Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[CH3:24][C:25]1[CH2:26][C:27](=[O:40])[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH:33]3[CH3:39])[N:29]=1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[OH:19][C:4]1[C:3]([NH:2][N:20]=[C:26]2[C:27](=[O:40])[N:28]([C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[CH2:35][CH2:34][CH:33]4[CH3:39])[N:29]=[C:25]2[CH3:24])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1.[C:10]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=2)[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1
Reactant: Cc1cc(N)c(O)c(-c2cccc(C(=O)O)c2)c1
Reactant: CC1=NN(c2ccc3c(c2)C(C)CC3)C(=O)C1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)C(C)CC3)C(=O)C1=NNc1cc(C)cc(-c2cccc(C(=O)O)c2)c1O
Product: O=C(O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 218.2 %

Procedure:
3′-Amino-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid hydrochloride 11f (360 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1 N) upon cooling by an ice-water bath, followed by dropwise addition of 1.5 mL of aqueous sodium nitrite (85 mg, 1.22 mmol). After the mixture was stirred for 20 minutes, 5-methyl-2-(3-methyl-indan-5-yl)-2,4-dihydro-pyrazol-3-one 38f (228 mg, 1.0 mmol) was added. The mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, followed by addition of 2 mL ethanol. The reaction mixture was warmed up to room temperature and reacted overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was dissolved in 30 mL of water. After mixing well, the mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid. The mixture was filtered and the filter cake was dried followed by addition of 10 mL dichloromethane. The mixture was stirred for 1 hour and filtered. The filter cake was dried to obtain the title compound 2′-hydroxy-5′-methyl-3′-{N′-[3-methyl-1-methyl-indan-5-yl)-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-biphenyl-3-carboxylic acid 39 (240 mg, yield 49.8%) as a red solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=O)[CH3:2].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=1.[CH2:32](O)[CH2:33]CC>Cl.NC1C=CC(NC(=O)C)=CC=1.O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:30][CH:31]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:32][CH3:33]
Reactant: CCCCO
Reactant: CCOC(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: O
Product: CCCCOC(=O)C=C(Nc1ccc(NC(C)=O)cc1)c1ccc(C2CCCCC2)cc1
Temperature: 400 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
Into a 1 liter single-neck round-bottom flask equipped with a Soxhlet extractor apparatus with condenser, magnetic stirrer and nitrogen inlet was placed 50.25 g (0.183 moles) of 3-(4-cyclohexylphenyl)-3-oxo-propionic acid ethyl ester, 25 g (0.167 moles) of 4′-aminoacetanilide, 1.55 g (0.008 moles) 4′-aminoacetanilide hydrochloride salt and 500 mL of dry n-butanol. Into the Soxhlet thimble (33×118 mm) was placed highly activated 4A sieves (1.7-2.4 mm beads). These sieves are activated immediately before use under high vacuum with heating (400° C. for 30 min). The mixture was then brought to reflux such that the butanol azeotropically removed water, driving the equilibrium reaction, and the water was removed from the butanol by the sieves before being returned to the reaction pot. The reaction was allowed to continue for 48 hrs. It was necessary to replace the charge of sieves after the first 24 hrs. Transesterification to the butyl ester along with removal of ethanol occurs concomitantly with enamine formation. After 48 hrs the reaction pot was cooled, then placed in a −40° C. freezer and crystals were allowed to form over 24 hrs. The crystals were collected by vacuum filtration and the solids washed with cold ethanol. The product was then dried in a vacuum oven to give 73.8 g (98%) of the desired enamine.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)=[O:2].[OH-:28].[K+]>C(O)C.C(Cl)Cl.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)([OH:28])=[O:2]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-formyl-2-fluoro-1-triphenylmethylimidazole (356 mg.) in ethanol (5 ml.) and CH2Cl2 (3 ml.) was treated with silver nitrate (0.37 g.) in water (0.5 ml.) followed by the dropwise addition of 5 ml. of potassium hydroxide solution (5 ml. of a solution of 2.1 g. KOH in 35 ml. water). The mixture was stirred at room temperature for two hours, filtered and the filtrate extracted with ether. The aqueous layer was acidified with concentrated HCl and extracted with CHCl3. The organic layer was dried over MgSO4, filtered and the solvent evaporated to give 4-carboxy-2-fluoro-1-triphenylmethylimidazole (261 mg.) as a white solid having the following n.m.r. in d6DMSO: 7.0-7.68 (m, 16H); 11.5-12.5 (br, 1H).
Reaction SMILES: [NH:1]1[N:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:4]2[CH2:3][CH2:2]1.[ClH:13].[C:14](=[NH:19])([O:16]CC)[CH3:15].C([OH:22])C>>[ClH:13].[C:15]1(=[O:22])[N:19]([N:1]2[N:5]3[CH2:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[CH:4]3[CH2:3][CH2:2]2)[C:14]1=[O:16]
Reactant: c1ccc2c(c1)CN1NCCC21
Reactant: CCOC(C)=N
Reactant: CCO
Agent: Cl
Product: O=c1c(=O)n1N1CCC2c3ccccc3CN21

