Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:17])[NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[N:10]=2)[CH2:3]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[Si:18]([O:15][CH2:14][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:17])[CH3:16])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: C[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.1 %

Procedure:
To a solution of 3-hydroxy-1-[4-((1S)-2-hydroxy-1-methylethylcarbamoyl)-1,3-thiazol-2-yl]azetidine (910 mg, 3.54 mmol) (obtained as described in Reference Example 35(3)) in dimethylformamide (46 ml) were added t-butyldimethylsilyl chloride (586 mg, 3.89 mmol) and imidazole (265 mg, 3.89 mmol) in an ice bath, and the reaction mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1→1:4) as the eluant to afford 1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (935 mg, yield 71%) as a pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])=[O:4]>CN(C=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[C:3](=[O:4])[CH2:2][O:12][C:6]=2[CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
CsCO3 (5.36 g) was added in portions over 10 min to an ice cold solution of Example 1109A (3.2 g) in DMF (140 mL). The resulting mixture was stirred for 30 min then diluted with water and extracted with ether (3×). the combined extracts were dried (Na2SO4), and concentrated to give 1.6 g of the title compound. MS ESI(−) m/e 151.1 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH:24]=[C:5]2[CH2:6][CH2:7][N:8]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[CH:24]=[C:5]2[CH2:6][CH2:7][N:8]([C:15]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=4[CH3:32])=[CH:20][CH:21]=3)=[O:23])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1
Reactant: Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cn(C)nc3-c3ccccc32)cc1
Reaction time: 4.5 h

Procedure:
To a mixture of 0.420 g of 2,4,5,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo[4,3-d][1]benzazepine and 275 μl of triethylamine in 6 ml of methylene chloride and 2 ml of dioxane is added a solution of 215 μl of 2-methylbenzoyl chloride in 1.5 ml of dioxane. The reactants are stirred under argon for 4.5 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride and washed with 10% NaHCO3 and brine. The organic layer is treated with activated carbon, dried with MgSO4 and evaporated in vacuo to give 660 mg of a tan foam residue. The residue is purified by column chromatography on silica gel by elution with 30% ethyl acetate-methylene chloride to give 590 mg of the desired product as white crystalline solid, m.p. 246°-248° C.; HR FABMS: (M+H)=437.1972.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].O>CS(C)=O>[N+:1]([CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCCCBr
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[Si](C)(C)CCCC[N+](=O)[O-]
Reaction time: 3 h
Yield: 44.8 %

Procedure:
4-Nitrobutyltrimethylsilane was prepared as follows: To a solution of 1.9 g (0.028 mol) of sodium nitrite in 30 ml of dimethyl sulfoxide was added 2.92 g (0.014 mol) of 4-bromobutyltrimethylsilane. After 3 hrs, 30 ml of water was added and the mixture was extracted with three 15 ml portions of carbon tetrachloride. The carbon tetrachloride solution was washed with 10 ml of water and dried over magnesium sulfate. The NMR spectrum showed 30% nitrite ester (CH2ONOδ4.57), and 70% nitro compound. Distillation gave 1.1 g (45%) of 4-nitrobutyltrimethylsilane, bp 54°-6° (0.9 mm).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[O:5][C:4](=[O:13])[C:3]=1[C:14](=[O:17])[CH2:15][CH3:16].[Na].C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[O:5][C:4](=[O:13])[C:3]=1[C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CCC(=O)c1c(O)cc(CCCCO)oc1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)c1c(O)cc(CCCC=O)oc1=O
Temperature: 28 °C
Reaction time: 3 h

Procedure:
To 4-hydroxy-6-(4-hydroxybutyl)-3-propionyl-2H-pyran-2-one (XV; 1.47 g; 6.12 mmol) in 60 ml CH2Cl2 and 2.19 ml pyridine, was added sodium periodinate (6.13 g; 15.3 mmol; Aldrich). The reaction was stirred at 28° C. for 3 h, neutralized with saturated NaHCO3, extracted with 3×150 ml CH2Cl2, dried with brine and Na2SO4, and evaporated. The product was purified via silica flash chromatography (20% EtOAc in hexanes).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C.[CH2:28]([O:30][CH:31]=[CH:32][C:33](Cl)=[O:34])[CH3:29]>C(N(CC)CC)C>[CH2:28]([O:30][CH:31]=[CH:32][C:33]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:34])[CH3:29]
Reactant: c1ccc(CN2CCC(Nc3ccccc3)CC2)cc1
Reactant: CCOC=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CCOC=CC(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 89.3 %

