Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([C:9]1[S:10][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24]C(=O)C)[CH:20]=3)[CH:15]=2)=[N:12][N:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.Cl>C(O)C>[CH2:3]([C:9]1[S:10][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=3)[CH:15]=2)=[N:12][N:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1nnc(-c2ccc3cc(OC(C)=O)ccc3c2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCc1nnc(-c2ccc3cc(O)ccc3c2)s1
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
1.50 g (22.7 mM) of potassium hydroxide was dissolved in 72 ml of ethanol at 60°-65° C. To the solution, 2.90 g (8.18 mM) of 2-hexyl-5-(6-acetoxynaphthalene-2-yl)-1,3,4-thiadiazole was added, followed by stirring for 20 minutes at 60°-65° C. The reaction mixture was poured into 200 ml of iced water and 3 ml of concentrated hydrochloric acid was added thereto to precipitate a crystal. The crystal was recovered by filtration and washed with water to obtain 1.90 g of 2-hexyl-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 71.9 %). ##STR138##
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[CH:12]([N:13]1[CH2:16][CH:15]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Methane sulphonyl chloride (0.5 mL, 6.43 mmol) was added to a solution of 1-(diphenylmethyl)-3-hydroxyazetidine (1.38 g, 5.77 mmol) and Et3N (0.9 mL, 6.46 mmol) in toluene (10 mL) at 0° C. The reaction mixture was stirred and warmed to room temperature overnight. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried over MgSO4 and concentrated to give pale yellow oil (756 mg, 41%) which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C[C@H](N)C(N[C@H](C(N[C@H](C(N1[C@H](C(O)=O)CCC1)=O)CC(O)=O)=O)CC(N)=O)=O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: CC(C)(CO)CCCBr
Reactant: C1=COCCC1
Agent: C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(CCCBr)COC1CCCCO1
Temperature: 25 °C
Yield: 108.2 %

Procedure:
5-Bromo-2,2-dimethyl-1-pentanol (77.4 g, 357 mmol) was dissolved in dichloromethane (400 mL), andp-toluenesulfonic acid (6.9 g, 36 mmol) was added. The mixture was stirred under argon, chilled in an ice-bath, then was added 3,4-dihydro-2H-pyran (37.2 g, 428 mmol) and stirred, gradually letting warm to rt overnight. The reaction mixture was then filtered through neutral alumina (100 g); the alumina was rinsed with additional dichloromethane (600 mL). After evaporating to about 500 mL, the organic layer was extracted with sat. NaHCO3 (3′ 200 mL), then dried over MgSO4. The solution was concentrated under reduced pressure to produce the expected product (107.83 g, 97% yield) as a yellow oil. 1H NMR (CDCl3), d (ppm): 4.55 (m, 1H); 3.83 (m, 1H); 3.51 (m, 1H); 3.47 (d, 1 H, J=9.0); 3.38 (t, 2 H, J=6.8); 2.98 (d, 1 H, J=9.0); 1.94-1.75 (m, 2H); 1.75-1.44 (m, 6H); 1.40 (t, 2 H, J=8.5); 0.93-0.87 (m, 6H). 13C NMR (CDCl3), d (ppm): 99.0, 76.2, 61.9, 37.9, 34.6, 34.0, 30.6, 27.9, 25.6, 24.64, 24.56, 19.4. HRMS calcd. for C12H24BrO2 (MH+): 279.0960, found 279.0955.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CO>[CH2:15]([N:9]1[C:8]2[C:7](=[O:13])[NH:6][C:5](=[O:14])[N:4]([CH3:3])[C:12]=2[N:11]=[CH:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A 10% aqueous sodium hydroxide solution (10 ml) was added to a suspension of 3-methylxanthine (4.15 g) in methanol (25 ml) and the mixture was stirred for 1 hour at 70° C. Benzyl bromide (4.275 g, 2.97 ml) was added dropwise at 70° C. and the mixture was stirred at 70-80° C. for an additional 5 hours. After cooling to room temperature, the mixture was treated with water (50 ml). The precipitate was filtered, dissolved in 1 N aqueous sodium hydroxide solution (50 ml) and the solution was acidified to pH 4-5 with concentrated hydrochloric acid. The precipitate was filtered and washed with water (3×20 ml) to provide 7-benzyl-3-methylxanthine (4.45 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18]>ClCCCl.O>[C:5]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:9][C:10](=[O:18])[CH2:11]2)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
171 g (1.28 mol) aluminium chloride in 500 ml 1,2-dichloroethane are cooled in the ice bath. Then 78 g (1.1 mol) acetylchloride are added dropwise, so that the temperature does not exceed 10° C. After 1 h, 71.3 g (0.53 mol) 2-indolinone (1,3-dihydro-indol-2-one) are added in 4 batches and the temperature is kept at 10–12° C. The reaction mixture is left overnight to warm up slowly to ambient temperature. Then the solution is slowly added to 1 kg ice with vigorous stirring. The slurry is diluted with 1 l water and stirred for another 30 min. Then the precipitate is suction filtered.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1C(OC)=O.CN1CCNCC1.O>CN1CCCC1=O>[NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: COC(=O)c1sc2ccccc2c1N
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1csc2ccccc12
Temperature: 178 °C

