Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:17]I>C(#N)C>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[CH3:17].[I-:1]
Reactant: CI
Reactant: CN1C=C[NH+](C)C1C=Cc1ccccn1
Agent: [I-]
Solvent: CC#N
Product: CN1C=C[NH+](C)C1C=Cc1cccc[n+]1C

Procedure:
1,3-Dimethyl-2-[2-(2-pyridinyl)ethenyl]-1H-imidazolium iodide (6.5 g) and 10 ml of methyl iodide are refluxed in 20 ml of acetonitrile for one hour. The resulting solid is filtered off and crystallized from methanol to yield 5.5 g of the title compound, melting point 75° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[NH:17][C:18]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:19])[C:8]1=[O:26].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[O:46]=[C:47](Cl)OC(Cl)(Cl)Cl.CCOCC>ClCCl>[Cl:25][C:22]1[S:21][C:20]([C:18]([NH:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[C:15](=[O:16])[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][CH:29]=[C:3]([CH2:2][N:1]=[C:47]=[O:46])[CH:4]=2)[C:8]3=[O:26])=[O:19])=[CH:24][CH:23]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: CCOCC
Product: O=C=NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 430 mg (1.0 mmol) of N-{2-[3-(aminomethyl)benzyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-5-chloro-2-thiophenecarboxamide and 433 mg (2.0 mmol) of 1,8-bis-(dimethylamino)naphthalene in 222 ml of dichloromethane is added dropwise to an ice-cooled solution of 0.12 ml (0.96 mmol) of diphosgene in 7.5 ml of dichloromethane. After 5 min at 0° C., the mixture is warmed to room temperature and stirred for 35 min, and 40 ml of ether are then added. Insoluble particles are filtered off and the filtrate is concentrated and dried under high vacuum. The resulting solid is immediately reacted further, without further purification. Yield: 454 mg (99.5% of theory).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3([CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12]3=[O:22])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O1CCOCC1.C(O)C.[CH2:34]([NH:36][C:37]([C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:38])[CH3:35].C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:16]1([N:13]2[CH2:14][CH2:15][C:11]3([N:7]([CH2:6][C:5]4[CH:23]=[CH:24][C:2]([C:42]5[CH:41]=[CH:40][C:39]([C:37]([NH:36][CH2:34][CH3:35])=[O:38])=[N:44][CH:43]=5)=[CH:3][CH:4]=4)[CH2:8][CH2:9][CH2:10]3)[C:12]2=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCNC(=O)c1ccc(B(O)O)cn1
Reactant: O=C1N(C2CCCCC2)CCC12CCCN2Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: CCNC(=O)c1ccc(-c2ccc(CN3CCCC34CCN(C3CCCCC3)C4=O)cc2)cn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-bromobenzyl)-7-cyclohexyl-1,7-diazaspiro[4.4]nonan-6-one (15 mg, 0.000038 mol; prepared according to procedures analogous to those described for the synthesis of Example 1, steps 1-7) in 1,4-dioxane (1 mL, 0.01 mol) and ethanol (200 μL, 0.003 mol) was added sequentially: {6-[(ethylamino)carbonyl]pyridin-3-yl}boronic acid (15 mg, 0.000077 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (1:1) (3 mg, 0.000004 mol), potassium carbonate (1.0 E1 mg, 0.000077 mol), and water (400 μL, 0.02 mol). The resulting mixture was made in a vial which was then sealed, evacuated, and purged with N2 (g). The mixture was then heated to 90° C. and stirred for 16 h. The crude reaction mixture was then purified by prep. HPLC/MS to afford the desired product. LC/MS: 461.3 (M+1H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:32]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[NH:37]1[CH2:43][C:41](=[O:42])[NH:40][C:38]1=[O:39].N1CCCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:43]4[C:41](=[O:42])[NH:40][C:38](=[O:39])[NH:37]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=O)cnn23)c1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)c1
Temperature: 80 °C
Yield: 69 %