Procedure:
To a mixture of N-(1-benzyl-4-piperidinyl)aniline (0.9 g), diisopropyl ether (30 ml) and triethylamine (0.5 g) is added β-ethoxyacrylic acid chloride (0.7 g) in portions at 60° C. After refluxing for 1 hour, the reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is dried and concentrated and to the resulting residue is added n-hexane and the formed crystals are separated by filtration and recrystallized from n-hexane to give N-(β-ethoxyacryloyl)-N-(1-benzyl-4-piperidinyl)aniline (1.1 g) as white powders, m.p. 106°-108° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[CH:14][N:15]4[C:24]5[CH:23]=[CH:22][CH:21]=[C:20](F)[C:19]=5[C:18]5=[N:26][CH2:27][CH2:28][N:17]5[C:16]=34)[N:8]=2)[CH2:6][CH2:5]1>CN(C=O)C>[CH:4]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[CH:14][N:15]4[C:24]5[CH:23]=[CH:22][CH:21]=[C:20]([N:2]([CH3:3])[CH3:1])[C:19]=5[C:18]5=[N:26][CH2:27][CH2:28][N:17]5[C:16]=34)[N:8]=2)[CH2:6][CH2:5]1
Reactant: CNC
Reactant: Fc1cccc2c1C1=NCCN1c1c(-c3noc(C4CC4)n3)ncn1-2
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c1C1=NCCN1c1c(-c3noc(C4CC4)n3)ncn1-2

Procedure:
Dimethylamine was bubbled through a stirred suspension of 5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-12-fluoro-2,3-dihydrodiimidazo[1,5-a:1',2'-c]quinazoline (1.0 g, 3 mmol) in dry DMF (25 ml) for 5 min. at ambient temperature. Again after 2 h dimethylamine was passed through the reaction mixture for 5 min. and stirring was continued for one more hour. The resulting solution was evaporated in vacuo and the residue was treated with 4 ml of 1M NaOH and 20 ml of water. The insoluble material was filtered off, rinsed on the filter until the wash water was no longer basic, and dried. Recrystallization from isopropyl alcohol gave the title compound as pale yellow crystals, m.p. 148°-150° C. Yield 0.50 g (47%). (Compound 47).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].N1C(C)=CC(C)=CC=1C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 40 %

Procedure:
A stirred solution of 123 g (0.80 mole) of 5-chloroindoline, 134 g (0.70 mole) of 1,4-dichloronitrobenzene and 97 g (0.80 mole) of collidine in 1000 ml of dimethylformamide was heated under nitrogen at 150° C. for 48 hours. The mixture was then cooled, filtered from some insolubles, and the solvent was removed in vacuo with warming. The residue was partitioned between 1000 ml of dichloromethane and 500 ml of water. The water layer was removed and the organic phase was washed twice with 2N-hydrochloric acid, once with 2N-sodium hydroxide, once more with water, dried over Na2SO4 and concentrated to an oil weighing 230 g. This was dissolved in 170 ml of methanol and stirred at room temperature and then at 0° C. The resultant crystals were collected, washed well with cold methanol, and dried. This afforded 86.5 g (40% yield) of product, m.p. 130°-133° C. 4 g of 5-chloro-1-(4-chloro-2-nitrophenyl)indoline were recrystallized from methanol in 85% yield (overall yield: 34%); m.p. 133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].[CH3:7][N:8]([CH3:22])[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=O)[CH:18]=2)[NH:13][CH:12]=1>CO>[CH3:1][O:2][C:3]([NH:5][N:6]=[CH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:10][CH2:9][N:8]([CH3:22])[CH3:7])=[O:4]
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Reactant: COC(=O)NN
Solvent: CO
Product: COC(=O)NN=Cc1ccc2[nH]cc(CCN(C)C)c2c1
Yield: 104 %