Procedure:
To a solution of methyl 3-aminobenzothiophene-2-carboxylate [prepared by the method of J. R. Beck, J. Org. Chem. 1972, 37, 3224] (6.5 g, 31.4 mmol) in N-methylpyrrolidinone (30 ml) was added 1-methylpiperazine and the reaction mixture was heated to 178° C. for 4 h. After cooling the mixture was poured into water and the product extracted with diethyl ether (3×100 ml), the extracts were washed with water (1×100 ml) and brine (1×100 ml), combined and dried (MgSO4). Concentration of the extracts yielded 3-aminobenzothiophene (5.9 g), which was used without purification. To a solution of 3-aminobenzothiophene (5 g, 32 mmol) in N-methylpyrrolidinone (50 ml) was added piperazine (8.7 g, 102 mmol) and the mixture heated to reflux under nitrogen for 14 h. Cooled and poured into water and extracted with dichloromethane (4×100 ml). The extracts were washed with brine (50 ml), combined and dried (MgSO4). On concentration of the extracts a white solid came out of solution which was collected by filtration to yield the title compound (0.78 g, more product left in solution); δH (DMSO-d6 +(TFA), 3.3 (3H, m, 4×piperazinyl CH2), 7.08 (1H, s, 3-H), 7.39 (2H, m, 2×ArH), 7.83 (1H, m, ArH), 7.95 (1H, m, ArH), and 9.30 (1H, br s, NH).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=O)=[C:8]([Cl:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].COC1C(C)=C2C(C(O)=CC(C3SC=C(C(F)(F)F)N=3)=N2)=CC=1>>[Cl:22][C:8]1[C:7]([O:23][CH3:24])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Product: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1Cl
Yield: 70 %

Procedure:
8-Chloro-7-methoxy-2-(4-trifluoromethyl-thiazol-2-yl)-quinolin-4-ol 203d was synthesized from compound 202d as a yellow powder in 70% yield, following the procedure as described for compound 203b. MS (ESI, EI+): m/z=361 (MH+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2cnccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc2cnccn12
Temperature: 50 °C
Yield: 91.7 %

Procedure:
A mixture of 3-bromoimidazo[1,2-a]pyrazine (0.15 g, 0.76 mmol; prepared according to J. Bradac, et al. J. Org. Chem. (1977), 42, 4197-4201), 0.09 g (0.91 mmol) of ethynyltrimethylsilane, 0.044 g (0.038 mmol) of Pd(PPh3)4, 0.014 g (0.076 mmol) of CuI, and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.15 g of product: 216 m/z (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(OC([NH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=O)(C)(C)C.C(N(CC)CC)C.[OH-]>C(Cl)Cl.CO>[CH3:5][O:4][C:2]([N:16]1[CH2:17][CH2:18][CH:14]([NH2:13])[CH2:15]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)N1CCC(N)C1
Reaction time: 0.5 h

