Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cs+].[Cs+].[Cs+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[CH:18]1([Mg]Cl)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([C:14]2([OH:17])[CH2:13][CH2:12][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:16][CH2:15]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: OC1(C2CCCCC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of cesium trichloride (5.0 g) in tetrahydrofuran (45 ml) was stirred at room temperature for 6 hours. 1,4-Dioxaspiro[4.5]decan-8-one (1.4 g) was added to the solution and stirred at room temperature for 1 hour. To the solution was added dropwise with stirring cyclohexylmagnesium chloride (2.0M solution in diethyl ether) (6.7 ml) at 0° C. The reaction mixture was quenched with 10% acetic acid aqueous solution. Diethyl ether was added to the solution. The organic layer was taken, washed with brine, sodium hydrogen carbonate solution, brine and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol (1.266 g).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12](O)=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].C(O)(=O)C(O)=O.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH:48][C:49]([C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[N:53]([CH:60]([CH3:62])[CH3:61])[N:52]=2)=[O:50])[CH2:42][CH2:41]1>CN(C)C=O>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([NH:39][CH:40]4[CH2:41][CH2:42][N:43]([CH2:46][CH2:47][NH:48][C:49]([C:51]5[C:59]6[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=6)[N:53]([CH:60]([CH3:62])[CH3:61])[N:52]=5)=[O:50])[CH2:44][CH2:45]4)=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C34CC5CC(CC(O)(C5)C3)C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of 1.07 g (5.45 mmol) of 3-hydroxy-1-adamantylcarboxylic acid and 0.88 g (5.45 mmol) of 1,1'-carbonyldiimidazole in 10 mL of dimethylformamide was stirred for 2 hours at ambient temperature. To this solution was dropwise added 1.80 g (5.45 mmol) of the product of Example 23 in 7 mL of dimethylformamide. The reaction was stirred for 18 hours and then concentrated in vacuo, diluted with dichloromethane and solids removed by filtration. The crude product was purified by chromatography (silica, 9:1 dichloromethane-methanol) to provide 1.30 g (47%) of the desired product as a foam. Further treatment of the product with 0.23 g (2.62 mmol) of oxalic acid in 20 mL of ethanol provided, upon concentration of the solution, 1.51 g of the oxalate salt (LSN343031). 1H NMR (500 MHz, DMSO-d6) d 8.51 (t, 1H), 8.19 (d, 1H), 7.9 (br s, 3H), 7.78 (d, 1H), 7.44 (t, 1H), 7.40 (d, 1H), 7.27 (t, 1H), 5.06 (m, 1H), 3.84 (m, 1H), 3.72 (m, 2H), 3.52 (m, 2H), 3.24 (br t, 2H), 3.07 (br t, 2H), 2.11 (br s, 2H), 1.82 (m, 4H), 1.64 (m, 6H), 1.55 (m, 10H), 1.48 (br s, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>ClCCl.CN(C=O)C.CC(C)=O.O>[Si:1]([O:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:33]=[N+:34]=[N-:35])=[O:25])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](OCc1ccc(C(=O)O)cc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[Si](OCc1ccc(C(=O)N=[N+]=[N-])cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step A ##STR116## A solution of 4-(tert-butyldiphenylsilyloxy)methylbenzoic acid (2 g) in dry dichloromethane (25 ml) was treated with thionyl chloride (1.1 ml) and dry DMF (3 drops). After stirring for 2 hours at room temperature, any volatile material was removed in vacuo. The crude acid chloride thus obtained was taken up in acetone (25 ml) and mixed under stirring at 0° C. with a solution of sodium azide (0.97 g) in water (4 ml). After few minutes most of the acetone was removed in vacuo and the reaction mixture extracted with benzene. The organic extracts were washed with brine, dried and evaporated to small volume, leaving a concentrated solution of 4-(tert-butyldiphenylsilyloxy)methylbenzoyl azide, which was used as such for the following step; IR (film) 2155, 1705 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.[NH4+].[Cl-]>CC(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:18]2[CH2:17][CH2:16][CH:15]([O:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[C:11]([F:10])([F:25])[F:26])[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccccc1OC1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 100-mL flask equipped with a magnetic stirbar was added 5-bromo-2-chloropyrimidine (3.80 g, 19.5 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (6.90 g, 24.5 mmol) and 2-propanol (25 mL). The suspension was treated with N,N-diisopropylethylamine (8.6 mL, 49 mmol) and stirred at room temperature for 10 min and then heated to 100° C. for 16 h. After this time, the mixture was cooled to room temperature, poured into a 250-mL separatory funnel containing saturated aqueous NH4Cl (125 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude solid was triturated in diethyl ether to yield the title compound as an off-white solid. MS (ESI, Q+) m/z 403, 405 (M+1 for 35Br and 37Br).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:3]=1[NH2:4].[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:3]=1[N:4]=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)c1cc(N)c(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(N=C=S)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
2.34 g (0.1 mol) of 2,4-dichloro-5-ethoxycarbonylaniline were dissolved in 80 ml of chloroform and after the solution was cooled to below 10° C., 14.9 g (0.13 mol) of thiophosgene were added to the solution dropwise and after stirred for 2 hrs. at room temperature, the whole was heated under reflux for 3 hrs., followed by concentration to obtain 27 g of pale brown crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[Cl:10].C(N(CC)CC)C.O1CCCC1.[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37](Cl)=[O:38]>>[Cl:10][C:4]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:3]=1[N:2]([CH3:1])[C:37]([C:24]1[S:23][C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=1)=[O:38]
Reactant: CNc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
To a solution of N-methyl-2,4-dichloroaniline (0.133 g, 0.755 mmol) and triethylamine (0.105 mL, 0.755 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.100 g, 0.378 mmol) portion wise as a solid. Reaction was stirred at room temperature with monitor for formation of desired product. The reaction was stirred overnight. After aqueous workup, the crude was taken into DMF at a concentrated of 100 mg/ml and purified by preparative RP-HPLC to give 108. Yield=30% of theoretical. MS: (ESI+) 405.5
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])C.Br[O-:19].[Na+]>O1CCOCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:19])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: [O-]Br
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 90 %

