Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[N:9]=[CH:8]1.[CH3:18][NH2:19]>CO.CCO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[N:19][CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: O=Cc1ccc2c(c1)ncn2C1CCCCO1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CN=Cc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 64 (1.0 g, 4.34 mmol) in MeOH (10 mL) at 0° C. was added a solution of MeNH2 in EtOH (33%, 2 mL). After stirring at RT for 2 h, the mixture was concentrated under reduced pressure to afford 1.0 g (94%) of N-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methylene)-methanamine (66) as yellow oil: MS (ESI) m/z=244.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:27][CH2:26][C:20]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:18][CH2:19][C:20]3([CH2:25][CH2:24][N:23]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:22][CH2:21]3)[CH2:26][CH2:27]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)CC#N)CC4)n2)nn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a solution of 5-chloro-N2-(1,5-dimethyl-1H-pyrazol-3-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (200.5 mg, 0.5142 mmol) in dichloromethane (28 mL) and N,N-dimethylformamide (7 mL) were added 2-cyanoacetic acid (110.3 mg, 1.297 mmol), N,N-diethylethanamine (156.5 mg, 1.547 mmol) and HATU (585.4 mg, 1.540 mmol). The mixture was stirred at room temperature for 4 h and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the title compound as a white solid (128.5 mg, 54.68%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16].N1C=CC=CC=1>C1COCC1>[ClH:9].[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:13]=2[NH:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:19][CH:20]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Product: Cl
Temperature: 22 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a 780 L Hastelloy reactor, was charged 4-cyanobenzoyl chloride (E) (17.2 Kg, 1.1 eq) and THF (92 Kg, 3.5 parts). Reactor contents were agitated at 22° C. (19 to 25° C.) until all of the solids had dissolved. The resulting solution was transferred to a lower receiver and the reactor was rinsed forward with THF (26 Kg, 1 part). Compound D (26.4 Kg, 1 eq), THF (396 Kg, 15 parts) and pyridine (2.90 Kg, 0.4 eq) were charged to a clean reactor. The pump and lines were rinsed forward with THF (34 Kg, 1.3 parts). Via a metering pump, the 4-cyanobenzoyl chloride/THF solution was charged to the reactor, keeping the temperature at ≦30° C. and rinsing forward with THF (ca. 10 Kg). The resulting yellow-colored slurry was agitated at 22° C. (19 to 25° C.) for ca 2 hrs. In-process HPLC taken after 2 hrs showed a compound of Formula D content of 0%, indicating completion of the reaction. The slurry was filtered onto a pressure nutsche fitted with F-19 filter cloth. The reactor, pump, lines, and wet cake were rinsed with three portions of ethanol (ca. 15 Kg each). The wet filter cake was discharged (65.4 Kg) and transferred back to the reactor for slurry wash in ethanol (317 Kg, 12 parts) at 22° C. (19 to 25° C.) for ca. 1 hr. The slurry was filtered onto the pressure nutsche and the reactor, pump, lines, and wet filter cake were rinsed with two portions of ethanol (ca. 15 Kg each) and two portions of THF (ca. 15 Kg each). The wet filter cake was dried under vacuum with a maximum temperature of warm glycol bath (to heat the reactor jacket) of 40° C. After 14.5 hrs of drying, LOD was 0.75%. The dried material was milled (screen 0.125″) to give 31.8 Kg of product, which was dried under vacuum for another 10.5 hrs. LOD after drying was 1.8%, and the product was discharged (31.5 Kg) in 74.8% yield (expected 60-90%). HPLC showed 100% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C(Cl)(=O)C(Cl)=O.[CH:24]1[CH:25]=[CH:26][N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[NH:30][CH2:29][C:28]=12.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH:24]1[CH:25]=[CH:26][N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH3:17])=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH2:29][C:28]=12