Procedure:
Add methyl chloroformate (460 μL, 560 mg, 6.0 mmol, 3.0 equiv) to a solution of 3-(tert-butoxycarbonylamino)pyrrolidine (TCI; 373 mg, 2.00 mmol, 1 equiv) and triethylamine (1.1 mL, 800 mg, 7.9 mmol, 3.9 equiv) in anhydr CH2Cl2 (4 mL). Vigorous gas evolution, a slight exotherm, and precipitation can occur. After stirring 30 min, rotary evaporate the reaction mixture (60° C.). Dissolve the resultant material in MeOH to quench any residual chloroformate and rotary evaporate the solution (60° C.). Add trifluoroacetic acid (5 mL) to this material causing gas evolution. Rotary evaporate the reaction solution (40° C.; azeotroping 2× with MeOH). Resulting in a yellow oil then dissolve in MeOH (30 mL) and add hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh; 9.3 g) to free-base the amine. Filter the mixture and evaporate the filtrate by rotary (40° C.; azeotroped 2× with CH2Cl2) to yield 914 mg (300%) of crude product as a light-brown oil. Mass spec indicates desired product is present. Absorb this oil to an SCX column (20 g) activated with 10% AcOH/MeOH. Push MeOH through the column to elute any non-amine material. Elute the product with 2.0 M N3 in MeOH to yield 269 mg (93.2%) of 3-amino-pyrrolidine-1-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CCCCC=1.C(O)C>C(OC(C)C)(C)C.[Pd]>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1
Reactant: Cn1ccc2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: Cn1ccc2ccc(O)cc21

Procedure:
The mixture consisting of 0.24 mole (57 g) of 6-benzyloxy-1-methylindole, 5.7 g of 10% palladium-on-charcoal, 114 ml of cyclohexene and 170 ml of 96% ethanol is heated for 30 minutes under reflux. The mixture is filtered hot to remove the catalyst. After evaporation of the filtrate under vacuum, an oil is obtained which, dissolved in isopropyl ether, gives the desired product after evaporation to dryness. It melts at 74° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:24]([Mg][Cl:28])[CH2:25][CH3:26].[Cl-].[CH2:30]1[CH2:34]OC[CH2:31]1>>[ClH:28].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]([OH:19])([CH2:31][CH2:30][CH3:34])[CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCC[Mg]Cl
Reactant: C1CCOC1
Reactant: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [Cl-]
Product: CCCC(O)(CCC)CCN1CCC(c2noc3cc(F)ccc23)CC1
Product: Cl
Reaction time: 17 h
Yield: 45 %

Procedure:
To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (4.5 g, 14.0 mmoi) in THF (120 ml) was added propylmagnesium chloride (21.1 ml, 42.0 mmol, 2.0M in ethepropylmagnesium chloride (21.1 ml, 42.0 mmol, 2.0M in ether) at room temperature under nitrogen (mild exotherm). The reaction mixture was stirred for 17 hours at which time it was carefully quenched with NH4Cl (sat., 30 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2X). The combined organics were washed with brine and dried (Na2SO4). Filtration and concentration gave the crude product which was purified via flash column chromatography (silica gel, 2% Et3N/ether). After flushing the product through alumina with ether, the hydrochloride salt was prepared in ether/EtOAc (1:1, 40 ml, 1 drop IPA) with ethereal HCl to give 2.5 g (45%) of the desired product as a white solid, m.p.=163°-164° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17].Cl>O>[Cl:13][CH2:14][CH2:15][C:16]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[F:12])=[O:17]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCCl)c1ccc(F)cc1F
Temperature: 50 °C
Yield: 75.2 %

Procedure:
Aluminum chloride (0.3 mol) was added carefully to 1,3-difluorobenzene (0.26 mol) and the mixture was heated with vigorous stirring till 50° C. 3-Chloropropionyl chloride (0.26 mol) was added dropwise over a 15 min. period at 40° C. (cooled on ice) and the mixture was stirred at 50° C. The mixture was poured into water (250 ml), ice (250 g) and HCl (25 ml) and it was stirred for 20 min. The formed precipitate was filtered off and extracted with CH2Cl2 and water, yielding 40 g (75%) of 3-chloro-1-(2,4-di-fluorophenyl)-1-propanone (interm. 1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[CH3:15][C:16]([CH3:19])([O-:18])[CH3:17].[K+].[Cl-].[NH4+].C(OCC)C>C1COCC1.O>[C:16]([O:18][C:11](=[O:12])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:14])[F:13])=[CH:5][CH:6]=1)([CH3:19])([CH3:17])[CH3:15]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.9 %

