Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:8][CH2:7][O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:9]([Mg]Cl)[CH2:10][CH3:11].[Cl-].[NH4+].Cl.O1C[CH2:20][CH2:19][CH2:18]1>>[CH2:9]([C:4]([OH:5])([CH2:18][CH2:19][CH3:20])[CH2:3][CH2:2][CH2:1][CH2:8][CH2:7][OH:6])[CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: O=C1CCCCCO1
Reactant: CCC[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCCC(O)(CCC)CCCCCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a 250 mL two necked flask equipped with a condenser containing e-caprolactone (3.3 mL, 30 mmol) and anhydrous tetrahydrofuran (60 mL) under nitrogen atmosphere, was added at 0° C. dropwise propylmagnesium chloride (33 mL, 66 mmol, 2.2 eq., 2.0 M solution in diethyl ether). After addition, the reaction was stirred for 10 minutes at room temperature before heating to reflux for 2 hours. The reaction was monitored by thin layer chromatography. The reaction was cooled to 0° C. and saturated aqueous ammonium chloride (18 mL) was added followed, at room temperature, by hydrochloric acid (18 mL, 1M aqueous). The organic phase was decanted and the aqueous phase extracted with dichloromethane (3×140 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (100 mL) before drying over magnesium sulfate. Evaporation of the solvent gave the title compound (6,543 g, 96%) as a viscous yellow oil. 1H NMR (CDCl3, 400 MHz) d?(ppm): 3.64 (t, J=6.7 Hz, 2H); 1.59 (tt, J=6.7 Hz, J=6.7 Hz, 2H); 1.46-1.24 (m, 15H); 0.88 (t, J=7.2 Hz, 6Hd). 13C NMR (CDCl3, 129.9 MHz) d?(ppm): 68.5; 64.2; 42.0 (2C′); 39.8; 33.1; 26.8; 23.7; 17.1 (2C′); 14.5 (2C′). MS (IC+) m/z (%): 220.2 [M+18] (99); 202.2 (75); 203.3 [M+1] (30); 185.2 (100); 176.2 (60); 141.2 (25).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH:19]([CH2:36]C([O-])=O)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1>CS(C)=O.[Na+].[Cl-]>[C:1]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:36][CH:19]([O:7][C:6](=[O:5])[CH3:8])[CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c[nH]c2ccccc12
Reactant: CCCCCCCCc1ccc(OCC(CBr)CC(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
0.50 g (2.30 mmol) tert-butylindole-3-carboxylate is dissolved in 15 ml absolute DMSO, mixed with 0.28 g (2.50 mmol) potassium-tert-butylate and stirred at 110° C. for 15 min. A solution of 0.89 g (2.31 mmol) [1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 15 ml absolute DMSO is added drop-wise. Following heating at 110° C. for 30 minutes and subsequent cooling, hydrolysis is carried out in saturated NaCl solution. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O1CCCC1>[CH2:23]([NH:31][C:6]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=1)=[O:8])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
A solution of 10 g of 6-chloro-nicotinic acid in 80 ml of N,N-dimethylformamide and 160 ml of tetrahydrofuran was treated with 10.75 g of 1,1'-carbonyldiimidazole and stirred at room temperature for 4 h. Thereafter, the reaction mixture was treated with 8.76 g of phenethylamine and stirred at 70° C. for a further 2 h. The mixture was cooled to room temperature, evaporated to dryness and the residue was taken up in 200 ml of dichloromethane. The organic phase was washed three times with 50 ml of water each time, dried over sodium sulfate and evaporated to dryness. Recrystallization of the residue from isopropanol yielded 11.9 g of 6-chloro-pyridine-3-carboxylic acid phenethyl-amide as a colorless product, m.p. 115° C.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[O:11]1[C:15]2[CH:16]=[CH:17]C=CC=2N=C1>>[O:11]1[CH2:15][CH:16]1[CH2:17][O:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc2ocnc2c1
Reactant: Oc1nc2ccccc2s1
Product: c1ccc2sc(OCC3CO3)nc2c1

Procedure:
Compound 44 was prepared in the manner of compound 6 substituting 2-hydroxybenzothiazole for compound 8 in partC-5 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[NH2:18])=[CH:5][CH:4]=1.[N:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:34][CH2:33][CH:29]([C:30]([Cl:32])=[O:31])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[ClH:32].[F:17][C:15]1[CH:14]=[CH:13][C:12]([NH:18][C:30]([CH:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)[CH2:34][CH2:33]2)=[O:31])=[C:11]([CH:16]=1)[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:19]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: COc1ccc(NC(=O)c2cc(F)ccc2N)cc1
Product: COc1ccc(NC(=O)c2cc(F)ccc2NC(=O)C2CCN(c3ccncc3)CC2)cc1
Product: Cl
Yield: 57.3 %

