Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]2=[CH:4][CH:3]=1.[CH3:13][C:14]([O:16]C(C)=O)=[O:15]>>[C:14]([O:16][CH2:1][C:2]1[N:7]=[C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]2=[CH:4][CH:3]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c([n+]1[O-])OCCO2
Product: CC(=O)OCc1ccc2c(n1)OCCO2
Yield: 99 %

Procedure:
A solution of 6-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine 5-oxide (60 g, 0.36 mol) in Ac2O (500 mL) was stirred at reflux for 5 hours. The reaction was cooled and the solvent was removed in vacuo to yield (2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)methyl acetate (75 g, 99%) as a dark oil, which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[CH2:16]([C:18]1[S:22][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:20][C:19]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:17].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH2:16]([C:18]1[S:22][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:27][CH2:28]2)=[N:20][C:19]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:17]
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: CCc1sc(N2CCNCC2)nc1-c1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(N2CCN(C(=O)Nc3cccnc3)CC2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 48.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (217 mg, 0.805 mmol), 1-(5-ethyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.732 mmol) and diisopropylethylamine (0.255 ml, 1.46 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (140 mg, 48.5%) as a solid.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([CH2:12]O)[CH2:10][N:9]([CH:14]([CH3:16])[CH3:15])[C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:26])=O.N1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:26][CH2:12][CH:11]1[CH2:10][N:9]([CH:14]([CH3:16])[CH3:15])[C:8](=[O:17])[C:7]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1CC(CO)C(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
A solution of 43 g. (0.14 mole) of 3,3-diphenyl-4-hydroxymethyl-1-isopropyl-2-pyrrolidinone in 250 ml. of chloroform was treated with 33 g. (0.28 mole) of thionyl chloride over a one minute period followed by the dropwise addition of 22 g. (0.23 mole) of pyridine over a 30 minute period. The mixture was refluxed 18 hours and then poured onto ice. The cold mixture was made basic by the addition of sodium hydroxide. The chloroform layer was separated, dried over sodium sulfate and concentrated. The residue was crystallized using charcoal from a 25% ethyl acetate -- 75% isopropyl ether mixture. The crystalline solid was recrystallized from a 75% ethanol -- 25% water mixture and then from isopropyl ether. The dried 4-chloromethyl-3,3-diphenyl-1-isopropyl-2-pyrrolidinone weighed 23 g. and melted at 114°-116° C.
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9]C)C.[CH3:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)C(=O)[NH:16][CH:15]=1.O.[OH-].[Na+]>C(Cl)Cl>[CH2:11]([O:8][C:9]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:14]([CH3:13])=[CH:15][N:16]=1)[CH3:12]
Reactant: CC[O+](CC)CC
Reactant: Cc1c[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOc1ncc(C)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.2 %

Procedure:
A solution of triethyloxonium tetrafluoroborate (9.0 g, 47 mmol) in DCM (62 mL) was added to a stirred solution of 5-methyl-1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one (9.0 g, 37 mmol) in DCM (124 mL) under a nitrogen atmosphere. The solution was stirred at RT for 2.5 h then treated with water (50 mL) then 1 M sodium hydroxide (50 mL). The phases were partitioned. The aqueous phase was washed with DCM (2×50 mL). The combined organic phase was dried (sodium sulfate). The solution of the crude product was filtered through 2×50 g flash SCX 2 cartridges. Each cartridge was rinsed with 10% methanol in DCM (100 mL) then the product fraction was eluted with 2M methanolic ammonia solution (100 mL). The fractions recovered with methanolic ammonia were combined and concentrated in vacuo to afford the title compound (7.92 g) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]#[N:14].C(OCC)(=O)C.Cl.O1CCCC1.P([S-])(OCC)(OCC)=[S:28]>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=[S:28])[NH2:14]
Reactant: CCOP(=S)([S-])OCC
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To a mixture of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetonitrile (15 g), 4 mol/L hydrogen chloride-ethyl acetate solution (40 mL) and tetrahydrofuran (50 mL) was added O,O-diethyl dithiophosphate (15 mL), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The extract was washed twice with water, and then washed with saturated brine and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as white crystals (yield 9.0 g, 51%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][OH:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:19]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][O:15][CH3:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1cn(Cc2ccccc2)nc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nn(Cc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
Into a 250-mL 3-neck round-bottom flask, was placed a solution of (1-benzyl-4-methyl-1H-pyrazol-3-yl)methanol (compound 268.2, 1.7 g, 8.4 mmol) in THF (50 mL). The solution was cooled to 0° C., then sodium hydride (470 mg, 11.8 mmol, 60% dispersion in mineral oil) was added in portions at 0° C., and then the mixture was stirred for 20 min. Iodomethane (750 μL, 12 mmol) was added at 0° C., then the resulting mixture was stirred for 2 h at room temperature. The reaction was carefully quenched by drop-wise addition of water (30 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to obtain the title compound as a yellow oil (1.5 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[O:20])[CH2:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Clc1ccc(SC2=CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(CCCN1CC=C(Sc2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 98 °C
Yield: 84.1 %