Procedure:
A solution of 4-(trifluoromethoxy)phenyl isocyanate (9.75 g, 48.0 mMol) in THF (100 mL) was cooled to 0° C., and a 1.0 M THF solution of potassium tert-butoxide (53 mL, 53 mMol) was added dropwise. The mixture was allowed to warm to room temperature, and stirred for 7 hours. The solution was poured into a mixture of saturated ammonium chloride solution (200 mL), and diethyl ether (200 mL). Enough water was added to redissolve the ammonium chloride that had crashed out, the mixture was shaken in a separatory funnel, and the layers were separated. The organic phase was washed with saturated ammonium chloride (100 mL), water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 10%-20% ethyl acetate/heptane to yield 11.7 g of white solids as product. NMR (500 MHz, DMSO) δ 9.54 (s, 1H), 7.54 (d, 2H, J=7 Hz), 7.23 (d, 2H, J=8 Hz), 1.45 (s, 9H). Yield=88%.
Reaction SMILES: B(O)(O)[C@H]1N(C([C@@H](N)C(C)C)=O)CCC1.CS(O)(=O)=O.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([NH2:25])=O.C(N(CC)CC)C.[Cl:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)Cl>[Cl:36][CH2:37][C:38]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]#[N:25])=[O:39]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#C[C@@H]1CCCN1C(=O)CCl
Temperature: 45 °C
Yield: 75.1 %

Procedure:
A 1000 mL double jacketed glass reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a reflux condenser, a dropping funnel and a nitrogen inlet was charged with 50.0 g (483 mmol) of L-Prolinamide and 230 mL of methylenechloride. The suspension was stirred and treated with 51.2 g (504 mmol) of triethylamine and cooled to −40° C. to −50° C. and a solution of 58.0 g (508 mmol) of chloroacetylchloride in 50 mL of methylenechloride was added within 60 to 90 min. The dropping funnel was rinsed with 5 mL of methylenechloride. The suspension was warmed up to −5° C. to 0° C. within 1 h. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding the solution of the Vilsmeier-Reagent from the first reaction within 1 to 15 min at −5° C. to 5° C. The dropping funnel was rinsed with 5 mL of methylenechloride and the resulting mixture was stirred for about 1 h at −5° C. to 5° C. The reaction mixture was then poured onto 175 mL of water within 10 to 30 min and at a temperature of 5° C. to 20° C. The reactor was rinsed with 5 mL of methylenechloride. The mixture was stirred at RT for at least 30 min. The phases were separated and the aqueous phase was twice extracted with a total of 170 mL of methylenechloride. The organic phases were unified and washed with 88 mL of water. The resulting organic phase was concentrated under vacuum (500 mbar to 50 mbar) at 20° C. to 50° C. The resulting oil was treated within 10 to 30 min with 325 mL of isopropanol and heated to 45° C. Subsequently, the solution was again cooled to 25° C. to 30° C. within 20 min and inoculated where after the product started to precipitate. The suspension was stirred for 1 h at this temperature and then cooled down to −15° C. to −20° C. within 4 h. The crystallization was completed by the addition of 85 ml of n-heptane and the mixture was kept stirring for another 2 h. The precipitate was filtered with suction, the filter cake was washed with cold (−10° C. to 20° C.) n-heptane (140 mL) and dried to constant weight (50° C., 50 mbar, 3 h) to afford 62.6 g of (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 83%, assay: 100% (m/m) based on HPLC). The HPLC analysis was performed with an external standard of pure (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile. Conditions for HPLC: Column Atlantis™ dC18 Waters, 3.9×150 mm, 3 μm, UV detection 205 nm, solutions for gradient: water (A), acetonitrile (B), pH 4.9 buffer KH2PO4 (C); flow 1.2 mL/min, 40° C.
Reaction SMILES: [CH:1]1[C:6]([C:7]([Cl:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)(=O)=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.O>CN1C(=O)CCC1>[CH:1]1[C:6]([C:7]([Cl:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[CH:21]1[C:16]([NH2:15])=[CH:17][CH:18]=[C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[O:23])[CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Agent: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)c2ccc(N)cc2)cc1
Reaction time: 2 h

