Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](Cl)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].N1([C:24]2[C:25](=[O:43])[N:26]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]4=[O:42])=[CH:32][CH:31]=3)[CH2:27][CH2:28][CH:29]=2)CCOCC1.C(N(CC)CC)C.Cl>CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:5]1[C:39]2[CH2:40][CH2:41][N:36]([C:33]3[CH:32]=[CH:31][C:30]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:24][C:25]4=[O:43])=[CH:35][CH:34]=3)[C:37](=[O:42])[C:38]=2[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=1)=[O:17])[CH3:2]
Reactant: O=C1CCCCN1c1ccc(N2CCC=C(N3CCOCC3)C2=O)cc1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 470 mg, 1.3 mmol) in EtOAc (4 mL) was treated with 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 334 mg, 1.3 mmol, 1.0 equiv) at 0-5° C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 263 mg, 0.33 mL, 2.6 mmol, 2.0 equiv) at 0-5° C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was cooled down to 5-10° C. before being treated dropwise with a 4.0 N aqueous HCl solution (1.7 mL, 6.5 mmol, 5.0 equiv) at 0-5° C. The resulting mixture was stirred at 5-20° C. for 4 h. The resulting slurry was then treated with water (10 mL) and EtOAc (10 mL) before the two layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65, 423 mg, 635 mg theoretical, 67% for two steps) as pale-yellow solids, which solidified upon standing in vacuo at room temperature. For 65, CIMS m/z 489 (M++H, C27H28N4O5).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([OH:29])[CH:28]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([O:29][CH2:2][C:3]4[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=4)[C:6]#[N:7])[CH:28]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(COc2cc3n(n2)CCN(C(=O)c2ccc(F)cc2)C3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
3-(bromomethyl)benzonitrile (0.086 g, 0.44 mmol) was added to a stirred suspension of 5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ol (0.105 g, 0.4 mmol) and Cs2CO3 (0.261 g, 0.8 mmol) in ACN (2 mL). The mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 3-[({5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl}oxy)methyl]benzonitrile (0.089 g, 59% yield) as a white solid. C21H17FN4O2. 1H NMR (500 MHz, CDCl3) δ ppm 4.08 (br. s., 4 H), 4.74 (br. s., 2 H), 5.22 (s, 2 H), 5.51 (br. s., 1 H), 7.15 (t, J=8.5 Hz, 2 H), 7.44-7.51 (m, 3 H), 7.60 (d, J=7.8 Hz, 1 H), 7.65 (d, J=7.8 Hz, 1 H), 7.74 (s, 1 H).
Reaction SMILES: C(O)[C@H]1[O:7][C@H](O[C@@H]([C@H](O)[C@@H](O)CO)[C@H](O)CO)[C@H](O)[C@@H](O)[C@@H]1O.[OH-].[K+].[CH2:26]([O:30][C:31]1[CH:44]=[CH:43][C:34]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])=[CH:33][CH:32]=1)[CH:27]1[O:29][CH2:28]1.Cl(O)(=O)=O>CS(C)=O.C(O)C.O>[C:35]([C:34]1[CH:43]=[CH:44][C:31]([O:30][CH2:26][CH:27]([CH2:28][OH:7])[OH:29])=[CH:32][CH:33]=1)(=[O:36])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OC[C@@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO
Reactant: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1
Agent: [K+]
Agent: [O-][Cl+2]([O-])O
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(OCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
Then, 2.921 g of maltitol and 476.0 mg of potassium hydroxide were dissolved in 20 ml of dimethylsulfoxide, and the mixture was stirred under flow of nitrogen for 30 minutes. A solution obtained by dissolving 719 mg of the resultant 4-glycidyloxy benzophenone dissolved in 1 ml of dimethylsulfoxide was dripped to it. Furthermore, heating and agitation was continued for 1 hour under flow of nitrogen, and the reaction system was cooled to the room temperature and neutralize with chloric acid. The reaction system was fractionated according to the column chromatography using the hyperporous polymer (Hiporous resin supplied from Mitsubishi Kasei Kogyo Kabushiki Kaisha) at first as a developing solvent with purified water, and then a mixture of ethyl alcohol and purified water with the mixing ratio of 1:1, and effluent fraction in which the mixing ratio of ethyl alcohol and purified water was 1:1 was condensed to obtained 500 mg of 1-(4-benzoylphenyl) glycerol maltitolether (Yield: 30%).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[C:5]1=[O:20])([CH3:3])[CH3:2].