Procedure:
A solution of 18 g of 4-acetyl-4'-methoxybiphenyl in 285 ml of dioxane was oxidized with a dilute sodium hypobromite. Recrystallization from ethanol and acetic acid gave 4'-methoxybiphenyl-4-carboxylic acid melting at 285° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11].C[Si](C)(C)[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:6]1[CH:5]=[CH:4][N+:3]([O-:11])=[C:2]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:7]=1)([O-:10])=[O:9]
Reactant: C[Si](C)(C)n1cncn1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc[n+]([O-])c(-n2cncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To a solution of 2-chloro-4-nitropyridine 1-oxide (2.00 g, 11.4 mmol) and 1-(trimethylsilyl)-1H-1,2,4-triazole (1.64 mL, 11.4 mmol) in DMF (40 mL), was added potassium carbonate (4.75 g, 34.4 mmol). The reaction mixture was allowed to stir at rt for 2 h. The DMF was evaporated and water was added. The precipitate was filtered and washed with water then hexane and dried under vacuum. The solid was purified by column to give 4-nitro-2-(1H-1,2,4-triazol-1-yl)pyridine 1-oxide (0.643 g, 27.1%) as a pale yellow solid. LCMS: (FA) ES+ 208.1, ES− 206.1.
Reaction SMILES: CC[O:3][C:4]([C:6]1[C:11]([C:12]([C:22]2[CH:27]=[C:26]([Br:28])[C:25]([OH:29])=[C:24]([Br:30])[CH:23]=2)=[C:13]2[CH:19]=[C:18]([Br:20])[C:16](=[O:17])[C:15]([Br:21])=[CH:14]2)=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[K]>>[CH:8]1[CH:7]=[C:6]2[C:4]([O:5][C:12]([C:22]3[CH:27]=[C:26]([Br:28])[C:25]([OH:29])=[C:24]([Br:30])[CH:23]=3)([C:13]3[CH:19]=[C:18]([Br:20])[C:16]([OH:17])=[C:15]([Br:21])[CH:14]=3)[C:11]2=[CH:10][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1ccccc1C(=C1C=C(Br)C(=O)C(Br)=C1)c1cc(Br)c(O)c(Br)c1
Agent: [K]
Product: O=C1OC(c2cc(Br)c(O)c(Br)c2)(c2cc(Br)c(O)c(Br)c2)c2ccccc21