Procedure:
At room temperature, 4.211 g (20 mmol) of trimellitic acid anhydride chloride (TMA) was added to a solution of 4.966 g (20 mmol) of bis(4-aminophenyl) sulfone in 68 ml of NMP, and the resulting mixture was stirred for 2 hours. Then, 2.9 ml (21 mmol) of triethylamine was added at 5° C. and stirred at room temperature for 10 hours. By dropwise adding the reaction mixture into 1.5 liters of water, there was obtained a polyamic acid (TMA/DDSO) as a solid product in a yield of 9.06 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Yield: 78.2 %

Procedure:
4-Bromophenol (100 g, 0.587 mol) was dissolved in acetone (1,100 ml) and after adding thereto in sequence anhydrous potassium carbonate (159.53 g, 1.156 mmol) and benzyl bromide (103.78 g, 0.607 mol), the solution was refluxed under heating for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized (the recrystallization operation was performed using hexane as a solvent) to obtain the titled compound (120.76 g, 0.459 mol, 79%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][CH3:12])=[O:10])=[C:7]([F:15])[CH:6]=1.[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1.[OH-].[Na+]>CC(O)=O.CCO.O>[C:1]([C:16]1([NH:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([NH:11][CH3:12])=[O:10])=[C:7]([F:15])[CH:6]=2)[CH2:19][CH2:18][CH2:17]1)#[N:2]
Reactant: CNC(=O)c1ccc(N)cc1F
Reactant: O=C1CCC1
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Temperature: 80 °C
Yield: 88.2 %

Procedure:
Sodium cyanide (5.8 g, 119 mmol) was added to a mixture of 4-amino-2-fluoro-N-methylbenzamide (5 g, 29.8 mmol) and cyclobutanone (4.4 mL, 59.5 mmol) in AcOH (90%, 25 mL) and EtOH (25 mL) hooked up to a NaOH scrubber and the resulting mixture was heated to 80° C. overnight. The mixture was cooled to room temperature and poured in water. The yellow precipitate was filtered, washed with water, and dried to afford 6.5 g of 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.81 (t, 1H), 7.56 (t, 1H), 7.37 (s, 1H), 6.46 (dd, 1H), 6.30 (dd, 1H), 2.80-2.71 (m, 5H), 2.41-2.31 (m, 2H), 2.13-2.00 (m, 2H)
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[F:14].[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1>C(O)(=O)C>[CH3:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:16]2([C:1]#[N:2])[CH2:19][CH2:18][CH2:17]2)=[CH:9][C:8]=1[F:14]
Reactant: CNC(=O)c1ccc(N)cc1F
Reactant: O=C1CCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Sodium cyanide (1.47 g, 30 mmol) was added to a mixture of N-methyl 4-amino-2-fluorobenzamide (1.68 g, 10 mmol) and cyclobutanone (1.4 g, 20 mmol) in 90% acetic acid (20 ml). The reaction mixture was stirred at 80° C. for 24 hours. The mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to dryness under vacuum. The solid was washed with a 50:50 mixture of ethyl ether and hexane (10 ml) to remove cyclobutanone cyanohydrin to afford after filtration B2 (2.19 g, 8.87 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ 1.87-1.95 (m, 1H), 2.16-2.27 (m, 1H), 2.35-2.41 (m, 2H), 2.76-2.83 (m, 2H), 2.97 (d, J=4.4 Hz, 3H), 4.68 (bs, 1H), 6.29 (dd, J=14.3, 1.8 Hz, 1H), 6.48 (dd, J=8.3, 1.8 Hz, 1H), 6.75 (q, J=4.4 Hz, 1H), 7.90 (dd, J=8.3, 8.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 15.7, 26.7, 33.9, 49.4, 100.2 (d, J=29.5 Hz), 110.6, 111.0 (d, J=11.8 Hz), 133.1 (d, J=4.2 Hz), 148.4 (d, J=12.0 Hz), 162.0 (d, J=244.1 Hz), 164.4 (d, J=3.6 Hz).