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a suspension of 2,2′-dimethyl-biphenyl-4-carboxylic acid of Step B (22.4 g, 99.0 mmol) in dry dichloromethane (500 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (5 mL) followed by the dropwise addition of a 2.0 M solution of oxalyl chloride in dichloromethane (60 mL, 120 mmol). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo and the residue redissolved in dry dichloromethane (200 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (500 mL), 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (21.9 g, 119 mmol) was added, followed by N,N-diisopropylethylamine (87 mL, 500 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was then washed with 1N hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 2.5 to 40% ethyl acetate in hexane gave a tan solid that was recrystallized from ethyl acetate/hexane to afford the title compound (12.4 g, 32%) as a pale orange solid. Purification of the mother liquors by flash chromatography yielded additional title compound (11.5 g, 30%) as a white solid, m.p. 145-148° C. MS [(+)ESI, m/z]: 393 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:23]>C(COC)OC.CCOCC>[Br:23][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(OC)c(CBr)c1)OC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.2 g of ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate was dissolved in 15 ml dimethoxyethane. 1.2 ml phosphorus tribromide was added thereto under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction solution was diluted with ether and washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, to give 2.6 g of ethyl 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate from fractions eluted with hexane-ethyl acetate (4:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][CH2:10][CH:11]=O>C(O)C>[ClH:8].[Cl:9][C:10]1[N:3]2[CH:4]=[CH:5][N:1]=[C:2]2[CH:7]=[CH:6][CH:11]=1
Reactant: Nc1cccc(Cl)n1
Reactant: O=CCCl
Solvent: CCO
Product: Cl
Product: Clc1cccc2nccn12
Temperature: 25 °C
Yield: 45 %

Procedure:
To a stirred solution of 2-amino-6-chloropyridine (20.00 g, 156 mmol) in ethanol (300 mL) at ambient temperature was added chloroacetaldehyde (26.1 mL of a 50% aqueous solution, 202 mmol). The reaction mixture was heated at refux for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with dichloromethane (400 mL) and the dichloromethane layer was decanted. The resultant brown gummy solid was treated with a mixture of methanol (20 mL) and diethyl ether (500 mL). The colorless solid so obtained was collected by filtration to afford 5-chloroimidazo[1,2-a]pyridine hydrochloride (13.26 g, 45% yield). The filtrate was combined with the aforementioned dichloromethane layer and the mixture concentrated in vacuo. The residue was dissolved in dichloromethane (500 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 40-95% gradient of ethyl acetate in hexanes to afford a second batch of 5-chloroimidazo[1,2-a]pyridine as a brown liquid in 39% yield (9.18 g): 1H NMR (300 MHz, DMSO-d6) δ8.02 (s, 1H), 7.74 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.31 (dd, J=7.5, 7.5 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H); MS (ES+) m/z 153.0 (M+1), 155.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([C:22]([O:24][CH3:25])=[O:23])[C:15](=[CH:20][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34](=[O:39])[CH2:33][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([C:22]([O:24][CH3:25])=[O:23])[C:15](=[CH:20][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccc(CCCc2ccc(O)c(C)c2)cc1C(=O)OC
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(CCCc2ccc(OCC(=O)C(C)(C)C)c(C)c2)cc1C(=O)OC

Procedure:
In a manner similar to Example 1g, by reacting 900 mg (2.6 mmol) of dimethyl 4-[3-(3-methyl-4-hydroxyphenyl)propyl]phthalate with 400 mg (2.9 mmol) of potassium carbonate and 390 μl (2.9 mmol) of 1-bromopinacolone. A colorless oil is obtained (m=910 mg; y=79%).
