Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[O:12][CH2:13][P:14](=[O:21])([O:18]CC)[O:15]CC.C[Si](I)(C)C.CO>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[O:12][CH2:13][P:14](=[O:15])([OH:21])[OH:18]
Reactant: CCOP(=O)(COc1ccccc1-c1nc2ccccc2s1)OCC
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: O=P(O)(O)COc1ccccc1-c1nc2ccccc2s1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a stirred solution of diethyl 2-(2-benzthiazolyl)phenoxymethylphosphonate (0.2 g, 0.53 mmol) dissolved in dry dichloromethane (2.7 ml) under an atmosphere of nitrogen was added trimethylsilyl iodide (0.31 ml). The red solution was stirred for 2 h then methanol (4.3 ml) was added. After 2 h the solvent was removed under reduced pressure and then water (3.5 ml) was added to the residue. The mixture was concentrated under reduced pressure. Water (2 ml) was added and the mixture was concentrated under reduced pressure. This was repeated four times. The residue was washed finally with water then acetone to give 2-(2-benzthiazolyl)phenoxymethylphosphonic acid (0.13 g, 77%) δH (270 MHz, DMSO) 8.43 (1H, d, J 8 Hz), 8.04 (2H, m), 7.53 (2H, m), 7.44 (2H, m), 7.21 (1H, t, J 8 Hz), 4.4 (2H, d, J 12 Hz), δP (109.7 MHz, DMSO) 14.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14]O)[C:5]2([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16].S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][Cl:25])[C:5]2([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]
Reactant: OCCCNC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: OC1(c2ccccc2)C(NCCCCl)=Nc2ccc(Cl)cc21

Procedure:
Reaction of 5-chloro-2-(3-hydroxypropylamino)-3-phenyl-3H-indol-3-ol with thionylchloride by a procedure analogous to that described in Example 2 gives 5-chloro-2-(3-chloropropylamino)-3-phenyl-3H-indol-3-ol.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[C:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])=[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]2=[O:1])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2C)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 14.4 %

Procedure:
To a solution of ethyl 4-oxo-2-(o-tolylamino)-4,5-dihydrofuran-3-carboxylate (0.098 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0 mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient temperature. The mixture was refluxed for 32 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.019 g, y. 27%).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:14]=[CH:13][C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27]I>>[C:3]([C:5]([C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:14]=[CH:13][C:12]=1[O:25][CH3:26])([CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CI
Reactant: CCOC(=O)C(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Yield: 92.7 %

Procedure:
Sodium hydride (65.5%, 665 mg), ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetate (5.7 g) and methyl iodide (3.55 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]propionate (5.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]1[CH:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[N:21]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:26][CH2:25][C:23]1[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: Cn1cc(CN)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)NCc2cnn(C)c2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a 100 mL round bottom flask containing 3-bromo-4-methoxybenzoic acid (500 mg, 2.16 mmol) and DCM (5 mL) was added oxalyl chloride (0.23 mL, 2.60 mmol) and DMF (0.1 mL, 0.13 mmol). The reaction mixture was stirred at RT for one hour and concentrated in vacuo. The resulting colorless oil was taken up in DCM (2.5 mL) and added to a mixture of (1-methyl-1H-pyrazol-4-yl)methanamine (241 mg, 2.16 mmol), TEA (0.60 mL, 4.33 mmol) and DCM (2.5 mL) at 0° C. The reaction mixture was stirred at RT for 0.5 hours then concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% MeOH in DCM) to afford 3-bromo-4-methoxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide (702 mg) MS [M+H+]=325.9.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:28])[C@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[CH:2]([CH3:3])[CH3:1]
Reactant: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4R)-2-methyl-4-(trityl-amino)-hexan-3-ol (0.53 g, 1 eq, 1.41 mmol) in DCM (2 mL)-under an argon atmosphere at room temperature, was added trifluoroacetic acid (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated from ether (10 mL) with hexane (90 mL) with stirring to give a yellow oil. The solvent was decanted from the oil, and the oil was washed with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil; Yield: 0.18 g (100%). (50% de 3S,4R: 50% de 3R,4R). 1H-NMR (6-DMSO, 250 MHz): δ 0.85-0.99 (m, 9H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 1.42-1.79 (m, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 2.95 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.18 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.37 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 7.58 (bs, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:14]=[CH:15]/[C:16]([O:18]CC)=O.C>C(O)C.C1(C)C(C)=CC=CC=1>[CH3:8][C:7]1[CH:6]=[C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:4]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[CH2:15][CH2:14]2
Reactant: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Cc1cc(-n2cnnn2)cc2c1NC(=O)CC2