Procedure:
To a solution of hydrazinecarboxylic acid methyl ester (0.90 g, 10 mmol) in methanol (10 ml) is added 3-(2-Dimethylamino-ethyl)-1H-indole-5-carbaldehyde (2.16 g, 10 mmol), and the mixture obtained is heated at reflux for 20 hours. After removal of the solvent, a yellow oil (3.0 g) is obtained, which is chromatographed on silica (chloroform:methanol 9:1 v:v to 4:1 v:v) to give 1.6 g (55.4%) of the product as a colourless foam. 1H-NMR (CDCl3, 300 MHz) δ 2.26 (s, 6H, N(CH3)2); 2.57, 2.84 (2 m, 2H each, CH2CH2NHMe2); 3.79 (s, 3H, OCH3); 6.90 (s, 1H, H-2); 7.11 (d, 1H, J=8.5 Hz, H-7); 7.45 (dd, 1H, J=1.5 Hz, H-6); 7.62 (br s, 1H, H-4); 7.77 (s, 1H, N═CH); 9.04 (br s, 1H, H-1); 9.33 (br s, 1H, NH). 13C-NMR (CDCl3, 75 MHz) δ 23.73 (CH2); 45.51 (N(CH3)2); 53.04 (OCH3); 60.39 (CH2NMe2); 112.07 (C-7); 114.66 (C-3); 119.52 (C-4); 120.72 (C-6); 123.14 (C-2); 125.14 (C-5); 127.52 (C-9); 137.71 (C-8); 147.25 (N═CH); 155.02 (NC═O).
Reaction SMILES: [C:1]([CH2:4][O:5][N:6]=[C:7]([C:26]1[N:27]=[C:28]([NH:31]C(=O)C(F)(F)F)[S:29][CH:30]=1)[C:8]([NH:10][CH:11]1[C:24](=[O:25])[N:13]2[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH2:18][S:19][CH3:20])[CH2:16][S:17][C@H:12]12)=[O:9])([OH:3])=[O:2].C([O-])(=O)C.[Na+].Cl>O>[C:1]([CH2:4][O:5][N:6]=[C:7]([C:26]1[N:27]=[C:28]([NH2:31])[S:29][CH:30]=1)[C:8]([NH:10][CH:11]1[C:24](=[O:25])[N:13]2[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH2:18][S:19][CH3:20])[CH2:16][S:17][C@H:12]12)=[O:9])([OH:3])=[O:2]
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Yield: 52.5 %

Procedure:
A solution of 7-[2-carboxymethoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (4.1 g) and sodium acetate (9.56 g) in water (41 ml) was stirred for 19.5 hours at ambient temperature. The resultant solution was adjusted to pH 2.0 with conc. hydrochloric acid. The precipitates were collected by filtration and dried over phosphorus pentoxide to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.8 g), mp 173°-176° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10]([N:12](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[C:10]([C:3]1[C:2]([F:1])=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=1)#[N:12]
Reactant: Cc1cc[n+]([O-])cc1F
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: Cc1ccnc(C#N)c1F

Procedure:
To a stirred solution of 0.95 g (7.48 mmol) of 3-fluoro-4-methylpyridine N-oxide 5-2 in 20 mL of acetonitrile was added 1.14 g (11.2 mmol) of triethylamine followed by 1.48 g (15.0 mmol) of trimethylsilyl cyanide. This reaction mixture was heated at reflux for 48 h, after which time the solution was concentrated at reduced pressure. The dark residue was dissolved in CHCl3, washed with saturated aqueous NaHCO3 and the aqueous layer back-washed with chloroform (4×). The combined organic layers were dried over MgSO4 and the solvents removed at reduced pressure to give an oil that was chromatographed on SiO2 using 75:25 hexane-EtOAc to give 5-3 as a yellow oil: 1H NMR (CDCl3) δ 8.39 (d, 1H, 4.8 Hz), 7.09 (br dd, 1H, 5.8, 5.8 Hz), 2.41 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[N:5][C:4]2[C:8](C(OC)=O)=[CH:9][NH:10][C:3]1=2.[OH-].[K+]>C(O)(=O)C>[N:5]1[C:4]2[CH:8]=[CH:9][NH:10][C:3]=2[C:2](=[O:1])[NH:7][CH:6]=1
Reactant: COC(=O)c1c[nH]c2c(=O)[nH]cnc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc[nH]c12

Procedure:
To methyl 4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxylate synthesized by the known method (Organic Process Research & Development 2009, 13, 928-932), 10% potassium hydroxide (240 mL) was added, and refluxed for 40 hours while stirring. After completion of the reaction, the reaction mixture was cooled to room temperature and neutralized with acetic acid to a pH of 6.5-7.5. The solid thus obtained was filtered and dried to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([OH:21])[CH:3]=1.[CH:22]#[C:23][CH:24](O)[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([O:21][CH:24]([CH3:25])[C:23]#[CH:22])[CH:3]=1
Reactant: C#CC(C)O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2O)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)Oc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
1.7 g (5.3 mmol) of 3-(4-chloro-2-hydroxyphenyl)-1-methyl-6-trifluoromethyluracil, 0.63 g (9.0 mmol) of 1-butyn-3-ol and 1.57 g (6.0 mmol) of triphenylphosphine were dissolved in 100 ml of tetrahydrofuran, and 1.0 g (6.0 mmol) of diethyl azodicarboxylate was dropwise added thereto under cooling with ice. After stirring at room temperature for 1 hour, the solvent was distilled off. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.86 g (yield: 93.9%) of the desired product as white crystals. Melting point: 96-99° C.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Br[CH2:11][CH2:12]Br.BrC(Br)C.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.CN(C)C=O>[C:2]1([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:12][CH2:11]1
Reactant: BrCCBr
Reactant: COC(=O)CC(=O)OC
Agent: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)CC1
Yield: 55 %

