Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:23])[CH2:4][C@@:5]23[CH2:18][CH2:17][N:16](C)[C@@H:13]([C@@H:14]2[CH:15]=1)[CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:20][CH3:21])=[C:7]([OH:22])[C:6]3=1.Cl.[H][H]>C(O)C.[Pd]>[OH:22][C:7]1[C:6]2[C@:5]34[CH2:18][CH2:17][NH:16][C@@H:13]([C@@H:14]3[CH2:15][C@H:2]([CH3:1])[C:3](=[O:23])[CH2:4]4)[CH2:12][C:11]=2[CH:10]=[CH:9][C:8]=1[O:20][CH3:21]
Reactant: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@@H]1C=C(C)C(=O)C3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1O)[C@]13CCN[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3
Yield: 68.3 %

Procedure:
To a solution of 14 (22.0 g, 70 mmole) in 95% ethanol (200 ml) was added concentrated HCl (12 ml) and 10% palladium on activated carbon (2.0 g). The mixture was hydrogenated at an initial pressure of 50 psi until the uptake of hydrogen ceased. The mixture was filtered from the catalyst and the filtrate evaporated to a small volume. The residue was dissolved in water, the solution made basic with concentrated NH4OH and extracted with three portions of chloroform. The chloroform extracts were washed with dilute NH4OH, dried and evaporated to a thick syrup which crystallized on the addition of ethyl acetate. The crystals were collected and dried to give 14.4 g (65%) of 16a as white needles, mp 163°-165°. Recrystallization from acetone gave analytically pure 16a as the hemi-acetone solvate, 166°-167° NMR: δ 6.55, s, 2H (aromatic); 6.40, broad, 1H (hydroxyl H); 4.22, d, 1H (H-5α, J=13 Hz); 3.77 (CH3O--); 2.38 (CH3N); 0.87, d, 3H (7α-CH3, J=6.5 Hz).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(Cl)c(Cl)c1
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3ccc(Cl)c(Cl)c3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 21.3 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(3,4-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.40 g, 2.88 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.48 g, 2.65 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.35 g, 32%) was obtained.
Reaction SMILES: CNC(=O)C1C=CC=C(C2C=CC([O:16][C@@H]3[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)=C(C)C=2)C=1.C([O:33][C@@H:34]1[C@@H:39]([O:40]C(=O)C)[C@@H:38]([CH2:44][O:45]C(=O)C)[O:37][C@H:36]([O:49][C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][C:51]=2[F:57])[C@H:35]1CC([O-])=O)(=O)C.[CH3:62][O:63][C:64]([C:66]1[CH:67]=[C:68](B(O)O)[CH:69]=[CH:70][CH:71]=1)=[O:65]>>[F:57][C:51]1[CH:52]=[C:53]([C:68]2[CH:67]=[C:66]([CH:71]=[CH:70][CH:69]=2)[C:64]([O:63][CH3:62])=[O:65])[CH:54]=[CH:55][C:50]=1[O:49][C@@H:36]1[C@@H:35]([OH:16])[C@@H:34]([OH:33])[C@H:39]([OH:40])[C@@H:38]([CH2:44][OH:45])[O:37]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2ccc(Br)cc2F)[C@@H](CC(=O)[O-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CNC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Product: COC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(F)c2)c1
Yield: 66 %

