Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C(C([O:9][C:10]2[CH:18]=[C:17]3[N:12]([CH2:13][C:14]4([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[N:22]([C:23]([C:25]5[C:26]([CH3:30])=[N:27][O:28][CH:29]=5)=[O:24])[CH2:21][CH2:20][N:15]4[C:16]3=[O:19])[N:11]=2)=O)=CON=1.[OH-].[Li+]>C1COCC1.CO>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:14]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]2[N:12]([NH:11][C:10](=[O:9])[CH:18]=2)[CH2:13]3)=[CH:36][CH:35]=1
Reactant: COc1ccc(C23Cn4nc(OC(=O)c5conc5C)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C23Cn4[nH]c(=O)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazin-7-yl 3-methyl-1,2-oxazole-4-carboxylate (120 mg, 0.23 mmol) in THF (1 mL) and methanol (1 mL) was added an aqueous solution of lithium hydroxide (0.1 M, 0.3 mL, 0.3 mmol). The mixture was stirred at room temperature until completion (2 h, monitored by LCMS). The solution was concentrated in vacuo and the residue partitioned between CH2Cl2 and 5% HCl (aq). The organic layer was separated and the aqueous layer further extracted with CH2Cl2. The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography using the Biotage SP4 (12 g cartridge, 0-10% methanol in CH2Cl2, 15 CV) to give 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]-pyrazine-5,7(8H)-dione (155) (36 mg, 38%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:26])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[OH:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (3.65 g, 24 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (5.00 g, 24 mmol), HATU [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium PF6] (11.0 g, 29 mmol) in anhydrous DMF (30 mL) is added DIPEA (8.30 mL, 50 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (150 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (400 g silica gel, gradient elution: 10-80% EtOAc in heptane) to give a pure product (3) as white solid (5.5 g, 67%).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[CH:19]#[C:20][CH2:21][CH3:22]>CN(C)C=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.[Cu](I)I>[C:19]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16])#[C:20][CH2:21][CH3:22]
Reactant: C#CCC
Reactant: NS(=O)(=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC#Cc1ccccc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
0.1 g of bis(triphenylphosphine)palladium(II) chloride, 0.05 g of copper iodide and 18.5 ml of triethylamine are added to a solution of 5 g of 2-iodobenzenesulfonamide in 70 ml of N,N-dimethylformamide. At room temperature, argon and 1-butyne are slowly introduced. After 18 hours the thin-layer chromatogram no longer shows any 2-iodobenzenesulfonamide. The dimethylformamide is evaporated off at 0.1 torr and 40°, and the residue is chromatographed on 300 g of silica gel (Merck ST 60, 40-63 μm). Methylene chloride is used as eluant. In that manner, after concentration of the product-containing fractions at 15 torr and 40°, white pulverulent 2-(but-1-yn-1-yl)-benzenesulfonamide is obtained: 1H-NMR (300 MHz, CDCl3): 8.0 (d, d, 1H); 7.35 (d, d, 1H); 7.29 (d, t, 1H); 7.23 (d, t, 1H); 5.13 (s, 2H); 2.32 (q, 2H); 1.18 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[N:15][NH:16][C:17](=[O:19])[CH2:18][CH:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[N:15][NH:16][C:17](=[O:19])[CH:18]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2=NNC(=O)CC2CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2cc(=O)[nH]nc2CC1
Yield: 79.2 %

Procedure:
7 g 3-oxo-2,3,4,4a, 5,6,8,9-octahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester was dissolved in 70 mL toluene and 6.7 g manganese dioxide was added to the reaction mixture. It was heated at reflux for 48 h. After completion of the reaction, the reaction mixture was diluted with chloroform and filtered through celite. The filtrate was concentrated and purified by column chromatography to afford 5.5 g of the desired product. (M+H)+=266
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([CH:15]=[N:16][N:17]=2)[CH:14]=1.C1C(=O)N([Cl:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:27][C:15]1[N:13]2[CH:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]([C:18]#[N:19])=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cc2nncn2cc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc2nnc(Cl)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 7 h
Yield: 105.1 %