[C:21]([O:25][C:26]([NH:28][C:29]([CH3:48])([CH3:47])[C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1)[C:34](O)=[O:35])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.O>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[C:29]([NH:28][C:26](=[O:27])[O:25][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:48])[CH3:47])[C:34]([N:16]2[CH2:17][CH2:18][CH2:19][C:6]3([C:5](=[O:20])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH:7]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15]2)=[O:35])=[CH:39]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)N1CC(c2ccccc2)C2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture comprising 2-isopropyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (ASW MedChem) (278 mg, 0.899 mmol), (R)-2-(2-(tert-butoxycarbonylamino)-2-methylpropanamido)-3-(1H-indol-3-yl)propanoic acid (Intermediate 3C) (350 mg, 0.899 mmol) and DIPEA (0.628 ml, 3.59 mmol) in DMF (4 ml) was treated with ®T3P (50% in DMF, 0.525 ml, 1.797 mmol) and stirred at RT for 2 h 20 min. The reaction mixture was diluted with water (5 ml) and extracted with EtOAc. The organic portion was dried (MgSO4) and concentrated in vacuo Purification of the crude product by chromatography on silica eluting with 1% MeOH in DCM afforded the title compound;
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10](OC)=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:24][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[C@@:13]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:12]=2[CH:11]=[C:10]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)[CH:9]=1
Reactant: OB(O)c1ccncc1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(-c3ccncc3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in method A7 above, but using intermediate 20B, 2-fluoropyridin-3-ylboronic acid and 4-pyridineboronic acid. MS m/z=456.8 [M+H]+. Calculated for C26H18F2N4O2: 456.14
Reaction SMILES: N[C:2]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH:3][C:4]#[N:5].[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>O1CCOCC1>[NH2:5][C:4]1[NH:16][C:14](=[S:15])[C:13]([C:11]#[N:12])=[C:2]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[CH:3]=1
Reactant: N#CC=C(N)c1ccco1
Reactant: N#CCC(N)=S
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccco2)cc(N)[nH]c1=S
Yield: 17 %

Procedure:
Following the method of Elnagdi and Erian (Arch. Pharm. 1991, 324, 853-858), to a stirred solution of 5.00 g (37.3 mmol) (E or Z)-3-amino-3-furan-2-yl-acrylonitrile in 50 ml dioxane at room temperature was added 7.46 (74.5 mmol) 2-cyanothioacetamide and the reaction mixture heated at reflux for 72 hours. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/1 then ethyl acetate) afforded 1.40 g (17%) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3-carbonitrile as an orange crystalline solid, ES-MS m/e (%): 218 (M+H+, 100), and 0.46 g (6%) 2,6-diamino-4-furan-2-yl-nicotinonitrile as an orange crystalline solid, ES-MS m/e (%): 201 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]=[C:14]([C:25](O)=[O:26])[C:15]3[C:16]([CH3:24])=[CH:17][N:18]([CH:21]([CH3:23])[CH3:22])[C:19]=3[CH:20]=2)[CH:8]=[CH:9][C:10]=1[F:11])[CH3:3].Cl.[NH2:29][CH2:30][C:31]1[C:32](=[O:39])[NH:33][C:34]([CH3:38])=[CH:35][C:36]=1[CH3:37].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]=[C:14]([C:25]([NH:29][CH2:30][C:31]3[C:32](=[O:39])[NH:33][C:34]([CH3:38])=[CH:35][C:36]=3[CH3:37])=[O:26])[C:15]3[C:16]([CH3:24])=[CH:17][N:18]([CH:21]([CH3:22])[CH3:23])[C:19]=3[CH:20]=2)[CH:8]=[CH:9][C:10]=1[F:11])[CH3:3]
Reactant: Cc1cn(C(C)C)c2cc(-c3ccc(F)c(CN(C)C)c3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(F)c(CN(C)C)c3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a stirred suspension of 6-{3-[(dimethylamino)methyl]-4-fluorophenyl}-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (210 mg, 0.570 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl salt (140 mg, 0.742 mmol) and HOAt (100 mg, 0.735 mmol) in DMF (15 mL) was added N-methylmorpholine (82 μl, 0.746 mmol) and EDC free base (110 mg, 0.709 mmol). The reaction was stirred for 4 h at RT and concentrated to near dryness under vacuum. Water was added till the product ppt. out. The suspension was triturated, filtered, rinsed with cold water then dried under vacuum to give the product 6-{3-[(dimethylamino)methyl]-4-fluorophenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide (186 mg, 0.370 mmol, 64.9% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ=11.47 (br. s., 1 H), 8.15 (t, J=4.9 Hz, 1 H), 8.04 (d, J=5.3 Hz, 1 H), 7.90-7.86 (m, 1 H), 7.39 (t, J=9.2 Hz, 1 H), 7.35 (s, 1 H), 7.27 (d, J=1.3 Hz, 1 H), 5.87 (s, 1 H), 4.88 (dt, J=6.6, 13.3 Hz, 1 H), 4.36 (d, J=5.1 Hz, 2 H), 4.26 (br. s., 2 H), 2.69 (s, 6 H), 2.24 (s, 3 H), 2.17 (s, 3 H), 2.11 (s, 3 H), 1.44 (d, J=6.6 Hz, 6 H). MS(ES)+m/e 503.0 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(=O)N(C)C)C2=O)CC1
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-chloro-N,N-dimethylacetamide, to give the desired product as a white solid (71%).
