Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].COB(CC)CC.[BH4-].[Na+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C.CO>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Temperature: -85 °C
Reaction time: 60 h

Procedure:
Crude (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate, 21 g (0.0924 mol), is dissolved in 940 mL of tetrahydrofuran and 190 mL of methanol under a nitrogen atmosphere. This solution is cooled to -85° C. and 95 mL of a 15% solution of methoxydiethylborane in tetrahydrofuran is added. The reaction is cooled to -97°0 C. and 6.5 g (0.172 mol) of sodium borohydride is added in 0.5 g portions over 1.5 hours. The reaction is maintained between -93° C. and -97° C. for 13 hours and allowed to warm to room temperature and stand for 60 hours under a nitrogen atmosphere. The reaction is quenched by the addition of 25 mL (0.359 mol) acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 500 mL methanol, concentrated by vacuum distillation, redissolved with 500 mL methanol and reconcentrated by vacuum distillation to give a dark brown oil. This oil is taken up in 500 mL of ethyl acetate and filtered through a plug of silica gel with the aid of 250 mL ethyl acetate. The solution is evaporated to give 15 g of crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate which is used without further purification.
Reaction SMILES: [C:1]([N:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:5]1[CH:10]=[C:9]([C:11](=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[C:14](=[O:16])[NH2:15])(=O)[CH3:2].Cl>CO>[C:11]([C:9]1[CH:10]=[C:5]2[C:6]([C:14](=[O:16])[N:15]=[C:1]([CH3:2])[N:4]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:7][CH:8]=1)(=[O:13])[NH2:12]
Reactant: CC(=O)N(Cc1ccc(Cl)cc1Cl)c1cc(C(N)=O)ccc1C(N)=O
Agent: Cl
Solvent: CO
Product: Cc1nc(=O)c2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1Cl
Yield: 102.2 %

Procedure:
2-((N-Acetyl)-(2,4-dichlorobenzyl)amino)-1,4-dicarbamoylbenzene (1.50 g) in a mixture of concentrated hydrochloric acid (10 ml) and methanol (30 ml) was heated under reflux for 30 min. After concentration, the object compound (1.46 g) was obtained as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14]N3CCN(C(C(OCC)=O)CC(OCC)=O)CC3)[O:11][C:10]2=[O:33])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(N)=CC=1)#N.[O:43]1CC1CO.C(C1C=CC(NCC(O)CO)=CC=1)#N.C(=O)(OCC)OCC.CC(C)([O-])C>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][OH:43])[O:11][C:10]2=[O:33])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CC(C(=O)OCC)N1CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reactant: OCC1CO1
Agent: CC(C)(C)[O-]
Agent: N#Cc1ccc(N)cc1
Agent: N#Cc1ccc(NCC(O)CO)cc1
Solvent: CCOC(=O)OCC
Product: N#Cc1ccc(N2CC(CO)OC2=O)cc1

Procedure:
1.3 g of 3-(4-cyanophenyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl)oxazolidin-2-one [obtainable by reaction of 4-cyanoaniline with 2,3-epoxypropan-1-ol to give N-[4-cyanophenyl]-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-(4-cyano-phenyl)-5-hydroxymethyloxazolidin-2-one, subsequent esterification with methanesulfonyl chloride and reaction with "B"] and 1.1 g of hydroxylamine hydrochloride are boiled for 2 hours in 125 ml of ethanol in the presence of 2.24 g of sodium ethoxide. The reaction mixture is then filtered and concentrated in vacuo. The residue is dissolved in water, the solution is adjusted to pH 3 using 2N hydrochloric acid and the resulting precipitate is filtered off with suction. After recrystallizing from water/glacial acetic acid, 3-[4-amino(hydroxyimino)methylphenyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one, m.p. 186°, is obtained.
Reaction SMILES: [C:1]([C:8]1NC=CN=1)([C:3]1NC=CN=1)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=1.C(O)(C)C>ClCCl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][CH:1]([CH3:8])[CH3:3])=[O:19])=[CH:16][N:15]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)OC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114 %

