Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])[CH3:3].[ClH:24].[O:25]([NH2:27])[CH3:26].N1C(C)=CC=CC=1C>C1COCC1>[ClH:24].[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]([NH:27][O:25][CH3:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:4])[CH3:3]
Reactant: CON
Reactant: CC(C)(C)c1cc(C(Br)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CONC(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 24 h

Procedure:
Over a 20 minute period a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-α-phenylbenzyl bromide, Example 17, (6.23 g, 0.0166 mole) in 100 mL THF is added to a mixture of methoxylamine hydrochloride (4.18 g, 0.05 mole) and 5.62 g (0.0524 mole) of 2,6 lutidine in 175 mL THF. The reaction mixture is heated under reflux for 16 hours. An additional 5.62 g (0.0524 mole) of 2,6 lutidine and 2.0 g (0.0239 mole) of methoxylamine hydrochloride is added and reflux is continued for 24 hours. The mixture is evaporated to dryness and the residue is taken up in Et2O, washed with H2O, 1N HCl, saturated NaHCO3 and brine. After evaporation to dryness the residue is treated with 5 mL of 20% ethereal HCl (w/v). Creamy white crystals form and are filtered off and recrystallized from EtOAc-Et2O to give an off-white solid, 3.6 g (57 %), m.p. 183°-185° C.
Reaction SMILES: [ClH:1].N[N:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[ClH:1].[CH3:13][N:14]1[CH2:19][CH2:18][C:17]2[N:3]3[C:8]4[C:9](=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH2:4]3)[C:16]=2[CH2:15]1
Reactant: NN1CCOc2ccccc21
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: CN1CCc2c(c3cccc4c3n2CCO4)C1

Procedure:
By a procedure similar to Example 110, 4-amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride is reacted with 1-methyl-4-piperidone to yield the title compound, m.p. 245°-246°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].CO[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCCCCC>[CH2:25]([O:24][C:22]([C:21]1[O:8][C:7]2[C:6]([F:9])=[C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]([CH3:16])=[C:3]([C:17]#[N:18])[C:2]=2[N:1]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)COC
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
4-Amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (5.0 g, 20.64 mmol) and ethyl methoxyacetate (18.18 g, 82.56 mmol) were stirred at 100° C. for 23 hours under nitrogen atmosphere. The reaction liquid was cooled to room temperature, and left at the same temperature for 17 hours. At 0° C., hexane was added to the suspension, and left at the same temperature for 1 hour. With washing with hexane, the precipitated crystal was collected by filtration. The crystal was collected, dried at 50° C. under reduced pressure for 4 hours, and then at room temperature for 12 hours to obtain the entitled compound (6.39 g, 96%) as a pale brown powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]([NH2:26])([CH3:25])[CH3:24]>CN1C(=O)CCC1.C(Cl)Cl>[C:23]([NH:26][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:25])([CH3:24])[CH3:22]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Yield: 21.4 %

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (1) (125 mg, 0.42 mmol) and 2-methylpropan-2-amine (154 mg, 2.10 mmol) (Sigma-Aldrich) in NMP (0.84 mL) was heated in a sealed tube at 165° C. for 2.5 d. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. brine (4×100 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give 2-(2-(tert-butylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30 mg) (0.09 mmol, 21% yield) as a yellow oil which was slightly impure. This material was dissolved in MeOH (˜20 mg/mL) and injected (2×1.0 mL) onto the Shimadzu preparatory LC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% MeCN/water with 0.1% TFA); the pure fractions were combined, basicified with NaHCO3 (saturated, aq.), extracted with CHCl3/IPA(3:2), separated, dried over Na2SO4, and concentrated via rotary evaporation to give 2-(2-(tert-butylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (340) (19 mg, 0.08 mmol, 14% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.62 (s, 9H) 2.99 (t, J=6.94 Hz, 2H) 3.65 (td, J=6.85, 2.35 Hz, 2H) 4.84 (s, 1H) 5.71 (br. s., 1H) 6.56 (d, J=9.00 Hz, 1H) 7.10 (d, J=1.76 Hz, 1H) 7.21 (t, J=7.73 Hz, 1H) 7.38 (d, J=7.63 Hz, 1H) 7.75 (d, J=9.00 Hz, 1H) 7.96 (d, J=7.63 Hz, 1H) 13.24 (br. s., 1H). MS (ESI, pos. ion) m/z: 353.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])=[O:12].[CH2:21]=[C:22]([CH2:25]O)[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:21]=[C:22]1[CH2:25][N:10]([C:3]2[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[S:11](=[O:13])(=[O:12])[N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:23]1
Reactant: C=C(CO)CO
Reactant: CCOC(=O)CNS(=O)(=O)Nc1c(Cl)cc(Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1CN(CC(=O)OCC)S(=O)(=O)N(c2c(Cl)cc(Cl)cc2Cl)C1
Temperature: -20 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
Ethyl 2-((N-(2,4,6-trichlorophenyl)sulfamoyl)amino)acetate (300 mg, 0.83 mmol), 2-methylenepropane-1,3-diol (73 mg, 0.83 mmol) and triphenylphosphine (544 mg, 2.08 mmol) were dissolved in anhydrous THF (30 mL) in a reactor, and then cooled down −20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (420 mg, 2.08 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (305 mg, 89%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 2H), 5.25 (s, 1H), 5.16 (s, 1H), 4.36 (s, 2H), 4.27-4.20 (m, 4H), 4.08 (s, 2H), 1.33-1.28 (t, 3H, J=7.1, 7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C@H:9]3[CH2:13][NH:12][C:11](=O)[C@@H:10]3[C:4]=2[CH:3]=1.Cl.C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C@H:9]3[CH2:13][NH:12][CH2:11][C@@H:10]3[C:4]=2[CH:3]=1
Reactant: O=C1NC[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1ccc2c(c1)[C@H]1CNC[C@@H]1c1ccccc1O2
Temperature: -2 °C
Reaction time: 20.5 h

