Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[N:2]1.[CH:9](=[C:16]([C:19]#[N:20])[C:17]#[N:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1>CCO>[NH2:20][C:19]1[N:2]2[N:1]=[CH:5][CH:4]=[C:3]2[C:6]([C:7]#[N:8])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]=1[C:17]#[N:18]
Reactant: N#CC(C#N)=Cc1ccccc1
Reactant: N#CCc1cc[nH]n1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(-c2ccccc2)c(C#N)c2ccnn2c1N
Yield: 14.3 %

Procedure:
To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (100 mg, 0.93 mM) in absolute EtOH (4.7 mL) at 25° C. was added benzylidene malononitrile (144 mg, 0.93 mM) and piperidine (0.009 mL, 0.09 mM). The mixture then refluxed for 1.0 hr. The solvent evaporated. Chromatography done on silica gel (60×2.5 cm) with CH2Cl2 afforded 7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (34.6 mg, 14%) LCMS: MH+=260; HRMS: m/z 260.0938 (MH+), Calcd. C15H9N5: m/z 260.0936; δC (DMSO) CH: 99.0, 128.5, 128.5, 128.8, 128.8, 129.8, 145.4; C: 75.4, 86.9, 115.5, 116.0, 134.8, 138.9, 148.1, 149.4.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C[Si](C)(C)CCOCOCCCCCCCCCCCCCCCC(O)=O.[CH:53]1([N:59]=[C:60]=[N:61][CH:62]2[CH2:67][CH2:66][CH2:65]CC2)CCCCC1>O1CCCC1>[CH3:1][N:59]([C:60]1[CH:65]=[CH:66][CH:67]=[CH:62][N:61]=1)[CH3:53]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[Si](C)(C)CCOCOCCCCCCCCCCCCCCCC(=O)O
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 121 mg of radicicol, 470 mg of 16-[(2-trimethylsilylethoxy)methoxy]hexadecanoic acid, 7 ml of dry tetrahydrofuran, 240 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 481 mg of the title compound were obtained.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[CH:10])[CH2:5][CH2:4]1.FC(F)(F)CCC(C#N)C#N.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl.C(C(C#N)(CCC(F)(F)F)CC1CCC(C#C)CC1)#N>CN(C)C=O>[Br:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@@H:6]([C:9]#[CH:10])[CH2:5][CH2:4]1
Reactant: C#CC1CCC(CBr)CC1
Agent: C#CC1CCC(CC(C#N)(C#N)CCC(F)(F)F)CC1
Agent: Cl
Agent: N#CC(C#N)CCC(F)(F)F
Solvent: CN(C)C=O
Product: C#C[C@H]1CC[C@@H](CBr)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 3.68 g of 1-bromomethyl-4-ethynylcyclohexane (trans/cis=about 3/1) in 20 mL of N,N-dimethylformamide were added 3.13 g of 3,3,3-trifluoropropylmalononitrile, 3.21 g of potassium iodide and 2.67 g of potassium carbonate, followed by stirring at 70° C. for 5 hours. The reaction mixture was cooled to room temperature and then 50 mL of a 1 N aqueous hydrochloric acid solution was added thereto. The reaction mixture was extracted three times with 30 mL of ethyl acetate. The combined organic layer was washed sequentially with 100 mL of a saturated aqueous sodium hydrogen carbonate solution and 100 mL of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3.20 g of the trans isomer (hereinafter referred to as the present compound (1t)) and 1.01 g of the cis isomer (hereinafter referred to as the present compound (1c)) of 1-(2,2-dicyano-5,5,5-trifluoropentyl)-4-ethynylcyclohexane (hereinafter referred to as the present compound (1)) represented by the following formula:
Reaction SMILES: Cl.C[O:3][C:4](=[O:15])[C@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([NH:26][S:27]([C:30]2[C:31]3[N:32]=[CH:33][CH:34]=[N:35][C:36]=3[CH:37]=[CH:38][CH:39]=2)(=[O:29])=[O:28])[CH:18]=1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@@H:5]([NH:14][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([I:16])=[CH:18][C:19]=2[NH:26][S:27]([C:30]2[C:31]3[N:32]=[CH:33][CH:34]=[N:35][C:36]=3[CH:37]=[CH:38][CH:39]=2)(=[O:29])=[O:28])[C:4]([OH:3])=[O:15])=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)cc1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E. HPLC: RT=9.74 min. MS (ESI−): mass calcd. for C24H18ClIN4O5S, 635.97; m/z found, 635/637 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.93 (d, J=12.8, 1H), 8.99 (d, J=1.6, 1H), 8.92 (s, 1H), 8.54 (d, J=7.4, 1H), 8.31 (d, J=8.5, 1H), 8.10 (s, 1H), 7.90-7.87 (m, 1H), 7.30-7.22 (m, 3H), 7.05 (d, J=8.4, 2H), 6.84 (d, J=8.2, 1H), 6.29 (d, J=7.9, 1H), 4.93-4.80 (m, 1H), 3.24 (dd, J=14.3, 5.8, 1H), 3.16 (dd, J=14.2, 5.9, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[C:29]([Cl:31])[C:28]([C:32]([F:35])([F:34])[F:33])=[C:27]([Cl:36])[CH:26]=3)[CH:19]=2)[CH:14]=[C:13]([Cl:37])[C:12]=1[C:38]([F:41])([F:40])[F:39]>ClCCCl>[Cl:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:6]([O-:9])=[O:7])=[C:20]([O:24][C:25]3[CH:26]=[C:27]([Cl:36])[C:28]([C:32]([F:33])([F:34])[F:35])=[C:29]([Cl:31])[CH:30]=3)[CH:19]=2)[CH:14]=[C:13]([Cl:37])[C:12]=1[C:38]([F:41])([F:40])[F:39]
Reactant: FC(F)(F)c1c(Cl)cc(Oc2cccc(Oc3cc(Cl)c(C(F)(F)F)c(Cl)c3)c2)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)c(C(F)(F)F)c(Cl)c2)cc1Oc1cc(Cl)c(C(F)(F)F)c(Cl)c1
Temperature: 0 °C