Procedure:
Carbonyl diimidazole (18.6 g, 0.115 mol) was added to a suspension of 6-chloronicotinic acid (16.6 g, 0.105 mol) in dichloromethane (250 mL). After all of the solid had dissolved the reaction solution was stirred at ambient temperature for 1 hour and then isopropyl alcohol (100 mL) was added. The dichloromethane was removed under vacuum. A catalytic amount of sodium isopropoxide was added to the solution and the solution was heated at reflux for 1 hour. The solution was then concentrated under vacuum. The resulting residue was slurried with water and then extracted with diethyl ether. The extract was dried over magnesium sulfate and then concentrated under vacuum to provide 23.9 g of isopropyl 6-chloronicotinate.
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:15][CH:14]=[CH:13][CH:12]=2.O>CN(C=O)C>[CH3:21][CH:20]1[O:22][C:8]2[CH:9]=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[NH:18][CH2:19]1
Reactant: CC(O)CNc1c(Br)cnc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CNc2c(cnc3ccccc23)O1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
Potassium tertiary butoxide (5 g) was added to a solution of 3-bromo-N-(2-hydroxypropyl)-4-quinolinamine (9 g) in 30 ml of DMF and the mixture stirred at 140° C. for 4 hours. The mixture was cooled to room temperature and poured into 200 ml of water. The product was extracted with dichloromethane and purified by HPLC (solvent: DCM:MeOH=10:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:24])([CH3:23])[CH2:11][C:12]([OH:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH:13]=O.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[N:29][NH:30][C:31]2=[O:36]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:22][C:12]1([C:15]([F:20])([F:21])[C:16]([F:18])([F:19])[F:17])[CH2:11][C:10]([CH3:23])([CH3:24])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]1[NH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[N:29][NH:30][C:31]2=[O:36]
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)C(F)(F)F
Reactant: Nc1cccc2c(=O)[nH]ncc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)C(F)(F)F)C2Nc1cccc2c(=O)[nH]ncc12
Yield: 2.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 250 mg of 4-(2-methoxy-4-methyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 118 mg of 5-amino-phthalazin-1-one. As in Example 3, 65 mg of the imine is reacted by reaction with 0.38 ml of titanium tetrachloride (1 M in dichloromethane) in 6 ml of dichloromethane, and 8 mg of the title compound is obtained.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])=[C:12]([C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]([CH3:25])[CH:15]=2)[CH:13]=1>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[O:26][C:11]1[CH:10]=[CH:9][C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:13][C:12]=1[C:14]1[C:23]2[C:18](=[CH:19][N:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]([CH3:25])[CH:15]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)c2ccncc2c1=O
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3cnccc23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.3 %

Procedure:
Ethanesulfonyl chloride (25.4 mg, 0.198 mmol) was added to 4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-2-methyl-2,7-naphthyridin-1-one (25.0 mg, 0.066 mmol) and TEA (20.0 mg, 0.198 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at room temperature for 18 h and then purified by preparative HPLC to give the title compound (8.5 mg, 27.4%) as yellow gum. 1H NMR (Methanol-d4, 400 MHz) δ 9.54 (s, 1H), 8.68 (d, J=4.4 Hz, 1H), 8.00 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.09-6.99 (m, 2H), 6.96-6.94 (d, J=8.4 Hz, 1H), 6.91-6.85 (m, 1H), 3.70 (s, 3H), 3.15 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H). LCMS: 472.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12]>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:1][C:2]2[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=2)=[O:19])=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A solution of 10.9 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 10.2 g (0.055 mole) 4-nitrobenzoyl chloride in 200 ml toluene was heated at reflux for 20 hours. Upon cooling to room temperature, the crude product precipitated from the reaction mixture and was isolated by filtration. After washing with hexane, 13.5 g (73% yield) of pure product was obtained; m.p. 214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:5]=[C:10]=[S:11]
Reactant: NCc1ccccc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=NCc1ccccc1Cl
Yield: 46.7 %

Procedure:
The title compound was prepared following the procedure described for Intermediate-2 using 2-chloro benzyl amine (5.0 g, 35 mmol), thiophosgene (4.38 g, 38.5 mmol) and N-ethyl di-isopropyl amine (13.5 g, 105 mmol) to afford 3.0 g of the desired product. 1HNMR (DMSO-d6): δ 5.00 (s, 2H), 7.41 (m, 2H), 7.54 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=O)[CH3:2].[CH:17]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)C.[BH4-].[Na+]>O>[CH:17]1([NH:24][CH:1]([C:4]2[CH:16]=[CH:15][C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7][C:6]=3[CH:5]=2)[CH3:2])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: NC1CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(NC1CCCCCC1)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
2-Acetylfluorene (4.17 g, 20 mmol) and cycloheptylamine (2.38 g, 21 mmol) were heated together at 130° C. for 14 hrs and, then, distilled under reduced pressure. To the residue were added ethanol (20 ml) and sodium borohydride (0.76 g, 20 mmol) and the mixture was stirred at room temperature overnight. The mixture was then diluted with water (100 ml) and extracted with chloroform (80 ml×2 times). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was then purified by silica gel column chromatography to give 1.58 g of the amine compound.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[C:35]([CH:40]=O)[CH:34]=[CH:33]2>C1COCC1>[Br:2]/[CH:3]=[CH:40]\[C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([F:29])[CH:31]=2)[N:36]=1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2cc(F)ccc2n1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc2nc(/C=C\Br)ccc2c1
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To as suspension of (bromomethyl)triphenylphosphonium bromide (14.94 g, 34.3 mmol) in 100 mL of THF was added potassium tert-butoxide (3.84 g, 34.3 mmol) portionwise under Ar. Then the reaction mixture was stirred for 1 h at this temperature. 6-Fluoroquinoline-2-carbaldehyde (5 g, 28.5 mmol) in 40 mL of THF was added. The resulting reaction mixture was stirred for 5 h at −75° C. and allowed to warm up overnight. The reaction mixture was diluted with petrol ether and the solid was sucked off. The mother liquid was concentrated, diisopropyl ether was added and the formed precipitate was sucked off. The mother liquid was purified by column chromatography (cyclohexane/EA) to give 4.7 g (65.3%) of the title compound as brown solid. LC-MS: m/e 254.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br>CN(C)C=O>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: COC(CBr)OC
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CN1C(=O)NC(C)(C)C1=O)OC
Temperature: 25 °C