Procedure:
Using the procedure described in Example 138, N-(4-methoxyphenyl)-2-amino-5-fluorobenzamide (1.8 mmol) and N-(4-pyridyl)isonipecotoyl chloride (3.6 mmol), purifying with RPHPLC Method A, yielded 500 mg (58%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][C:10]([C:12]2[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=2)[C:15]([N:17]2[C:22](=[O:23])[C:21]([F:24])=[CH:20][N:19]([CH2:25][O:26][CH2:27][CH3:28])[C:18]2=[O:29])=[O:16])=[O:11])[CH:3]=1.C([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])C.[O:40]1[CH2:45][CH2:44]OCC1>>[CH2:10]([O:9][C:38]1[CH:39]=[C:21]([CH:37]=[C:36]([O:40][CH2:45][C:44]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[N:35]=1)[C:22]([O:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][C:10]([C:12]2[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=2)[C:15]([N:17]2[C:22](=[O:23])[C:21]([F:24])=[CH:20][N:19]([CH2:25][O:26][CH2:27][CH3:28])[C:18]2=[O:29])=[O:16])=[O:11])[CH:3]=1)=[O:23])[C:12]1[CH:13]=[CH:14][CH:30]=[CH:31][CH:32]=1
Reactant: CCOCn1cc(F)c(=O)n(C(=O)c2cccc(C(=O)Oc3cc(O)c(Cl)cn3)c2)c1=O
Reactant: C1COCCO1
Reactant: CCN(CC)CC
Product: CCOCn1cc(F)c(=O)n(C(=O)c2cccc(C(=O)Oc3cc(OC(=O)c4cc(OCc5ccccc5)nc(OCc5ccccc5)c4)c(Cl)cn3)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (0.23 mL) and dimethylformamide (0.01 mL) were added dropwise to a solution of Compound 2a (217 mg) obtained in Reference Example 1 and toluene (4 mL), and the mixture was stirred at 80° C. for 4.5 hours. After the resulting mixture was cooled, the solvents were evaporated. Without purification, the residual acid chloride was dissolved in dioxane (2 mL) to obtain a dioxane solution of acid chloride to be used in the following reaction. The dioxane solution of acid chloride was added dropwise under ice cooling to a solution of Compound 8a (100 mg) obtained in Reference Example 7 or Reference Example 8, triethylamine (0.01 mL) and dioxane (10 mL). The resulting mixture was stirred at room temperature for 8 hours, and the solvents were then evaporated. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane (1:1)) to obtain Compound I-1 (119 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:9]=[C:10]([Sn](C)(C)C)[C:3]=12.[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:9]=[C:10]([F:26])[C:3]=12
Reactant: F[B-](F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc([Sn](C)(C)C)c3c(Cl)ccnc32)cc1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
488 mg (1.03 mmol) of 4-chloro-1-[(4-methylphenyl)sulfonyl]-3-(trimethylstannyl)-1H-pyrrolo[2,3-b]pyridine are initially charged in 20 ml of anhydrous acetonitrile. 368 mg (1.03 mmol) of Selectfluor® are then added in one portion, and the mixture is allowed to stir at RT overnight. For work-up, the precipitate formed is filtered off with suction and the filtrate is concentrated. The residue is purified by preparative HPLC. The product is a solid.
Reaction SMILES: Cl[C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[NH:9][C:10]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:11]([CH3:13])[N:12]=2)[CH:7]=1.[H][H]>[Pd].C(N(CC)CC)C.CO>[CH3:13][C:11]1[N:12]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([NH:22][CH3:23])=[CH:4][C:5]=2[O:20][CH3:21])[NH:9][C:10]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: CNc1cc(OC)c(-c2nc(C)c(-c3cccnc3)[nH]2)cc1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1ccc(-c2nc(C)c(-c3cccnc3)[nH]2)c(OC)c1
Yield: 22.3 %