Procedure:
A cooled mixture of concentrated sulfuric acid (6.5 ml.) and nitric acid (4.4 ml.) is added with stirring to an ice cold solution of 1,3-bis(2,6-dichloro-α,α,α-trifluoro-p-tolyloxy)-benzene (11.1 g. 0.021 mol) in 1,2-dichloroethane (30 ml.). After thirty minutes at room temperature, the phases are allowed to separate and the organic phase washed twice with water. Benzene (200 ml.) is added and the solution washed twice with dilute sodium carbonate solution, dried, filtered through activated silica gel (~25 g.), and the solvents removed. The residual crystals are triturated with pentane, filtered, and dried to obtain 1,3-bis(2,6-dichloro-α,α,α-trifluoro-p-tolyloxy)-4-nitrobenzene (9.9 g., 82%) m.p. 137.5°-140.5° C., 90% pure.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>CCOC(C)=O>[CH3:14][N:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:29][C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)=[CH:28][CH:27]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][C:10]1=[O:15]
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: CN1CCC(c2cccnc2F)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN1CCC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1=O
Temperature: 100 °C
Yield: 42.9 %

Procedure:
4-(2-Fluoropyridin-3-yl)-1-methylpiperidin-2-one (0.07 g, 0.33 mmol), 4-(pyridin-2-ylamino)phenol (0.144 g, 0.77 mmol), cesium carbonate (0.274 g, 0.84 mmol), and 1-methyl-2-pyrrolidinone (1 mL) were combined in a sealed tube and heated at 100° C. for 18 h. The cooled mixture was diluted with EtOAc and washed with water; the aqueous layer was back-washed with EtOAc (1×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 20% to 80% EtOAc (10% MeOH)/Hexanes afforded 1-methyl-4-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)piperidin-2-one (0.053 g, 42.1% yield) as a tan amorphous solid. MS (ESI, pos. ion) m/z: 375.0 (M+1). IC50 (uM) 0.005.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: O=C1CCCCN1
Product: CCCc1c(OCCCN2CCCCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one was prepared as for Example 10 from piperidin-2-one and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:15])=[O:14]>C(Cl)CCl>[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N+:18]=1[O-:9])(=[O:15])=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Cc1ccccn1
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cccc[n+]1[O-]
Reaction time: 8 h

