Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:32][C:33](=[O:44])[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]=O)=[CH:38][CH:37]=1)[OH:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:44])[CH:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:42][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22](=[O:23])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:3]=2)=[CH:40][CH:41]=1)[OH:35])[CH3:31]
Reactant: CCOC(=O)C(O)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOC(=O)C(O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and (4-formyl-phenyl)-hydroxy-acetic acid ethyl ester according to the procedure of step 1, Example 66. MS (ES) m/z 585.3.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([N:8]=[N:9][C:10]1(Cl)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6].O>CO>[CH:5]([N:8]=[N:9][C:10]1([N:1]=[N+:2]=[N-:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6]
Reactant: CC(C)N=NC1(Cl)CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N=NC1(N=[N+]=[N-])CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 9.75 grams (0.15 moles) of sodium azide in 100 mls of 70% aqueous methanol in a 250 ml erlenmeyer flask cooled in an ice bath, was added 18.85 grams (0.1 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) over 15 minutes while holding the reaction temperature below 10° C. After the addition was complete the mixture was stirred an additional 20 minutes at room temperature, poured into 200 ml water and extracted into 100 ml of pentane. The pentane solution was washed successively with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 18.4 grams (94.4 % crude yield). It was not shock sensitive and its infrared spectrum was in agreement with the structure of 1-isopropylazo-1-azidocylohexane (strong azide band at 2100 cm-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[CH:36][C:37]([F:41])=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[CH:36][C:37]([F:41])=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: NC1CCc2cc(F)ccc21
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCc3cc(F)ccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-5-fluoro-indane
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CO.O1CCCC1.[OH-].[Li+].Cl>O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1

Procedure:
A solution of ethyl 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoate (35.39 g, 87.6 mmol) in 3:1 methanol/tetrahydrofuran (350 mL) was treated with lithium hydroxide (4.41 g, 183.9 mmol) in water (90 mL). The mixture was heated at reflux for 2 h., cooled, concentrated and acidified with hydrochloric acid (2M, 92.5 mL, 185 mmol). The dark precipitate was filtered, washed with water, and dried under vacuum. The solid was ground to a powder with a mortar and pestle, triturated with methanol (500 mL) then filtered again to yield 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid as a muddy solid. This material was washed with ether, air dried overnight, and ground to a fine powder with mortar and pestle. On the basis of mass recovery (34.49 g) the yield was assumed to be quantitative. 1H NMR (300 MHz, d6-DMSO) δ 9.47 (1H, s); 8.53 (1H, d, J=5.2 Hz); 8.24 (2H, d, J=8.5 Hz); 8.08 (2H, d, J=8.8 Hz), 7.66 (2H, d, J=9.1 Hz); 7.37 (1H, d, J=5.2Hz); 6.93 (2H, d, J=9.1 Hz); 3.73 (4H, m); 3.04 (4H, m). LC-ESI-MS (method C): rt 7.3 min.; m/z 377.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Br:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Br:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Br:20]
Reactant: C1COCCN1
Reactant: Nc1c(Br)cc(C(=CC(=O)O)c2ccc(Cl)cc2)cc1Br
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Br)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Br

Procedure:
This compound was prepared from 4-amino-β-(4'-chlorophenyl)-3,5-dibromo-cinnamic acid (isomer ratio A:B=5:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(F)c3)CC2)c(C)c1
Yield: 68.1 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 66 and oxazolidin-2-one (87 mg), the title compound (271.1 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=O.C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)(=O)C>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([CH2:3][OH:2])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: OCc1cnc2ccc(Cl)cc2c1-c1ccccc1
Yield: 83.5 %

