Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C=O.[NH2:12][C:13](N)=O>>[NH2:12][CH2:13][CH2:2][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CC(=O)c1ccccc1
Reactant: NC(N)=O
Agent: C=O
Product: NCCC(O)c1ccccc1

Procedure:
The compounds of formula (I) may be prepared by condensing an acetophenone of general formula (II): ##STR3## (in which R1 and R2 are as defined above) in a Mannich reaction with formaldehyde and a primary or secondary amine, reducing the amino-ketone thus formed to a 3-amino-1-phenyl-propan-1-ol, and subsequently dehydrating this 3-amino-1-phenyl-propan-1-ol. The compound so produced is of general formula (I) in which A is CH=CH; subsequently, if desired, this compound may be hydrogenated to produce a compound of formula (I) in which A is CH2CH2.
Reaction SMILES: C([O:3][C:4](=[S:20])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)C.F[C:22](F)(F)[C:23]([O:25][C:26](=O)[C:27](F)(F)F)=O.O1C=CC=C1>ClCCl>[O:25]1[CH:26]=[CH:27][CH:22]=[C:23]1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([OH:3])=[S:20]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=S)C(CCCCCC(=O)O)c1ccccc1
Solvent: c1ccoc1
Solvent: ClCCl
Product: O=C(CCCCCC(C(O)=S)c1ccccc1)c1ccco1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred, ice-cold solution of 7.75 g. of ethyl-7-carboxy-2-phenylthioheptanoate in 25 ml. of dichloromethane is added 3.5 ml. of trifluoroacetic anhydride during 2 minutes. The solution is stirred at ambient temperature for 10 minutes, recooled to 0° C. and treated with 9 ml. of furan during 2 minutes. The resulting solution is stirred at ambient temperature for 18 hours and then partitioned with 1:1 ether-petroleum either and aqueous sodium bicarbonate. The organic phase is washed with water and brine, dried and evaporated. The resulting crude ester (6.75 g.) is dissolved in 75 ml. of ethanol containing 4.95 g. of 85% potassium hydroxide and 10 ml. of water. This solution is refluxed for 20 minutes, cooled and concentrated in vacuo. The residue is partitioned with water and ether. The aqueous layer is acidified with dilute hydrochloric acid and extracted with ether. This extract is washed with water and brine, dried and evaporated, giving the product as an oil, identified as having a PMRδ 2.80 (2, t, J=7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([O:14][CH3:15])=[CH:10][C:11]=1[O:12][CH3:13])[O:5]COC.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:22][C:23](=[O:24])[NH:1][C:2]2[CH:3]=[C:4]([OH:5])[C:9]([O:14][CH3:15])=[CH:10][C:11]=2[O:12][CH3:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCOc1cc(N)c(OC)cc1OC
Product: COc1cc(OC)c(NC(=O)Nc2ccccc2)cc1O

Procedure:
(3-Amino-4,6-dimethoxyphenoxy)methoxymethane and phenyl isocyanate were treated in the same manner as described in Example 1 to give 3-(3-phenylureido)-4,6-dimethoxyphenol (melting point: 162°-164° C.).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH2:54])[CH3:50]>CN(C=O)C.O>[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1)[CH3:50]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a stirred solution of 4-phenylamino-benzoic acid (3.0 g, 0.01401 mol) in DMF (10 mL), was added DIPEA (5.4 g, 0.04205 mol), HOBt (2.27 g, 0.01682 mol) and EDCI.HCl (6.69 g, 0.03504 mol) at ambient temperature. After 2 minutes amino-acetic acid ethyl ester hydrochloride (2.33 g, 0.01682 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration, washed with water followed by hexane and dried to afford 4 g (95%) of (4-phenylamino-benzoylamino)-acetic acid ethyl ester. To a stirred solution (4-phenylamino-benzoylamino)-acetic acid ethyl ester (4 g, 0.01337 mol) in a mixture of THF (15 mL), methanol (15 mL) and H2O (8 mL) was added LiOH.H2O (2.24 g, 0.0535 mol). The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated. The residue was diluted with water and acidified with 10% aqueous citric acid solution. The resulting precipitate was isolated by filtration and dried to afford 3.3 g (91%) of (4-phenylamino-benzoylamino)-acetic acid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[CH3:7].[C:9]([Cu])#[N:10].CCOCC>CN(C=O)C>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([C:9]#[N:10])[S:3][CH:4]=1
Reactant: Cc1c(Br)csc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(Br)csc1C#N