Procedure:
Meta-chloroperbenzoic acid, 85% solution, 1.27 g., 6 mmoles) was added to 2-(methylsulfonylmethyl)-pyridine .08 g., 6 mmoles) in 10 mls. of ethylene chloride. The resulting solution was allowed to stand at room temperature overnight and then was chilled and filtered. The filtrate was evaporated and cyrstallization of the oily residue was induced by scratching. Recrystallization from toluene and isopropanol gave 0.6 g. of the title compound as white needles (melting range 153-155° C.). Analysis for C7H9NO3S:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH2:19])[CH:13]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: Nc1cccc(N)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
A mixture of 5-bromo-2-chloro-3-nitro-pyridine (2.4 g, 10.1 mmol), benzene-1,3-diamine (2.7 g, 25 mmol) and DIPEA (5.3 ml, 30 mmol) in dry NMP (20 ml) was stirred and heated at 120° C. under N2 for 2 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→50% EtOAc/petrol) to give the title compound (2.5 g) as a red solid. 1H NMR (400 MHz, DMSO-d6): 9.78 (1H, s), 8.66 (1H, d), 8.60 (1H, d), 7.00 (1H, t), 6.83-6.71 (2H, m), 6.39 (1H, d), 5.13 (2H, s).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:30])([CH3:29])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([S:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]([Cl:36])([Cl:35])[CH2:33]O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:31][C:32]([Cl:36])([Cl:35])[CH2:33][O:17][C:16](=[O:18])[CH:15]([S:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([CH3:30])([CH3:29])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=1
Reactant: OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid (4.79 g, 10.68 mmol) and 2,2,2-trichloroethanol (1.67 g, 11.22 mmol) in anhydrous DCM (300 mL) was first added EDCxHCl (2.66 g, 13.89 mmol) then DMAP (13 mg, 0.1 mmol) under nitrogen atmosphere at 0° C. After complete addition the cooling bath was removed and the reaction mixture was stirred at ambient temperature until no starting material was left. The mixture was diluted with water and aq. HCl (2N) and extracted with DCM. The combined organic layers were dried (MgSO4) and the solvent was evaporated under reduced pressure to afford the crude product which was directly proceeded to the next step (5.47 g, 88.3%). 1H NMR (400 MHz, CDCl3): δ 7.16 (t, 2H), 7.10 (d, 2H), 7.01 (t, 2H), 6.87 (t, 2H), 4.61 (q, 4H), 3.48 (dd, 1H), 3.12 (dd, 1H), 2.73-2.89 (m, 5H), 0.85 (s, 9H), 0.00 (s, 6H). Mass Spectrum: M−H+ 579.03.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:31])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:20]=[C:19]([F:30])[CH:18]=2)=[CH:7][CH:6]=1)#[N:2].C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC.CO>C1(C)C=CC=CC=1>[F:30][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]2)[CH:20]=1)[C:16]([NH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][C:1]2[N:36]=[N:37][NH:38][N:2]=2)=[CH:6][CH:7]=1)=[O:31]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC#N)c4ccccc34)c2)CC1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCc4nn[nH]n4)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
N-(4-Cyanomethoxynaphthalen-1-yl)-3-fluoro-5-(4-methylpiperidin-1-yl)-benzamide (54 mg, 129 mmol), trimethylsilylazide (0.1 ml, 760 mmol) and dibutyltin oxide (5 mg) are heated to reflux in anhydrous toluene (3 ml) for 5 hours. After cooling to room temperature methanol (5 ml) is then added and the mixture stirred at room temperature for 30 min. The mixture is then evaporated to dryness and the residue recrystallized from ethyl acetate/hexanes to give 3-fluoro-5-(4-methylpiperidin-1-yl)-N-[4-(2H-tetrazol-5-ylmethoxy)-naphthalen-1-yl]-benzamide as a grey powder (22 mg). 1H NMR 300 MHz (DMSO-d6) 10.3 (s, 1H), 8.32 (dd, 1H, J=8.7 and 2.7 Hz), 7.87 (d, 1H, J=9.3 Hz), 7.54-7.62 (m, 2H), 7.42-7.5 (m, 2H), 7.17 (dd, 1H, J=15.9 and 9.3 Hz), 6.97 (d, 1H, J=13.2 Hz), 5.7 (s, 2H), 3.85 (d, 2H, J=19.8 Hz), 2.77 (m, 2H), 1.5-1.78 (m, 3H), 1.25 (m, 2H), 0.95 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:5]OCC)=O.[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].C[O-].[Na+]>>[CH3:1][C:2]1[NH:20][C:18](=[O:19])[C:17](=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:15]#[N:16]
Reactant: N#CCC(N)=O
Reactant: CCOC=C(C(C)=O)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccncc1