Procedure:
While stirring a mixture of 6-chloro-4-phenyl-3-quinolinecarboxylic acid methyl ester (8.0 g) and ethyl ether (100 ml) at 0° C., lithium aluminum hydride (1.0 g) was added, followed by stirring for 30 minutes. After water (5 ml) was added, the mixture was stirred at room temperature for 30 more minutes. After ethyl acetate was added; the insoluble material was filtered off. The flitrate was washed by successively with aqueous potassium carbonate and saturated aqueous sodium chloride and then dried, after which the solvent was distilled off, to yield 6-chloro-3-hydroxymethyl-4-phenylquinoline as colorless crystals (6.05 g).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4C3CCCCO3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36](C=O)C>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]1([N:8]2[C:7]3[C:2]([C:35]#[N:36])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=[C:9]2[C@@H:11]([NH:13][C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH3:12])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)C=O
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2cccc(Br)c2n1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(C#N)c2n1-c1ccccc1
Temperature: 150 °C
Yield: 73 %

Procedure:
[(S)-1-(7-Bromo-1-phenyl-1H-benzoimidazol-2-yl)ethyl][9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (300 mg, 0.58 mmol) was dissolved in DMF (1 mL) in a microwave vial and zinc cyanide (68 mg, 0.58 mmol) and Pd(PPh3)4 (67 mg, 0.058 mmol) added. The vial was sealed and evacuated and purged with argon (×3). The vial was heated at 150° C. by microwave irradiation for 15 min. The resulting colourless solution was poured onto a mixture of EtOAc and water. A white solid precipitated and was dispersed between the 2 phases. The solid was isolated by filtration and dissolved in DCM and the resulting solution washed with NaHCO3 (satd. aq. soln.). The DCM fraction was passed through a PTFE cartridge. The DCM was removed in vacuo and the residue purified by passage through an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product fractions were combined and evaporated and the residue purified by chromatography (Si—PCC) eluting with 0-8% MeOH in DCM. The product fractions were concentrated in vacuo to give white solid. This was triturated in ether, filtered and dried in vacuo to give 279 as a white solid (160 mg, 73%). 1H NMR (DMSO-d6, 400 MHz) δ: 8.09 (1H, br s), 8.03 (1H, s), 7.98 (2H, d, J=8.2 Hz), 7.66-7.59 (3H, m), 7.56-7.37 (4H, m), 7.33 (1H, t, J=7.9 Hz), 5.35-5.21 (1H, m), 1.54 (3H, d, J=6.9 Hz). LCMS (Method K): RT 3.07 min; m/z 381 [M+H]+
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH2:15][CH3:16]>CN(C)C=O.CCOCC>[C:1]([N:8]([CH2:9][C:10]#[CH:11])[CH2:15][CH3:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Di-tert-butyl dicarbonate (42.8 g, 196 mmol) in dichloromethane (100 mL) was added dropwise to a solution of propargylamine (11.02 g, 200 mmol) in dichloromethane (200 mL) at room temperature with magnetic stirring. After 2 h, the reaction mixture was washed with aqueous 1N hydrochloric acid (300 mL) and saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layers were washed with dichloromethane (300 mL). The dichloromethane solutions were combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40S, EtOAc - hexanes V/V 1:9 as solvent) to give crude N-Boc-propargyl amine. (32.32 g). The crude N-Boc-propargyl amine (3.1 g, 20 mmol) was dissolved in dry dimethylformamide (20 mL) with magnetic stirring and cooled in an ice-water bath. Sodium hydride (0.61 g, 24 mmol) was added in small portions. After stirring for 15 min., iodoethane (3.74 g, 24 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. then diluted with ether and extracted with water and saturated brine. The aqueous layers were back washed with ether and the ether layers were combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40M, ethyl acetate - hexanes as solvent to give N-Boc-N-ethylpropargyl amine. (Yield 3.19 g, 87%).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:22][CH2:23][OH:24]>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:22][CH2:23][OH:24])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
5.75 g (24 mmoles) of 5-benzyl-benzimidazoline-2-thione, a solution of 1 g of sodium hydroxide and 8 ml of water, 2 ml (30 mmoles) of 2-chloroethanol and 30 ml of ethanol are refluxed for an hour. The reaction mixture is evaporated and extracted with water and dichloromethane, then the aqueous phase is extracted with dichloromethane. The residue of the combined organic phases is solidified under ether. After filtration and crystallization from ethyl acetate 4.63 g (68.1%) of title product are obtained. M.p.: 108°-109° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].O.[PH2:8]([O-:10])=[O:9].[Na+].[CH2:12]=[CH2:13]>OO.O>[CH2:12]([P:8]([OH:10])([CH:3]([CH3:4])[CH2:2][C:1]([OH:6])=[O:5])=[O:9])[CH3:13]
Reactant: C/C=C/C(=O)O
Reactant: C=C
Reactant: O=[PH2][O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)C(C)CC(=O)O
Yield: 58 %