Procedure:
To the reaction flask, tert-butyl 3-(5-(3-chlorophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate (122 mg, 0.3 mmol) was added to ethanol (1.3 mL) along with hydantoin (26 mg, 0.3 mmol) and piperidine (26 μL, 0.3 mmol). The reaction was heated at 80° C. for 2 hours in the microwave then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, tert-butyl 3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate, was recovered as a solid in 69% yield. LCMS (M+1=546)
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4](Cl)=[C:3]([C:8]#[N:9])[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][Si:30]([CH3:32])([CH3:31])[C:33]#[C:34][C:4]1[N:5]=[CH:6][CH:1]=[CH:2][C:3]=1[C:8]#[N:9]
Reactant: N#Cc1cccnc1Cl
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ncccc1C#N
Temperature: 25 °C
Yield: 74.9 %

Procedure:
In a suitably sized pressure vessel, commercially available 2-chloro-nictinonitrile (1.5 g, 10.8 mmol) was combined with triphenylphosphine (0.228 g, 8 mole %) and palladium (II) acetate (0.083 g, 3.5 mol %) in triethylamine (20 mL). Nitrogen was bubbled through the resulting suspension at room temperature for five minutes then trimethylsilylacetylene (8.5 mL, 60.1 mmol) was added, the vessel sealed and immersed in an 80° C. oil bath. After 18.5 h the pressure tube was cooled to room temperature and the contents were filtered. The filtrate was concentrated under vacuum and the crude product purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give the title compound (1.62 g, 75%) as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)CC(NS(C)(=O)=O)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.25 g, 1.7 mmol) and triethylamine (0.5 mL) in CH2Cl2 (10 mL) was treated with methansulfonyl chloride (0.25 mL). The resulting solution was stirred overnight at room temperature. The reaction mixture was treated with ethyl acetate (100 mL) and washed sequentially with aqueous 1N HCl solution (3×20 mL), saturated aqueous NaHCO3 solution (3×20 mL), and brine (3×20 mL). The organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography (silica gel, 1:1 ethyl acetate/heptane) to give the title compound as a pale peach powder (0.15 g, 51%), mp=83-84° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.B.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH2:8][CH3:9])=[CH:11][CH:12]=1
Reactant: CC(=O)NCc1ccc(F)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
N-(4-Fluorobenzyl)acetamide (1.344 g, 8.039 mmol) was dissolved in THF (100 ml) and was cooled to zero degrees under argon atmosphere. (Methylthio)methene compound with borane (1:1) (1.527 g, 20.098 mmol) was added and the mixture was refluxed overnight at RT. HCl (15 ml, 10%) was gently added and was stirred overnight. The solvent was removed by evaporation. Diethyl ether (20 ml) was added and the product was extracted to the water phase by K2CO3 (3×15 ml). The water phase was acidified by HCl (10 ml, 10%) and the product was extracted to the organic phase by EtOAc (3×15 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.309 g of N-(4-fluorobenzyl)ethanamine (yield 25.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:28]=2Cl)=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN1C(=O)CCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:28]=2[O:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:9])=[O:26])[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.1 %

Procedure:
To a solution of 5-fluoro-2-methylphenol (43.0 mg, 341 μmol) in NMP (1.5 ml) was added sodium hydride (15.0 mg, 375 μmol; 60% dispersion in mineral oil), and the suspension was stirred at room temperature under an argon atmosphere for 20 min. After addition of 50.0 mg (114 μmol) of the compound of step 1, the reaction mixture was stirred for 2 h at 150° C. in a microwave reactor. The mixture was filtered and purified by preparative HPLC. The eluate was lyophilized overnight to give 23 mg of the title compound.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].O.[NH2:11][NH2:12]>C(O)C>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[NH:12][N:11]=1)[CH3:1]
Reactant: CCC(=O)CC(=O)CC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1cc(CC)[nH]n1
Temperature: 25 °C
Yield: 99728.3 %

Procedure:
A solution of 3,5-heptanedione (10.0 g, 0.078 mmol) in ethanol (40 ml) was treated dropwise with hydrazine hydrate (4.2 ml, 0.086 mmol) at room temperature producing an exotherm that was cooled by use of an ice bath. After the addition was complete the reaction mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure. The oil was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane (×2). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound (9.66 g) as a pale yellow oil that partly solidified on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:18][CH:17]=2)[CH:15]=1.[CH3:30][N:31]1[CH2:36][CH:35]=[C:34](B(O)O)[CH2:33][CH2:32]1.[F-].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][N:31]1[CH2:32][CH:33]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)[CH2:35][CH2:36]1
Reactant: CN1CC=C(B(O)O)CC1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC=C(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Temperature: 150 °C