Procedure:
In another of its aspects the invention resides in the process which comprises reacting 2-(lower-alkoxy)-1-(pyridinyl)ethenyl lower-alkyl ketone of formula II with cyanoacetamide or malonamide in the presence of a condensing agent and neutralizing the reaction mixture to produce 1,2-dihydro-6-R-2-oxo-5-PY-nicotinonitrile or 1,2-dihydro-6-R-2-oxo-5-PY-nicotinamide of formula III, where R, R', PY and Q have the meanings given for formula III. In preferred embodiments 2-ethoxy(or methoxy)-1-(4- or 3-pyridinyl)ethenyl methyl(or ethyl) ketone is reacted with cyanoacetamide or malonamide in the presence of an alkali lower-alkoxide, preferably sodium methoxide, and then the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl(or ethyl)-2-oxo-5-[4(or 3)-pyridinyl]nicotinonitrile or 1,2-dihydro-6-methyl(or ethyl)-2-oxo-5-[4(or 3)-pyridinyl]nicotinamide, respectively. In a particularly preferred embodiment 2-ethoxy-1-(4-pyridinyl)ethenyl methyl ketone is reacted with cyanoacetamide in the presence of sodium methoxide and the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl-2-oxo-5-(4 -pyridinyl)nicotinonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:19]2[CH2:21][CH2:20]2)[C:13]=1[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N(C(OC(C)(C)C)=O)C1SC=C(C2CC2)C=1C(OCC)=O)=O)(C)(C)C.[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:19]2[CH2:20][CH2:21]2)[C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(C2CC2)csc1NC(=O)OC(C)(C)C
Agent: CCOC(=O)c1c(C2CC2)csc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1scc(C2CC2)c1C(=O)O
Temperature: 60 °C
Yield: 170.4 %

Procedure:
To a stirred mixture of ethyl 2-t-butoxycarbonylamino-4-cyclopropylthiophene-3-carboxylate (2.7 g, 8.7 mmol) and ethyl 2-bis(t-butoxycarbonyl)amino-4-cyclopropylthiophene-3-carboxylate (4.5 g, 10.9 mmol) in methanol (150 ml), a solution of potassium hydroxide (5.3 g, 95 mmol) in water (55 ml) was added. After heating at 60° C. for 6 h, the mixture was concentrated in vacuo and the residue taken up in water (50 ml) followed by acidification (pH=5) with acetic acid under cooling on ice. The precipitate was filtered off and recrystallized from ethyl acetate/ petroleum ether to afford (4.2 g, 70%) of 2-t-butoxycarbonylamino-4-cyclopropylthiophene-3-carboxylic acid. M.p. 175°-176° C. 1H-NMR (CDCl3, δ): 0.6 (m, 2H), 0.9 (m, 2H), 1.55 (s, 9H), 2.35 (m, 1H), 6.2 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [S:1]([NH:5][C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[C:11]#[N:12])(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+].Cl>CCO>[NH:5]1[C:6]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:11]([NH2:12])=[N:2][S:1]1(=[O:4])=[O:3]
Reactant: N#CC1=C(NS(N)(=O)=O)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1=NS(=O)(=O)NC2=C1CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-sulfamoylaminocyclopent-1-enecarbonitrile (Example 107a) (108 mg, 0.57 mmol) in EtOH was treated with NaOH (2.0 N, 0.5 mL), and the resultant solution was heated to 100° C. and stirred at that temperature for 4 h. After it was cooled down to room temperature, the reaction solution was carefully neutralized with 2N HCl while it was vigorously stirred at 0° C. The reaction solution was dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with 10% MeOH in dichloromethane to give the title compound. 1H NMR (400 MHz, DMSO-d6) 1.69-1.63 (m, 2H), 2.2 (t, J=7.6 Hz, 2H), 2.3 (t, J=6.8 Hz, 2H), 5.12 (s, 2H). MS 188 (MH+).
Reaction SMILES: ClC1C=CC=CC=1C1C=CC(C(=O)C)=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](=O)[CH3:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.[H][H]>C1C=CC=CC=1>[CH2:30]([C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:25][CH:26]=1)[CH3:31]
Reactant: CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: [H][H]
Agent: CC(=O)c1ccc(-c2ccccc2Cl)cc1
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 7 h

