Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6](=[O:19])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(#N)C>[C:1]([N:4]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]([O:19][C@@H:34]2[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]2[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of 1-acetyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.26 g) in acetonitrile (20 mL) were added potassium carbonate (1.01 g) and 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl bromide (2.96 g) under stirring at room temperature. In addition, the mixture was heated to 50° C. and stirred for 3 hours. After the completion of the reaction, the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-acetyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (2.68 g).
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2[C:3]([N:8]=1)=[N:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=[N+]([O-])c1ncccc1Cl
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2ncccc2n1-c1ccccc1
Yield: 43.2 %

Procedure:
Method A applied to 3-chloro-2-nitropyridine (79 mg) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as brown viscous oil (45 mg, 43% yield). 1H NMR (DMSO) δ 2.54 (s, 3H), 7.35-7.68 (m, 6H), 7.77 (d, J=8.8Hz, 1H), 8.58 (br s, 1H); 13C NMR δ 14.0, 118.9, 120.1, 126.8, 128.5, 129.6, 130.1, 133.9, 143.0, 151.6, 156.7. HRMS (FAB): cal. for C13H12N3 [M+H+]: 210.1031; found: 210.1026.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([N:11]4[CH2:15][CH2:14][CH2:13][C:12]4=[O:16])([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]#[N:33])=[O:26]>CS(C)=O.CCOC(C)=O>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:4]12[CH2:10][CH:8]3[CH2:9][C:2]([NH:1][CH2:24][C:25]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]#[N:33])=[O:26])([CH2:3]1)[CH:6]([CH2:7]3)[CH2:5]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(N1CCCC1=O)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCC1=O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred mixture of 1-(3-aminotricyclo[3.3.1.03,7]non-1-yl)pyrrolidin-2-one prepared as in preparation 9 (0.25 g, 1.1 mmol) and K2CO3 (0.46 g, 3.3 mmol) in DMSO (5 mL) at an ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.2 g, 1.1 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.16 g) in 40% yield. m/z (M+1) 357; 1H NMR (CDCl3) 300 MHz δ 4.78 (d, J=7.4 Hz, 1H), 3.70-3.38 (m, 2H), 3.46 (s, 2H), 3.41 (t, J=7.0 Hz, 2H), 2.60 (dd, J=4.0, 10.2 Hz, 1H), 2.40-1.75 (m, 17H), 1.72-1.62 (m, 1H), 1.58-1.50 (m, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([Si:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:9]1[O:10][CH:11]=[C:12]([CH:14]=O)[CH:13]=1)[CH3:7]>CCCCCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([Si:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:9]1[O:10][CH:11]=[C:12]([CH:14]=[CH2:1])[CH:13]=1)[CH3:7]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1coc([Si](CC)(CC)CC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
n-Butyl lithium (a 2.5 M solution in hexane; 4.4 ml, 11.0 mmol) was added dropwise to a suspension of methyltriphenylphosphonium bromide (3.93 g, 11 mmol) in THF (40 ml) at 0 degrees C. under argon. After 2 hours stirring at 0 degrees C., a solution of 2-triethylsilyl-4-furaldehyde (1.54 g, 7.33 mmol) in THF (2 ml) was added. Stirring was continued at room temperature for 14 hours and the mixture was quenched with methanol/water 40 ml (1:1). Extraction (pentane) and evaporation of the dried (magnesium sulfate) extracts gave a residue, which was purified by flash chromatography on silica using pentane to give the titled furan. Rf (pentane) 0.75.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](Cl)[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)CC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[NH:18][N:19]=[C:12]([NH2:13])[C:11]3=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2ccc(N)cc2)nc1Cl
Solvent: O
Solvent: CCCO
Product: Nc1ccc(-c2ccc3c(N)n[nH]c3n2)cc1
Temperature: 130 °C
Yield: 98.4 %

Procedure:
In an appropriately sized microwave reactor, 0.97 mmol (222 mg) of 6-(4-aminophenyl)-2-chloronicotinonitrile is suspended in 3.3 ml of 1-propanol. 0.28 ml (0.290 g, 5.80 mmol, 6 eq.) of hydrazine hydrate is added. The suspension is heated for 45 minutes at 130° C. in a microwave oven. The mixture is filtered and the solid is dried so as to obtain a green solid (215 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[O:23])=[O:10])=[N:6][CH:7]=1.S>CCN(CC)CC.N1C=CC=CC=1>[CH3:20][O:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[O:10])=[C:12]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[N:6]([CH3:7])[CH2:5][CH2:4][N:31]=3)=[CH:28][CH:29]=2)=[O:23])[CH:13]=1
Reactant: COc1cc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Br)cn2)cc1OC
Agent: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2ccc(C3=NCCN3C)cc2)c(C(=O)Nc2ccc(Br)cn2)cc1OC
Reaction time: 8 h