Procedure:
3.1 g (0.019 mol) of 2,3,3a,8-tetrahydro-1H-pyrazolo[5,1-a]isoindole and 3.3 g (0.03 mol) of ethyl acetimidate hydrochloride in 100 ml of absolute ethanol are stirred at room temperature for 15 hours. After removing the ethanol, the residue of 1-acetimido-2,3,3a,8-tetrahydro-1H-pyrazolo[5,1-a]isoindole hydrochloride is crystallised using ethyl acetate/isopropanol. Melting point 255°-257° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([OH:26])[C:3]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:27][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:4]([OH:26])[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=1
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
A suspension of 3-bromo-5-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-benzene-1,2-diol (0.390 g, 0.78 mmol) and potassium carbonate (0.108 g, 0.78 mmol) in DMF (4 mL) was stirred at 0 ° C. under a dry N2 atmosphere for 20 min. Benzyl bromide (0.093 mL, 0.78 mmol) was added dropwise to this mixture over a period of ten minutes. After the mixture was stirred at 0 ° C. for 6.5 h., the reaction mixture was quenched with aqueous hydrochloric acid to pH 1 and further diluted with water (60 mL) and aqueous mixture was extracted with methylene chloride (2×60 mL). The combined organic extracts were washed with water and dried with brine. Silica gel (5 mL) was added. Solvent was removed and the adsorbate was flash chromatographed (eluents: petroleum ether:methylene chloride 6:4 to petroleum ether:ethyl acetate 6:4) to provide a mixture (271 mg, 59%) of the title compound (87%) and 2-bromo-4-(6) -bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-6-benzyloxy-phenol (13%). The mixture was used for next reaction without separation: NMR (CDCl3): δ8.35 (d, J=8 Hz, 1 H), 7.79 (d, J=8 Hz, 1 H), 7.72-7.33 (m, 9 H), 7.18 (d, J=2 Hz, 1 H), 7.17 (ddd, J=8, 7, 1 Hz, 1 H), 6.93 (d, J=2 Hz, 1H), 6.87 (d, J=8 Hz, 1 H), 5.71 (s, 1H), 5.32 (t, J=7 Hz,2 H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.O.[C@@:24]12([CH2:34][S:35]([OH:38])(=[O:37])=[O:36])[C:31]([CH3:33])([CH3:32])[CH:28]([CH2:29][CH2:30]1)[CH2:27][C:25]2=[O:26].O>C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.[CH3:32][C:31]1([CH3:33])[C:24]2([CH2:34][S:35]([OH:38])(=[O:37])=[O:36])[C:25]([CH2:27][CH:28]1[CH2:29][CH2:30]2)=[O:26]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Solvent: O
Solvent: CCO
Product: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Temperature: 35 °C
Reaction time: 3 h

Procedure:
(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (100 g), (1R)-(-)-10-camphorsulfonic acid monohydrate (85.3 g), and radiolite (1 g) in ethanol (1,000 ml) were heated under reflux. It was cooled to 35° C., and 0.2 g of seed crystals were added thereto, thereafter it was agitated at an interior temperature of 20~30° C. for 3 hr, and after ethanol (1,000 ml) was added therto, it was agitated overnight at 20~30° C. The following day, water (25 ml) was added thereto and it was agitated for 1 hr at 20~30° C., and after the temperature was raised to 33~37° C., it was agitated for 30 min. It was cooled to 20~30° C., thereafter the precipitated crystals were collected by filtration, washed with ethanol (100 ml), and dried overnight under vacuum to obtain (+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSA salt as colorless coarse crystals.
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)[CH2:13][O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.O[Br:38]>ClCCl>[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)[CH2:13][O:12][CH:10]1[Br:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1OC[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: OBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: BrC1OC[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,3,4-tri-O-benzyl-xylopyranose was dissolved in dry dichloromethane (50 mL) and dry DMF (3.0 mL) was added. The reaction mixture was cooled at 0° C. and added dropwise oxayl bromide (1.4 mL). The reaction mixture was stirred for 1 hour at 0° to 5° C. and then diluted with dichloromethane (250 mL), washed with water (2×250 mL), dried over Na2SO4, filtered and evaporated to provide the title compound. The yield was quantitative for this step.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[C:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]#N)=[N:13][CH:14]=1)([OH:8])=[O:7].O.[OH:18]S(O)(=O)=O>CCOCC.O1CCCC1>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:18])[CH2:1][CH2:2][CH3:3])=[N:13][CH:14]=1)([OH:8])=[O:7]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CCC[Mg]Br
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(C(=O)O)cn1