Procedure:
A mixture of 2-(5-Chloro-4-methylamino-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.50 g) and 10% palladium on carbon (7.5 g) in a mixture of triethylamine (0.64 ml) and methanol (20 ml) was hydrogenated at ambient temperature under atmospheric pressure of hydrogen gas. After removal of the insoluble substance by filtration, the filtrate was evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give 4-methyl-2-(4-methylamino-2-methoxyphenyl)-5-(3-pyridyl)imidazole (0.10 g).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:40])[C:14]([N:16]([C:18]2[C:19]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH3:39])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46].C(N(CC)CC)C>ClCCl.O>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:41])[C:14]([N:16]([CH3:17])[C:18]2[C:19]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH3:39])=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:30][O:31][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:28][CH2:29]3)=[N:22][CH:23]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(CO)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCC(COS(C)(=O)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 60.9 %

Procedure:
To a solution of 0.42 g (0.69 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 7 ml dichloromethane were added 83 mg (0.72 mmol) methanesulfonyl chloride and 73 mg (0.72 mmol) triethylamine at 0° C. After 30 min the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.29 g (63%) of the title compound as a white solid.
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)([O:3]C)=O.N(C[C@@H]1CCCN1)[C:20]1C=CC=C[CH:21]=1.[Cl-].[Mg+2].[Cl-].C([Mg]Br)C>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH2:20][CH3:21]
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Yield: 28 %

Procedure:
2-Carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane prepared from 1.76 g of (S)-2-(anilinomethyl)pyrrolidine, as described in Example 8, was dissolved in 50 ml of THF, then admixed with 1.05 g of anhydrous magnesium chloride and refluxed by heating for 10 minutes. To the mixture cooled to -70° C., was added dropwise an ether solution containing 1.46 equivalents of ethylmagnesium bromide. The resulting mixture was treated as described in Example 12 to obtain 694 mg (28%) of 2-propionyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ(ppm)=1.0 (3H, triplet), 1.4-2.1 (4H, multiplet), 2.1-2.6 (2H, multiplet), 2.6-3.3 (3H, multiplet), 3.5-3.9 (2H, multiplet), 4.2 (1H, singlet), 6.1-7.1 (5H, multiplet).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]1([C:12]([CH3:14])=[CH2:13])[CH2:9][CH:8](CO)[O:7][C:5]1=[O:6].[OH-].[Na+].C1C[O:21]CC1.I([O-])(=O)(=O)=O.[Na+]>O>[CH3:1][CH:2]([CH3:15])[CH2:3][C@:4]1([C:12]([CH3:14])=[CH2:13])[CH2:9][C@H:8]([OH:21])[O:7][C:5]1=[O:6]
Reactant: C1CCOC1
Reactant: C=C(C)C1(CC(C)C)CC(CO)OC1=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Product: C=C(C)[C@@]1(CC(C)C)C[C@H](O)OC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
A mixture of [S-(R*,R*)]-α-(2-methylpropyl)-α-(propen-2-yl)-γ-hydroxymethyl-γ-butyrolactone (682 mg, 3.21 mmol), NaOH (350 mg, 8.75 mmol), THF (40 mL), and H2O (10 mL) is stirred for 19 hours at room temperature. Additional NaOH (114 mg, 2.85 mmol) is added after 16 hours. The mixture is concentrated and the residue taken up into MeOH (43 mL). A solution of sodium periodate (862 mg, 4.03 mmol) and H2O (4.3 mL) is added and the mixture stirred at room temperature for 3 hours. After concentration, the aqueous residue is acidified (HCl) and extracted with CH2Cl2 (3×40 mL). The organic layers are dried (MgSO4), filtered, and concentrated to provide 625 mg (98%) of the title compound as a semi-solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:31]([C:26]1[NH:27][C:28]2[C:24]([CH:25]=1)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=2)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 12 h
Yield: 70.8 %

Procedure:
(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine (4.62 g) was dissolved in dichloromethane (50 ml), 5-chloroindole-2-carboxylic acid (3.63 g), 1-hydroxybenzotriazole monohydrate (2.43 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.45 g) were added at room temperature, and the mixture was stirred for 12 hours. After 0.1N hydrochloric acid was added, and the mixture was extracted with dichloromethane, the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:3) to obtain the title compound (5.3 g) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[CH3:48][S:49]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(OS(C)(=O)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reaction time: 2.5 h
Yield: 26.3 %

