Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.CO>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(CN2CCCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Reaction time: 10 h
Yield: 85.2 %

Procedure:
After 2-amino-4-(4-nitrophenoxy)pyridine (160 mg) was dissolved in tetrahydrofuran (7 ml) under a nitrogen atmosphere, triethylamine (0.289 ml) and phenyl chloroformate (0.260 ml) were added while stirring in an ice water bath. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and to the resultant residue was added N,N-dimethylformamide (8 ml). 4-(Pyrrolidin-1-ylmethyl)piperidine dihydrochloride (668 mg) and triethylamine (0.772 ml) were added and stirred for 4 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The separated organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (295 mg) as a pale yellow oil. 4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (295 mg) was dissolved in tetrahydrofuran (7 ml) and methanol (7 ml) under a nitrogen atmosphere, 10% palladium on carbon (147 mg) was added and stirred under a hydrogen atmosphere for 10 hr. The atmosphere in the reaction vessel was replaced with nitrogen, and the catalyst was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white foam (233.7 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:26])O[C:14](=[O:25])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:3]1.[NH3:27].O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:26])[NH:27][C:14](=[O:25])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc([N+](=O)[O-])c3)C(=O)OC2=O)c2ccccc21
Reactant: N
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cccc([N+](=O)[O-])c3)C(=O)NC2=O)c2ccccc21
Reaction time: 6 h
Yield: 75 %

Procedure:
A solution of 3-(1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione (9 g, 26 mmol) in DMF (20 mL) was heated to about 140° C. Aqueous ammonia (20 mL) was added in portions and the heating was continued for 6 h. Water (20 mL) was added and the reaction mixture was allowed to stand at room temperature overnight. The orange colored solid was filtered off, washed with water and dried under vacuum to afford 3-(1-methylindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (6.7 g, 75%).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][NH:6][CH2:7][C:8]#[CH:9].[ClH:10]>C(O)C>[ClH:10].[CH3:3][CH:2]([N:6]([CH2:7][C:8]#[CH:9])[CH3:5])[CH3:4]
Reactant: C#CCNC
Reactant: CC(C)Br
Agent: Cl
Solvent: CCO
Product: C#CCN(C)C(C)C
Yield: 16 %

Procedure:
2-Bromopropane (3.08 g, 25 mmoles) and N-methylpropargylamine (3.45 g, 50 mmoles) in absolute ethanol (50 mL) were heated at reflux for 48 h. On treatment of the ethereal solution of the free base with ethanolic hydrochloride acid, an oil first separated, and then white needles subsequently precipitated very slowly from the supernatant (16% yield of white needles, recrystallized from methanol-ether), m.p.=155°-156° C. The oil and the needles gave identical mass spectra.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31]C)[O:11][C:10]1([CH2:54]O)[CH2:52][OH:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:52][OH:53])[CH2:54][O:31]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.3 %

Procedure:
To a solution of [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 15n (0.57 g, 0.72 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (0.22 mL, 2.88 mmol) at room temperature. The mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 15o as pale yellow oil (475 mg, 88.3%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.59 (d, 1H), 7.48 (s, 2H), 7.36-7.23 (m, 12H), 7.17 (m, 5H), 6.84 (d, 2H), 5.22 (t, 1H), 4.78 (m, 4H), 4.32 (d, 1H), 4.12 (m, 3H), 3.95 (d, 1H), 3.87 (m, 1H), 3.78 (m, 3H), 3.59 (dd, 1H), 3.52 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)[CH3:15]
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cc2c(=O)[nH]cnc2cn1
Temperature: 130 °C