Procedure:
4a was prepared using the same procedure as for 5b with [(2R,3S,4S,5R,6R)-4,5-diacetoxy-6-(acetoxymethyl)-2-(4-bromo-2-fluoro-phenoxy)tetrahydropyran-3-yl]acetate and 3-methoxycarbonylphenyl boronic acid as the reactants. Yield: 66%. 1H NMR (300 MHz, METHANOL-d4) δ ppm 8.21 (t, J=1.65 Hz, 1H), 7.99 (td, J=1.44, 7.83 Hz, 1H), 7.84 (ddd, J=1.10, 1.92, 7.69 Hz, 1H), 7.35-7.62 (m, 4H), 5.55 (d, J=1.92 Hz, 1H), 4.10 (dd, J=1.79, 3.43 Hz, 1H), 3.94 (s, 3H), 3.86-4.00 (m, 1H), 3.59-3.86 (m, 4H). MS (ESI): found [M+Na]+, 431.1.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+]([O-])=O)=[CH:11][CH:12]=3)[CH:7]([CH:20]3[O:24][CH2:23][CH2:22][O:21]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].[O-:25][CH2:26][CH3:27].[K+]>>[CH2:26]([O:25][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][CH:15]=3)[CH:7]([CH:20]3[O:21][CH2:22][CH2:23][O:24]3)[C:8]=2[CH:9]=1)[CH3:27]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2
Reactant: CC[O-]
Agent: [K+]
Product: CCOc1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2

Procedure:
Following the same procedure described in Example 1, from 10 parts of 2-(2,7-dinitro-9-fluorenyl)-1,3-dioxolane and 12.5 parts of potassium ethoxide there was obtained 9 parts of product, its 1H and 13C NMR was consistent with the assigned structure.
Reaction SMILES: BrC1N2C=NC=C2C(=O)N(C[C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)C=1.[ClH:21].Br[C:23]1[CH:24]=[CH:25][C:26]2[N:30]=[CH:29][NH:28][C:27]=2[CH:31]=1>>[NH:28]1[C:27]2[CH:31]=[CH:23][C:24]([C:15]3[CH:14]=[C:13]([Cl:21])[CH:18]=[CH:17][C:16]=3[OH:19])=[CH:25][C:26]=2[N:30]=[CH:29]1
Reactant: COc1ccc(Cn2cc(Br)n3cncc3c2=O)cc1
Reactant: Cl
Reactant: Brc1ccc2nc[nH]c2c1
Product: Oc1ccc(Cl)cc1-c1ccc2[nH]cnc2c1
Yield: 43 %

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations to replace 5-bromo-7-(4-methoxybenzyl)imidazol[1,5-a]pyrazin-8(7H)-one with 6-bromo-1H-benzo[d]imidazole hydrochloride salt, 2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenol was obtained as a beige solid in 43% yield (0.110 g): MS (ES+) m/z 245.0 (M+1), 246.9 (M+1).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][N:27](C(OCC)=O)[CH2:26][CH2:25]1>>[F:9][C:8]([F:11])([F:10])[CH2:7][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Product: FC(F)(F)Cn1c(NC2CCNCC2)nc2ccccc21

Procedure:
Prepare by the method of Preparation 14 using 2,2,2-trifluoroethyl trifluoromethanesulfonate and (1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH2:22])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:21][NH:22][C:32](=[O:33])[CH2:31][C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(I)cc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)Cc2cc(F)cc(F)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a stirred solution of 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.24 mmol) in CH2Cl2 (0.5 mL) at room temperature under Ar was added a solution of 3,5-difluorophenylacetyl chloride (0.28 mL of a 1 M solution in CH2Cl2, 0.28 mmol) followed by pyridine (0.25 mL). The mixture was stirred at room temperature for 16 h then diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and saturated brine (5 mL) and dried over Na2SO4. Filtration and rotary evaporation gave the crude 4-{[2-(3,5-difluoro-phenyl)-acetylamino]-methyl}-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.09 g, ˜65%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.CN(C(ON1N=[N:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42]C1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:50]1[CH:51]=CC2N(O)N=NC=2[CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:51]([N:43]([CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42]1)[C:12](=[O:14])[C:11]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=[C:9]([Br:8])[CH:10]=1)[CH:50]=[CH2:55]
Reactant: O=C(O)c1cc(Br)cc(OCCNc2ccncc2)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: On1nnc2ccccc21
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C(=O)c1cc(Br)cc(OCCNc2ccncc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
To a stirred solution of 3-bromo-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate salt (0.034 g), TBTU (0.048 g) and HOBt (0.014 g) in DMF (0.3 ml) was added DIPEA (0.026 ml) followed by N-allylcyclopentyamine (0.022 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.022 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:7][CH:8]=1.NN>C(O)C.C(Cl)(Cl)Cl>[NH2:16][CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cccc(C2CCCN2CCN)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[2-(3-methoxyphenyl)-1-pyrrolidinyl]ethyl}-1H-isoindole-1,3(2H)dione (0.92 g) in ethanol (30 ml) and chloroform (5 ml) was added anhydrous hydrazine (98%, 0.42 ml) at ambient temperature, under nitrogen. The reaction mixture was warmed under reflux for 1.5 hrs, cooled to ambient temperature, and filtered. The filter cake was washed with ethanol and the combined filtrates were concentrated. The residue was diluted with dichloromethane/ether. The organic solvents were decanted and concentrated to give N-(2-aminoethyl)-2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.[C:27]([N:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1(C)C=CC=CC=1.O1CCCC1>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH:37]3[CH2:38][CH2:39][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:35][CH2:36]3)=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 61.1 %