Procedure:
To a solution of compound obtained in Example 259 (100 mg, 0.20 mmol) in 10% Et3N/pyridine (10 mL) at 0° C. was bubbled dry H2S gas to saturation. The mixture was stirred at ambient temperatures overnight, and the conversion was complete. The solvent was removed to dryness, and the residue was suspended in anhydrous acetone. (10 mL), followed by addition of MeI (1 mL). The reaction mixture was refluxed for 1 hour. The solvent was removed by rotary evaporation. To the residue was added anhydrous MeOH (10 mL) and N-methylethylenediamine (1 mL). The resulting mixture was refluxed for 1 hour, concentrated and subjected to RP-HPLC purification to give the title compound. MS found for C25H24BrN5O4 (M+H)+: 538.1, 540.1.
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: CCOC=C(C(C)=O)c1ccncc1
Reactant: N#CCC(N)=O
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: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:11]=1/[CH:29]=[CH:30]/[C:31]([O:33][CH3:34])=[O:32])[CH3:2]>CO.[Pd]>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][C:11]1[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:35]
Reactant: CCOC(=O)CCCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCCOc1cccc(CCCCCCOC2CCCCO2)c1CCC(=O)OC

Procedure:
A 0.86 g (1.76 mmol) sample of rac-(E)-5-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenoxy]pentanoic acid ethyl ester was hydrogenated in 50 mL of methanol, over 50 mg of 10% palladium on carbon, at room temperature and 1 atmosphere. Rac-2-(5-ethoxy-5-oxopentyloxy)-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester, an oil, was isolated by filtration of the catalyst and concentration of the filtrate, in quantitative yield.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([O:8][C:9](=[O:26])[CH2:10][C:11]1[N:24]=[C:23](O)[C:14]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[S:22][C:13]=2[N:12]=1)[CH3:7]>>[CH2:6]([O:8][C:9](=[O:26])[CH2:10][C:11]1[N:24]=[C:23]([Cl:3])[C:14]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[S:22][C:13]=2[N:12]=1)[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1nc(O)c2c3c(sc2n1)CCCCC3
Product: CCOC(=O)Cc1nc(Cl)c2c3c(sc2n1)CCCCC3
Yield: 34.3 %

Procedure:
The POCl3 (20 ml, 215 mmol)) was added to (4-hydroxy-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (5.5 g, 0.01795 mol) and the solution was refluxed for 2 h. The reaction was quenched into 200 g of ice and extracted with 3×100 ml ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated under vacuum. The crude was purified by chromatography on silica gel using 10% ethyl acetate in hexanes to give (4-chloro-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (2 g, 34%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 4.19 (q, 2H), 4.02 (s, 2H), 3.30-3.37 (m, 2H), 2.92-2.98 (m, 2H), 1.85-1.95 (m, 2H), 1.65-1.78 (m, 4H), 1.25 (t, 3H); LC-MS: [M+H]=325.0 & 327.1 m/z.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([C:8]([O:10][C:11]([C:27]([F:30])([F:29])[F:28])([C:15]#[C:16][Si](C(C)C)(C(C)C)C(C)C)[CH2:12][CH:13]=[CH2:14])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:11]([C:15]#[CH:16])([C:27]([F:28])([F:29])[F:30])[CH2:12][CH:13]=[CH2:14])=[O:9])=[CH:31][CH:32]=1)([O-:3])=[O:2]
Reactant: C=CCC(C#C[Si](C(C)C)(C(C)C)C(C)C)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CC=C)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Yield: 25.4 %