Procedure:
A mixture of 11.2 g of 4-[(4-chlorophenyl)thio]-1,2,3,6-tetrahydropyridine, 10.0 g of 4-chloro-p-fluorobutyrophenone and 6.9 g of potassium carbonate is heated at 98° C. for 1 hour. The mixture is taken up in benzene and filtered. Evaporation of the filtrate gives a brown oil which is treated with a large excess of 1 N hydrochloric acid. The resulting precipitate is collected to afford 8.9 g (46%) of tan powder, m.p. 208°-210° C. Recrystallization from acetonitrile yields off-white crystals, m.p. 220°-222° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1.0 g (3.35 mmole) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 1.15 g (13.4 mmole) of piperazine, 1.36 g (13.35 mmole) of triethylamine and 60 ml of acetonitrile is refluxed for three hours and then stirred at room temperature for 16 hours. The precipitate is removed by filtration, washed with acetonitrile and dried in vacuo at 60° C. to give 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, mp 257°-259° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([OH:10])=[C:8]([C:11]#[N:12])[O:7][C:6]=2[CH:13]=1.[CH3:14][NH:15][NH2:16]>C1C=CC=CC=1>[CH3:14][NH:15][NH:16][C:11]([C:8]1[O:7][C:6]2[CH:13]=[CH:2][CH:3]=[CH:4][C:5]=2[C:9]=1[OH:10])=[NH:12]
Reactant: N#Cc1oc2cc(Cl)ccc2c1O
Reactant: CNN
Solvent: c1ccccc1
Product: CNNC(=N)c1oc2ccccc2c1O
Yield: 43.7 %

Procedure:
3-Hydroxybenzo[b]furo-2-carbonitrile (1.40 g, 8.8 mmol, described in Example 3) was dissolved with heating in benzene (50 mL) and methyl hydrazine (1 mL, ca. 19 mmol) was added. The solution was stirred and refluxed for 2 hr and evaporated to dryness. The pasty residue (ca. 2 g) was applied in chloroform solution to chromatography on neutral alumina. Elution with 2% MeOH in CHCl3 (v/v) gave 3-hydroxybenzo[b]furan-2-carboximidic acid, 2-methylhydrazide (0.79 g): IR (CHCl3) 3510, 3480, 3450, 3200, 1635 and 1595 cm-1 ; and NMR (CDCl3) δ2.65 (3H, s), 5.7 (3H, broad), ca. 7.4 (1H, br), 7.2 (3H, m) and 7.75 (1H, d).
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH2:19][C:20]([NH:22][NH2:23])=[O:21])#[N:18]>CN(C)C=O>[C:17]([C:19]1[C:20](=[O:21])[NH:22][N:23]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[N:18]
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: N#CCC(=O)NN
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Yield: 95 %