Procedure:
A mixture of 6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (397 mg, 1.37 mmol, prepared according to Example 15, Step 6.4) and NCS (275 mg, 2.06 mmol) in DMF (8 mL) was heated at 50° C. and stirred for 7 h. The reaction mixture was diluted in AcOEt (50 mL) and washed with water (2×25 mL). The organic layer was dried over Na2SO41 filtered, and evaporated to give the crude title compound (466 mg, quant.). MS: 323 [M+1]+; HPLC: AtRet=2.11.
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[N:28]=[CH:27][N:26](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:25]=5)[CH:22]=4)[N:17](C4CCCCO4)[N:16]=3)[CH:10]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:11]2[CH:10]=[C:9]([NH:8][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH:14]=[CH:13][CH:12]=2)=[N:25]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Cyclopentyl-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparative HPLC. (0.043 g, 46% yield over 2 steps): 1H NMR (CD3OD) δ 8.73 (s, 1H), 8.36 (br s, 1H), 8.17 (s, 1H), 8.10 (d, 1H), 7.76–7.67 (m, 3H), 7.5 (t, 1H), 2.85 (quintet, 1H), 2.04–1.63 (m, 8H); ES-MS (m/z) 373.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
A suspension of 10% palladium-on-carbon (100 mg) in ethanol was added to a solution of (R)-(1-(4-amino-5-nitropyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (200 mg, 0.62 mmol) in ethanol (10 mL) at room temperature under a nitrogen atmosphere. The mixture was hydrogenated using a balloon filled with hydrogen gas at room temperature for 2 h. The suspension was filtered through a pad of Celite under a nitrogen atmosphere and the filtrate was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH3:9].C([Li])CCC.C([O:17][B:18](OCC)[O:19]CC)C>O1CCCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:18]([OH:19])[OH:17])[CH3:9]
Reactant: CCOB(OCC)OCC
Reactant: CCc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 25 g (135 mmol) of 1-bromo-2-ethylbenzene in 280 mL of dry tetrahydrofuran, kept at −78° C. in an oven-dried 3 neck flask, was added slowly (keeping the temperature below −68° C.) 67.5 mL of 2.5N n-Butyl lithium in hexanes solution (169 mmol, 1.25 eq.). The reaction was stirred for an additional 1 h, and then 69 mL (405 mmol, 3 eq.) of triethylborate was added slowly, keeping the temperature below −68° C. The reaction was stirred for an additional 40 minutes and then the dry ice bath was removed, the reaction was allowed to warm up to room temperature, and then was poured into 300 mL of ice cold saturated ammonium chloride solution. 200 mL of ice cold ethyl acetate was added, and the mixture stirred for another 30 min. The layers were separated. The organic layer was washed with water, and brine. It was then dried over magnesium sulfate, and concentrated to give 19 g (92% yield) of product. The boronic acid was used without purification in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1scc(-c2ccc(OC)cc2)c1-c1ccc(C#N)cc1C
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CCOC(=O)CCc1scc(-c2ccc(OC)cc2)c1-c1ccc(C#N)cc1C
Yield: 73.7 %

Procedure:
To a solution of (E)-ethyl 3-(3-(4-cyano-2-methylphenyl)-4-(4-methoxyphenyl)thiophen-2-yl)acrylate (Scheme I, 5A, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (0.27 g, 0.669 mmol) in ethanol (40 mL) was added 10% Pd/C (0.25 g), and the reaction mixture was stirred at 20° C. under 20 Psi of hydrogen for 30 h. The reaction mixture was filtrated, and concentrated to give ethyl 3-(3-(4-cyano-2-methylphenyl)-4-(4-methoxyphenyl)thiophen-2-yl)propanoate (Scheme I, 6A, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (0.2 g, yield 73.7%). 1H NMR (DMSO-d6 300 MHz): δ 7.71 (m, 2H), 7.45-7.40 (m, 2H), 6.92 (m, 2H), 6.75 (m, 2H), 4.03-3.96 (m, 2H), 3.66 (s, 3H), 2.76-2.71 (m, 3H), 1.80 (s, 2H), 1.22 (s, 1H), 1.14-1.09 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1c(-c2ccccc2)c(=O)[nH]c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(-c2ccccc2)c(Cl)nc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 4-methyl-3-phenylquinolin-2-one (1.18 g.) and phosphorus oxychloride (60 ml.) was heated under reflux for 2 hr. The mixture was cooled and poured into ice-water (200 ml.), and the resulting mixture was extracted with ethyl acetate (3×50 ml.). The ethyl acetate extract was washed successively with saturated sodium carbonate solution (3×50 ml.) and water (50 ml.), dried (Na2SO4), and evaporated in vacuo to dryness. The residue was crystallised from cyclohexane to give 2-chloro-4-methyl-3-phenylquinoline, m.p. 88°-90°.
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C(O)(=O)C>[CH2:20]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:12][N:11]=[C:9]12)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCn1/c(=N/N=Cc2ccccc2)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(-c3ccccc3)nnc12
Yield: 21.5 %