Procedure:
85.46 g (0.667 mol) of 5,5-dimethylhydantoin, 110.6 g (0.80 mol) of anhydrous potassium carbonate and 124.0 g (0.7336 mol) of 2-bromoacetaldehyde dimethyl acetal in 600 ml of dimethylformamide are reacted for about 6 hours analogously to Example 1 in a glass apparatus. The reaction mixture is subsequently cooled to room temperature and filtered with suction, the filtrate is evaporated in a rotary evaporator, and the residue is dried at 110° C./0.1 mbar. The crude yield is 143.2 g (99.3% of theory) of 3-(2,2-dimethoxyethyl)-5,5-dimethylimidazolidine-2,4-dione. 21 g of the crude product are dissolved in 50 ml of 0.1N sodium hydroxide solution at room temperature, and the solution is extracted 3 times by shaking with 30 ml of tert-butyl methyl ether in each case in a separating funnel. The organic phases are combined, the solution is dried using anhydrous sodium sulfate and subsequently filtered, the clear filtrate is evaporated in a rotary evaporator, and the residue is dried for 1 hour at 60° C./0.1 mbar, giving 12.3 g of pure, highly viscous 3-(2,2-dimethoxyethyl)-5,5-dimethylimidazolidine-2,4-dione having the following analytical data:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].Cl[C:9](Cl)(Cl)[CH2:10][N+:11]([O-:13])=[O:12].Cl>CO.ClCCl.O>[N+:11]([CH:10]=[C:9]1[NH:1][CH2:2][CH2:3][CH2:4][S:5]1)([O-:13])=[O:12]
Reactant: NCCCS
Reactant: O=[N+]([O-])CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Into 50 ml of methanol were added 8.1 g of 1-amino-3-propanethiol and 5.0 g of caustic soda, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, a solution of 5.4 g of 2,2,2-trichloro-1-nitroethane diluted in 20 ml of methanol was added dropwise slowly over 15 minutes, and the reaction was carried out for one hour. The reaction was exothermic and the liquid temperature was maintained at lower than 10° C. (about 8° C.). After the reaction, the reaction mixture was neutralized to pH 7 with 6 N aqueous hydrochloric acid, and then with addition of 50 ml of water, extraction with 100 ml of dichloromethane was repeated four times. The extracts were concentrated to give 2.91 g of tetrahydro-2-(nitromethylene)-1,3-thiazine (yield: 60.1%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH:16]=[C:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:11]1)(=O)[CH3:8].[OH-].[Na+]>CCOCC>[CH2:7]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH:16]=[C:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:11]1)[CH3:8]
Reactant: CC(=O)N1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1