Procedure:
0.53 g (1.9 mmol) of trans-11-chloro-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (compound trans-XVIIa) was suspended in 5 mL of anhydrous tetrahydrofuran and cooled to −2° C. 8.8 mL of borane-tetrahydrofuran complex (8.7 mmol) were added dropwise and the obtained solution was allowed to warm up to room temperature. The reaction mixture was stirred for 20.5 h and 5 mL of anhydrous tetrahydrofuran were added. After further 25 h at room temperature, 8.8 mL of borane-tetrahydrofuran complex (8.7 mmol) were added and the mixture stirred for 4 h before adding 1.25 M hydrogen chloride in ethanol (25.2 mL, 31.5 mmol). After 3 days the reaction mixture was rotary evaporated and toluene (25 mL) and 1 M sodium hydroxide (10.5 mL) were added to the residue. More toluene (25 mL) and water (10 mL) were added and the mixture vigorously stirred for about 2.5 h. Then the layers were separated and the aqueous layer was extracted with toluene (25 mL), twice. The organic layers were combined and washed with 0.1 M sodium hydroxide (4 mL), dried with anhydrous sodium sulfate, filtered and rotary evaporated.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8]N)[CH:3]=1.[C:11]([OH:18])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.S(=O)(=O)(O)O>O>[CH3:16][C:14]1[NH:8][C:4]2[C:5]([C:13]=1[CH2:12][C:11]([OH:18])=[O:17])=[CH:6][CH:7]=[C:2]([CH3:10])[CH:3]=2
Reactant: Cc1cccc(NN)c1
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2c(CC(=O)O)c(C)[nH]c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.1 %

Procedure:
A mixture of 3-tolylhydrazine hydrochloride (1 g), levulinic acid (1.3 g) and 10% aqueous sulfuric acid (20 ml) was stirred for 6 hours under a nitrogen atmosphere at 80° C. The reaction mixture was allowed to cool, water was added, and then extraction was performed with ethyl acetate and the organic layer was concentrated under reduced pressure. Saturated sodium bicarbonate was added to the obtained residue and vigorously stirred therewith, and then dichloromethane was added and the mixture was again vigorously stirred. The aqueous layer was collected, rendered acidic with concentrated aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Methanol (20 ml) and concentrated sulfuric acid (1 ml) were added to the obtained residue, and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool, water was added, and then extraction was performed with dichloromethane. The organic layer was collected and dried over sodium sulfate, and then concentrated under reduced pressure. A 2-(2,6-dimethyl-1H-indol-3-yl)acetic acid methyl ester component was purified from the obtained residue by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate. A 2 N sodium hydroxide aqueous solution (10 ml) and methanol (10 ml) were added to the obtained 2-(2,6-dimethyl-1H-indol-3-yl)acetic acid methyl ester, and the mixture was heated to reflux for one hour. The reaction mixture was allowed to cool, water was added, and then the mixture was rendered acidic with concentrated aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was collected and dried over sodium sulfate, and then concentrated under reduced pressure to obtain 0.13 g of the title compound as a colorless powder (13% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cncc(Br)c1
Product: CCOC(=O)c1cncc(-c2ccc(CC)cc2)c1