Procedure:
To a stirred solution of propyl magnesium bromide (67.5 mmol) in 80 ml of ether, 5-carboxy-2-cyano-pyridine (30.7 mmol), dissolved in 100 ml of tetrahydrofuran, is added dropwise. The mixture is refluxed for 20 h. After cooling, 10 ml of water and 5 ml of 5N H2SO4 are added. Extraction of the aqueous phase with ether and evaporation of the solvent yield 3.5 g of crude product. Purification by silica gel column chromatography (n-hexane: ethyl acetate: HCOOH 7:3:0.1) yields the title compound, m.p. 128°-130°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([OH:11])=[C:4]([F:12])[CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:12])[C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cc(Br)cc(F)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Br)cc(F)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 4-bromo-2-fluoro 6-nitrophenol(1 g, 4.2 mmol) and tin (II) chloride (4.78 g, 21.2 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(710 mg, 82%). 1H NMR (CD3OD): d 6.51-6.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([S:11][CH3:12])=[CH:10][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([S:11]([CH3:12])=[O:22])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2c(c1)OC(C)(C)O2
Solvent: ClCCl
Product: CS(=O)c1ccc2c(c1)OC(C)(C)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 19.6 g of 2,2-dimethyl-5-(methylthio)-1,3-benzodioxol in 500 ml of methylene chloride was treated at 0° C. with 20.3 g of 85% m-chloroperbenzoic acid. The mixture was subsequently stirred at 0° C. for 1 hour. A white precipitate resulted. The reaction mixture was extracted with 400 ml of 17% aqueous sodium carbonate solution and 400 ml of water. The organic phase was dried over sodium sulphate and freed from solvent in a vacuum. The residue was taken up in a small amount of methylene chloride and chromatographed on silica gel, with elution being carried out with ethyl acetate/n-hexane/methylene chloride (1:1:1, v/v/v). After crystallization from ethyl acetate/n-hexane, there was obtained 2,2-dimethyl-5-(methyl-sulphinyl)-1,3-benzodioxol as white crystals having a melting point of 87°-88° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].O[CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>Cl>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[CH2:7][S:5][CH2:4][CH2:3][NH2:2]
Reactant: OCc1cccs1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCSCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(b)(i) Cysteamine hydrochloride (9.95 g) was dissolved in concentrated hydrochloric acid (50 ml) and the solution was cooled to 0°. 2-Hydroxymethylthiophene (10 g) was added dropwise to the stirred solution which was maintained at below 5°. The mixture was stirred overnight at room temperature, adjusted to pH 10 with concentrated aqueous sodium hydroxide and extracted with ethyl acetate. The extracts were evaporated and the residue was distilled at 158°-164°/760 mm Hg to give 2-(2-thienylmethylthio)ethylamine which was converted into the hydrochloride, m.p. 108°-111°, by treatment with ethanolic HCl and ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[NH2:55][CH:56]1[CH2:59][N:58]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:57]1>ClCCl>[C:63]([O:62][C:60]([N:58]1[CH2:57][CH:56]([NH:55][C:18]([C:17]2[CH:16]=[C:15]([CH:10]3[C:9]([CH3:25])([CH3:24])[CH2:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=4)[NH:11]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:59]1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CN(C(=O)OC(C)(C)C)C3)c1)N2
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol, 1.0 eq.) in dichloromethane (10.0 ml) was added N-hydroxy benzotriazole (89.2 mg, 0.66 mmol, 1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (253.0 mg, 1.32 mmol, 3.0 eq.), followed by 4-methylmorpholine (133.5 mg, 1.32 mmol) and the resultant mixture was stirred at room temperature for 30 min. Then tert-butyl 3-aminoazetidine-1-carboxylate (90.9 mg, 0.53 mmol, 1.2 eq.) was added to the flask and the reaction mixture was stirred for an additional 30 min. LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 234 mg of methyl 2-(3-(1-(tert-butoxycarbonyl) azetidin-3-ylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was used in next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)/[CH:8]=[CH:9]/[C:10]([OH:12])=O)(=[O:3])[CH3:2].[Cl:16][CH2:17][CH:18]1[C:26]2[C:21](=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=2)[NH:20][CH2:19]1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)/[CH:8]=[CH:9]/[C:10]([N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[CH:18]([CH2:17][Cl:16])[CH2:19]1)=[O:12])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2CCl
Reactant: CC(=O)Nc1cccc(/C=C/C(=O)O)c1
Product: CC(=O)Nc1cccc(/C=C/C(=O)N2CC(CCl)c3ccc([N+](=O)[O-])cc32)c1
Yield: 80 %