Procedure:
Benzil 63.1 grams (0.3 mole) along with 30 grams (0.3 mole) of cyanoacetohydrazide in 200 mls of dimethylformamide was heated at 110° C. for five hours. The solution was cooled and the precipitant solid was filtered and washed with ethyl alcohol. The filtrate was vacuum distilled and the residual solid was washed with ethyl alcohol and filtered. There was isolated 74.5 grams, a 95% yield, of a solid which melted at 280°-281° C. Calculated for C17H11N3O, C, 74.7; H, 4.1; N, 15.4. Found: C, 74.4; H, 4.16; N, 15.2. The infrared spectra showed the nitrile at 4.5μ; the ##STR57## band for an amide at 6.0μ.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.Cl[CH2:35][C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37]>CN(C)C=O>[CH2:14]([O:13][C:11]([C:7]1[N:8]([CH2:35][C:36](=[O:37])[N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:9]2[C:5]([C:6]=1[NH:16][C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1Nc1ccncc1
Reactant: CCN(CC)C(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccncc2)c2ccc(Cl)cc2n1CC(=O)N(CC)CC
Temperature: 0 °C
Yield: 14.8 %

Procedure:
Under nitrogen, stir and cool to 0° C. a mixture of ethyl 6-chloro-3-(4-pyridinylamino)indole-2-carboxylate (0.50 g, 1.58 mmol) in dimethylformamide (5 mL). Add a 1M solution of potassium tert-butoxide in tetrahydrofuran (1.7 mL, 1.7 mmol) over a 2 min period, and stir for 10 min. Add 2-chlor-N,N-diethylacetamide (0.22 mL, 1.6 mmol) in one portion and stir at ambient temperature overnight. Quench the reaction into water (35 mL), and extract the aqueous mixture with ethyl acetate (2×20 mL). Combine the extracts, wash with water (25 mL), brine (25 mL) and dry over MgSO4. Concentrate under vacuum, and chromatograph the residue on a Redisep silica gel cartridge (10 g) eluting with 5% methanol/dichloromethane to 20% methanol/dichloromethane. Combine all homogenous fractions and concentrate to obtain a solid. Recrystallize the solid from ethyl acetate and obtain 0.1 g of the title compound as a white solid: MS 429(M+H), m.p. 212–214° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O>[N:17]([CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[N+:18]=[N-:19]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 1-t-butoxycarbonyl-3-(methanesulfonyloxy)azetidine (4.71 g, 18.7 mmol) (obtained as described in Reference Example 57(1)) in dimethylformamide (140 ml) was added sodium azide (3.65 g, 56.1 mmol), and the mixture was stirred in an oil bath (90° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed 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 (4:1) as the eluant to afford 3-azido-1-(t-butoxycarbonyl)-azetidine (3.44 g, yield 93%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[I:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Nc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc(Nc2ccc(I)cc2)n1
Temperature: 125 °C
Reaction time: 21 h
Yield: 14 %

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and 2-chloro-4-methoxypyrimidine (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg). (2) Under an argon atmosphere, N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg) was added to a suspension of sodium hydride (11 mg) in anhydrous DMF (5 ml), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.0096 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=3/1) to obtain N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (46 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[CH:11]1[CH:16]=[C:15]([CH:17](O)[C:18](O)=[O:19])[C:14]([Cl:22])=[CH:13][CH:12]=1>>[Cl:22][C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=1[CH:17]1[C:9]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:10]=2)[NH:8][C:18]1=[O:19]
Reactant: O=C(O)C(O)c1ccccc1Cl
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc2c(c1)C(c1ccccc1Cl)C(=O)N2

Procedure:
This compound is prepared according to the procedure described in step B of Preparation 66 from N-4-ethoxyphenyl-DL-2-chloromandelamide (120°-130° C.), itself obtained according to the procedure described in step A of Preparation 2 from 4-ethoxyaniline and DL-2-chloromandelic acid. This gives the expected product. M.p.=176°-180° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([Cl:17])=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.0 g (59.7 mmol) trans-4-tert-Butylcyclohexanecarboxylic acid are dissolved in 400 ml dichloromethane plus a few drops of DMF, 9.09 g (71.6 mmol) ethanedioyl dichloride are added and the solution is stirred at room temperature for one hour. The mixture is then stirred at reflux for two hours and, after cooling down to room temperature, evaporated to dryness in vacuo. The residue is then dissolved in toluene two times and again evaporated to dryness in vacuo. The residue is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH:4]=[O:5].S([O-])(O)(=O)=O.[Na+].[C-:14]#[N:15].[K+]>O>[F:1][C:2]([F:7])([F:6])[CH2:3][CH:4]([OH:5])[C:14]#[N:15]
Reactant: [C-]#N
Reactant: O=CCC(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CC(O)CC(F)(F)F
Temperature: 0 °C