Procedure:
Alternatively, 6-chloro-pyrido[3,4-d]pyrimidin-4-one (26.14 g) was treated with 2N dimethylamine in ethanol (200 ml) and heated at 130° C. in a Parr bomb for 3 days. The cooled mixture was filtered and triturated from isopropanol to give the title compound (16.61 g) as a yellow solid; m/z (M+1+) 191.
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].Cl.CN(C=O)C>CO>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
In 30 ml of MeOH is dissolved 2.8 g of BOC-Tyr-(D)-Met-Gly-OEt. After cooling, 12 ml of N-aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 1 hour. After cooling, 60 ml of 0.2 N-aqueous hydrochloric acid solution is added, and the precipitated crystals are collected by filtration, followed by washing with cold water. Thus obtained is 2.3 g of the desired product, m.p. 184°-186° C., Rf1 =0.24, [α]D21 +13.3° (c=0.46, DMF).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[C:24]([Cu])#[N:25]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2cccc(Oc3ccccc3)c2c1O
Product: COC(=O)c1nc(C#N)c2cccc(Oc3ccccc3)c2c1O

Procedure:
The title compound was synthesized from 1-Bromo-4-hydroxy-5-phenoxy-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=320.8.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:36])([F:35])[C:11]1[CH:12]=[C:13]([CH2:21][O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][C@H:24]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([O:22][CH2:21][C:13]2[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=[C:11]([C:10]([F:9])([F:35])[F:36])[CH:12]=2)[C@@H:24]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3ccccc3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
Benzyl bromide (0.134 ml) was added to a mixture of (+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine (prepared from the hydrochloride salt, Example 5) (0.5 g) and potassium carbonate (0.468 g) in N,N-dimethylformamide (2 ml) and the mixture stirred at 23° C. for 2.5 h. Water (20 ml) was added and the mixture extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (1×10 ml) and brine (1×10 ml) then dried (K2CO3) and concentrated to leave an oil. Purification on silica gel eluting with hexanes-ethyl acetate (19:1 then 9:1 then 4:1 then 1:1) provided the title compound as a solid, m.p.=89°-93° C. Found: C, 66.11; H, 5.25; N, 2.81. Calcd. for C27H25NOF6 ; C, 65.71; H, 5.11; N, 2.84%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1.Cl>O1CCOCC1.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]>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]3[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(-c3ccc(F)cc3)c21
Temperature: 80 °C
Yield: 47.6 %

Procedure:
To a stirred solution of 7-chloro-3-(4-methoxyphenyl)-1-propyl-1H-indazole (0.247 g, 0.82 mmol) in anhydrous dioxane (6 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.015 g, 0.016 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene HCl (0.014 g, 0.033 mmol). 4-Fluorophenylmagnesium bromide (0.74 mL, 1.48 mmol, 2M in diethyl ether) was added and the reaction heated to 80° C. for 18 hours. After this time an additional 50% of reagents were added and the reaction heated for an additional 18 hours. The reaction mixture was treated with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1) to provide the title compound as a white solid (0.139 g, 0.39 mmol, 47%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[OH-].[K+].[CH3:15]S(C)=O.IC>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:15]
Reactant: CS(C)=O
Reactant: Oc1ccc2ccccc2c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A 500 mL three-necked round-bottomed flask was charged with 1-bromonaphthalen-2-ol (30.0 g, 134.5 mmol), potassium hydroxide (KOH) (11.3 g, 201.7 mmol) and DMSO (300 mL), and the mixture was stirred under nitrogen atmosphere for 10 minutes, After cooling the mixture by using ice-water bath, iodomethane (28.6 g, 201.7 mmol) was slowly added dropwise thereto. Then, the resultant mixture was stirred under nitrogen atmosphere at ambient temperature for 12 hours, and then at 50° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was mixed with water (500 mL), and extracted with diethyl ether. Organic mixture was washed three times with distilled water, and dried over anhydrous magnesium sulfate (MgSO4). After removing the solvent by using a rotary evaporator, the residue was purified via silica gel column chromatography (eluent: n-hexane) to obtain 1-bromo-2-methoxynaphthalene (22.0 g, yield: 69.0%) as white solid.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].[C-:20]#[N:21].[Na+]>CN(C)C=O>[C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:20]#[N:21])=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCBr)ccc(C(C)=O)c1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCC#N)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
A solution of 30.0 g. (91.1 mmoles) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl bromide and 4.91 g. (100.2 mmoles) of sodium cyanide in 225 ml. of dimethylformamide was heated to 75°-85° C. for about 17 hours. The reaction mixture was cooled to room temperature, filtered, and evaporated in vacuo at 75° C. Cold 0.1N hydrochloric acid was added to the residue, and the residue was extracted into ethyl acetate. The ethyl acetate layer was twice washed with 0.1N hydrochloric acid, dried over sodium sulfate, and evaporated in vacuo to yield 21.02 g. of 5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentane nitrile as a dark amber oil which crystallized as it cooled.
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[N+:13]([C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N+:13]([C:16]1[N:21]=[CH:20][C:19]([O:22][CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])nc2)C1
Temperature: 125 °C
Yield: 58.8 %

