Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS([O:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.S([O-])(=O)(=O)C.C1(C)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:40]2[CH2:39][CH2:38][CH2:37][C:36]=2[C:35]=1O>CN(C)C=O>[CH3:32][O:33][C:34]1[C:35]([O:7][C@H:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9]2)=[C:36]2[C:40](=[CH:41][CH:42]=1)[CH2:39][CH2:38][CH2:37]2
Reactant: COc1ccc2c(c1O)CCC2
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1O[C@H]1CCN(Cc3ccccc3)C1)CCC2
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
In 540 ml of anhydrous dimethylformamide 5 g of 2,3-dihydro-5-methoxy-1H-inden-4-ol were dissolved. The solution was stirred, placed under a steam of nitrogen and 1.5 g of a 60% dispersion of sodium hydride in oil was added. The reaction mixture was stirred at room temperature for half an hour. The temperature was raised to 100° C. and a solution of 7.78 g of (R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine in 78 ml of anhydrous dimethylformamide was added dropwise over 1 hour. Another 3,0 g of mesylate in 30 ml of anhydrous dimethylformamide were added dropwise over 0.5 hours and the reaction continued for another 1.5 hours at 100° C. Evaporation in vacuo gave a semi solid that was partitioned between water and ethyl acetate. The ethyl acetate extract was dried and evaporated in vacuo. The derived product was isolated by chromatography over silica using toluene/-ethanol as the eluent giving 9.45g of (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidine as an oil. M.S. (C.I.) (M/Z): 324 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][CH2:13][NH2:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: NCCC1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Clc1ccc(C2(CCN3CCCC3)CCC2)cc1

Procedure:
2-[1-(4-Chlorophenyl)cyclobutyl]ethylamine (12 g) prepared as described in Example 1, 1,4-dibromobutane (12.4 g) and anhydrous sodium carbonate (14.3 g) were mixed in xylene (100 ml) and the mixture heated under reflux with stirring for sixteen hours. The mixture was cooled, filtered and the xylene removed by evaporation to give a residue which on distillation gave N-2-[1-(4-chlorophenyl)cyclobutyl]ethylpyrrolidine (b.p. 148°-150°/1.5 mm Hg) (Formula 1 R1,R2 =H; R3 and R4 together with the nitrogen atom forming a pyrrolidine ring; R5 =4-Cl; R6, R7 and R8 =H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[C:16]([CH2:18][C:19]([OH:21])=[O:20])#[N:17].N1C=CC=CC1=O>C1(C)C=CC=CC=1.O>[C:16]([C:18](=[CH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:19]([OH:21])=[O:20])#[N:17]
Reactant: COc1ccc(C=O)cc1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: O=c1cccc[nH]1
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C=C(C#N)C(=O)O)cc1

Procedure:
A stirred mixture of p-anisaldehyde (60.7 ml), ammonium acetate (7.5 g), cyanoacetic acid (42.5 g), pyridone (70 ml) in toluene (390 ml) is refluxed using a Dean Stark trap until about 9 ml of water is collected. The reaction mixture is cooled and the solid precipitate filtered and stirred with 10% aqeuous HCL. The solid is filtered and recrystallized from methanol yielding the desired product.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20]O)[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:41]1C=CN=C1.II.[I-].[N-]=[N+]=[N-].[Na+].[N-]=[N+]=[N-]>C(Cl)Cl.CN(C=O)C.CC(=O)OCC.C1COCC1.O>[NH2:41][CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][C:11](=[O:12])[O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH2:16]1
Reactant: c1c[nH]cn1
Reactant: O=C(N[C@H]1CC[C@H](CO)CC1)OCc1ccccc1
Agent: II
Agent: N#N
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of trans-4-benzyloxycarbonylaminocyclohexane-methanol (1.32 g, 5.01 mmol), triphenylphoshine on polystyrene (15.04 mmol) and imidazole (483 mg, 7.02 mmol) in dry CH2Cl2 (150 mL) was added iodine (2.06 g, 8.02 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide (1.64 g, 4.39 mmol) was redissolved in DMF (15 mL) and treated with sodium azide (303 mg, 4.61 mmol). The reaction mixture was heated to 80° C. until completion of the reaction. The mixture was then diluted with EA, washed with brine (3×), dried over MgSO4, filtered and concentrated under reduced pressure. To a mixture of the crude azide (1.27 g, 4.40 mmol) in THF (21 mL) were added polymer-supported Ph3P (2.0 eq.) and water (7 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. 0.5M Na2CO3 and the layers separated. The aq. layer was extracted with EA (2×) and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give benzyl (trans-4-(aminomethyl)cyclohexyl)carbamate as a white solid. LC-MS-conditions 07b: tR=0.57 min; [M+H]+=263.46.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CNC(=O)C2CC2)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
Triethylamine (1.87 g, 18 mmol) was added dropwise to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 7 mmol) in dichloromethane (40 ml). The mixture was cooled in an ice bath to 4° C. Cyclopropylcarbonyl chloride (0.99 g, 9 mmol) was added slowly at 4-8° C. After addition, the mixture was stirred in ice bath for 30 min and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the product was purified by flash chromatography (dichloromethane/ethyl acetate 9 to 1) to give 2.1 g (93%) of the product as a white solid: 1H NMR (CDCl3) (7.87 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.77 Hz, 1H), 6.31 (m, 1H), 4.43 (d, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 1.36-1.29 (m, 1H), 0.99-0.93 (m, 2H), 0.76-0.69 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[CH3:14][S:15](Cl)(=[O:17])=[O:16].Cl>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2