Procedure:
The procedure of Example 3 was repeated, except that the 4'-(2-chlorophenyl)acetophenone was replaced with an equal amount of 4'-(4-chlorophenyl)acetophenone, the amount of benzene employed was increased to 200 ml, and the amount of sulfuric was reduced to 5 drops. After seven hours, hydrogen pressure had dropped to 35.5 psig. Evaporation of the benzene left a solid which, according to nuclear magnetic resonance analysis, contained only about 67 percent of the desired ethylbenzene. Consequently, the solid was subjected to the hydrogenation procedure again, using 200 ml of benzene, 2 g of catalyst, and 1 ml of concentrated sulfuric acid. The solid obtained upon evaporation of the benzene was recrystallized from hexane, giving 1-ethyl-4-(4-chlorophenyl)benzene, mp 103°-127 104°. The following elemental analysis was obtained:
Reaction SMILES: [C:1]([C:4]1([OH:22])[CH2:13][C:12]2[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[C:6]2([S:21][CH2:20][CH2:19][S:18]2)[CH2:5]1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:34][C:35](C)=[O:36].O>C1C=CC=CC=1.C(O)CO.C(OCC)C>[CH2:34]1[CH2:35][O:36][C:1]([C:4]2([OH:22])[CH2:13][C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[CH:10][C:11]=3[O:14][CH3:15])[C:6]3([S:21][CH2:20][CH2:19][S:18]3)[CH2:5]2)([CH3:2])[O:3]1
Reactant: CC(C)=O
Reactant: COc1ccc(OC)c2c1CC(O)(C(C)=O)CC21SCCS1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: OCCO
Product: COc1ccc(OC)c2c1CC(O)(C1(C)OCCO1)CC21SCCS1
Temperature: 25 °C

Procedure:
2.0 g of rac-3'-acetyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] [prepared as described in Example 5(i)] were dissolved in 150 ml of benzene containing 15 ml of ethyleneglycol, 80 mg of toluene-4-sulphonic acid and 5 ml of acetone. The mixture was heated under reflux for 6 hours using a Dean-Stark water separator and then cooled to room temperature. The mixture was washed with two 100 portions of 10% aqueous potassium hydrogen carbonate and two 100 ml portions of water, dried over magnesium sulphate and evaporated to give a white foam. Trituration with diethyl ether gave rac-3'-(1,1-ethylenedioxyethyl)-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in the form of colourless crystals of melting point 162.5°-163° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].COC1C=CC(C[NH:23][C:24]2[C:33]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@H:35]3[CH3:40])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29](B4OC(C)(C)C(C)(C)O4)[CH:30]=3)[N:25]=2)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:23][C:24]1[C:33]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][C@H:35]2[CH3:40])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=3[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:10])[CH:30]=2)[N:25]=1
Reactant: COc1ccc(CNc2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3cc2N2CCOC[C@H]2C)cc1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1Br
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOC[C@H]3C)cc2c1
Temperature: 140 °C

Procedure:
A mixture of (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.115 g, 0.429 mmol), (R)—N-(4-methoxybenzyl)-3-(3-methylmorpholino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.07 g, 0.143 mmol), potassium phosphate, anhydrous (0.121 g, 0.572 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.014 g, 0.029 mmol), and Pd2(dba)3 (0.013 g, 0.014 mmol) was purged with N2 followed by the addition of degassed dioxane (1 mL) and degassed water (0.5 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using 0-5% MeOH/DCM to afford a yellow oil. To the product was added TFA (10 mL, 130 mmol) and the solution was heated at 60° C. for 18 h until the starting material was consumed. The mixture was concentrated and chromatographed on silica gel using 0-5% 2 M NH3 in MeOH/DCM to afford a yellow solid as (R)-(2-(2-amino-3-(3-methylmorpholino)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 431 (M+1).