Procedure:
29 g (126 mmol) of ethyl 5-bromonicotinate and 23 g (152 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to General Method 1A. Yield: 32 g (82% of theory)
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[CH:31][C:24]=12>C1COCC1.C(OCC)(=O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:25]2=[N:26][CH:27]=[N:28][C:23]([O:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:24]2[CH:31]=[N:30]1
Reactant: COC[C@H](C)OC[C@H](O)C(=O)Nc1ccc(C)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Sodium hydride (21.24 mg, 0.53 mmol) was added to (S)-2-hydroxy-3-((S)-1-methoxypropan-2-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate Y5) (95 mg, 0.35 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (122 mg, 0.46 mmol) in dry THF (2 mL) was added. The reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (160 mg, 91%). 1H NMR (400 MHz, DMSO) δ 1.09 (d, 3H), 2.24 (s, 3H), 3.23 (s, 3H), 3.26-3.38 (m, 2H), 3.77-3.86 (m, 1H), 4.00-4.16 (m, 2H), 5.85-5.91 (m, 1H), 7.55-7.70 (m, 4H), 7.73-7.78 (m, 1H), 7.88 (d, 1H), 8.16-8.19 (m, 1H), 8.54 (s, 1H), 8.59 (s, 1H), 10.79 (s, 1H). m/z (ESI+) (M+H)+=497.20; HPLC tR=2.36 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:27]=[CH:26][C:16]([CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)[S:11][CH:12]=1)=[O:7].[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[NH2:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[S:11][CH:12]=[C:8]([C:6]([C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[N:9]=2)=[CH:27][CH:26]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2csc(-c3ccc(CN)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
At 0° C., to a solution of 68a (200 mg) in 10 mL CH2Cl2 was added a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT for 4 h. The precipitate (2r) was filtered and washed with diethyl ether. Yield: 81.3%. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.38 (br, 3H), 8.10 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.62 (s, 2H), 4.11 (s, 2H), 3.87 (s, 6H), 3.80 (s, 3H). MS (ESI) m/z 385.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:11][C:10](=[O:12])[NH:9][CH2:8]1)[CH2:6][C:5]2=[O:16].[BH4-].[Na+]>CO.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:11][C:10](=[O:12])[NH:9][CH2:8]1)[CH2:6][CH:5]2[OH:16]
Reactant: O=C1CC2(CN1)CC(=O)c1cc(Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CC2(CN1)CC(O)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
210 g of 5-chlorospiro[indane-1,3'-pyrrolidine]-3,5'-dione are dissolved in 2,5 liters of methanol, and a solution of 20 g of sodium borohydride in 250 cc of water and 5 cc of caustic soda solution is added at room temperature at such a rate that the temperature in the reaction vessel does not exceed 25°. The solution is stirred at room temperature for 2 hours, is then poured on ice and extracted several times with chloroform. The 5-chloro-3 -hydroxyspiro[indane-1,3'-pyrrolidin]-5'-one, obtained after concentrating the chloroform solution by evaporation, is a mixture of diastereoisomers, having a M.P. of 155°-180°, and containing approximately equal parts of the 1RS,3SR and the 1RS,3RS isomer. Pure (1RS,3SR)-5-chloro-3-hydroxyspiro[indane-1,3'-pyrrolidin]-5'-one, having a M.P. of 213°-216°, may be obtained by extracting repeatedly with chloroform and subsequently recrytallizing twice from methanol.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3]Cl.[Br-].[C:7]1([N:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[NH:17][C:16](=[O:25])[CH2:15][C:14]2=[O:26])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([CH2:3][C:2]([CH3:5])=[CH2:1])[C:16](=[O:25])[CH2:15][C:14]2=[O:26])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: C=C(C)CCl
Agent: [Br-]
Product: C=C(C)CN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
In the same manner, by acting (2'-methylallyl) chloride or bromide in the presence of a metallation agent, starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, there is obtained 1-phenyl 5-(2'-methylallyl) 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine (R1 = H, R2 = Cl, R3 = ##STR20## R4 = C6H5) melting at 149°-151° C. upon recrystallisation in 50% ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([O:20][C:21](=[O:66])[CH2:22][C:23]1([CH2:55][C:56](=[O:65])[O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[O:27][N:26]=[C:25]([C:28]2[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:29]=2[CH2:35][CH2:36][C:37]([N:39]2[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[CH2:41][CH2:40]2)=[O:38])[CH2:24]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[CH2:58]([O:57][C:56](=[O:65])[CH2:55][C:23]1([CH2:22][C:21](=[O:66])[O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:27][N:26]=[C:25]([C:28]2[CH:33]=[C:32]([O:34][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:31]=[CH:30][C:29]=2[CH2:35][CH2:36][C:37]([N:39]2[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:46])[CH2:41][CH2:40]2)=[O:38])[CH2:24]1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(CC1(CC(=O)OCc2ccccc2)CC(c2cc(O)ccc2CCC(=O)N2CCC(C(=O)OCc3ccccc3)CC2)=NO1)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(CC1(CC(=O)OCc2ccccc2)CC(c2cc(OC(=O)c3ccc([N+](=O)[O-])cc3)ccc2CCC(=O)N2CCC(C(=O)OCc3ccccc3)CC2)=NO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.5 %