Procedure:
30 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (Example 65) was dissolved in 2 mL of toluene and 2 mL of tetrahydrofuran, to which 54 mg of 1-Boc-4-piperidone and 38 mg of sodium triacetoxyborohydride were added, and stirred at room temperature for 19 hours. To the reaction mixture, water was added, extracted with chloroform, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 28 mg (60%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:10])=[CH:4][CH:3]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br-:10].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 200 °C

Procedure:
4-Fluorophenylethyl bromide (700 mg, 3.44 mmol) was dissolved in toluene (4 mL), triphenylphosphine (904 mg, 3.44 mmol) added and the solution heated for 10 min in a sealed flask at 200° C. under microwave heating. After cooling to rt, the solvent was decanted and the title compound was obtained quantitatively as the remaining glassy solid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]1OCC[O:10]1)[C:3]2([CH3:15])[CH3:14].CC(C)=O.Cl>O>[CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]=[O:10])[C:3]2([CH3:15])[CH3:14]
Reactant: CC1(C)C(CC2OCCO2)CC2CC21C
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)C(CC=O)CC2CC21C
Yield: 78.7 %

Procedure:
A mixture of 11.0 g (52 mmol) of 2-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl)-[1,3]-dioxolane, 80 ml of acetone, 40 ml of water, 1.5 ml of conc. hydrochloric acid and 10 g of silica gel was stirred at reflux for 4 hours. After filtration, the solution was diluted with diethyl ether, washed with water, dried (MgSO4) and evaporated in vacuo. Kugelrohr distillation of the residue gave 6.8 g (79% yield) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1)#[N:2]>CO.[Pt](=O)=O>[NH2:2][CH2:1][CH2:3][CH:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CC#N)COc1ccccc1-3
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCN)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
Platinum(IV) oxide (0.5 eq.) was added to a solution of methyl 7(R,S)-(cyanomethyl)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.20 M) in MeOH. The atmosphere in the reaction vessel was exchanged for H2, and the reaction stirred vigorously at RT for 4 h. The reaction vessel was flushed with N2, and the reaction mixture filtered through a plug of CELITE (washing well with MeOH and EtOAc). Volatiles were removed in vacuo to afford the crude product which was purified by FC (EtOAc/MeOH/Et3N 93:5:2) affording the product as a yellow oil (12%). (ES+) m/z 433 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]1([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.CN(C)C=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3([CH3:30])[CH3:29])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(C)(C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(C(N)=O)cnn3cc(Br)cc23)C(C)(C)C1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (310 mg, 1.129 mmol, Intermediate 2), tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (387 mg), N,N-diisopropylethylamine (0.592 mL, 3.39 mmol) and N,N-dimethylformamide (2 mL) was pumped under vacuum and backfiled with nitrogen twice. The reaction vial was sealed and heated to 90° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate twice. The organic layer was washed with brine and concentrated. Silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, gave the title compound as a brown solid (0.3510 g, 67% yield). MS (ES+) m/z: 466.1, 468.1 (M+H); LC retention time: 4.488 min (analytical HPLC Method H).
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:13])[CH2:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].CC(C)([O-])C.[Li+]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[NH:12][C:10](=[O:11])[CH2:9][C@@H:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@H](CC(N)=O)Nc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccccc1
Temperature: -10 °C
Yield: 82 %