Procedure:
Tetrabromophenolphthalein ethyl ester, potassium salt (yellow-brown)
Reaction SMILES: C([Li])CCC.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])(=O)=O)(C)C.[CH:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl>CCCCCC.COCCOC.C(OCC)C>[CH:39]1([CH:38]([OH:45])[C:26]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 1.5M solution (29 cc) of n-butyllithium in hexane is added to a solution of β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (9.15 g) in 1,2-dimethoxyethane (100 cc) kept under a nitrogen atmosphere at a temperature in the region of -75° C. The orange solution obtained is then stirred for 15 minutes at a temperature in the region of 0° C., and then cooled to a temperature in the region of -40° C. Benzaldehyde (2.2 cc) is then added, and then the reaction mixture is stirred for 1 hour at a temperature in the region of 20° C. A 1N aqueous solution (100 cc) of hydrochloric acid is then added with stirring, followed by ethyl ether (100 cc). The aqueous phase is separated; the organic phase is extracted with a 0.1N aqueous solution (25 cc) of hydrochloric acid. The aqueous phases are combined, washed with ether (2×50 cc) and then made alkaline to a pH in the region of 10 with sodium hydroxide solution, and then extracted with ethyl acetate (3×50 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. In this way 4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) (5.2 g) is obtained in the form of white crystals melting at 75° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([CH:11]2[CH2:13][CH2:12]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:15].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[C:1]1([CH2:7][CH2:8][CH:9]=[CH:11][CH2:12][CH2:13][Br:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OC(CCc1ccccc1)C1CC1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: BrCCC=CCCc1ccccc1

Procedure:
6-Phenyl-3-hexenyl bromide [V; Ar is C6H5, R is H] was prepared from 16.5 g. of 2-phenylethyl cyclopropyl carbinol (Preparation B6), 21.5 g. of phosphorus tribromide, 17.65 g. of lithium bromide and 20.7 g. of zinc bromide according to the procedure given above in Preparation C1, affording 21 g. of product as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:43]#[N:44])([CH2:21][CH2:22][C:23]([C:41]#[N:42])([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)C(OCC)=O)C(OCC)=O)[CH:6]=[C:7]([S:13][CH3:14])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([CH2:21][CH2:22][CH:23]([C:29]2[CH:30]=[C:31]([O:39][CH3:40])[C:32]([O:37][CH3:38])=[C:33]([O:35][CH3:36])[CH:34]=2)[C:41]#[N:42])[C:43]#[N:44])[CH:6]=[C:7]([S:13][CH3:14])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1c(OC)cc(C(C#N)(CCC(C#N)(C(=O)OCC)c2cc(OC)c(OC)c(OC)c2)C(=O)OCC)cc1SC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1c(OC)cc(C(C#N)CCC(C#N)c2cc(OC)c(OC)c(OC)c2)cc1SC
Temperature: 95 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of diethyl 2-(3-methoxy-5-(methylthio)-4-propoxyphenyl)-2,5-dicyano-5-(3,4,5-trimethoxyphenyl)-1,6-hexanedioate (12.0 g, 0.019 mol) in ethanol (250 ml) was added potassium hydroxide (4.4 g, 0.079 mol). The reaction was heated to 95° C. for 20 minutes, then filtered, and the filtrate concentrated. Methanol (300 ml) was added to the residue, and the solution was stirred at room temperature overnight. The reaction was filtered and the precipitate dried to yield 2-(3-methoxy-5-(methylthio)-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1,6-hexanedinitrile in a 66% yield. (m.p. 131°-132.5° C.).
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:15])C.[N+]([O-])(O)=O.C[C:22]1C=C(C)N(C(N)=N)[N:23]=1>C(O)C>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]1[CH2:5][C:4](=[O:16])[NH:23][C:22]1=[N:15]2
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCOC(=O)CNCc1c(C)cccc1N
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Cc1cccc2c1CN1CC(=O)NC1=N2
Yield: 61.9 %

Procedure:
A mixture of N-(2-amino-6-methylbenzyl)glycine ethyl ester (1.097 g, 0.0049 mole) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.993 g, 0.0049 mole) in absolute ethanol (15 ml) was heated at reflux for 64 hours. The mixture then was filtered and the product washed with hot ethanol to yield the title compound (0.610 g, 61%); identical (ir, nmr) with authentic material prepared according to the procedure of J. Med. Chem., 18, 224 (1975)).
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Cl[C:22]1[CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([CH3:28])=[N:26][CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:22]2[CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:5][C@H:4]1[O:3][CH3:2])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)c1cc(Cl)cnc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cnc1C
Yield: 86.4 %