Procedure:
3,3,3-Trifluoropropanal was added to a mixture of sodium hydrogensulfate and water, with vigorously stirring at 0° C., followed by further stirring for 10 minutes. An aqueous solution of potassium cyanide was dropwise added, followed by reaction with stirring at 0° C. for 1 hour and then work-up and purification to obtain 4,4,4-trifluoro-2-hydroxybutanenitrile.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[N:7]([CH:9]=O)C.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[ClH:18].NO>>[Cl:18][C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[C:9]#[N:7]
Reactant: Cl
Reactant: O=C1CCCCC1
Reactant: CN(C)C=O
Agent: NO
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=C(Cl)CCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Phosphorus oxychloride (11.5 mL; 124 mmol) was cooled in an ice-salt bath and DMF (10.0 mL; 130 mmol) was added over a period of 20 min (a sticky white solid was formed). Cyclohexanone (8.0 mL; 77 mmol) was added over 15 min (the sticky solid turned into a bright yellow solution). The mixture was heated at 50° C. and hydroxylamine hydrochloride (30 g; 432 mmol) was added in 5 portions at 5 min intervals maintaining the temperature between 45 and 55° C. via cooling if needed. The reaction mixture was poured into ice-water (300 mL) and the aqueous mixture was stirred for 1 h. The brown solid was filtered, washed with water and dried under reduced pressure over phosphorus pentoxide to afford 9.06 g (83%) of 2-chlorocyclohex-1-enecarbonitrile as a rust-brown solid. ESI/APCI (+): 160-162 (M+H+H2O). 1H-NMR (400 MHz, DMSO-d6) (ppm) δ: 2.48 (2H, m); 2.35 (2H, m), 1.74-1.77 (2H, M), 1.71-1.66 (2H, M).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:42](OC)[N:43]([CH3:45])[CH3:44].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26](/[CH:33]=[CH:42]/[N:43]([CH3:45])[CH3:44])[N:25]=[C:24]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 130 °C

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-methyl-2-morpholinopyrimidine-5-carboxylate (350 mg, 0.64 mmol) was dissolved in DMF (5 mL), dimethyl formamide dimethyl acetal (0.26 mL) was added and the mixture was heated to 130° C. for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give the desired product (0.23 g). 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 7.94 (d, J=12.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 5.89 (d, J=12.2 Hz, 1H), 4.30 (q, J=6.8 Hz, 2H), 3.80 (s, 2H), 3.75-3.65 (m, 8H), 3.33 (m, 4H), 3.32 (m, 6H), 2.41 (m, 4H), 1.38 (s, 9H), 1.32 (t, J=6.8 Hz, 3H); MS m/z 596.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[C:11]([CH3:12])=[N:10][N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2O)[NH:5][N:6]=1.[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])NN.C([OH:31])C>>[C:25]([O:24][C:20]([N:6]1[C:2]([OH:31])([CH3:1])[CH:3]=[C:4]([C:7]2[C:11]([CH3:12])=[N:10][N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=2)[NH:5]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)[nH]n1
Product: Cc1nn(-c2ccccc2)cc1C1=CC(C)(O)N(C(=O)OC(C)(C)C)N1

Procedure:
To 5,5′-Dimethyl-2′-phenyl-2H,2′H-[3,4′]bipyrazolyl-3′-ol (0.118 g, 0.457 mmol) (Example 25) in ethanol (4 ml) add tert-butyl carbazate (0.120 g, 0.914 mmol). Heat at reflux for 1.5 hours, after which evaporate the ethanol. Chromatography on silica gel, eluting with 50% ethyl acetate/heptane provides 0.101 g of a mixture of positional isomers A and B. Use the mixture for the next step.