2:10][NH:11]3)[CH2:8]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC2C=C(c3cccnc3)CC1C2
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1CC2CC(c3cccnc3)=CC1C2
Solvent: CO
Product: c1cncc(C2CC3CNC(C3)C2)c1
Reaction time: 48 h

Procedure:
To a solution of a mixture of t-butyl 3-(3-pyridinyl)-6-azabicyclo[3.2.1] oct-2-ene-6-carboxylate and t-butyl 3-(3-pyridinyl)-6-azabicyclo[3.2.1] oct-3-ene-6-carboxylate (150 mg) in methanol (5 ml) was added catalytic 10% Pd/C and the mixture was subjected to hydrogenolysis (45 psi) for 48 h. The reaction was filtered through Celite and concentrated by rotary evaporation, and then the residue was taken up in dichloromethane (1 ml) and treated with trifluoroacetic acid (2 ml). After 3 h, the mixture was concentrated to dryness by rotary evaporation, partitioned between water and dichloromethane, and the organic layer discarded. The aqueous layer was made basic with sodium hydroxide and extracted with dichloromethane. After drying over sodium sulfate, the filtered solution was concentrated to dryness by rotary evaporation and the residue purified by column chromatography, using a methanol/dichloromethane gradient (0-10% methanol with 1% ammonium hydroxide) as eluent. The product fractions were pooled and concentrated to give the desired product (20 mg). It was then re-chromatographed (same conditions) to give the free base (10 mg) as a brown oil.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].O.[OH-].[Li+].O1CCCC1.CO>O>[C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)c1cccc(C2(C#N)CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#CC1(c2cccc(C(=O)O)c2)CCCCC1
Yield: 90.5 %

Procedure:
Using methyl 3-(1-cyanocyclohexyl)benzoate (1.3 g, 5.3 mmol), lithium hydroxide-monohydrate (0.52 g, 13 mmol), tetrahydrofuran (18 mL), methanol (6.0 mL) and water (6.0 mL) as starting materials and in the same manner as in Reference Example 37, the title compound (1.1 g, 88%) was obtained as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[C:24]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:24]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[CH:30]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(-c2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2ccccc2-c2ccccc2)c1
Yield: 13 %

Procedure:
Phthalimide 29 was coupled with biphenyl-2-ylmethyl triphenylphosphonium bromide. Purification by flash chromatography (5% EtOAc-hexanes) gave (E)-2-(3-(3-(2-(biphenyl-2-yl)vinyl)phenyl)propyl)isoindoline-1,3-dione (0.100 g, 13%) and (E/Z)-2-(3-(3-(2-(biphenyl-2-yl)vinyl)phenyl)propyl)isoindoline-1,3-dione (0.230 g, 30%) as colorless oils. Trans-isomer: 1H NMR (400 MHz, CDCl3) δ 781-7.83 (m, 2H), 7.72-7.74 (m, 1H), 7.68-7.70 (m, 2H), 7.63-7.65 (m, 2H), 7.42-7.52 (m, 6H), 7.35-7.40 (m, 2H), 7.22-7.24 (m, 1H), 7.09-7.14 (m, 3H), 3.79 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.05-2.13 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1(CC)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH3:32])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1>>[ClH:1].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH3:32])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:29][CH2:30]2)[CH:24]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Product: COc1ccc(Cl)cc1N1CCN(CCCCC2C(=O)Nc3ccccc32)CC1
Product: Cl

Procedure:
The title compound is prepared according to process B by applying processing method 2 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(5-chloro-2-methoxyphenyl)-piperazine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:28]=[C:29]([C:34]#[N:35])[N:30]=[C:31]([CH3:33])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Reactant: Cc1cc(Br)cc(C#N)n1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3nc(C)cs3)c2)cc(C#N)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-6-methyl-pyridine-2-carbonitrile instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a yellow solid, MS (ISP): m/e=350.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11](S(C)(=O)=O)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:19]([NH2:21])=[O:20])=[N:3]1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O>[CH:22]1([NH:28][C:11]2[N:10]=[CH:9][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([C:19]([NH2:21])=[O:20])=[N:3][N:2]([CH3:1])[C:14]=4[C:13]=3[N:12]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:22]1([NH:28][C:11]2[N:10]=[CH:9][C:8]3[CH2:7][CH2:6][C:5]4[C:4]([C:19]([NH2:21])=[O:20])=[N:3][N:2]([CH3:1])[C:14]=4[C:13]=3[N:12]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(S(C)(=O)=O)ncc1CC2
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Product: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCCCC3)ncc1CC2
Product: Cn1nc(C(N)=O)c2ccc3cnc(NC4CCCCC4)nc3c21