Procedure:
The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (190 mg, 0.63 mmol), methyl 5-chloro-2-methylpyridine-3-carboxylate (117 mg, 0.63 mmol), palladium acetate (14.2 mg, 0.06 mmol), BINAP (78.6 mg, 0.13 mmol) and cesium carbonate (617 mg, 1.89 mmol), to obtain 225 mg of the title compound as a brown oily substance (86%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([Br:26])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2cccnc2N)cc1F
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate (5.64 g, 22.90 mmol) in acetonitrile (229 mL) was added NBS (4.16 g, 23.36 mmol) in two portions at 0° C. The reaction mixture was stirred at 0° C. for 20 min. After quenched with sat Na2S2O3 and NaHCO3, and stir for 30 min. The reaction mixture was extracted with EtOAc 3 times, the organic washed by sat NaHCO3, water and brine. Dried and concentrated. The crude material was triturated with ether to provide 7.05 g of methyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate in 95% yield. LCMS (m/z): 327.1 (MH+), 0.66 min.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn]>[C:1]([O:5][C:6]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:19]#[N:20])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1ncc(Br)cc1[N+](=O)[O-]
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Product: CC(C)(C)OC(=O)c1ncc(C#N)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-3-nitro-pyridine-2-carboxylic acid tert-butyl ester (888 mg, 2.93 mmol) in DMF (8.8 ml) was added zinc cyanide (206 mg, 1.76 mmol) and zinc dust (2 mg, 0.03 mmol). The mixture was purged with nitrogen (3 times)bis(tri-tert-butylphosphine)palladium(0) (150 mg, 0.293 mmol) was added and the mixture was heated to 80° C. for 4 h. After cooling to 0° C. water was added and the mixture extracted with EtOAc, the combined organic layers were washed with half saturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as beige solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]([CH:13]([CH3:15])[CH3:14])[C@@H:8]([CH3:16])[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]([CH:13]([CH3:15])[CH3:14])[C@@H:8]([CH3:16])[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: CC(C)N1c2ncc(CO)cc2NC(=O)[C@@H]1C
Reactant: Clc1ccc(C2=CCNCC2)cc1
Product: CC(C)N1c2ncc(CN3CC=C(c4ccc(Cl)cc4)CC3)cc2NC(=O)[C@@H]1C

Procedure:
Compound 60 was prepared using a procedure analogous to that described in connection with compound 1D, except that (S)-7-(hydroxymethyl)-4-isopropyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one was used instead of (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine was used instead of 1-(4-chlorophenyl)piperazine. 1H NMR (CHLOROFORM-d) δ (ppm): 8.33 (s, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.21-7.36 (m, 4H), 7.04 (d, J=1.5 Hz, 1H), 6.06 (br. s., 1H), 4.64-4.84 (m, 1H), 4.28 (q, J=6.7 Hz, 1H), 3.52 (s, 2H), 3.05-3.27 (m, 2H), 2.65-2.79 (m, 2H), 2.54 (br. s., 2H), 1.37 (d, J=6.8 Hz, 3H), 1.25-1.33 (m, 6H); [M+H] calc'd for C23H27ClN4O, 411. found, 411.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=O)=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.N1C=CC=CC=1.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.O.[NH2:46][NH2:47]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([NH:46][NH2:47])=[O:20])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: NN
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: Cn1cc(C(=O)NN)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-(2-fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (5.62 g, 14.5 mmol) in DMF (50 mL) was added pyridine (3.5 mL, 43.4 mmol) then followed by dropwise addition of pentafluorophenyl trifluoroacetate (4.5 mL, 43.4 mmol). The mixture was stirred at room temperature for 24 hours. To this mixture was added hydrazine monohydrate (2.8 mL, 58 mmol). The reaction mixture was stirred at room temperature for another 24 hours. The precipitated white solid was collected by filtration and washed with water (5 mL) and hexanes. After drying, the 4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid hydrazide was obtained as a white solid (6.55 g, 81%). 1H NMR [(CD3)2SO, 400 MHz] δ 9.90 (s, 1H), 9.63 (s, 1H), 8.15 (s, 1H), 7.73 (d, 1H), 7.58 (d, 1H), 7.26 (t, 1H), 5.58 (s, 1H), 4.42 (br s, 1H), 2.50 (t, 3H). Anal. Calcd for C15H14FIN2O3: C, 43.3; H, 3.4; N, 6.7. Found: C, 43.7; H, 3.1; N, 7.0.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH2:33]([SH:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(O)C>[CH2:1]([O:17][CH2:18][CH:19]([CH2:25][S:49][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC(CSCCCCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 18 h

Procedure:
To a stirred solution of 20 g of ethyl 2-[(hexadecyloxy)methyl]-2-propenoate in 60 ml of ethyl alcohol containing 10 ml of triethylamine is added 53 ml hexadecylmercaptan. Following stirring for 18 hours, the volatile components are removed and the residue is chromatographed by HPLC on silica gel using 9:1 hexanes:ethyl acetate. Fractions containing product are combined and the solvents evaporated to give 32.9 g of the desired product as a white waxy solid.