Reaction SMILES: O[CH2:2][C@H:3]1[N:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[N:17]2[N:21]=[CH:20][CH:19]=[N:18]2)=[O:9])[CH2:6][C@H:5]([CH3:22])[O:4]1.CS(Cl)(=O)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)=[N:33][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)(Cl)Cl.O>[F:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:39]=[N:38][N:37]([CH2:2][C@H:3]3[N:7]([C:8]([C:10]4[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=4[N:17]4[N:18]=[CH:19][CH:20]=[N:21]4)=[O:9])[CH2:6][C@H:5]([CH3:22])[O:4]3)[CH:36]=2)=[N:33][CH:34]=1
Reactant: Fc1ccc(-c2cn[nH]c2)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@H](C)O[C@H]2CO)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@H](C)O[C@H]2Cn2cc(-c3ccc(F)cn3)cn2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
By using ethyl(2RS,5S)-5-methyl-3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazolidine-2-carboxylate obtained in Reference Example 5 (0.11 g, 0.33 mmol) as the raw material, the same procedure as in Reference Example 2 was carried out to obtain the diastereomer mixture of [2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (colorless oil). The obtained diastereomer mixture was purified by thin layer chromatography (1 mm, hexane/EtOAc=50/50) to obtain [(2S,5S)-2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (colorless oil). To a solution of the obtained [(2S,5S)-2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (30.2 mg, 0.10 mmol) and TEA (0.021 mL, 0.15 mmol) in CHCl3 (0.8 mL), MsCl (0.011 mL, 0.15 mmol) were added under cooling with ice water and the resulting mixture was stirred for 1 hour. Water was added to the reaction mixture under cooling with ice water, followed by extraction with CHCl3. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. 5-Fluoro-2-(1H-pyrazol-4-yl)pyridine (0.033 g, 0.20 mmol) and Cs2CO3 (0.065 g, 0.20 mmol) were added to a solution of the obtained residue (0.5 mL). The resulting mixture was reacted for 1 hour at 120° C. under irradiation of microwave. The reaction mixture was allowed to cool, water was added thereto, followed by extraction with CHCl3, the extract was passed through an ISOLUTE Phase Separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (0.020 g) (colorless oil).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][CH:12]=[CH:13][C:8]=2C=1)=[O:5])[CH3:2].[Cl:14]N1C(=O)CCC1=O.[CH:22]([Cl:25])(Cl)Cl>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:14])=[CH:13][C:8]=2[C:22]=1[Cl:25])=[O:5])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2sc(Cl)cc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a 0° C. solution of 6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (180 mg, 0.92 mmol) in acetic acid (2 mL) and CHCl3 (2 mL) was added N-chlorosuccinimide (294 mg, 2.2 mmol) over 30 min. The reaction mixture was slowly allowed to warm to room temperature over several hours, stirred overnight, concentrated to remove the chloroform, diluted with water, basified with 5 N NaOH, and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The product was purified by Chromatron-chromatography (4:1 hexanes:ether) and obtained as a white solid (180 mg, 74%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C=O.C(Cl)Cl.C(N(CC)CC)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:26]([OH:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCC(O)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.3 g (20 mmol) of 1,5-diacetyl-2-indolinone (Ex. II) are dissolved in 20 ml of dimethylformamide and 490 mg dimethylaminopyridine (DMAP) and 6 ml triethylamine are added and the mixture is cooled in the ice bath. 3.8 ml (22 mmol) octanoic acid chloride in 20 ml of dimethylformamide are added to this solution and the mixture is stirred for a further 10 min. Then the reaction mixture is added to 150 ml of methylene chloride and 150 ml of 1 N hydrochloric acid. The organic phase is separated off, dried over sodium sulphate and concentrated by rotary evaporation.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.O[C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2cccnc12
Reactant: COC(=O)[C@@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of quinolin-8-ol (300 mg, 2.07 mmol) in THF (5 mL) was added (R)-methyl 2-hydroxypropanoate (215 mg, 2.07 mmol), PPh3 (647 mg, 2.47 mmol) and DEAD (430 mg, 2.47 mmol). The mixture was stirred at 25° C. for 16 hours. Subsequently, 1M HCl was added (10 mL) and the solution was washed with EtOAc (20 mL×3). The pH of the aqueous solution was raised by addition of aqueous NaHCO3 (10 mL), and then this solution was washed with EtOAc (10 mL×3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was directly for the next step. LCMS (m/z): 232.1/233.1 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][C@@H]2COC(=O)N2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:14]I.[C:16]([O-:19])(O)=[O:17].[Na+]>C(Cl)Cl>[I:14][C@@H:3]1[C@@H:4]2[CH2:5][C@@H:6]([C:16](=[O:17])[O:19]2)[C@H:1]([CH3:7])[CH2:2]1