Procedure:
To a solution of crude 1-(trifluoromethyl)-1-[(triisopropylsilyl)ethynyl]but-3-en-1-yl 4-nitrobenzoate from Step 2 (˜0.755 mmol) in THF (3 mL) at room temperature was added a THF solution of tetrabutylammonium fluoride (1.0 M, 0.906 mL, 0.906 mmol). After 2.5 h the reaction mixture was poured in H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (Na2SO4) and concentrated. The residue was subjected to chromatography on silica gel (toluene/hexane 40:60 to 60:40) affording the title compound (60 mg). 1H NMR (500 MHz, acetone-d6): 8.44 (d, 2H), 8.29 (d, 2H), 5.94 (m, 1H), 5.29 (d, 1H), 5.21 (d, 1H), 3.74 (s, 1H), 3.27 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][N:41]([CH3:43])[CH3:42])=[CH:38][N:37]=[N:36]2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][N:41]([CH3:43])[CH3:42])=[CH:38][N:37]=[N:36]2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1F
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-fluoro-phenyl)-carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and 3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K8) (344 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (211 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH:43]=[CH:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH:43]=[CH:42]2)=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2C=CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4C=CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (30 mg) in anhydrous DMF were added 2-(cyclohex-2-enyloxy)ethyl 4-methylbenzenesulfonate (intermediate BV) (1.5 eq) and Cs2CO3 (2 eq). The mixture was stirred at room temperature for 16 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into water, extracted with EA, washed with water and brine, and then dried with anhydrous Na2SO4 and concentrated to an oil. The crude oil was purified by preparative-HPLC to obtain compound BW (17.1 mg). 1H NMR (CD3OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.87˜5.76 (s, 2H), 4.59 (s, 1H), 4.11˜3.89 (m, 6H), 3.89˜3.76 (m, 3H), 3.72˜3.68 (m, 1H), 3.49˜3.40 (m, 3H), 2.03˜1.98 (m, 2H), 1.89˜1.84 (m, 1H), 1.80˜1.62 (m, 2H), 1.79˜1.51 (m, 1H); MS ESI (m/z) 506 (M+H)+, calc. 505.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21]C(C)(C)C)=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:33]4[C:37](=[O:38])[NH:36][C:35](=[O:39])[NH:34]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([OH:21])=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:33]4[C:37](=[O:38])[NH:36][C:35](=[O:39])[NH:34]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(=Cc2cnn3c(Nc4cccc(C(=O)O)c4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Tert-butyl 3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate (97 mg, 0.2 mmol) was dissolved in 2 mL of TFA/DCM (1:1) and stirred at room temperature for 1 hour. Excess solvent and TFA were removed by evaporation under a stream of nitrogen. The residue was diluted with water then the mixture was filtered. The product, 3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoic acid, was collected as a solid in 85% yield. LCMS (M+1=490)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][C:4]=1[F:19])[CH3:2].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:22])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][C:4]=1[F:19])[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1F
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1F

Procedure:
According to General Method 3A, 1.5 g (4.8 mmol) of methyl 5-(4-ethyl-3-fluorophenyl)piperidine-3-carboxylate and 1.3 g (6.3 mmol) of 4-nitrophenyl chloroformate were reacted. Yield: 2.1 g (92% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:16]([Cl:17])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)[CH:7]=1.[S-:19][C:20]#[N:21].[NH4+].BrBr.O>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([F:18])[C:6]([N:8]3[C:16]([Cl:17])=[C:15]4[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]4)=[N:9]3)=[CH:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2cc(-n3nc4c(c3Cl)CCCC4)c(F)cc2s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
2-(5-Amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (22.97 g) was dissolved in 95% aqueous acetic acid (79.53 g), and ammonium thiocyanate (15.92 g) was added thereto at room temperature (ca. 20° C.). To the resultant mixture, a solution of bromine (15.89 g) in acetic acid (23.77 g) was dropwise added in 105 minutes. After being allowed to stand overnight, the mixture was heated to 100° C., and hot water (173 ml) was added thereto, followed by filtration. The filtrate was cooled and neutralized with sodium carbonate. The precipitated crystals were collected by filtration and dried to give 2-(2-amino-6-fluorobenzothiazol-5-yl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (8.77 g). m.p., 212.4° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:21]1[O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]3[C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[N:3]=[C:4]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:5]=4[N:11]=[CH:10][N:9]=3)=[CH:15][C:16]=2[O:22]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccc4c(c3)OCO4)c2n1
Product: c1nc(SCc2ccc3c(c2)OCO3)c2nc(N3CCNCC3)nc(N3CCOCC3)c2n1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(3,4-methylenedioxybenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 200°-202° C.) and piperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:30])([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cccc2c1C(=O)C(C)(c1ncnn1C)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (100 mg, 0.25 mmol) and potassium carbonate (70 mg, 0.51 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hr. Then the solution was cooled to 0° C. and a solution of iodomethane (0.1 mL) in N,N-dimethylformamide (1 mL) was added dropwise at 0° C. over 1 hr, stirred at room temperature overnight. The mixture was quenched with water (30 mL), extracted with ethyl acetate, washed with brine, and then the extraction was evaporated to get the crude product, which was used in next step without further purification (80 mg, yield 77%). LC-MS (ESI) m/z: 409 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[C:15](Cl)(=[O:17])[CH3:16]>>[C:15]([N:11]1[CH2:12][CH:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)([CH2:14]2)[CH2:10]1)(=[O:17])[CH3:16]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Using the method of Example 19, 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane (Example 1) is reacted with acetyl chloride to give 3-acetyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane and then is converted to 1-(p-chlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane which is obtained as a brown oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:4]([O:6]C)=[O:5])[CH3:2].[OH-].[K+]>O.C(O)C>[CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)O

Procedure:
The procedure in Example 6 is followed but using methyl 2-ethyl-6-[(4,6-diphenyl-2-pyridyl)oxy]hexanoate (3.15 g), potassium hydroxide pellets (0.9 g) dissolved in distilled water (20 cc) and ethanol (100 cc). The reaction mixture is refluxed for 8 hours. The product is purified by recrystallisation in an n-hexane-ethyl acetate (2-1) mixture (40 cc), white crystals (m.p.=115° C.)