Procedure:
A suspension of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol1-yl]phenyl)prop-2-enoate (2.5 g) in ethanol (250 cm3) was hydrogenated at 60° and 15 p.s.i. (1.04×105Pa) pressure over 10% palladised charcoal (1 g) for 11/2 hours. The cooled mixture was filtered through "Solkafloc" (Trade Mark) and evaporated in vacuo to afford a solid. A suspension of this solid in xylene (100 cm3) was heated under reflux for 7 hours. The mixture was then cooled and the product filtered off and washed with dichloromethane:methanol, 5:1, to afford 3,4-dihydro-8-methyl-6-(tetrazol-1-yl)-2-(1H)-quinolone, m.p. 271°-272°, (1.37 g).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH:6]=[C:5]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([F:18])[CH:11]=3)[C:4]=2[CH:3]=[N:2]1.[H][H]>CO>[F:18][C:12]1[CH:11]=[C:10]([CH:5]2[CH2:6][CH2:7][CH2:8][C:9]3[NH:1][N:2]=[CH:3][C:4]2=3)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: [H][H]
Reactant: N#Cc1ccc(C2=CCCc3[nH]ncc32)cc1F
Solvent: CO
Product: N#Cc1ccc(C2CCCc3[nH]ncc32)cc1F
Yield: 20.2 %

Procedure:
4-(6,7-Dihydro-1H-indazol-4-yl)-2-fluoro-benzonitrile (0.102 g, 0.43 mmol) 5% Pd/C wt/wt % (0.04 g) is added to MeOH (5.0 mL) and the mixture is stirred under 45-35 psi of hydrogen for 3 hours. The mixture is filtered through a plug of diatomaceous earth and concentrated to dryness. The residue is purified by silica gel chromatography eluting with 1:1 hexanes/ethyl acetate to give the title compound (0.021 g, 18%). ES/MS m/z 242 (M+H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N+:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])#[C-:34]>CN(C)C=O>[CH:1]1([C:7]2[O:9][CH:34]=[N:33][C:35]=2[C:36]([O:38][CH3:39])=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(O)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
To an ice-cold mixture of cyclohexanecarboxylic acid (5.40 g, 42.1 mmol) and K2CO3 (23.3 g, 168.4 mmol) in N,N-dimethylformamide (60 mL) were added diphenylphosphoryl azide (16.1 g, 58.5 mmol) and methyl isocyanoacetate (5.0 g, 50.5 mmol). After being stirred at room temperature for 16 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated NaHCO3 solution, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting light yellow solid was recrystallized from hexane-ethyl acetate to give the title compound (4.47 g, 51%) as an off-white solid. The mother liquid was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 30:70) to give a light yellow solid. This solid was triturated with hexane-diisopropyl ether to give the title compound (2.05 g, 23%) as a light yellow solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>CS(C)=O.O>[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: BrCc1ccc(I)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A mixture of 4.36 g (20.0 mmol) of p-iodotoluene (purchased from Tokyo Kasei), 3.92 g (22.0 mmol) of N-bromosuccinimide (purchased from Tokyo Kasei) and 60 ml of carbon tetrachloride (purchased from Wako Junyaku Kogyo) was refluxed under irradiation by an incandescent lamp for 4 hours to give 2.67 g (yield: 45.0%) of 4-iodobenzyl bromide (as a white crystalline). Subsequently, to a solution of 0.49 g (10.0 mmol) of sodium cyanide (purchased from Kokusan Kagaku) in 10 ml of dimethyl sulfoxide (purchased from Aldrich) heated at 50° C. was added 1.48 g (5.0 mmol) of the above 4-iodobenzyl bromide, the mixture was stirred at ambient temperature for 3 hours, the resultant reaction mass was dissolved in water and extracted with hexane, and hexane was removed to give 0.84 g (yield: 68.9%) of 4-iodophenylacetonitrile as a white crystalline.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH:24]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:9]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(Br)c1ccc(OC)cc1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(O)c1cccc(OC(C(=O)OCC)c2ccc(OC)cc2)c1
Reaction time: 40 h

