Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8](O)=[O:9]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=C(O)CCc1cccs1
Solvent: C1CCOC1
Product: OCCCc1cccs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Borane methylsulfide complex (6.4 mL, 12.8 mmol) was added to a solution of 3-(2-thienyl)propanoic acid (1.0 g, 6.4 mmol) in THF (18 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and at room temperature for 3 additional hours. After cooling down to 0° C., the reaction was quenched by addition of a saturated solution of potassium carbonate (5 mL). The aqueous layer was separated and extracted with ethyl acetate (2×15 mL) and diethyl ether (2×15 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as a colorless oil (1.0 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[N:20]=[C:21](Cl)[CH:22]=[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.CC([O-])=O.[Na+]>[Pd].CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]3[N:20]=[CH:21][CH:22]=[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nnc3c(C(=O)OC(C)(C)C)cc(Cl)nn23)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nnc3c(C(=O)OC(C)(C)C)ccnn23)cc1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of tert-butyl 3-(4-(tert-butoxycarbonylamino)phenyl)-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (66D) (300 mg, 0.67 mmol) in a mixed solvent of EtOH (4 mL) and MeOH (1 mL) was bubbled through argon for 5 min, and then NaOAc (66.2 mg, 0.81 mmol) was added, followed by 5% Pd/C (50 mg). The vessel was evacuated and flashed with H2 gas three times and stirred under H2 (1 atm) for 1 h. Analysis by LC/MS indicated the starting material was consumed. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure. The obtained crude residue was purified using a silica gel cartridge (40 g) eluting with a gradient of EtOAc (0-100%) in hexanes to afford 150 mg (54%) of the title compound as a yellow foam. HPLC/MS (Method B): retention time=3.02 min, [M+H]+=412.3.
Reaction SMILES: [Si]([O:8][C@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@H:10]1[CH3:29])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][C@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=2)[C@H:10]1[CH3:29]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
To a solution of 4-[(6S,7S)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-(trifluoromethyl)benzonitrile (309.4 mg) in tetrahydrofuran (3 mL)-methanol (3 mL) was added 6 mol/L hydrochloric acid (3 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless solid (yield: 152.3 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH3:18])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.N>C1COCC1.CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[CH2:17][CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: CCN1CCC[C@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCN1CCC[C@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of Intermediate 61a (190 mg, 0.75 mmol), Ph3P (395 mg, 1.51 mmol) and Et3N (419 μL, 3.01 mmol) in THF (6.00 mL) at 0° C. was added hexachloroethane (357 mg, 1.51 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (157 mg, 89%). LCMS (Method 2): Rt 0.28 min, m/z 235.2 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C=CC=CC=1CO.C([Cl:33])C1C=CC=CC=1.CC(C)([O-])C.[K+].N1C=CC=CC=1.S(Cl)(Cl)=O>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][Cl:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: OCc1ccccc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: OCc1ccccc1O
Agent: [K+]
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: ClCc1ccccc1OCc1ccccc1
Yield: 81 %

Procedure:
To a solution of 46.5 (0.217 mole) 2-benzyloxybenzyl alcohol (prepared by reaction of 2-hydroxybenzyl alcohol with benzyl chloride in ethanol containing an equimolar amount of potassium t-butoxide at 100° C.) in 100 ml chloroform was added 17.2 g (0.217 mole) pyridine followed by dropwise addition of a solution of 25.8 g (0.217 mole) thionyl chloride in 60 ml chloroform. The resulting mixture was heated at reflux for 1.5 hours, cooled, washed with water, brine and dried (MgSO4). Evaporation of solvent gave 45.8 g crude oil which was distilled in vacuo to yield 40.7 g (81%) of product as a colorless oil, b.p. 141° C.(1 Torr).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10]3=[N:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:9]3[C:8]=2[CH:20]=1)([O-])=O.[OH-].[Na+]>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10]3=[N:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:9]3[C:8]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)COc1ccc([N+](=O)[O-])cc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1cn2c(n1)COc1ccc(N)cc1-2
Temperature: 40 °C
Yield: 61.2 %