Procedure:
1.5 g of 1-methyl-8-(methylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were dissolved in 100 mL of dry dimethylsulfoxide and 1.15 mL of cyclohexylamine were added. After 16 hours at 80° C. under nitrogen the solvent was evaporated at reduced pressure. The residue was then redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness. By chromatography on a silica gel column (eluant dichloromethane/acetone 9/1) 300 mg of 8-(cyclohexylamino)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide and 200 mg of 8-(cyclohexylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide and were obtained (30% yield overall).
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(OC)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 86 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of ethyl 4-hydroxy-7-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.52 g, 1.6 mmol), tert-butyl 2-aminoacetate hydrochloride (0.39 g, 2.3 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.61 g, 4.7 mmol). The mixture was warmed to 86° C. and stirred for 4 hours, M+1=418. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.35 g of the title compound as a pale yellow solid. MS (m/z)=418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=C([CH2:23][C:24](O)=[O:25])C=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][C:42]1[N:43]([CH3:47])[CH:44]=[CH:45][CH:46]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:23][C:24]([NH:39][CH2:40][CH2:41][C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)=[O:25])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Reactant: O=C(O)Cc1cccnc1
Reactant: Cn1cccc1CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1cccc1CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hr with a stream of nitrogen bubbling through it. A solution of 2-(2-aminoethyl)-1-methylpyrrole (5.40 g, 0.0435 mole) in tetrahydrofuran (6 ml) was added and the mixture was stirred at room temperature under nitrogen overnight. The solvent was evaporated under reduced pressure and the resulting oil was triturated in water (100 ml) which caused a solid to form. The solid was collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol and filtered hot. Water was added to the cloud point. Upon cooling, a solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 4.31 g (63%) of title compound, mp 171°-172.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2].CCO>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 106.5 %

Procedure:
To ((3R,5R)-1-benzyl-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (prepared as described in WO2004014893) (0.6 g, 1.971 mmol) Pd(OH)2 on carbon (0.1 g) and EtOH (10 mL) were added and the reaction mixture was stirred at RT under 1 atm of H2. After 2 hours the palladium was filtered off and the solvent was evaporated to give 0.45 g of ((3R,5R)-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester as a colorless oil (>95% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([Cl:30])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:24]1[C:23]2[CH:22]=[C:21]([C:19]3[O:18][N:17]=[C:16]([CH2:15][O:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:20]=3)[O:29][C:28]=2[CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(Cl)nccc4o3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Clc1nccc2oc(-c3nc(COC4CCNCC4)no3)cc12
Reaction time: 1 h

Procedure:
A stirred solution of 4-[5-(4-chlorofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 57, 150 mg, 346 μmol) in CH2Cl2 (4 mL) was treated with H2O (6 μL) and TFA (1.5 mL). After 1 h, the reaction was concentrated in vacuo, then the excess TFA was removed through azeotropic distillation with PhMe under reduced pressure. The remainder was partitioned between EtOAc and 2M NaOH. The aqueous phase was extracted further with EtOAc, then the combined EtOAc extracts were washed with brine and dried (MgSO4). Filtration and solvent evaporation furnished 4-chloro-2-[3-(piperidin-4-yloxymethyl)-[1,2,4]oxadiazol-5-yl]furo[3,2-c]pyridine: m/z (ES+)=335.1 [M+H]+. A mixture of this amine (105 mg, 315 μmol), 2-bromopyrimidine (55 mg, 346 μmol) and DBU (95 μL, 630 μmol) in dioxane (2 mL) was stirred at ambient temperature for 16 h. The reaction was concentrated and the residue purified by column chromatography (EtOAc-IH, 3:7) to yield the title compound: RT=3.40 min; m/z (ES+)=413.1 [M+H]+.