Procedure:
To a solution of lithium aluminum hydride (100 mg) in anhydrous ether was added a solution of 5-(4-acetylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene (350 mg) in anhydrous ether under ice-cooling, and the resulting mixture was stirred under reflux for 3 hours. The reaction mixture was cooled, admixed with 10% aqueous sodium hydroxide solution and extracted with ether. The ether extract was dried over anhydrous sodium sulfate and evaporated to afford 5-(4-ethylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 224°-225° C. (oxalate).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([N:18]=[N+]=[N-])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([NH2:18])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(CC(C)N=[N+]=[N-])cc(C#N)c21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCc2cc(CC(C)N)cc(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of 1-acetyl-5-(2-azidopropyl)indoline-7-carbonitrile (0.20 g) in ethanol (16 ml) was added 5% palladium on barium sulfate (102 mg), and the mixture was stirred at room temperature for 8 hours under an atmosphere of hydrogen. After the catalyst was filtered off, the filtrate was concentrated to dryness to give 0.18 g of 1-acetyl-5-(2-aminopropyl)indoline-7-carbonitrile melting at 94°-96° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:12][C:13]1[N:18]=[C:17]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C:2]2([CH3:1])[C:8]([O:10][CH3:11])=[O:9])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C1(C)COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C)COCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
Methyl 3-methylmorpholine-3-carboxylate (4.21 g, 26.4 mmol) was dissolved in THF (60 ml) to form a clear solution. 2,4-Dichloro-5-nitropyrimidine (5.13 g, 26.4 mmol) was added and the solution was cooled to −10° C. Diisopropylethylamine (6.93 ml, 39.7 mmol) was added while the temperature was maintained at −8 to −10° C. The reaction was stirred for 4 hours at 0° C. and for 16 hours at room temperature. The solvent was removed under reduced pressure. EtOAc (120 ml) was added and the mixture was washed with water (3×30 ml). The organic solution was concentrated to afford 8.4 g of crude methyl 4-(2-chloro-5-nitropyrimidin-4-yl)-3-methylmorpholine-3-carboxylate as an oil. The crude material was used in the next step without further purification. MS [M+H] calculated for C11H13ClN4O5, 317. found, 317.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[S:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[N:29]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(-c4ccccn4)cs3)(CC1)CC2
Yield: 15.5 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-(2-pyridyl)thiazole (60.3 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(2-pyridyl)thiazol-2-yl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl)pyrrolidine-2-carbonitrile (11.6 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[C:10](F)[C:11]([C:14]#[N:15])=[N:12][CH:13]=1.CN1C(=O)CCC1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:25][OH:26]>CCOC(C)=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([O:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])[C:11]([C:14]#[N:15])=[N:12][CH:13]=1
Reactant: CCOC(=O)CO
Reactant: N#Cc1ncc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)COc1cc(Cl)cnc1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.1 %

Procedure:
To a mixture of cesium carbonate (1.63 g, 5.01 mmol) and 5-chloro-3-fluoropicolinonitrile (0.784 g, 5.01 mmol) was added NMP (5 mL) and ethyl glycolate (0.52 mL, 5.49 mmol). The reaction mixture was stirred at RT for 20 min, heated to 80° C. for 1 h and additional ethyl glycolate (0.10 mL) was added. Stirring was continued at 80° C. for 2 h and the reaction mixture was cooled to RT. The reaction was and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel eluting with a gradient of 0% to 15% EtOAc in DCM gave ethyl 2-((5-chloro-2-cyanopyridin-3-yl)oxy)acetate (0.83 g, 3.46 mmol, 69% yield) as a white solid. LC/MS (ESI+) m/z=240.9 (M+H). Calculated for C10H9ClN2O3 240.0.
Reaction SMILES: [OH:1][CH:2]([CH:24]([O:26][CH2:27][O:28][CH3:29])[CH3:25])[CH2:3][N:4]1[C:9]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][C:7]([C:17]([F:20])([F:19])[F:18])=[C:6]([C:21]#[N:22])[C:5]1=[O:23].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:29][O:28][CH2:27][O:26][CH:24]([CH3:25])[C:2](=[O:1])[CH2:3][N:4]1[C:9]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][C:7]([C:17]([F:18])([F:19])[F:20])=[C:6]([C:21]#[N:22])[C:5]1=[O:23]
Reactant: COCOC(C)C(O)Cn1c(-c2cccc(C)c2)cc(C(F)(F)F)c(C#N)c1=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COCOC(C)C(=O)Cn1c(-c2cccc(C)c2)cc(C(F)(F)F)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
1-(2-Hydroxy-3-methoxymethoxy-butyl)-2-oxo-6-m-tolyl-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile 29 (0.21 g, 0.52 mmoles) was combined with N-methylmorpholine N-oxide (NMO, 92 mg, 0.79 mmoles) and 4 Å molecular sieves (powder, 170 mg) in 5 mL of anhydrous DCM within a 7 mL reaction vial. The mixture was stirred at room temperature for 10 min. After this period tetrapropylammonium perruthenate (TPAP, 10 mg, 0.028 mmoles) was added and the mixture was stirred at room temperature for an additional 3 hours. After this period the reaction mixture was purified directly using flash silica chromatography (0-40% EtOAc/Hexane) to yield 0.191 g (90% yield) of 1-(3-Methoxymethoxy-2-oxo-butyl)-2-oxo-6-m-tolyl-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile as a yellow residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]([N:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: COc1ccc2[nH]cc(C(c3ccccc3)N(C)C)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-methoxy-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.