Procedure:
Using the method of Example 2, 516 g (6 mol) of crotonic acid were first admixed, at from 75 to 90° C. in the presence of 73.4 g of a 7% strength hydrogen peroxide solution, with 636 g (6 mol) of sodium hypophosphite monohydrate dissolved in 860 g of water. The resultant reaction mixture was then reacted with ethylene in the presence of 73.4 g of a 7% strength hydrogen peroxide solution. Appropriate work-up gave 623 g (58% of theory) of 3-(ethylhydroxyphosphinyl)butyric acid as colorless solid; chlorine content: <0.1 ppm.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.O[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:55])[CH2:37][N:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][N:47]=3)=[CH:40][C:39]2=[O:54])=[C:32]([CH3:56])[CH:31]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>COC(C)(C)C>[Br:25][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:55])[CH2:37][N:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][N:47]=3)=[CH:40][C:39]2=[O:54])=[C:32]([CH3:56])[CH:31]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: COc1ccc(COc2ccn(CC(=O)c3ccc(CO)cc3C)c(=O)c2)nc1
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Solvent: COC(C)(C)C
Product: COc1ccc(COc2ccn(CC(=O)c3ccc(CBr)cc3C)c(=O)c2)nc1
Reaction time: 8 h
Yield: 80 %

Procedure:
1-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1d employing 1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 11c) instead of preparation 1c. The reaction mixture is stirred overnight. Tert-butyl methyl ether is added and the resulting precipitate is filtered off and dried.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.[Cl:15][C:16]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:23][CH:24]=1.O>CN(C)C(=O)C>[Cl:15][C:16]1[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=[CH:29][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([S:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CSC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 81 %

Procedure:
1.2 g of ethyl thioglycolate and 1.2 g of triethylamine were dissolved in 20 ml of N,N-dimethylacetamide. To the thus obtained solution was dropwise added 3.5 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetyl chloride at 10° C. After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 3 hours to complete reaction. After completion of the reaction, 50 ml of water was added to the reaction mixture, followed by extraction twice with 30 ml portions of ether. The ether layer was washed with water and dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure to obtain a crude product. The obtained crude product was subjected to purification by the silica gel column chromatography to obtain 3.5 g of S-ethoxycarbonylmethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylthioacetate.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:19](OC1C=CC=CC=1)=[O:20].Cl.Cl.Cl.[N:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:34][CH2:33][CH2:32]1>O1CCCC1.CO.C(N(CC)CC)C>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:19]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][N:31]4[CH2:32][CH2:33][CH2:34]4)[CH2:42][CH2:41]3)=[O:20])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1CN(CCN2CCNCC2)C1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCN(CCN2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(4-Nitrophenoxy)pyridin-2-ylamine (60 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere. Triethylamine (0.109 ml) and phenyl chloroformate (0.0975 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 30 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was then added N-dimethylformamide (3 ml). And then an 1.0 M solution of 1-[2-(azetidin-1-yl)ethyl]piperazine trihydrochloride in methanol (0.884 ml) and triethylamine (0.261 ml) were added thereto, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (30 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (30 ml), water (30 ml), and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (122 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])O[C:5]2=[O:13].[NH2:14][CH2:15][C:16]([OH:18])=[O:17]>C1(C)C(C)=CC=CC=1>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[C:5](=[O:13])[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:7]2=[O:12]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: NCC(=O)O
Solvent: Cc1ccccc1C
Product: O=C(O)CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Temperature: 160 °C
Yield: 92.2 %