Procedure:
4-Nitrobenzoyl chloride (405 mg) was added in small portions to a solution of benzyl 1-(3-(2-(5,5-bis(2-(benzyloxy)-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoyl)piperidine-4-carboxylate (800 mg) in pyridine (4 mL) at 0 C. The obtained mixture was stirred at room temperature for 45 minutes. To the reaction mixture, ethyl acetate and 1 M hydrochloric acid were added 0 C, followed by extraction with ethyl acetate. Combined organic layers were washed with diluted aqueous ammonia ((28% aqueous ammonia (0.5 mL)/water (25 mL))×2), 1 M hydrochloric acid, and brine and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (939 mg).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)[CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.[CH2:54](O)[CH2:55][CH2:56][OH:57]>CCOC(C)=O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([C:18]3[CH:19]=[C:20]([NH:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([CH3:35])[CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[O:57][CH2:56][CH2:55][CH2:54][O:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Nc2cccc(C(=O)CCN3CCC(Cc4ccccc4)CC3)c2)c2ccccc2n1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cccc(C3(CCN4CCC(Cc5ccccc5)CC4)OCCCO3)c2)c2ccccc2n1

Procedure:
To the mixture of the compound of Example 209 (0.31 g, 0.67 mmol) in toluene/propane-1,3-diol (7 ml/7 ml) was added p-TsOH (0.32 g, 1.68 mmol) at room temperature. The resulting mixture was heated under reflux in a Dean-Stark setup overnight before the reaction was diluted with EtOAc (80 ml). The mixture was washed with 1 N NaOH (2×50 ml) and brine (50 ml). The organic layer was dried over Na2SO4 and concentrated on a rotavap to dryness. The residue was purified by reverse phase HPLC to afford the desired product as an off-white solid (74 mg, 42% with 50% starting material recovered). The compound of Example 348 was synthesized in the same manner as for Example 191 using 1-benzylpiperazine instead of compound 36.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[CH3:20]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[O:13][CH2:12][CH2:11][N:7]([CH2:8][CH2:9][OH:10])[C:6]([NH:5][CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])=[O:14])=[CH:23][CH:22]=1)[CH3:20]
Reactant: O=C(NCc1ccccc1Cl)N(CCO)CCO
Reactant: CCc1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OCCN(CCO)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 3-(2-chlorobenzyl)-1,1-bis(2-hydroxyethyl)urea (2.3 g, 8.46 mmol), in THF were added DMAP and 4-ethylphenylisocyanate (1.24 g, 8.46 mmol). The reaction mixture was stirred for 1 h and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-(2-chlorobenzyl)-1-(2-hydroxyethyl)ureido)ethyl 4-ethylphenylcarbamate (1.7 g, 48%). LRMS (M+H+) m/z 420.1.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH:24]=3)[CH:11]=2)[C:6]([CH3:41])([CH3:40])[CH2:5]1)(=O)C.CCO>Cl>[CH3:40][C:6]1([CH3:41])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30][CH2:31][CH:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH:24]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3NCc3ccnc(OCCC4CCN(C)CC4)c3)cc21
Agent: Cl
Solvent: CCO
Product: CN1CCC(CCOc2cc(CNc3ncccc3C(=O)Nc3ccc4c(c3)NCC4(C)C)ccn2)CC1

Procedure:
N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide (300 mg, Example 871) was dissolved in conc. HCl (20 ml) and EtOH (20 mL) and heated at 70° C. for 4H. The mixture was concentrated and the residue was diluted with sat'd NaHCO3 and CH2Cl2. The organic layer was dried over Na2SO4 and concentrated to obtain the desired compound. M+H 515. Calc'd for C30H38N6O2: 514.