Procedure:
A mixture of 199a (2.24 g, 7.9 mmol), 6-nitropyridin-3-ol (1 g, 7.2 mmol) and Cs2CO3 (2.6 g, 7.9 mmol) in DMF (8 mL) was heated at 125° C. in a sealed tube for overnight. The mixture was filtered off and washed with ethyl acetate (20 mL×2). The filtrate was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 199b (1.25 g, 59%). MS: [M+H]+ 296.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([CH:12]=O)=[CH:10][CH:9]=[C:8]([C:14]([F:17])([F:16])[F:15])[N:7]=1.[CH3:18][O:19][C:20](=[O:41])[CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:18][O:19][C:20](=[O:41])[CH:21]=[CH:12][C:11]1[C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:9][CH:10]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCCc1nc(C(F)(F)F)ccc1C=O
Product: COCCCc1nc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 80 %

Procedure:
N-Methoxy-2-(3-methoxy-propyl)-N-methyl-6-trifluoromethyl-nicotinamide (156 mg, 0.509 mmol) was reacted with 1M-LAH in THF solution to give 2-(3-methoxy-propyl)-6-trifluoromethyl-pyridine-3-carbaldehyde quantitatively as oil. The crude product was used directly in the following reaction. 2-(3-Methoxy-propyl)-6-trifluoromethyl-pyridine-3-carbaldehyde was reacted with methyl(triphenylphosphoranylidene)acetate (204 mg, 0.61 mmol) to give 3-[2-(3-methoxy-propyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid methyl ester (124 mg, 80%).
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[OH:4].[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:21][C:17]1[CH:16]=[C:15]([CH:2]([NH:1][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[OH:4])[CH:20]=[CH:19][N:18]=1
Reactant: O=C1CCCC1
Reactant: NC(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: OC(c1cccc(C(F)(F)F)c1)C(NC1CCCC1)c1ccnc(F)c1
Yield: 90.5 %

Procedure:
The 2 -amino-2-(2-fluoro-pyridin-4-yl)- 1 -(3-trifluoromethyl-phenyl)-ethanol (5) (1.0 g, 3.3 mmol), cyclopentanone (0.42 g, 5.0 mmol), and Na(OAc)3BH (1.4 g, 6.7 mmol) in 1,2 dichloroethane (20 mL) were stirred under argon at RT for 15 hrs. The resulting mixture was treated with sat. aqueous NaHCO3 (50 mL), extracted with ethyl acetate (3×75 mL), dried (sodium sulfate), and concentrated. The resulting residue was purified by silica gel chromatography using 50% ethyl acetate in methylene chloride to give the title product (1.1 g, 92%). 1H NMR (300 MHz, CDCl3) d 8.05 (d, J=4.9 Hz, 1 H, Pyr), 7.51 (d, J=7.9 Hz, 1 H, Ar), 7.36 (t, J=7.8 Hz, 1 H, Ar), 7.32 (s, 1 H, Ar), 7.22 (d, J=7.9 Hz, 1 H, Ar), 6.81 (d, J=4.9 Hz, 1 H, Pyr), 6.64 (s, 1 H, Pyr), 5.00 (d, J=4.6 Hz, 1 H, PhCHOH), 4.01 (d, J=4.9 Hz, 1 H, CHCHNH), 2.99 (quin, J=3.0 Hz, 1 H, CH2CHCH2), 1.85-1.25 (m, 8 H, CH2).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:19])=[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ncnc2c1CCC2
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: [O-][n+]1cnc(Cl)c2c1CCC2
Reaction time: 8 h
Yield: 51.3 %

