Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:39])[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]2)[CH:13]=[CH:12][N:11]=1.[CH3:40]NC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:37]([S:34]([N:31]1[CH2:30][CH2:29][CH:28]([C:19]2[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=[C:16]([C:14]4[CH:13]=[CH:12][N:11]=[C:10]([N:9]5[CH2:39][CH2:3][O:5][CH2:40][CH2:8]5)[CH:15]=4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:33][CH2:32]1)(=[O:36])=[O:35])[CH3:38]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(N(C)C)c4)cc23)CC1
Reactant: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(N5CCOCC5)c4)cc23)CC1
Yield: 21.1 %

Procedure:
The title compound was prepared according to the general procedure of 5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (1 mL) for dimethylamine to afford 12 mg of the title compound (21.1%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:43][C:38]1[CH:37]=[C:36](/[C:34](/[CH3:35])=[CH:33]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (63 mg, 0.32 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol), L-proline (7 mg, 0.064 mmol) and potassium phosphate (136 mg, 0.64 mmol) were added and the reaction mixture was stirred for min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.38 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) followed by HPLC. Yield: 11 mg as the TFA salt. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.95 (d, 1H), 7.70 (m, 2H), 7.30 (s, 2H), 7.10 (d, 1H), 7.0 (d, 1H), 4.30 (m, 2H), 3.40 (m, 2H), 3.0 (m, 2H), 2.90 (s, 3H), 2.40 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: Ic1ccccc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Yield: 100.8 %

Procedure:
A mixture of 4-nitropyrazole (270 mg, 2.38 mmol), iodobenzene (485 mg, 2.38 mmol), 8-hydroxyquinoline (60 mg, 0.41 mmol) and K2CO3 (600 mg, 4.34 mmol) in DMSO (3 mL) was degassed with argon before being charged with CuI (45 mg, 0.23 mmol). The mixture in a sealed tube was heated at 130 C for 20 h. Water was added to induce precipitation. The precipitate was collected to give 4-nitro-1-phenyl-1H-pyrazole (454 mg).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][CH:12]([F:15])[CH2:13][OH:14]>>[F:11][CH:12]([F:15])[CH2:13][O:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: OCC(F)F
Product: O=[N+]([O-])c1cccnc1OCC(F)F

Procedure:
Prepared analogously to example XII.1 using 2-fluoro-3-nitropyridine (142 mg) and 2,2-difluoroethanol (98 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4](Br)[CH2:5][CH2:6][Br:7].[NH2:10][C:11]1[C:12]([F:19])=[CH:13][C:14]([Cl:18])=[C:15]([SH:17])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][O:2][C:3](=[O:9])[CH:4]([S:17][C:15]1[CH:16]=[C:11]([NH2:10])[C:12]([F:19])=[CH:13][C:14]=1[Cl:18])[CH2:5][CH2:6][Br:7]
Reactant: Nc1cc(S)c(Cl)cc1F
Reactant: COC(=O)C(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(CCBr)Sc1cc(N)c(F)cc1Cl

Procedure:
28.6 g of 2,4-dibromobutyric acid methyl ester are added dropwise at room temperature to a mixture of 17.8 g of 5-amino-2-chloro-4-fluoro-thiophenol and 15.2 g of potassium carbonate in 160 ml of methyl ethyl ketone (exothermic reaction). The reaction mixture is then heated under reflux for 2 hours. After cooling of the reaction mixture, the inorganic portion of the mixture is filtered off and washed with methyl ethyl ketone. Concentration of the organic solution by evaporation and chromatographic purification of the residue by means of silica gel chromatography yield 25.5 g of 2-(5-amino-2-chloro-4-fluoro-phenylthio)-4-bromobutyric acid methyl ester having a melting point of from +97° to +99° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:43])=[C:38]([CH:42]=1)[C:39](Cl)=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:43])=[C:38]([C:39]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:40])[CH:42]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1cc(OCc2ccccc2)ccc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 5-(benzyloxy)-2-chlorobenzoyl chloride (compound F3) as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([CH2:17][CH:18]=O)[C:6]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([CH3:8])[CH3:7])C.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:6]([CH:5]1[CH2:17][CH2:18][N:21]([C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)[C:4]1=[O:20])([CH3:7])[CH3:8]
Reactant: CCOC(=O)C(CC=O)C(C)(C)c1ccc(Cl)cc1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(c1ccc(Cl)cc1Cl)C1CCN([C@H]2CC[C@H](O)CC2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dissolve 3-(2,4-Dichloro-phenyl)-3-methyl-2-(2-oxo-ethyl)-butyric acid ethyl ester (Preparation 61) in THF and treat with trans-4-Amino-cyclohexan-1-ol (2.0 eq), acetic acid (6.0 eq) and NaBH(OAc)3 (4.0 eq). Allow reaction to stir at room temperature for 17 h and heat to 60° C. for six hours. Cool to room temperature, filter, dilute filtrate with EtOAc, wash with 0.1 N HCl, brine, dry over sodium sulfate and filter. Chromatography (silica, 1:1 to 3:7 hexanes/EtoAc) yields the titled compound in 53% yield: Mass spectrum (API-ES positive) m/z=372.0 (M+H).
Reaction SMILES: Cl.[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.Br[CH2:19][CH2:20][O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[I-].[K+]>[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][O:21][CH3:22])[CH2:14]2)[N:4]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCCN1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 65 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine mono hydrochloride (0.350 g, 1.09 mmol) in N,N-dimethylformamide (10 mL) was added 2-bromoethylmethyl ether (0.159 g, 0.11 mL, 1.15 mmol), potassium carbonate (0.462 g, 3.34 mmol), and potassium iodide (0.008 g, 0.05 mmol). The reaction mixture stirred at 65° C. for 18 h and then additional 2-bromoethylmethyl ether (0.066 g, 0.040 mL, 0.48 mmol), potassium carbonate (0.130 g, 0.940 mmol), and potassium iodide (0.008 g, 0.05 mmol) were added. The reaction mixture was stirred for an additional 18 h and was then concentrated. The residue was partitioned between dichloromethane (10 mL) and water (10 mL). The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-3-iodo-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid (0.313 g, 84%) which was used in subsequent reactions without further purification. RP-HPLC Rt 5.089 min, 80% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 389 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C-:11]#[N:12].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)#[N:12]
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: [C-]#N
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cnc2[nH]ccc2c1
Temperature: 125 °C