Procedure:
5.0 g (0.018 mole) of methyl 8-nitro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate were suspended in a mixture of 20 ml of acetic acid and 15 ml of concentrated hydrochloric acid and to the solution thus obtained were added 15 g (0.055 mole) of stannous chloride. The mixture obtained was stirred and warmed to 40° C. After about an hour, a crystalline product started to appear and the mixture was then cooled for two hours in an ice bath. The product (chlorostannate salt) was filtered off and washed with ether. The salt was then dissolved in water and the pH of the solution obtained was adjusted to pH 9 using dilute sodium hydroxide solution. The free amino compound was extracted with chloroform and the combined chloroform extracts were dried, filtered and evaporated. The residue was triturated with ether to obtain 2.7 g (61% yield) of methyl 8-amino-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate in the form of brown crystals with a melting point of 213°-4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.C(O)(=O)C.[CH2:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[CH:22]([CH3:24])[CH3:23]>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:31]1[CH2:30][CH2:29][N:28]([C:26]([O:25][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:27])[CH2:33][CH2:32]1
Reactant: CC(C)COC(=O)N1CCNCC1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(cc1OC)C(=CN1CCN(C(=O)OCC(C)C)CC1)C(=O)N2
Reaction time: 0.33 h

Procedure:
5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 2.5 g. acetic acid and 6.5 g. piperazine-N-carboxylic acid isobutyl ester (U.S. Pat. No. 3,635,979) in 40 ml. benzene was refluxed using a water separator to remove the water as it formed. After 20 minutes, 200 ml. benzene was added and the solution extracted with potassium carbonate and water. The benzene solution was treated with magnesium sulfate and charcoal, filtered, concentrated and the residue crystallized from isopropyl alcohol and ether to give 5.50 g. product, m.p. 195°-197° C.
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]([N+:22]([O-])=O)=[CH:18][N:17]=1.[Cl-].[NH4+].O>C(O)C.C(OCC)(=O)C.CCCCCC.[Fe]>[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[N:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cn3)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1OC
Yield: 64 %

Procedure:
6,7-Dimethoxy-4-((5-nitro-2-pyridyl)oxy)quinoline (654 mg, 2.00 mmol), iron powder (559 mg, 10.0 mmol) and ammonium chloride (1.07 g, 20.0 mmol) were heated and stirred in ethanol (20 ml)-water (5 ml) at 80° C. for 20 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. After washing the organic layer with water and saturated saline and drying over anhydrous magnesium sulfate, the drying agent was filtered out and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out and washed with ethyl acetate and then blow-dried to obtain the title compound (380 mg, 1.28 mmol, 64%) as light yellow crystals.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:58]([O:60]CC)=[CH2:59])CCC>O1CCOCC1.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>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:9]=1[C:58](=[O:60])[CH3:59]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 100 °C

Procedure:
A degassed mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-91,154 mg, 0.19 mmoL), Pd(PPh3)4 (22 mg, 0.019 mmoL), tributyl(1-ethoxyvinyl)stannane (103 mg, 0.28 mmoL) in dioxane (3 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered through 9:1 SiO2:KF plug and concentrated in vacuo. The crude tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9j) was treated with 50% TEA in H2O (4 mL) until the disappearance of starting material in LCMS. Concentration afforded crude 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (Int-9k), which was then heated under microwave conditions with N2H4.H2O (800 uL) and NMP (6 mL) first at 100° C. for 30 min and then at 200° C. for 1 h. Purification with prep-LC provided 3-methyl-6-(6-phenylpyridin-3-yl)-4-(piperidin-4-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidine (Int-91): LCMS tR=2.49 Min (10 min run, UV254m). Mass calculated for, M+409.2, observed LC/MS m/z 410.6 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[H-].[Na+].[CH3:13]I>CN(C=O)C>[CH3:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6]
Reactant: CI
Reactant: Cc1ccc(C#N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1C
Temperature: 0 °C