Procedure:
A suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), 1-Methyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (Boron Molecular, 221 mg; 0.99 mmol; 3.0 eq.), PdCl2(PPh3)2 (23 mg; 0.03 mmol; 0.10 eq.), cesium fluoride (151 mg; 0.99 mmol; 3.0 eq.) in dioxane (3 mL) and water (1.5 mL) was degassed with nitrogen flow and heat in MW at 150° C. for 10 min. The reaction mixture was filtered through a celite pad, water was added to the filtrate. Aqueous phase was extracted three time with DCM using separators tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as a yellow powder. 1H NMR (300 MHz, DMSO) δ 13.36 (brs, 1H), 9.39 (s, 1H), 8.31 (s, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.78-7.47 (m, 4H), 6.32-6.11 (m, 1H), 3.84-3.49 (m, 6H), 3.46-3.25 (m, 2H), 3.11-2.98 (m, 2H), 2.71-2.58 (m, 4H), 2.30 (s, 3H). HPLC (Condition A): Rt 2.22 min (purity 94.5%). MS (ESI+): 470.3, MS (ESI−): 468.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:27]([CH:24]3[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]3)=[O:28])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2cnc3ccc(Br)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture of 7-bromo-2-hydrazinylquinoxaline (3 g, 12.55 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3.16 g, 13.81 mmol), EDCI (2.89 g, 15.06 mmol), HOBt (2.03 g, 15.06 mmol), and TEA (1.9 g, 18.83 mmol) in DMF (100 mL) was stirred at r.t. overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (3×100 mL). The combined layers were dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 4-(2-(7-bromoquinoxalin-2-yl)hydrazinecarbonyl)piperidine-1-carboxylate as pale yellow solid (3.5 g, yield 62%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][C:8]([CH3:10])=O.C(O)(=O)C.C(O[BH3-])(=O)C.[Na+]>ClC(Cl)C>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH:8]([CH3:10])[CH3:7]
Reactant: NCCCCO
Reactant: CC(C)=O
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)NCCCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-aminobutanol (2.0 mg, 22.4 mmol) in 110 ml of dichloroethane were added acetone (3.3 ml, 44.8 mmol), acetic acid (5 eq.), and sodium acetoxyborohydride (11.9 g, 56.09 mmol). The cloudy mixture was stirred at ambient temperature for about 18 hours. The reaction was quenched with saturated sodium bicarbonate. Sodium hydroxide (1 M) was added to adjust the pH to about 10. The aqueous layer was extracted with a mixture of isopropyl alcohol and methylene chloride (1:3). The organic fractions were combined and dried over sodium sulfate, filtered, and concentrated. The desired intermediate was further purified by bulb to bulb distillation to yield 1.4 grams as a dear oil. If desired, additional yield may be recovered by extracting the aqueous fraction with 3:1 toluene:butanol.
Reaction SMILES: [C:1]([CH:3]1[C:7](=O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[NH:19][N:18]=1>C(O)C>[NH2:2][C:1]1[N:19]2[N:18]=[C:17]([CH3:16])[CH:21]=[C:20]2[N:22]=[C:7]2[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C:3]=12
Reactant: Cc1cc(N)[nH]n1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Solvent: CCO
Product: Cc1cc2nc3c(c(N)n2n1)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C