Procedure:
To a solution of 5-Bromo-7-azaindole XXX (300 mg, 1.52 mmol) in DMF (10 ml), sodium cyanide (150 mg, 3.06 mmol), cuprous iodide (45 mg, 0.24 mmol), and Tetrakis (triphenylphosphine) palladium(0) (100 mg, 0087 mmol) were added. The reaction was placed under argon heated at 125° C. for 48 hours after which the reaction was allowed to cool to ambient temperature before diluting with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×, 150 ml). The organic layers were then combined and washed with saturated bicarbonate solution (3×, 100 ml), before drying over sodium sulfate and evaporate under reduced pressure. The crude material was purified by preparative TLC, eluting with a solution of 70% hexane, 30% ethyl acetate with triethylamine as an additive to yield the titled compound as an off-white solid. (150 mg, M−1=142.0)
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].N1C=CC=CC=1.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][Si:21]([O:12][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:23])[CH3:22]
Reactant: C[Si](C)(C)Cl
Reactant: C=CCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCCCCCCCCC(=O)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 3-liter, 3-neck flask equipped with an addition funnel, mechanical stirrer and reflux condenser were added undecylenic acid (Lucidol, 480 grams, 2.6 mol), pyridine (240 grams, 3.03 mol) and toluene (900 milliliters). Trimethylsilyl chloride (326 grams, 3.0 mol) was then added slowly via the addition funnel over 2.5 hours. After stirring at 25° C. for 16 hours, the precipitate was filtered off and washed with toluene. The flitrates were combined and the toluene was removed using a rotary evaporator. The residue was distilled through a packed column under reduced pressure and four fractions were collected. A first cut was collected between 25° C. and 115° C. at 1 millimeter of mercury. A second cut was collected between 115° C. and 119° C. at 1 millimeter of mercury. The third cut, collected between 115° C. and 120° C. at 1 millimeter of mercury, was identified by infrared spectroscopy, and with 13C and 1H NMR spectrometries as the trimethylsilyl ester of undecylenic acid (320.4 grams). A fourth cut, collected between 115° C. and 121° C. at 1 millimeter of mercury, was a light-yellow oil. There was no evidence of free acid in fraction 3 using infrared spectroscopy. The carboxylic acid infrared absorption of undecylenic acid was found at 1,720 cm-1. The trimethylsilyl ester group absorbed at 1,640 cm-1.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[O:12])#[N:2].[CH3:22]I>>[CH3:22][O:12][C:11]1[N:13]=[C:1]([NH2:2])[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=2[N:10]=1
Reactant: CI
Reactant: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Product: COc1nc(N)c2c(C)c(C)sc2n1
Yield: 86 %