Reaction SMILES: [OH-:1].[Na+:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]4[CH2:28][O:27][C:26](=[O:29])[C:14]=4[CH:15]=[C:16]4[C:24]=3[C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=[C:17]4[Cl:25])=[CH:11][C:6]=2[O:5][CH2:4]1>CO>[Na+:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([CH2:28][OH:1])=[C:14]([C:26]([O-:27])=[O:29])[CH:15]=[C:16]4[C:24]=3[C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=[C:17]4[Cl:25])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: O=C1OCc2c1cc1c(Cl)cc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])c1cc2c(Cl)cc3c(c2c(-c2ccc4c(c2)OCO4)c1CO)OCO3
Temperature: 70 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1 N aqueous NaOH solution (1.56 mL) was added to the solution of 37 (57 mg, 0.15 mmol) in MeOH (25 mL). The mixture was stirred at 70° C. for 1 h. The solvent was evaporated to give a crude product, which was purified by silica gel column chromatography using CH2Cl2/MeOH (3:1, v/v) to afford 44 (55 mg, 87%) as a white powder. mp 220° C. (decomp.); 1H NMR (DMSO-d6) δ 8.39 (s, 1H, H4), 7.54 (s, 1H, H6), 6.89 (d, 1H, H5′, J=8.7 Hz), 6.73 (d, 1H, H2′, J=1.5 Hz), 6.63 (dd, 1H, H6′, J=1.5, 8.7 Hz), 6.05 (AB, 2H, 3′,4′-OCH2O—, Δδ=18.9 Hz), 5.81 (AB, 2H, 7,8-OCH2O—, A5=8.1 Hz), 4.12 (s, 2H, 2-CH2OH); MS (FAB, positive) m/z 425 [M+H+2]+, 423 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[N+:25]([CH:28]([CH3:31])[CH2:29]O)([O-:27])=[O:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([O:8][CH2:29][CH:28]([N+:25]([O-:27])=[O:26])[CH3:31])=[O:7]
Reactant: CC(CO)[N+](=O)[O-]
Reactant: Cc1nn(-c2cc(OC(C)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1nn(-c2cc(OC(C)C(=O)OCC(C)[N+](=O)[O-])c(Cl)cc2Cl)c(=O)n1C(F)F
Yield: 82 %

Procedure:
A stirred mixture of 0.5 g (0.0013 mole) of 2-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionic acid (Compound A1), 1.0 g (0.0095 mole) of 2-nitro-1-propanol and 0.05 g (0.0003 mole) of p-toluenesulfonic acid monohydrate in 60 mL of toluene was heated at reflux. The water generated in the reaction was removed by collection in a Dean-Stark trap. After refluxing for a total of two hours, the solvent was removed by distillation under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and washed first with water then with an aqueous 10% sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield 0.5 g of 2-nitropropyl 2-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound B1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.O(N(C)[C:16](=[O:18])[CH3:17])C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:16]([C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: Brc1cncnc1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1cncnc1
Temperature: -78 °C
Yield: 40.9 %

Procedure:
5-Bromopyrimidine (3.18 g, 20 mmol) was dissolved in 50 mL of tetrahydrofuran. While cooled to −78° C., 15 mL of 1.6 M n-butyllithium in hexane solution was added dropwise with stirring. After the solution was stirred for 30 minutes, a solution of N-methoxyl-N-methylacetamide (2.58 g, 25 mmol) in tetrahydrofuran solution (10 mL) was added slowly. The mixture was stirred at −78° C. for 1 hour and then allowed to be warmed slowly. When the temperature of the mixture was at 0° C., aqueous ammonium chloride solution was added. The solution obtained was extracted with ethyl acetate for 3 times. The pooled extracts were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using 5% methanol/methylene chloride as eluent to obtain 1 g of the title compound (45% yield). MS (M+1)=123.05.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][Si](C=[N+]=[N-])(C)C.[ClH:19].CCOC(C)=O>C(#N)C.C1COCC1>[Cl:19][CH2:12][C:6]([C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([F:11])[CH:4]=1)=[O:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cl