Procedure:
To a solution of 5-aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.519 g.) in pyridine (5 ml.) was added methanesulfonyl chloride (0.28 ml.) under ice-cooling, followed by stirring. The reaction mixture was poured into cooled dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent. The residue was recrystallized from ethanol. By the above procedure there was obtained 5-methylsulfonylaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as colorless needles melting at 152°-154° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
1.44 g (1.25 mmol)Pd(PPh3)4 was added under argon at room temperature to a solution of 6-bromo-pyridine-3-carbaldehyde in 60 ml 1,2 dimethoxyethane and stirred for 15 min. 63 ml (125 mmol) of 2 M sodium carbonate solution and 2.5 g (13.16 mmol) of 3-(trifluoromethyl-)-phenylboronic acid were added and the mixture heated to boiling temperature for 18 hours (h). The reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 1.18 g (36%) of 6-(3-Trifluoromethyl-phenyl)-pyridine-3-carbaldehyde
Reaction SMILES: [F-].[K+].[CH3:3][C:4]1[O:8][C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:32])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si](C)(C)C)=[CH:22][N:21]=3)=[O:18])[C@H:11]([NH:33][C:34]([C:36]3[S:37][C:38]4[CH2:39][N:40]([CH3:45])[CH2:41][CH2:42][C:43]=4[N:44]=3)=[O:35])[CH2:10]2)=[N:6][N:5]=1>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17](=[O:18])[C:16]([NH:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([C:7]3[O:8][C:4]([CH3:3])=[N:5][N:6]=3)[CH2:10][C@H:11]2[NH:33][C:34]([C:36]2[S:37][C:38]3[CH2:39][N:40]([CH3:45])[CH2:41][CH2:42][C:43]=3[N:44]=2)=[O:35])=[O:32])=[N:21][CH:22]=1)#[CH:27]
Reactant: Cc1nnc([C@H]2CC[C@H](NC(=O)C(=O)Nc3ccc(C#C[Si](C)(C)C)cn3)[C@H](NC(=O)c3nc4c(s3)CN(C)CC4)C2)o1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(NC(=O)C(=O)N[C@H]2CC[C@H](c3nnc(C)o3)C[C@H]2NC(=O)c2nc3c(s2)CN(C)CC3)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.6 %

Procedure:
Potassium fluoride (116 mg) was added to a solution of the compound obtained in Example 401 (617 mg) in methanol (30 mL), and the mixture was stirred for 7 hours at room temperature. The solvent was removed under reduced pressure, and methylene chloride and water were added to the residue to partition the mixture. The organic layer was dried over sodium sulfate anhydrate, and the solvent was removed under reduced pressure. The residue was purified through silica gel flash column chromatography (methylene chloride:methanol=93:7). The thus-obtained solid was dissolved in methanol, water was added thereto, and the solvent was removed under reduced pressure, to thereby yield the title compound (287 mg).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:23][CH2:22][N:21]3[C:24](=[O:33])[C:25]([CH2:30][CH2:31]O)([CH2:27][CH2:28][OH:29])[CH2:26][C@H:20]3[C@@H:19]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(Cl)(=O)=O>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:23][CH2:22][N:21]3[C:24](=[O:33])[C:25]4([CH2:30][CH2:31][O:29][CH2:28][CH2:27]4)[CH2:26][C@H:20]3[C@@H:19]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:8]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CC(CCO)(CCO)C(=O)N2CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1ccccc1[C@H]1[C@@H]2CC3(CCOCC3)C(=O)N2CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 22.8 %