Procedure:
To a stirred solution of 250 mg (1.19 mmol) of tert-butyl 3-cyano-4-oxopyrrolidine-1 carboxylate in ethanol (5 mL) was added 115 mg (1.19 mmol) of 3-methyl-1H-pyrazol-5-amine. The reaction mixture was refluxed for 1 h, cooled to ambient temperature and the solvent evaporated in vacuo. The resulting residue was chromatographed on a Biotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanes gradient) to yield the title compound as a white solid. LC/MS 290.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:43][CH2:44][C:45]1[C:46]([OH:53])=[N:47][C:48]([CH3:52])=[CH:49][C:50]=1[CH3:51]>ClCCl.O.C(N(CC)CC)C>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:43][CH2:44][C:45]2[C:46]([OH:53])=[N:47][C:48]([CH3:52])=[CH:49][C:50]=2[CH3:51])=[O:13])=[CH:14][CH:15]=1)[CH3:6]
Reactant: CC(Oc1ccc(F)cc1F)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccc(F)cc3F)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
To a solution of 4-(1-(2,4-difluorophenoxy)ethyl)benzoic acid (127 mg, 0.5 mmol) in dichloromethane (80 mL) was added N-hydroxybenzotriazole (101.25 mg, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mm ol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added, the solution was stirred at room temperature for 12 hours, water was added and washed 3 times, the organic layer was evaporated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(2,4-difluorophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (78 mg, 38%).
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]>CN(C=O)C.C(Cl)Cl>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: [S-]c1ccccc1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
A solution of sodium thiophenolate (3.96 g, 30 mmol) in 60 mL of DMF was heated at 50° C. with 4-chloro-3-nitrotoluene (2.65 mL, 20 mmol) with stirring for 2 days. Cooled to room temperature and diluted with CH2Cl2. Washed with water and dried the organic layer over Na2 SO4. Filtered and concentrated under vacuum giving the title compound (4.29 g, 87%) 1H NMR (300 MHz, CDCl3) δ ppm: 2.36 (s, 3H) 6.76 (d, J=8.09 Hz, 1H) 7.16 (d, J=8.46 Hz, 1H) 7.45 (m, 3H) 7.58 (m, 2H) 8.03 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1.O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC1C=CC=CC=1C(OC)=O>>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1
Agent: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1

Procedure:
Following the procedure described in EXAMPLE 6, and making non-critical variations using methyl 4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate to replace methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate, the title compound was obtained (100%): 1H NMR (300 MHz, CDCl3) δ 12.96 (s, 1H), 7.90 (d, 2H), 7.43 (d, 2H), 7.22 (t, 1H), 7.17 (d, 1H), 7.00 (t, 1H), 6.94 (d, 1H), 6.68 (s, 1H), 6.21 (s, 1H), 5.90 (s, 2H), 4.98 (s, 2H), 4.76 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 167.5, 156.0, 148.9, 142.6, 142.3, 141.8, 132:1, 130.5, 130.3, 129.3, 127.7, 124.2, 123.7, 120.1, 109.9, 103.5, 101.9, 93.8, 80.4, 58.0, 43.4.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:33])[CH:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10]2.C1C[O:37][CH2:36]C1>>[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:33])[C:19]([CH2:36][OH:37])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10]2
Reactant: C1CCOC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Cc1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C(O[C@H]1CN2CCC1CC2)C(CO)(Cc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Lithium diisopropylamide (0.0048 mol) 2.40 ml of a 2M solution (in heptane/THF/ethylbenzene) was added to a stirred solution of 1.5 g (0.0045 mol) of 2,3-diphenylpropionic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester in 30 ml of THF at −70° C. under a N2 atmosphere. CH2O (gas) was bubbled into the reaction mixture via a steady stream of dry N2 during 10 min at −70° C. and then while the mixture was warmed at room temperature. The reaction was quenched by addition of saturated ammonium chloride solution (100 ml) and the resultant mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, dried over MgSO4 and evaporated to yield 1.9 g of an oil. This 1.9 g were combined with 3.28 g of a previous preparation and the product obtained (5.18 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia from 97.5:2.5:0.25 to 90:10:1. Appropiate fractions were combined and evaporated to obtain the two diastereomers: Intermediates I-22a and I-22b
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:33][CH2:32][N:24]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=[C:23]2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][N:48]=[C:47]([CH3:51])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][N:48]=[C:47]([CH3:51])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cc1nccc(Nc2cc(Br)cn(C)c2=O)n1
Product: CC(=O)OCc1c(-c2cc(Nc3ccnc(C)n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 69.9 %

Procedure:
Following Example 148b, 464 mg of 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a and 443 mg of 162b were reacted to give 162c as a yellow solid (386 mg, 70%). LCMS: [M+H]+ 553