Procedure:
15 g (0.11 mol) of 3-hydroxy-4-methylbenzonitrile dissolved in 30 ml of DMF were added dropwise to a suspension of 0.11 mol of NaH in 30 ml of DMF, and the mixture was stirred until no further H2 evolution was observed. Then 10.6 ml (0.17 mol) of methyl iodide were added dropwise, and the mixture was stirred at room temperature for 1 h. The solution was poured into ice-water, and the product was extracted with ether/ethyl acetate 7:1. After the solvent had been stripped off, the product began to crystallize slowly. 14.8 g (89%) were obtained. 1H-NMR (CDCl3 ; δ in ppm): 7.2 (m, 2H); 7.02 (s, 1H); 3.85 (s, 3H); 2.25 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH3:13])=[N:7][C:6]=1Cl)[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH3:13])=[N:7][C:6]=1[NH:19][CH:16]1[CH2:18][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(SC)nc1Cl
Reactant: NC1CC1
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(SC)nc1NC1CC1
Yield: 69.1 %

Procedure:
A solution of 8.7 g (34.8 mmol) of 2-chloro-5-fluoro-6-methylsulfanylnicotinic acid ethyl ester (J. Med. Chem., 1993; 36:2676) and 5.7 g (100 mmol) of cyclopropylamine in 100 mL of acetonitrile is heated at reflux for 18 hours. After TLC showed the presence of unreacted starting material, 4.12 g (72 mmol) of cyclopropylamine is added and the reaction mixture is refluxed for 48 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (250 mL) and water (100 mL). The organic layer is washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane to give 6.5 g of the title compound, mp 67-69° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[C:12]([C:14]1[CH:19]=[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1)#[N:13]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: N#Cc1cccc(B(O)O)c1
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: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc(C#N)c2)nc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Methyl 6-chloronicotinate (467 mg, 2.72 mmol) and (3-cyanophenyl)boronic acid (400 mg, 2.72 mmol) were added to 1,4-dioxane (25 mL). To this was added 6.80 mL of a 2 M solution of aqueous potassium carbonate and tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.136 mmol). The above reagents were heated at reflux for 5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (20 mL), the phases were separated and the organic layer was dried over anhydrous MgSO4, filtered and evaporated to a pale yellow solid. The solid was purified using chromatography on silica eluting with a mixture of heptane: ethyl acetate 90:10, 80:20, 70:30. The product fractions were combined and evaporated to give methyl 6-(3-cyanophenyl)nicotinate as a white solid (278 mg). LCMS (ES+) 239 (M+1) 1H NMR (400 MHz CDCl3) ppm 4.00 (s, 3H) 7.62 (t, J=8.2 Hz, 1H) 7.76 (m, 1H) 7.83 (d, J=10.6 Hz, 1H) 8.31 (m, 1H) 8.40 (m, 2H) 9.30 (s, 1H).
Reaction SMILES: [C:1]([CH:3]([CH2:6][C:7](=O)[CH3:8])[C:4]#[N:5])#[N:2].Cl.CNC.[CH3:14][OH:15]>>[CH3:14][O:15][C:1]1[NH:2][C:7]([CH3:8])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(=O)CC(C#N)C#N
Reactant: CO
Agent: CNC
Agent: Cl
Product: COc1[nH]c(C)cc1C#N
Temperature: 25 °C

Procedure:
A solution of 2-cyano-4-oxopentanenitrile (2.75 g) and dimethylamine hydrochloride (16.25 g) in 100 ml of methanol was heated at reflux for 24 h. The mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was dissolved in 50 ml of H2O and extracted with EtOAc. The organic extracts were dried over Na2SO4. Silica gel chromatography afforded a white solid (0.8 g), m.p. 105° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])[CH:4]=[CH:3]1.Br[C:31]1C=CC=C2C=1C=CN2.CI.BrCCCCC>>[CH3:31][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])=[CH:6]1
Reactant: Brc1cccc2[nH]ccc12
Reactant: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCO3
Solvent: CI
Solvent: CCCCCBr
Product: Cn1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)ccc1=O