Procedure:
To a solution of (1S,8aS)-N-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-7,7-bis(2-hydroxyethyl)-N-methyl-6-oxo-1-o-tolylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (70 mg, 0.11 mmol) in 5 mL of DCM, was added MsCl (38 mg, 0.33 mmol) at 0° C. The mixture was stirred for 1.5 h, and concentrated in high vacuum. The residue was treated with mixture of H2O (5 mL) and TEA (0.5 mL) and then heated to 65° C. until the reaction was completed. The reaction mixture was extracted with DCM (2×15 mL) and the organic layers were dried over anhydrous Na2Sa4 and then concentrated in high vacuum. The residue was purified by Prep-HPLC to give the title compound (15 mg, yield: 23%). 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (s, 1H), 7.46 (s, 2H), 7.22 (m, 4H), 5.47 (d, J=7.0 Hz, 1H), 4.08 (d, J=12.8 Hz, 1H), 3.95 (d, J=9.7 Hz, 2H), 3.81 (dd, J=7.6, 4.0 Hz, 1H), 3.65 (d, J=9.1 Hz, 1H), 3.36 (dd, J=13.4, 6.3 Hz, 2H), 3.20 (d, J=11.6 Hz, 1H), 3.05 (td, J=12.3, 3.4 Hz, 1H), 2.91 (dt, J=11.8, 5.9 Hz, 1H), 2.63 (s, 3H), 2.46 (s, 3H), 2.11 (dd, J=17.6, 6.9 Hz, 1H), 1.89 (dd, J=13.1, 7.2 Hz, 1H), 1.79 (dd, J=17.0, 7.0 Hz, 1H), 1.49 (s, 2H), 1.31 (t, J=8.1 Hz, 6H), 1.18 (s, 3H), 0.86 (s, 2H); m/z (ES+): 598 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[N:28]([CH3:30])[CH3:29])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:31][CH2:32][CH2:33][CH2:34][P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38]>CCCCO>[CH3:29][N:28]([CH3:30])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH2:19][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:31][CH2:32][CH2:33][CH2:34][P:35](=[O:42])([O:36][CH2:37][CH3:38])[O:39][CH2:40][CH3:41])[N:11]=2)[CH2:14][CH2:15]1
Reactant: CCOP(=O)(CCCN)OCC
Reactant: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(Cl)nc3ccccc23)CC1
Solvent: CCCCO
Product: CCOP(=O)(CCCNc1nc(NC2CCN(Cc3c(OC)cccc3N(C)C)CC2)c2ccccc2n1)OCC
Temperature: 117 °C

Procedure:
Following General Procedure D, Compound 47 (50 mg, 0.12 mmol) and diethyl 3-aminopropylphosphonate (69 mg, 0.36 mmol) in n-BuOH (3 mL) were heated to 117° C. for 24 h with a reflux condenser. The product (Compound 81) was purified by preparative silica gel TLC plate 1000μ using 5% (7N NH3-MeOH) and 95% CH2Cl2 solution as eluent.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O.C(Cl)Cl>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
To a solution of 5-nitro-2-thiophenecarboxaldehyde (1.00 g, 6.24 mmol) in acetone (50 ml) was added Jones reagent (8N in acetone, 8.12 ml, 65 mmol) at −20° C. After stirring for 1H, 30 ml of isopropanol was added to the mixture. H2O was added to the mixture and excited with CH2Cl2. The extract was washed with water, brine, dried (Na2SO4), and concentrated to give 967 mg (90%) of yellow amorphous.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:30]=[CH:29][C:14]3[C:15]([CH3:28])=[C:16]([C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[O:17][C:13]=3[CH:12]=2)[CH:6]=1.CO.O.[OH-].[Li+]>O1CCCC1>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:18]([C:16]1[O:17][C:13]2[CH:12]=[C:11]([C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=3)[CH:30]=[CH:29][C:14]=2[C:15]=1[CH3:28])=[O:27]
Reactant: COC(=O)Cc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(CC(=O)O)c3)ccc12
Temperature: 50 °C