Procedure:
77.5 g of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine were dissolved in 2 liters of chloroform, and then a solution of 259 g of m-chloroperbenzoic acid in 0.1 liter of chloroform was added dropwise. The mixture was stirred overnight, whilst cooling with water, and then a solution of 375 g of sodium thiosulfate in 1.5 liters of water and a solution of 191 g of sodium carbonate in 0.7 liters of water were added successively dropwise, whilst ice-cooling. The chloroform layer was separated, and the aqueous layer was extracted with chloroform. The separated chloroform layer and extracts were combined and dried over anhydrous sodium sulfate. The chloroform was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using ethyl acetate as the eluent, to give 43.9 g of the title compound as colorless crystals melting at 85°-87° C. (with decomposition).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:24][OH:25])[CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].[C:26]([O:31][CH3:32])(=[O:30])[C:27]([CH3:29])=O.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:29][C:27]1([C:26]([O:31][CH3:32])=[O:30])[O:1][CH2:2][CH:3]([CH2:4][C:5]2[CH:23]=[CH:22][CH:21]=[C:7]([CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])[CH:6]=2)[CH2:24][O:25]1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC(CO)CO)c1
Reactant: COC(=O)C(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1(C)OCC(Cc2cccc(Cc3nc(-c4ccccc4)oc3C)c2)CO1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
To 5 ml of acetonitrile, 297 mg of 4-{3-[2,2-bis-(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole and 369 mg of methyl pyruvate were added. To the mixture was added 544 mg of boron trifluoride etherate (about 47%) with stirring at room temperature, and stirred for 14 hours at room temperature. The reaction solution was poured into an ice-cold water solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=3:1) to provide 185 mg of a mixture (cis:trans=2.5:1, based on NMR integral value) as colorless oil.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[CH2:14]([O:16][C:17](=[O:26])[C:18]([C:24]#[N:25])=[C:19]=COCC)[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:19]=[N:3][N:2]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[C:24]=1[NH2:25])=[O:26])[CH3:15]
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: CCOC=C=C(C#N)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2C)c1N
Temperature: 65 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 478 mg, 2.36 mmol, 1.0 eq) in 20 mL of ethanol were added ethyl(ethoxymethylene)cyanoacrylate (399 mg, 2.36 mmol, 1.0 eq) and triethylamine (329 μL, 2.36 mmol, 1.0 eq) and the mixture was heated at 65° C. for 5 hrs. After standing at room temperature overnight, additional 3-hydrazino-4-methylbenzoic acid hydrochloride (159 mg, 0.78 mmol, 0.3 eq) and triethylamine (110 μL, 0.78 mmol, 0.3 eq) and heated for 2.5. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel (gradient elution from 7/3 hexanes/EtOAc to 1/1 to elute byproducts followed by EtOAc and 9/1 EtOAc/MeOH to elute product) to provide the product as a brown solid (464 mg, 68%). HPLC (4 minute 10-95 gradient) tR1.87 min; MS m/z 290.1 [M+H]+; 1H NMR (CD3OD), δ 8.08 (d, J=7.0 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.19 (s, 3H), 1.35 (d, J=7.1 Hz, 3H), ppm; 13C NMR (CD3OD), δ 166.5, 163.8, 150.4, 141.7, 139.9, 135.3, 130.8, 129.5, 128.6, 93.8, 58.8, 15.8, 12.9 ppm.