Procedure:
A solution of benzaldehyde [(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2h-purin-2-ylidene]hydrazone (140 mg, 0.432 mmol) in acetic acid (5 ml) was stirred at 130° C. for 5 hours. The reaction mixture was concentrated in vacuo and purified by prep LCMS to yield the desired product (30 mg, 22% yield). LCMS calculated for C17H19N6O (M+H): 323.2. found: 323.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20]Br>>[Br:18][CH2:19][CH2:20][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1
Reactant: BrCCBr
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 2.1, 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol and 1,2-dibromoethane were converted to yield 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole as off-white solid, 105° C., MS: 411 (M, 2Br).
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([OH:12])=[O:11].[F-].[K+]>CN(C)C=O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([O:12][CH2:2][C:3]([CH2:5][O:12][C:10](=[O:11])[C:9]1[C:8]([Cl:7])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:17])=[O:4])=[O:11]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C(CBr)CBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COC(=O)c1c(Cl)cccc1Cl)COC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
Thus obtained bromomethyl ketone derivative (X, 4.36 g) and 2,6-dichlorobenzoic acid (2.28 g, 1.1 Eq) were dissolved in dimethylformamide (18 ml), KF (1.58 g, 2.5 Eq) was added, and the mixture was stirred for two hours to give 2,6-dichlorobenzoyloxymethyl ketone derivative (XIa). This compound was dissolved in methanol (20 ml) and reacted by adding NaBH4 (412 mg)-methanol solution (40 ml)(−10□˜room temperature, two hours). The reaction was stopped by acetic acid, and the reaction solution was distilled under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (50 ml×2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na2SO4), concentrated under reduced pressure, and separated-purified by column chromatography (ethyl acetate-hexane, 1:5) to give the title compound (4.80 g, Yield 86%) in a diastereomeric form.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[O:20][N:19]=[C:18]([CH2:21]Cl)[N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:40]1[CH2:45][C@@H:44]2[CH2:46][C@H:41]1[CH2:42][NH:43]2)=O)(C)(C)C>CC#N.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[O:20][N:19]=[C:18]([CH2:21][N:40]5[CH2:45][CH:44]6[CH2:46][CH:41]5[CH2:42][NH:43]6)[N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1cc(-c2nc(CCl)no2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2nc(CN3CC4CC3CN4)no2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 60 °C
Yield: 58.3 %

Procedure:
To a solution of 2-(4-chloro-benzyl)-5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-7-methyl-2,3-dihydroisoindol-1-one (40 mg, 0.103 mmol) in MeCN (4 mL) was added K2CO3 (0.309 mmol) and (1s,4s)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (31 mg, 0.154 mmol). The mixture was heated at 60° C. overnight. The reaction was cooled and diluted with water, then extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. Column chromatography on silica (1% 2M NH3 in MeOH/CH2Cl2) provided 2-(4-chlorobenzyl)-5-[3-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydroisoindol-1-one as a brown solid (27 mg). 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.99 (s, 1H), 7.37 (d, 2H), 7.26 (d, 2H), 4.77 (s, 2H), 4.30 (s, 2H), 3.94 (dd, 2H), 3.58 (d, 2H), 3.26 (d, 1H), 3.11 (d, 1H), 2.89 (d, 1H), 2.84 (s, 3H), 2.63 (d, 1H), 1.88 (d, 1H), 1.66 (d, 1H).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[CH2:28][C@@H:27]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[N:26]([C:35](=[O:49])[CH:36]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:25][C:24]=3[N:23]=[CH:22]2)=[CH:16][C:15]=1[CH3:50]>C(OCC)(=O)C>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[CH2:28][C@@H:27]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[N:26]([C:35](=[O:49])[CH:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:25][C:24]=3[N:23]=[CH:22]2)=[CH:16][C:15]=1[CH3:50])=[O:12])([OH:6])=[O:5]
Reactant: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)N(C)C)N(C(=O)C(c2ccccc2)c2ccccc2)C3)ccc1N
Reactant: O=C(O)c1ccccc1C(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)N(C)C)N(C(=O)C(c2ccccc2)c2ccccc2)C3)ccc1NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of phthalic acid (0.7223 g, 0.00435 mol) in ethyl acetate (10 ml) was added to a solution of (S)-1-(4-amino-3-methylphenyl)methyl-N,N-dimethyl-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo-[4,5-c]pyridine-6-carboxamide (II-2) (2.0077 g, 0.00396 mol) in ethyl acetate (30 ml) with stirring at room temperature. The mixture was stirred at room temperature for 23 hours, followed by filtration of the reaction mixture. The resulting white solid was washed with ethyl acetate (about 20 ml) and dried to obtain the objective compound (I-2, Compound No. 2) (2.4107 g; yield: 93.0%). MS 637 (EI): (M-18).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-])=O>C(OCC)(=O)C.[C].[Pd]>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of the objective compound (11.4 g, 57.8 mmol) of Step (1) in ethyl acetate (300 mL) was added under nitrogen atmosphere 10% palladium carbon (1.80 g) and the mixture was stirred at room temperature for 18 hours under hydrogen atmosphere. The catalyst was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The obtained solid was washed with ether-hexane (1:1) and dried in vacuo to give methyl 3-amino-4-hydroxybenzoate as a pale-brown solid (9.34 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(#N)C>[CH2:9]1[O:8][C:6]2=[CH:7][C:2]3[NH:1][C:33](=[O:34])[N:13]([CH2:14][CH2:15][CH2:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[CH2:12][CH2:11][C:3]=3[CH:4]=[C:5]2[O:10]1
Reactant: COc1ccc(SCCCN(C)CCCNCCc2cc3c(cc2N)OCO3)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccc(SCCCN(C)CCCN2CCc3cc4c(cc3NC2=O)OCO4)cc1OC