Procedure:
To a solution of 5,6-dichloroisobenzofuran-1,3-dione (2 g, 9.22 mmol) in xylene (10 ml), 2-aminoacetic acid (0.761 g, 10.14 mmol) was added, and the reaction was heated at 160° C. for 40 hours. The precipitate that formed during the reaction was filtered, washed with water and hexanes and dried affording 2-(5,6-dichloro-1,3-dioxoisoindolin-2-yl)acetic acid (2.33 g, 8.50 mmol, 92% yield).
Reaction SMILES: [BH4-].[Na+].[Te].[Br:4][C:5]1[CH:6]=[C:7]([CH:11]2[N:15]([CH3:16])[C:14](=[O:17])[C:13](Br)(Br)[CH2:12]2)[CH:8]=[N:9][CH:10]=1.C(OCC)(=O)C>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:11]2[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1
Reactant: CN1C(=O)C(Br)(Br)CC1c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1C(=O)CCC1c1cncc(Br)c1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Sodium borohydride (862 mg, 22.8 mmol) was dissolved in ethanol (20 mL) and tellurium metal powder (1.45 g, 11.4 mmol) was added in portions. The mixture was heated under reflux for 0.25 h and 5-bromo-3-(3,3-dibromo-1-methyl-5-pyrrolidin-2-onyl)pyridine (775 mg, 1.9 mmol) was added to the solution at 25° C. After stirring for 2 h, ethyl acetate (50 mL) was added and the solution was filtered through Celite and concentrated in vacuo. 1M HCl (10 mL) was added to the residue and the solution was adjusted to pH 11 with solid potassium carbonate. After extraction with ethyl acetate (50 mL) the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with brine (30 mL), dried (MgSO4) and concentrated. This material was chromatographed on silica gel with ethyl acetate:hexane (1:1) as eluant to afford 5-bromo-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine as a solid (329 mg, 68%). M.p. 85°-87° C.; 1H NMR (CDCl3, 300 MHz): δ 8.66 (d, J=2 Hz, 1H), 8.42 (d, J=2 Hz, 1H), 7.68 (t, J=2 Hz, 1H), 4.56 (t, J=7 Hz, 1H), 2.71 (s, 3H), 2.45-2.65 (m, 2H), 1.80-1.95 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>CO.[N+](C1C=CC=CC=1)([O-])=O>[N:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:22][C:9]=1[C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=1
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: Nc1ccccc1N
Solvent: CO
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(-c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
aa) A solution of 4.93 g of 5-nitrovanillin and 2.7 g of 1,2-phenylenediamine in 45 ml of methanol and 15 ml of nitrobenzene is heated to boiling under reflux. After 15 minutes crystals begin to separate from the red solution. After 18 hours the reaction mixture is cooled to room temperature and diluted with 60 ml of methanol. The crystals are filtered under suction and washed with methanol. There is obtained 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol of m.p. 198°-200° (from N,N-dimethylformamide/methanol).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: C=CCc1c(O)ccc(C(=O)NC)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dihydroxy-N-methyl-3-(2-propenyl)benzamide (770 mg, 3.7 mmol), the compound of Example 23 (650 mg, 1.55 mmol), and potassium carbonate (321 mg, 2.32 mmol) were added to about 20 ml of DMF, and the reaction mixture was stirred overnight at room temperature in a 100 ml pear-shaped flask. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, concentrated under vacuum and chromatographed on silica gel using 40% ethyl acetate/hexane as eluant to give the product.