Procedure:
Following the procedure described in PREPARATION 1A, and making non-critical variations using 1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4-bromoindole, and methyl iodide to replace 1-bromopentane, the title compound was obtained (78%): mp 115-118° C.; 1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m, 3H), 7.18 (d, 1H), 7.06 (t, 1H), 6.87 (d, 1H), 6.57-6.48 (m, 2H), 6.02 (s, 1H), 5.87-5.83 (m, 2H), 4.90 (d, 1H), 4.75-4.52 (m, 3H), 3.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 162.5, 155.9, 149.1, 142.4, 141.6, 139.7, 137.6, 132.1, 129.1, 124.4, 123.9, 121.3, 119.1, 114.0, 108.6, 102.8, 101.6, 93.7, 80.3, 58.2, 40.8, 38.0; MS (ES+) m/z 403.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CN(C)C=O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:2][C:3]([NH:5][C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])=[O:4])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(Cl)cc1)Nc1ccccc1C(=O)O
Temperature: 0 °C
Yield: 144.4 %

Procedure:
N(chloroacetyl)anthranilic acid 3.2 g (0.02 mol) and p-chloroaniline 3.95 g (0.005 mol) were dissolved in 4 ml of dimethylformamide and heated at 80° to 90° C. for 4 hours. The reaction solution was poured into ice water and deposited crystals were collected by filtration. These crystals were washed with ether and recrystallized from ethanol to obtain N-[(4-chlorophenylamino)acetyl]anthranilic acid 2.2 g (yield: 72.2%).
Reaction SMILES: C([CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#N.[C:23]([NH2:25])#[N:24]>C1COCC1.O=[Mn]=O>[NH:25]([CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH2:8][CH2:9]1)[C:23]#[N:24]
Reactant: N#CN
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2)CC1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(NC#N)c2ccccc2)CC1
Reaction time: 120 h

Procedure:
An excess amount of NiO2—H2O (25 g) was added into a solution of tert-butyl 4-(cyano(phenyl)methyl)piperazine-1-carboxylate (10 g) and cyanamine (7 g) in THF (100 ml). An additional cyanamine (25 g) and MnO2 (100 g) was added after 24 hours, and then the reaction was kept stirring for 5 days. The solids were removed by filtration. The filtrate was concentrated under vaccum to give a residue which was purified by silica gel column chromatography to provide tert-butyl 4-(cyanamido(phenyl)methyl)piperazine-1-carboxylate.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[N:17]=[C:16]([C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[N:17]=[C:16]([C:30]3[CH:31]=[C:32]([F:38])[C:33]([F:37])=[C:34]([F:36])[CH:35]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)N[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](NC(=O)c2cc(-c3cc(F)c(F)c(F)c3)nn2Cc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the intermediate from step E (isomer A, 0.3 g, 0.56 mmol) in 10 ml of THF/MeOH was added 5 N NaOH (1 mL). The reaction was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was acidified with 1N HCl (10 ml). The resulting mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4 filtered and concentrated in vacuo. This material was used in the next step without any further purification. 1H NMR (CD3OD, 500 MHz): 8.26 (d, J=2.1 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.59 (dd, J=6.6, 8.9 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 5.83 (s, 2H), 3.7 (m, 1H), 1.95 (d, J=10.1 Hz, 1H), 1.86 (d, J=10.3 Hz, 1H), 1.3 (m, 2H), 1.15 (m, 2H), 1.0 (m, 1H), 0.88 (s, 9H). LC-MS: 4.25 min; (M+H)=514.2.
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH:13]([CH3:18])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].C([BH3-])#[N:20].[Na+]>CO>[NH2:20][CH:14]1[CH2:15][CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH3:18]
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(N)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (5 g, 64.93 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (1.4 g, 7.56 mmol) in methanol (25 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.5 g, 7.93 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH ˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-carbethoxy-3-methylpiperidine. Yield 1.0 g (72%), C9H18N2O2, m/z 187 (M+1), PMR (CDCl3): 0.94 (dd, 3H), 1.22 (m, 1H), 1.26 (t, 3H), 1.6 (m, 1H), 1.82 (m, 1H), 2.4 (m, 1H), 2.82 (m, 1H), 3.34 (m, 2H), 3.64 (m, 1H) 4.14 (q, 2H).