Procedure:
Similar reaction of (E)-3-(acetylamino)cinnamic acid and crude 3-chloromethyl-6-nitroindoline (6) (prepared as in Example 2) gave a crude product which was recrystallised from DMF/MeOH/H2O to give 1-[(E)-3-(acetylamino)cinnamoyl]-3-chloromethyl-6-nitroindoline (13) (80%), mp 229-230° C. 1H NMR [(CD3)2SO] δ10.06 (s, 1 H, NH), 8.97 (s, 1 H, H-7), 7.99 (dd, J=8.3, 2.3 Hz, 1 H, H-5), 7.86 (s, 1 H, H-2), 7.73-7.61 (m, 2 H, H-4,4′), 7.66 (d, J=15.3 Hz, 1 H, PhCH═CH), 7.53 (d, J=7.8 Hz, 1 H, H-6), 7.38 (t, J=7.9 Hz, 1 H, H-5), 7.08 (d, J=15.4 Hz, 1 H, PhCH═CH), 4.65 (t, J 10.0 Hz, 1 H, H-2), 4.33 (dd, J=10.7, 5.2 Hz, 1 H, H-2), 4.14-4.00 (m, 3 H, H-3, CH2Cl ), 2.07 (s, 3 H, CH3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Br[CH:14]([CH2:20][CH3:21])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].Cl[CH:23](C)C(N(C)C)=O>>[CH2:20]([CH:14]([N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH3:23])=[N:4]1)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH3:21]
Reactant: CCC(Br)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CC(Cl)C(=O)N(C)C
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccccc2C)n1

Procedure:
Following the procedure of Example 1, but substituting 4-methyl-3-(o-tolyl)pyrazole for 4-methyl-3-phenylpyrazole and 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide there was obtained α-ethyl-N,N,4-trimethyl-3-(o-tolyl)pyrazole-1-acetamide having a boiling point of 155°-157°/0.05 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([NH2:22])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:30]C(N1C[C@H](O)C[C@H]1C(OC(C)(C)C)=O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:19]([C@H:18]2[CH2:17][CH2:16][CH2:20][NH:22]2)=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN2CCCC2C(N)=O)C1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)[C@H]2CCCN2)C1

Procedure:
The title compound was prepared by methods similar to Steps 1 and 2 of Example 45, using (2R)-N-({(3R)-1-(tert-butoxycarbonyl-3-piperidyl}methyl)pyrrolidine-2-carboxamide and N-benzyloxycarbonyl-O-(tert-butyl)-trans-4-hydroxy-L-proline.
Reaction SMILES: Br[C:2]1[C:3](=[O:31])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:58]1[CH:63]=[C:62](B(O)O)[CH:61]=[N:60][CH:59]=1>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:25][CH2:26]4)=[CH:7][CH:8]=3)[C:3](=[O:31])[C:2]=2[C:62]2[CH:63]=[N:58][CH:59]=[N:60][CH:61]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1cncnc1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(Cl)cc2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cncnc2)=C3c2ccc(Cl)cc2)CC1
Yield: 50 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(4-chlorophenyl)-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-1H-inden-1-one obtained in Step 1 of Example 53 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (50%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl-:1].[O:6]([CH2:5][C:3]([CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(CCl)COc1ccccc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(COc1ccccc1)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Reaction time: 0.08 h

Procedure:
1-Chloro-3-phenoxyacetone (13 g, 0.07 mole) dissolved in 20 ml chloroform was mixed with a solution of triphenylphosphine (19.7 g, 1 eq) in 30 ml chloroform at room temperature. The mixture was swirled for 5 minutes and benzene (20 ml) was added. A white crystalline compound appeared when most of the solvents had been evaporated. The product was collected by suction and washed with benzene. Second and third crops were collected by evaporation of the washings. The total yield was 23 g (73%); sublimation without melting at 90°; ir (KBr, cm-1) 3450-3280, 2770, 1720, 1595, 1585, 1485, 1435, 1220, 1110, 1030; nmr (DCCl3, ppm) 8.20-6.80 (m, 22H), 5.30 (br, 2H).