Procedure:
{3-[2-(2,4-Dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-phenyl}-acetic acid methyl ester (3160 mg, 6.97 mmol) was dissolved in tetrahydrofuran (50 mL), methanol (20 mL), water (10 mL), and lithium hydroxide (2650 mg, 110.65 mmol) was added to the solution. The mixture was heated at 50° C. for 3 h then cooled to room temperature. The volatile components were removed under vacuum and the pH of the resulting aqueous component was adjusted to 1 with HCl (1N). The aqueous layer was extracted several times with ethyl acetate and the combined organic extracts were dried over magnesium sulfate and condensed under reduced pressure. The crude residue was purified by MPLC with a gradient of 0 to 30% methanol/dichloromethane to give {3-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-phenyl}-acetic acid as a brown solid (2540 mg, 52% two steps). MS LC-MS (MH+ 439.1/441.1).
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)=[N:2]1
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: NCCCNc1nsc2nccnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4nccnc34)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
N1-(Isothiazolo[5,4-b]pyrazin-3-yl)propane-1,3-diamine (410 mg, 1.96 mmol) and 4′-methoxybiphenyl-4-carbaldehyde (410 mg, 1.96 mmol) were combined in 1,2-dichloroethane (8 mL) and treated with sodium triacetoxyborohydride (506 mg, 2.35 mmol). The mixture was shaken at room temperature for 3 h. The reaction was diluted with methylene chloride, quenched with water and the layers were separated. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with methylene chloride:methanol to yield N1-(isothiazolo[5,4-b]pyrazin-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (100 mg) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 8.79 (d, 1H), 8.72 (d, 1H), 7.90 (t, 1H), 7.54 (m, 4H), 7.40 (d, 2H), 6.98 (d, 2H), 3.82 (s, 2H), 3.80 (s, 3H), 3.48 (t, 2H), 2.70 (m, 3H), 1.85 ppm (m, 2H). MW=405 confirmed by LC-MS, tr=9.59 min (Method Y) MH+=404-406.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:32]=[C:33]=[O:34])[C:27]([O:30][CH3:31])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:34])[C:27]([O:30][CH3:31])=[CH:28][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccc(Cl)cc1N=C=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 99.7 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 3-chloro-6-methoxyphenyl isocyanate (111 mg) was added, and the admixture was refluxed with heat for 29 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 84 mg of the title compound (yield: 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:30]=[CH:29][C:12]([C:13]([NH:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[O:14])=[C:11]([NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)[N:10]=1)#[N:2].[ClH:41]>CO>[ClH:41].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:30]=[CH:29][C:12]([C:13]([NH:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[O:14])=[C:11]([NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)[N:10]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: CO
Product: N#Cc1ccccc1-c1ccc(C(=O)NCC2CCCN2)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyrrolidine-1-carboxylate (680 mg, 1.25 mmol) in MeOH (20 mL) was added HCl (2.0 mL, 8 mmol, 4 M in dioxane). The reaction was stirred at r.t. for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-N-(pyrrolidin-2-ylmethyl)nicotinamide hydrochloride which was used for next step without further purification. LRMS (M+H+) m/z 444.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:29]=[CH:30][N:31]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:29]=[CH:30][N:31]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1cccc(-c2cc(Nc3ccc(OC)c(OC)n3)c3nccn3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Reaction time: 4 h
Yield: 87.7 %

Procedure:
Ethyl 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (150 mg, 358 μmol) was dissolved in dioxane (18 mL). To this was added a solution of LiOH (85.6 mg, 3.58 mmol) in water (9 mL). The mixture was stirred for 4 h, acidified with 1N HCl, and concentrated in vacuo to give the crude acid which was recrystallized from isopropyl alcohol and methanol to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (123 mg, 314 μmol, 88%) as a light brown powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.97 (s, 1H) 8.60 (s, 1H) 8.52 (s, 1H) 8.17-8.30 (m, 2H) 8.05 (d, J=7.55 Hz, 1H) 7.60-7.72 (m, 2H) 7.41 (d, J=8.31 Hz, 1H) 7.12 (d, J=8.31 Hz, 1H) 4.05 (s, 3H) 3.76 (s, 3H); LC/MS: 391.8 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:23])[CH:18](Cl)[O:19][CH2:20][CH3:21])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:23])[CH:18]([O:19][CH2:20][CH3:21])[N:11]1[CH:12]=[CH:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:10]1)[CH3:15]
Reactant: CCOC(=O)C(Cl)OCC
Reactant: COc1ccc(-c2cc[nH]n2)cc1
Product: CCOC(=O)C(OCC)n1ccc(-c2ccc(OC)cc2)n1

Procedure:
3-(4-Methoxyphenyl)pyrazole (CAS 27069-17-6) was reacted with 2-chloro-2-ethoxy-acetic acid ethyl ester according to general procedure A to give (RS)-ethoxy-[3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetic acid ethyl ester. Colorless oil. MS 305.1 ([M+H]+)