Procedure:
To a stirred mixture of 10 g of 3-(α-hydroxyhexyl)phenol, 7.8 g of potassium carbonate, and 4 g of potassium iodide in 400 ml of DMF was added 13.2 g of Ethyl 2-bromo-2(4-methoxyphenyl)acetate and stirring was continuted at room temperature for 40 hours. The reaction mixture was then diluted with water, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. The oily residue (8 g) was chromatographed by HPLC using EtOAc-hexane (1:4) as eluent to give pure product.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([NH2:17])[CH:12]=[CH:11]3)=[O:7])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>[OH-].[K+]>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([NH2:17])[CH:12]=[C:11]3[C:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH:23]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: Nn1ccc2cc(C(=O)c3ccc(F)cc3)ccc21
Agent: [K+]
Agent: [OH-]
Product: CN1CC=C(c2cn(N)c3ccc(C(=O)c4ccc(F)cc4)cc23)CC1
Yield: 65.8 %

Procedure:
A solution of 2.54 gm (10 mMol) 5-(4-fluorobenzoyl)-amino-1H-indole and 1.7 gm (15.0 mMol) 1-methyl-4-piperidone in 20 mL 10% methanolic potassium hydroxide was heated to reflux for 3.5 hours and then allowed to stir without heating. After 18 hours the resultant suspension was filtered, the solid washed with methanol and then dried under reduced pressure to give 2.30 gm (65.8%) 5-(4-fluorobenzoyl)-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a tan powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(C2C=CC([C:41]3[CH:46]=[CH:45][C:44]([N:47]4[C:59]5[CH:58]=CC=C[C:54]=5C5C4=CC=CC=5)=[CH:43][CH:42]=3)=NC=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1COCC1>[CH:25]1[C:26]2[N:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[N:6]=[CH:7][C:2]([C:2]5[CH:7]=[N:6][C:5]([C:8]6[CH:13]=[CH:54][C:59]([N:47]7[C:44]8[CH:45]=[CH:46][CH:41]=[CH:42][C:43]=8[C:15]8[C:20]7=[CH:19][CH:18]=[CH:17][CH:16]=8)=[CH:58][CH:9]=6)=[CH:4][CH:3]=5)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)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: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-c3ccc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)nc3)cn2)cc1
Temperature: 80 °C
Yield: 180 %

Procedure:
A mixture of 6 (4.11 g, 10.3 mmol), 7 (4.60 g, 10.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.595 g, 0.515 mmol), Na2CO3 (5.41 g, 51.0 mmol), H2O (55 mL) and THF (92 mL) was degassed with argon for about 1 h while stirring. The stirring reaction mixture was then maintained under argon at about 80° C. for about 18 h. Upon confirming consumption of the starting materials by TLC (SiO2, 49:1 dichloromethane-acetone), the reaction was cooled to RT, filtered and filtrant washed with EtOAc and H2O to afford 8 (5.92 g, 90%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][C@@H:17](O)[CH2:16][C@H:15]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[N:24]=4)=[O:22])[CH2:14]3)[C:10]2=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(S(F)(F)[F:37])CC>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][C@@H:17]([F:37])[CH2:16][C@H:15]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[N:24]=4)=[O:22])[CH2:14]3)[C:10]2=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1nccc(C(=O)N[C@H]2C[C@H](O)CC3(CCN(c4cc(F)cc(F)c4)C3=O)C2)n1
Solvent: ClCCl
Product: Cc1nccc(C(=O)N[C@H]2C[C@H](F)CC3(CCN(c4cc(F)cc(F)c4)C3=O)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluorophenyl)-9-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide (crude, <0.121 mmol) in DCM (5 mL) was added DAST (20.3 μL, 0.154 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel (0 to 70% EtOAc in hexanes) to give 2 mg of the title compound, trans-2-methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-9-fluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J=5.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.82 (t, J=5.0 Hz, 1H), 7.26-7.21 (m, 1H), 6.54 (tt, J=8.8, 2.2 Hz, 1H), 5.22-5.05 (m, 1H), 4.55-4.43 (m, 1H), 3.79-3.66 (m, 2H), 2.71 (s, 3H), 2.45-2.25 (m, 3H), 2.09-1.92 (m, 3H), 1.74-1.54 (m, 2H). ESI-MS m/z: 419 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12]O[C:14](=[O:15])[C:3]=12.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][N:22]3[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:14](=[O:15])[C:3]=12
Reactant: Nc1c2c(nc3ccccc13)COC2=O
Reactant: NCCCCC1CCCCN1Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CN(CCCCC1CCCCN1Cc1ccccc1)C2=O
Temperature: 200 °C
Yield: 80.5 %