Procedure:
4-(4-Hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (178 mg, 0.330 mmol) was suspended in dichloromethane (14 mL), and the suspension was added with triethylamine (0.092 mL, 0.66 mmol) and methanesulfonyl chloride (0.031 mL, 0.40 mmol) under ice-cooling, followed by stirring for 2.5 hours. The reaction mixture was filtered, and the filtrate was added with water and extracted with ethyl acetate and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=10/0.5/0.5) to obtain 4-(4-methanesulfonyloxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (53.4 mg, yield 26%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][CH3:12])[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[NH:18]C(=O)C.O.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1>C(O)CC.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([O:13][CH2:25][CH2:24][CH3:29])[CH2:11][CH3:12])[C:7]([C:14]([F:15])([F:16])[F:17])=[CH:6][C:5]=1[NH2:18]
Reactant: CCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: O
Product: CCCOC(CC)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 240 h
Yield: 139.2 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-propyl)-4-trifluoromethyl-benzoic acid methyl ester (200 mg, 0.626 mmol) in 1-propanol (2 mL) at r.t. was treated with p-toluenesulfonic acid monohydrate (38 mg, 0.198 mmol) and the reaction was stirred for 10 d at r.t. The reaction mixture was diluted with water and EtOAc and basified to pH 8 with sat. aq KHCO3. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, EtOAc/hexanes (0:1→3:7)) to give the title product (88 mg, 44% yield) as light yellow oil. ESI-MS: m/z 320 [M+H]+, m/z 318 [M−H]−.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[CH2:3]1.C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:21])=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[CH2:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CSc1ncc(C(=O)O)c(N[C@@H]2CCC[C@H](O)C2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (4.5 g, 15.88 mmol) and HATU (9.06 g, 23.82 mmol) were dissolved in DMF (75 ml) and allowed to stir for 5 min at room temperature before adding ammonium chloride (4.25 g, 79 mmol) and DIEA (13.87 ml, 79 mmol). The reaction turned yellow upon addition of the base. The reaction was allowed to stir at room temperature for 1 h then partitioned between water and ethyl acetate. The organic layer was washed once with brine before drying over sodium sulfate, filtering, and concentrating to afford 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxamide (4.19 g, 14.84 mmol, 93% yield) as an off-white solid. MS (ESI) m/z 283.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][CH:20]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([NH:18][C:19]2[NH:23][N:22]=[CH:21][CH:20]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccn[nH]1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccn[nH]1)c1cccnc1Cl

Procedure:
175 g. of 2-chloro-3-pyridinecarboxylic acid chloride are dissolved in 750 ml. of anhydrous dioxane containing 110 g. of triethylamine. At 10°, 83 g. of 5-aminopyrazole dissolved in 100 ml. of dioxane are added dropwise with stirring. After the addition is completed, the mixture is stirred overnight at room temperature, filtered and the precipitate washed with dioxane. The solvent is removed in vacuo and the oily residue crystallized with ethyl acetate. The product, 2-chloro-N-(1H-pyrazol-5-yl)-3-pyridinecarboxamide, is recrystallized from ethyl acetate, yield: 103 g. (46%); m.p. 162.8°.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].Cl[CH2:7][C:8](Cl)=[O:9].[CH2:11]([NH2:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N)(C)C>CN(C=O)C.C(N(CC)CC)C>[NH2:4][C:3]1[N:24]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][C:8](=[O:9])[C:2]=1[C:1]#[N:5]
Reactant: CCCCCCCCCCCCCN
Reactant: O=C(Cl)CCl
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CCCCCCCCCCCCCN1CC(=O)C(C#N)=C1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
19.8 g of malononitrile were dissolved in 30 ml of DMF and cooled to 0° C. While cooling, 61 g of triethylamine and 27 g of chloroacetyl chloride were simultaneously added dropwise to this, and the mixture was stirred at 10° C. for 10 minutes. 65.7 g of tridecylamine were then added dropwise, and the reaction mixture was stirred at room temperature for 48 hours. 300 ml of isopropylamine were then added to the mixture, which was refluxed for 2 hours, 10 g of active carbon were added, and the mixture was filtered hot. After cooling, the precipitate was filtered off with suction, washed and dried at 50° C. 40 g (44% of theory) of the compound of the formula ##STR25## of melting point 214° to 215° C. were obtained. The IR, NMR, UV and mass spectra and the elemental analysis are consistent with the structural formula.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#N)=[CH:5][CH:4]=1.O.CC(O)=[O:16]>[Ni].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:16])=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(C=CC#N)cc1
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C=CC=O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To 2 g (12.6 mmol) 4-methoxycinnamonitrile in 10:10:20 ml H2O:HOAc:pyridine was added 5 g (47 mmol) NaH2PO2 (hypophosphite) followed by 2 g RaNi. After stirring 3 hours at 50° C., the reaction mixture was filtered, extracted with CH2Cl2, washed with dilute HCl, washed with H2O and evaporated to give 0.7 g (35% yield) 4-methoxycinnamaldehyde, a yellow solid, m.p. 47° C.