Procedure:
The cycloalkylation of dimethyl malonate with 1,2-dibromoethane in potassium carbonate/dimethylformamide is disclosed by D. A. White in Synthesis Communications 7/8 (1977) 559. Based on 1 mol of dimethyl malonate, 4 mols of dibromoethane and 2.4 mols of potassium carbonate in 1.2 liters of dimethylformamide are reacted for 22 hours, yielding 73% of theory of dimethyl cyclopropane-1,1-dicarboxylate (CDM). These are data of a poor space-time yield which stands in the way of using the method on an industrial scale. A further target must be to replace the 1,2-dibromoethane with 1,2-dichloroethane, for instance. However, dichlorides are not very reactive. The comparative example below shows that 1,2-dichoroethane produces CDM with a yield of 55% of theory, whereas 1,2-dibromoethane produces CDM with a yield of 96.5% of theory. The disposal of potassium chloride by electrolysis is simple, but the disposal of potassium bromide is not. Nonetheless, many attempts have been made to use the dichloride. Thus, J. Heiszman et al, Synthesis Communications 1987, 738, used benzene as a solvent medium and also used a phase transfer catalyst, which yielded diethyl cyclopropane-1,1-dicarboxylate (CDE) in over 20 hours at 80° C. The use of solvents such as benzene is no longer allowed. Phase transfer catalysts are difficult to dispose of and form amines during decomposition.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][N:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][N:2]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:8]=1[CH:9]=[O:10]
Reactant: CN(c1cccnc1)c1ncccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CN(c1cccnc1)c1ncccc1C=O
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
To a solution of {2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}methanol (180 mg) in 8 mL CH2Cl2 was added Dess-Martin periodinane (674 mg). The reaction was stirred at room temperature for 100 min. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added, and the mixture was stirred vigorously overnight, then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (Na2SO4) and concentrated to give 2-[methyl(pyridin-3-yl)amino]nicotinaldehyde in approximately 75% purity. This material was used directly in the next reaction.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]3)=[N:18]2)=[CH:13][CH:12]=1.O>CS(C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:31][CH2:30][N:29]([C:2]#[N:1])[CH2:28][CH2:27]3)=[N:18]2)=[CH:13][CH:12]=1
Reactant: N#CBr
Reactant: CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 104 %

Procedure:
To a stirred mixture of cyanogen bromide (21.67 g, 0.204 moles) and potassium carbonate (33.2 g, 0.24 moles) in dimethyl sulfoxide (400 ml) was added dropwise a solution of 1-(4-fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole (59.45 25 g, 0.192 moles), the free base of example 67, in hot dimethyl sulfoxide (375 ml). The reaction was stirred at ambient temperature for 4 days and then poured into H2O (500 ml). The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 64 g of a solid. The product was recrystallized twice from isopropyl alcohol yield 35.7 g (58%) of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, mp 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:17]([CH:6]([C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
(1)-a) To 19.0 g of methyl 4-(4-chlorobenzoyl)butyrate were added 14.5 g of aniline, 0.6 g of p-toluenesulfonic acid monohydrate and 200 ml of toluene, and the mixture was refluxed with dehydration for 22.5 hours. After removal of the solvent under reduced pressure, 100 ml of methanol and 2.5 g of sodium hydrogencarbonate were added, and the mixture was cooled to -20° C. Subsequently, 6.0 g of sodium borohydride was added portionwise over 1 hour, and the mixture was stirred at -30° to -20° C. for 1 hour and at -20° to -5° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with diluted hydrochloric acid, and aqueous sodium hydrogencarbonate solution and water, and dried, followed by evaporation of the solvent to give 23.7 g of methyl 5-anilino-5-(4-chlorophenyl)pentanoate as a pale brown oily product. Subsequently, to said oily product were added 75 ml of methanol and 100 ml of an aqueous 10% sodium hydroxide solution, and the mixture was heated under reflux for 1 hour. After removal of the solvent, the residue was diluted with 50 ml of water and then ashed with ether. The aqueous layer was adjusted to pH 6 to 7 with hydrochloric acid, extracted with ethyl acetate. The ethyl acetate extract was washed with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried, and treated with activated charcoal. After removal of charcoal and the solvent, the residue was recrystallized from isopropyl ether to give 17.8 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid as colorless prisms.