Procedure:
A clean, dry and nitrogen gas purged flask was charged with (S)-3-phenylamino-butyramide (3.25 g, 0.018 mmol) in THF (65 mL) and the mixture was cooled to −10° C. Benzyl chloroformate (3.12 mL, 0.022 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (18 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0° C. Fifteen minutes after the completion of base addition, the reaction (starting material gone by TLC) was quenched by adding EtOAc (65 mL) and 1.0 M hydrochloric acid (10 mL). The aqueous phase was then basified with 1N NaOH. The aqueous phase was extracted 3×EtOAc. The organics were collected together and with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO4), filtered, and concentrated. Flash chromatography using a Biotage system (10% EtOAc/90% hexane to 20% EtOAc/80% Hexane) afforded the title compound in 82% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O-:32][CH2:33][CH3:34].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([O:32][CH2:33][CH3:34])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C

Procedure:
100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of DMF. 28.4 mg (0.418 mmol) of sodium ethoxide was added at 0° C. and stirred heating to room temperature for 12 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:11])=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C(O)(=O)C>O1CCOCC1>[OH:1][C:2]1[C:7]2[C:8]([CH3:11])=[C:9](/[CH:14]=[CH:13]/[C:12]([O:16][CH2:17][CH3:18])=[O:15])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1coc2cccc(O)c12
Reactant: C=CC(=O)OCC
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/c1oc2cccc(O)c2c1C
Yield: 20.3 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzofuran (2.9 g, 20 mmoles) palladium III acetate (4.5 g, 20 mmoles), ethyl acrylate (2 g, 20 mmoles), acetic acid (50 ml) and dioxane (200 ml) was refluxed for 3 hours. The mixture was filtered and the filtrate concentrated and chromatographed to obtain 1 g of the title compound after recrystallization from toluene, m.p. 180°-182° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([C:26]([O-])=[O:27])[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].C1C=C[C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:34]1([NH:36][C:26]([C:21]2[N:20]=[N:19][N:18]([C:15]3[CH:16]=[CH:17][C:12]([C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:11])=[CH:13][CH:14]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[O:27])[CH2:35][CH2:33]1
Reactant: CCCc1c(C(=O)[O-])nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.9 %

Procedure:
Sodium 1-(4-{[(2-morpholin-4-ylethyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylate (642 mg, 1.34 mmol) obtained in Example 61b), HOBt (91.6 mg, 0.671 mmol, 0.5 eq.) and cyclopropylamine (0.125 ml, 1.74 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (315 mg, 1.61 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed with 2% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate and diethyl ether were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (397 mg, 0.932 mmol, 69.6%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10](C(=O)CCl)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].P([O-])(O)(O)=O.[Na+].ClC1C=CC=[C:27]([C:31]([O:33]O)=[O:32])C=1.C(Cl)(Cl)[Cl:36]>>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:33][C:31](=[O:32])[CH2:27][Cl:36])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1Cc2ccc(C(=O)CCl)cc2C1
Reactant: ClC(Cl)Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CC(=O)NC1Cc2ccc(OC(=O)CCl)cc2C1
Yield: 48 %

Procedure:
To a suspension of 5.03 g of 2-acetylamino-5-chloroacetylindan in chloroform are added 6.8 g of sodium dihydrogenphosphate and 10.06 g of m-chloroperbenzoic acid, and the mixture is refluxed for 5 hours under stirring. The reaction mixture is evaporated to remove solvent and the residue is extracted with ethyl acetate. The extract is washed successively with an aqueous sodium bicarbonate solution and an aqueous 10% hydrochloric acid solution, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate-n-hexane-isopropyl ether to give 2.6 g of 2-acetylamino-5-chloroacetoxyindan. Yield: 48%