Procedure:
Prepared in a similar manner to Example 25 from N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide (Example 4a) and methyl iodide in 86% yield. 1H NMR (400 MHz, CDCl3) δ2.35 (s, 3H), 2.36 (s, 3H), 3.53 (s, 3H), 6.0 (bs, 2H). MS 210 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:18]=[O:19])=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:4][CH:3]=1.[O:20]1CCOCC1.[OH-].[Na+].Cl>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:18]([OH:20])=[O:19])=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: COCOCc1nc(-c2ccc(Cl)cc2)oc1C=O
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: COCOCc1nc(-c2ccc(Cl)cc2)oc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
556 mg (2.25 mmol) of the compound from Example 41A and 14.7 ml of dioxane are added to a suspension of 802 mg (4.72 mmol) of silver(I) nitrate in 2 ml of water. A solution of 193 mg (4.84 mmol) of sodium hydroxide in 7.8 ml of water is then added slowly. The mixture is stirred at RT for 3 h. The mixture is then filtered through Celite, which is washed with warm water. The filtrate obtained is acidified by addition of 1 N hydrochloric acid and extracted three times with in each case 20 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:44][CH2:45][CH2:46][N:47]1C(=O)C2=CC=CC=C2C1=O.O.NN>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:44][CH2:45][CH2:46][NH2:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: NN
Agent: O=S(=O)([O-])O
Solvent: c1ccccc1
Solvent: O
Product: NCCCOC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 10 °C

Procedure:
A mixture that consists of 42.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-galactopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of benzene is cooled to 10° C. At 10° C., 40.2 g (150 mmol) of N-(3-bromopropyl)-phthalimide, dissolved in 100 ml of benzene, is added in drops over 40 minutes while being stirred vigorously. It is stirred for three hours at 10° C. 300 ml of benzene is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The filtrate residue is dissolved in 500 ml of ethanol, 25.03 ml of hydrazine hydrate (500 mmol) is added, and it is refluxed for six hours. It is allowed to cool to 0° C., deposited precipitate is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is dissolved in 400 ml of dichloromethane, this solution is washed twice with 5% aqueous sodium hydroxide solution, then once with water (in each case 300 ml). The organic phase is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethanol/triethylamine=20:2:0.1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:11](=[N:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C#N)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)ccc1N=C(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 90.3 %

Procedure:
To a solution of 4-amino-3-methyl benzonitrile (1.20 g, 9.08 mmol) in 75 mL of toluene is added benzophenone (1.74 g, 9.53 mmol) and p-toluenesulfonic acid (0.43 g, 2.1 mmol). The reaction vessel is fitted with a Dean-Stark trap and the solution is heated at reflux. After 24 h, the solution is cooled to ambient temperatures. The solution is concentrated. The crude material is purified by column chromatography eluting with a gradient of 3% EtOAc/hexanes to 10% EtOAc/hexanes. The title compound (2.43 g, 8.2 mmol) is obtained as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH2:4][NH:3]1.C1COCC1.O.[OH-].[Li+].Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: COC(=O)c1ccc2c(c1)CNC2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CNC2=O
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 100 mL round bottom flask containing methyl 1-oxoisoindoline-5-carboxylate (200 mg, 1.046 mmol) was added THF (6 mL) and H2O (2 mL) the mixture was stirred at 23° C. for 2 min. At this time, lithium hydroxide monohydrate (87 μL, 3.14 mmol) was added and the flask was gently heated on aluminum block for 5 min. The solid went into solution and LC/MS showed product formation. The contents of the reaction were poured into HCl (1 M, 15 mL) and extracted with DCM (15 mL). An emulsion formed, the layers separated, and a white solid formed at the boundary of the layers and stuck to the separatory funnel. This material was collected, dissolved in MeOH, and concentrated. After drying under high vacuum for 2 h, the 1-oxoisoindoline-5-carboxylic acid thus obtained was taken on directly to the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6](C(F)(F)F)[CH:5]=1.[CH3:31][S:32](C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=[O:34])=[O:33]>>[CH3:31][S:32]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1)[C:3]([N:2]([CH3:1])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:18])(=[O:34])=[O:33]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 284, from methyl-(4-phenyl-pyridin-3-yl)-amine (example 322, intermediate) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a). Off-white solid (34%). MS (ESI): m/z=435.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:27][CH:28]=1
Reactant: COc1cccc(C(=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)S(C)(=O)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(O)c1
Yield: 2.1 %

Procedure:
On carrying out the operation according to the procedure of Example 32 starting with 4.8 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine, 32 cm3 of a 1 M solution of boron tribromide in dichloromethane, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol (98/2 by volume) as eluent and collecting 20 cm3 fractions. Fractions 16 to 17 are concentrated to dryness under reduced pressure (2.7 kPa). 0.1 g 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine is obtained, after recrystallization from 5 cm3 of diethyl ether, in the form of a solid melting at 114° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 2.92 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 6.80 (3H, m, 3CH arom.), 7.20 (1H, t, J=7 Hz, CH arom.), 7.37 (4H, t, J=7 Hz, 4CH arom.), 7.47 (4H, d, J=7 Hz, 4 CH arom.)].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.O1CCCC1.B.O.Cl>O1CCCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCC(=O)O)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(CCCO)cc1
Reaction time: 1 h
Yield: 101.2 %

Procedure:
3-(4-Methylsulfanylphenyl)propionic acid (1.00 g) was dissolved in tetrahydrofuran (20 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 6.42 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and further at room temperature for 1 hr. Water was added to the reaction mixture, and 1 mol/l aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the object product (940 mg) as a colorless oil.