Procedure:
The title compound is prepared from N-[3-(2-(2-amino-4,5-methylenedioxy-phenyl)-ethylamino)-propyl]-N-[3-(3,4-dimethoxyphenylthio)-propyl]-methylamine and carbonyldiimidazole in acetonitrile analogously to Example 56.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:25][C:26]1[C:34]2[C:33](Cl)=[N:32][CH:31]=[N:30][C:29]=2[NH:28][CH:27]=1.C(N(CC)CC)C>C(O)(C)C>[Br:25][C:26]1[C:34]2[C:33]([N:19]3[CH2:18][CH2:17][C:16]([CH3:22])([C:14]([NH:13][C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=5)[CH:8]=4)=[O:15])[CH2:21][CH2:20]3)=[N:32][CH:31]=[N:30][C:29]=2[NH:28][CH:27]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCN(c2ncnc3[nH]cc(Br)c23)CC1
Temperature: 100 °C

Procedure:
To a solution of N-(3-(4-fluorophenoxy)phenyl)-4-methylpiperidine-4-carboxamide from example 1, step B, (36 mg, 0.1 mmol) in isopropanol (1 mL), was added to 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine from step A (24 mg, 0.1 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was heated at 100° C. for 10 minutes under microwave condition, and then concentrated under vacuum. The product was isolated by prep HPLC to give the title compound.
Reaction SMILES: FC1C=C(F)C=CC=1CN1C2C=CC=C(N)C=2C=N1.[N:20]1[CH:21]=[C:22]([C:29]([OH:31])=O)[N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][N:39]1[C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([NH2:48])[C:42]=2[CH:41]=[N:40]1>>[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][N:39]1[C:47]2[C:42](=[C:43]([NH:48][C:29]([C:22]3[N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[N:20][CH:21]=3)=[O:31])[CH:44]=[CH:45][CH:46]=2)[CH:41]=[N:40]1
Reactant: Nc1cccc2c1cnn2CC1CCCCO1
Reactant: O=C(O)c1cnc2ccccn12
Agent: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Product: O=C(Nc1cccc2c1cnn2CC1CCCCO1)c1cnc2ccccn12

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with imidazo[1,2-a]pyridine-3-carboxylic acid and 1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-amine, respectively. MS (APCI) m/z=376 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Br:10][C:11]1[N:12]=[N:13][C:14](Br)=[CH:15][CH:16]=1.C(N(CC)CC)C>C1COCC1>[Br:10][C:11]1[N:12]=[N:13][C:14]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]2)=[CH:15][CH:16]=1
Reactant: Brc1ccc(Br)nn1
Reactant: CN(C)C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(c2ccc(Br)nn2)CC1
Temperature: 70 °C
Yield: 89.7 %

Procedure:
N,N-dimethylpiperidin-4-amine (0.505 g, 3.94 mmol), 3,6-dibromopyridazine (0.511 g, 2.15 mmol), and triethylamine (0.599 mL, 4.30 mmol) were combined in 5 mL of THF. The solution was heated at 70° C. for 17 hours. The solution was cooled to room temperature and then purified on CombiFlash column (dry loaded), eluting with 10% methanol/0.5% NH4OH (˜28% in water)/DCM isocratic. The fractions containing the product were combined and concentrated under vacuum to give compound 201 (0.550 g, 89.8% yield) as an off white solid. 1H NMR (500 MHz, MeOD-d3) δ 7.51 (1 H, d, J=9.8 Hz), 7.24 (1 H, d, J=9.8 Hz), 4.45 (2 H, d, J=13.7 Hz), 2.98 (2 H, td, J=13.0, 2.2 Hz), 2.61 (1 H, tt, J=11.5, 3.8 Hz), 2.38 (6 H, s), 1.99-2.07 (2 H, m), 1.45-1.58 (2 H, m, J=12.5, 12.2, 12.2, 4.2 Hz) ppm; LCMS-ESI (POS), M/Z, M+1: Found 285.0.