Reactant: II
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1C[C@H](I)[C@@H]2C[C@H]1C(=O)O2

Procedure:
reacting said (1R,6R)-6-methyl-3-cyclohexene-1-carboxylic acid (5) with I2, KI and NaHCO3 in methylene chloride to produce (1R,2R,4S,5s)4-iodo-2-methyl-6-oxabicyclo[3.2.1]octan-7-one (8),
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:26][C:25](C)([CH3:27])[CH2:24][C:23](C)(C)[CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CC1[C:36](B(O)O)=[C:35](C)[O:34][N:33]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[C:21]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([CH3:17])=[N:33][O:34][C:35]=3[CH3:36])=[CH:11][CH:10]=2)[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:26][CH2:25][CH2:27][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 114.7 %

Procedure:
The procedure described for 202 was followed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.079 g, 0.56 mmol), Na2CO3 (0.060 g, 0.56 mmol), and THF/H2O (5 mL, 4:1). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 0.120 g (78%) of the title compound 206 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 9.28 (s, 1H), 7.28 (d, J=6.00 Hz, 2H), 7.18 (d, J=6.0 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.67 (d, J=6.3 Hz, 2H), 2.37 (s, 3H), 2.23-2.22 (br, m, s, 4H), 1.52 (br s, 8H). LCMS (ESI): m/z 372 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: C1CNCCN1
Reactant: NC(=O)c1ccc(Cl)nc1
Product: NC(=O)c1ccc(N2CCNCC2)nc1
Yield: 6.2 %

Procedure:
Using 6-chloronicotinamide (5.00 g) and piperazine (27.6 g), and by reaction in the same manner as in Example 196 (1) at 100° C., 1-(5-carbamoyl-2-pyridyl)piperazine (0.41 g) was obtained as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1OC1CCCC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(Cl)nc1OC1CCCC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
To a solution of 6-chloro-2-cyclopentyloxy-nicotinamide (1.56 g, 6.48 mmol) and pyridine (3.14 mL, 38.88 mmol) in acetonitrile (30 mL), phosphorus oxychloride (1.77 mL, 19.44 mmol) was added over a period of 5 min. The reaction was stirred at 55° C. for 1 h. Acetonitrile was evaporated in vacuo and the resulting residue was then neutralized with 1N NaOH at 0° C. until pH reached to ˜7. The reaction mixture was extracted with EtOAc (100 mL). The organic layer was collected and the aqueous was further extracted with EtOAc (3×50 mL). All organics were combined washed with brine (2×25 mL), dried over anhyd. Na2SO4, filtered, and concentrated to give the title compound (1.63 g, 94%) as yellow oil, which was carried forward without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 5.49-5.42 (m, 1H), 2.25-1.78 (m, 2H), 1.80-1.64 (m, 4H), 1.60 (t, J=6.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[CH:6]=1.C([BH3-])#N.[Na+]>>[F:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH3:11])[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccc(C)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(C)c(F)c1

Procedure:
Reduction of 3-fluoro-4-methyl-benzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 1-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8: 2) (57% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.25 (3H, broad s, CH3), 3.50 (3H, s, OCH3), 3.99 (2H, broad s, NCH2), 5.71 (1H, broad, NH), 7.01 (2H, m, aromatics), 7.13 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 140-142° C. Anal. calcd for C9H12FNO—HCl: C, 52.56; H, 6.37; N, 6.81. Found: C, 52.63; H, 6.30; N, 6.78.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O.O>[N:23]([C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9])=[N+:24]=[N-:25]
Reactant: O=C(O)c1ccccn1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
To a solution of picolinic acid (1.0 g, 8.12 mmol) in a mixture of acetone (10 mL) and water (3 mL) was added triethylamine (1.7 mL, 12.2 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (1.32 g, 12.2 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (0.844 g, 13.0 mmol), and the mixture was stirred for another 1.5 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (817 mg, 68%). 1HNMR (CDCl3) (δ) 8.74 (d, 1H), 8.15 (d, 1H), 7.88 (m, 1H), 7.55 (m, 1H).