Reactant: O=C(Cl)c1ccc(Br)c(F)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCl)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-3-fluorobenzoyl chloride (5.6 g, CAS 695188-21-7) in acetonitrile (30 ml) and THF (30 ml) at 0-5° C. was added dropwise (trimethylsilyl)diazomethane (13.7 ml, 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 30 min TLC analysis showed the reaction was complete. Hydrochloric acid (3.81 ml, 37% aq.) was then added dropwise at 0-5° C. over 10 minutes and the reaction mixture was then stirred at room temperature for a further 20 minutes. The reaction mixture was poured into EtOAc and extracted sequentially with aq. Na2CO3 solution, water and saturated brine. The organic layer was then dried over Na2SO4 and concentrated in vacuo to afford 2-chloro-1-(4-bromo-3-fluoro-phenyl)-ethanone (5.67 g) as a yellow solid which was used in the next step without further purification. MS (EI): 203 ([{81Br}M-CH2Cl]+), 201 ([{79Br}M-CH2Cl]+), 175 ([{81Br}M-CH2Cl—CO]+), 173 ([{79Br}M-CH2Cl—CO]+).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][C:13](Cl)=[O:14])(=[O:10])[CH3:9].[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][CH3:20]>C1(C)C=CC=CC=1>[F:16][C:17]([F:22])([F:21])[CH2:18][N:19]([CH3:20])[C:13](=[O:14])[CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CNCC(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N(C)CC(F)(F)F
Temperature: 20 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
10 g (0.1 mol) of triethylamine and 13.6 g (0.1 mol) of acetoxyacetyl chloride were added to a solution of 9.9 g (0.1 mol) of N-(2,2,2-trifluoroethyl)-N-methylamine in 150 ml of toluene and the mixture was stirred at 20° C. for 15 hours. It was then filtered and the filtrate was distilled. 17 g (79.8% of theory) of N-(2,2,2-trifluoroethyl)-N-methyl-acetoxyacetamide of boiling point 110° C./3 mbar were obtained. ##STR11## was obtained analogously; ND20 :1.4333. ##STR12##
Reaction SMILES: N1CCC2(C=CC3C=CC=CC=3O2)CC1.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24].[C:26]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].N1CCCC1>CO>[C:26]([N:33]1[CH2:34][CH2:35][C:36]2([CH2:24][C:23](=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16]2)[CH2:37][CH2:38]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1=CC2(CCNCC2)Oc2ccccc21
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2

Procedure:
The compounds prepared in Examples Z1-Z14 and depicted in Table Z1 were prepared according to the Schemes Z1-Z6. The preparation of spiro[2H-1-benzopyran-2,4′-piperidine] derivatives 15 (Example Z1), 16 (Example Z2) and 18 (Example Z3) is outlined in Scheme Z1. The 2′-hydroxyacetophenone derivatives 1, 2 and 3 (commercially available from Aldrich Chemical Company) were condensed with 1-Boc-4-piperidone 4 in methanol in the presence of pyrrolidine to provide N-Boc-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one derivatives 5-7 respectively. Compounds 12-14 were prepared by conversion of the ketones 5-7 to the enol triflate derivatives 8-10 and subsequent Suzuki coupling reaction with 4-(N,N-diethylaminocarbonyl)phenylboronic acid 11. The Boc protecting groups of 12-14 were subsequently removed using trifluoroacetic acid to generate the corresponding spiro[2H-1-benzopyran-2,4′-piperidine] derivatives 15 (Example Z1), 16 (Example Z2) and 17. Demethylation of the methyl ether 17 using boron tribromide in anhydrous dichloromethane afforded the phenolic derivative 18 (Example Z3). Hydrogenation of 15 in methanol in the presence of palladium hydroxide (Pearlman's catalyst) afforded the 3,4-dihydrospiro[2H,1-benzopyran-2,4′-piperidine] derivative 19 (Example Z4) (Scheme Z2). Treatment of 15 with formaldehyde in the presence of sodium cyanoborohydride gave the N-methyl derivative 20 (Example Z5) (Scheme Z2).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step A and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-33 5°±2.5° (c=0.5% in chloroform).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]>ClCC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][Br:1]
Reactant: BrBr
Reactant: Cc1ccc(-c2ccccc2C#N)cc1Br
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Reaction time: 0.5 h
Yield: 33370.6 %

Procedure:
5.6 g (0.035 mmol) of bromine, dissolved in 20 ml of tetrachloroethane, are added dropwise at 100°-110° with UV irradiation to a solution of 8.9 g (0.033 mol) of 3'-bromo-4' -methyl-1,1'-biphenyl-2-carbonitrile in 900 ml of tetrachloroethane after addition of 0.1 g of benzoyl peroxide. After 30 minutes, the reaction mixture is cooled and evaporated in vacuo. The crystalline residue is recrystallized from ethyl acetate and gives 4.1 g of the title compound of m.p. 152°-153°.