Procedure:
To 1.74 gm of 9-aminofuro[3,4-b]quinolin-1(3 H)-one was added 3.20 gm of 4-aminobutyl-1-benzylpiperidine, and the mixture was heated in a sealed tube for 6 hours at 200° C. while stirring. After cooling, the reaction mixture was recrystallized from ethyl acetate to obtain 3.00 gm of 9-amino- 2-(4-(1-benzYIpiperidYl)butyl)-2,3-dihydropyrrolo[3,4-b]quinolin-1-one (Compound (I) with R1 =R3 =H, R2 =NH2, A=>N-(CH2)n -, Y=>C=O, m=1, and n=4).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:16][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:12][C:13]([CH3:16])([OH:15])[CH2:14]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CC(c2ncc3c(Cl)nccn23)C1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CC(c2ncc3c(Cl)nccn23)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
3-(8-Chloroimidazo[1,5-α]pyrazin-3-yl)cyclobutanone (1.95 g, 8.80 mmol) in anhydrous THF (77.78 mL) at −78° C. under an atmosphere of nitrogen was treated slowly with a 3.0 M solution of methylmagnesium chloride in THF (5.9 mL). The solution stirred for 3 hr at −78° C. then quenched with 40 mL of semi-saturated aqueous NH4Cl (NH4Cl dilution in 1:1 mixture with water) at −78° C. and allowed to warn up to rt. The mixture was then extracted with EtOAc (3×40 mL) and the combined extracts washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was purified by chromatography over silica gel eluting with 1:1 EtOAc/DCM to 4% MeOH in (1:1) EtOAc/DCM to afford desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 3 H), 2.74-2.60 (m, 4 H), 3.75-3.39 (m, 1 H), 7.35 (d, J=5.04 Hz, 1 H), 7.71 (d, J=5.00 Hz, 1 H) and 7.86 (s, 1 H). MS (ES+): m/z 238.15 and 240.17 [MH+].
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1.CC(C)=[O:24]>>[F:21][C:2]([F:1])([F:20])[C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:24])=[O:13])=[CH:14][CH:15]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(-n2c(C(F)(F)F)nc3ccccc32)cc1
Product: O=C(O)c1ccc(-n2c(C(F)(F)F)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde (0.58 g, 2 mmol) in acetone (25 mL) was added Jone's reagent (1.0 mL, 2.0 M) at 0° C. After stirring at room temperature for 2 h, the mixture was partitioned between EtOAc and saturated NaHCO3 solution. After usual workup, the crude material was separated by silica gel chromatography (50% Hexane/EtOAc to EtOAc) to afford the intermediate acid 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzoic acid as a while solid (490 mg).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N:6]1([CH:7]=[CH:8][CH2:9][CH3:10])[CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: C1CCNC1
Reactant: CCCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC=CN1CCCC1
Reaction time: 8 h
Yield: 97 %

Procedure:
108 g of freshly distilled butyraldehyde were added dropwise at 0° C. to a mixture of 213 g of pyrrolidine and 213 g of potassium carbonate. The mixture was allowed to stand overnight at room temperature, diluted with 300 ml of toluene, and the residue was filtered off. The filtrate was then subjected to vacuum distillation at 85° to 90° C. (80 mbar), giving 102 g of 97% pure 1-pyrrolidinobutene, which corresponds to 63.7% of the theoretical yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15]Cl)[C@@H:10]([CH2:18][OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CC(O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C@@H:10]([CH2:18][O:19][CH2:15][C:14]2=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)[C@@H](CO)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)COC[C@H]2C1
Yield: 90.8 %

Procedure:
To a solution of (R)-4-(2-chloro-acetyl)-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (710 mg, 2.45 mmol) in THF (16 mL) at 0° C. was added potassium tert-butoxide (326 mg, 2.91 mmol). The resulting mixture was stirred for 75 min before the addition of AcOH (0.6 mL). The resulting mixture was partitioned between water and DCM and the aqueous layer extracted with further DCM. The combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as a colourless oil (570 mg, 91%).