Procedure:
A mixture of 2,4-dibromo-3-methylthiophene (20.0 g, 78.1 mmol) and CuCN (6.30 g, 70.3 mmol) in 150 mL of DMF was stirred at reflux for 4 hours before cooling down. The reaction mixture was poured into 1 L of ether with stirring and the precipitate was removed by filtration. The filtrate was washed with water (3×100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography (petrol ether: EtOAc=50:1) to afford 4-bromo-3-methylthiophene-2-carbonitrile.
Reaction SMILES: Br.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=[NH:13])[NH2:12].C[O-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH2:31][C:32]3[CH:33]=[C:34]([C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:36][CH:37]=3)[C:29](=[O:42])[N:28]([CH2:43][C:44]([NH:46]N)=O)[N:27]=2)=[CH:22][CH:21]=1>CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH2:31][C:32]3[CH:33]=[C:34]([C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:36][CH:37]=3)[C:29](=[O:42])[N:28]([CH2:43][C:44]3[NH:12][C:11]([CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([F:14])([F:15])[F:2])=[N:13][N:46]=3)[N:27]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NN)c2=O)c1
Reactant: N=C(N)Cc1ccccc1C(F)(F)F
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(Cc3nnc(Cc4ccccc4C(F)(F)F)[nH]3)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
77 mg (0.27 mmol) of 2-[2-(trifluoromethyl)phenyl]ethaneimidamide hydrobromide were dissolved in 1 ml of dry methanol, 74 μl (0.27 mmol) of a 25% strength methanolic sodium methoxide solution were added and the mixture was stirred for 30 min 75 mg (0.18 mmol) of the compound from Example 16A were then added, and the mixture was stirred initially at RT for 16 h and then under reflux for 5 h. The mixture was then directly purified chromatographically [Method 19]. This gave 67 mg (64% of theory) of the target compound as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:6]3=[C:5]([CH3:17])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[OH-].[Na+]>C1C=CC=CC=1>[ClH:25].[CH2:29]([O:28][C:26]([N:14]1[CH2:15][CH2:16][C:6]2[C:7](=[N:8][C:9]3[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]=2[CH3:17])[CH2:12][CH2:13]1)=[O:27])[CH3:30]
Reactant: Cc1ccc2nc3c(c(C)c2c1)CCNCC3
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2nc3ccc(C)cc3c(C)c2CC1
Product: Cl
Temperature: 0 °C

Procedure:
1.1 gm (5 millimols) of 9,11-dimethyl-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline were dissolved in 30 ml of benzene, and a solution of 1 gm (10 millimols) of triethylamine in 10 ml of benzene and then 1.08 gm (10 millimols) of ethyl chloroformate were added, and the resulting mixture was heated at its boiling point for 2 hours. The cooled reaction mixture was admixed with 50 ml of ice water, and the aqueous mixture was made alkaline with 2 N sodium hydroxide. The benzene phase was separated, and the aqueous layer was extracted with chloroform. The benzene phase and the chloroform extract were combined, dried over sodium sulfate, and the solvents were distilled off. For conversion into the hydrochloride, the residual base was dissolved in hot acetone, and the solution was acidified with isopropanolic hydrochloric acid, whereupon the hydrochloride crystallized out.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.Cl[Si](C)(C)C.[O:17]1[CH2:21]CC[CH2:18]1.C[C:23](C)([O-:25])C.[K+]>COC(OC)OC>[CH3:18][O:17][CH:21]([O:25][CH3:23])[N:6]1[C:5]2[CH:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]=2[N:8]=[C:7]1[CH3:9]
Reactant: C1CCOC1
Reactant: Cc1nc2cc(I)ccc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: C[Si](C)(C)Cl
Agent: [K+]
Solvent: COC(OC)OC
Product: COC(OC)n1c(C)nc2cc(I)ccc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture solution of 5-iodo-2-methyl-1H-benzimidazole (10 g, 39 mmol), trimethoxy-methane (200 ml), and chlorotrimethylsilane (0.075 ml, 0.59 mmol) was heated and stirred at 100° C. for five hours under a nitrogen atmosphere while distilling off the solvent (a reaction conversion rate of 97%). The reaction mixture was cooled to 40° C., and then a tetrahydrofuran solution (0.87 ml, 0.87 mmol) of potassium tert-butoxide was added thereto. This was concentrated under reduced pressure to provide crude 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)=[O:2].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[CH:1]([N:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)=[O:2]
Reactant: O=CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(CN2CCN(C=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A mixture comprising 9 g of 1-formyl-4-(4-nitrobenzyl)-piperazine, 180 ml of methanol and 14.6 of nickel chloride hexahydrate, was cooled in ice bath, and 4.6 g of sodium borohydride was slowly added thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 30 minutes. The reaction solution was distilled off under reduced pressure, and the residue was dissolved by an addition of 200 ml of 10% hydrochloric acid, and adjusted to pH 10 with 28% aqueous ammonia. Then, the mixture was extracted with ethyl acetate. The extract solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether to obtain 8.0 g of the above-identified compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[OH:5]
Reactant: Nc1cccc(Cl)c1C=O
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOC(C)=O
Product: Nc1cccc(Cl)c1C(O)c1ccc(F)cc1
Yield: 57 %

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from 2-amino-6-chlorobenzaldehyde (0.30 g, 1.9 mmol) and 4-fluorophenylmagnesium bromide (1 M in THF, 3.8 mL) to afford 0.28 g (57%) of (±)-(2-amino-6-chlorophenyl)-(4-fluorophenyl)methanol after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]([CH2:16][CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]([CH2:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(=CC(=O)OC)Nc1ccc(Cl)cc1
Reaction time: 2.5 h
Yield: 70.5 %

Procedure:
In a 300 ml-flask were placed 4-chloroaniline (25.0 g, 196 mmol), methyl 3-oxopentanoate (28.1 g, 216 mmol) and toluene (100 ml). To this solution was added p-toluenesulfonic acid monohydrate (0.19 g, 0.98 mmol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 23 kPa for 2.5 hours, while removing the water formed by refluxing by using a Dean-Stark trap. The heating was then discontinued, nitrogen leaked in, and the reaction mixture cooled. The solvent was evaporated off by using a rotary evaporator, and the residue was distilled under reduced pressure to give 33.1 g of the title compound. The yield was 70.5%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][SH:8].C(O)C.Br[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]>O>[CH3:7][S:8][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]
Reactant: CS
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(SC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A reaction mixture containing 21 g. of potassium carbonate, 25 g. of methanethiol, and 30 ml. of ethanol was cooled in an ice-water bath. 33.5 g. of 3-bromo-4-nitroveratrole were added thereto. The reaction mixture was stirred for 1 hour under cooling and was then allowed to warm up to ambient temperature, at which temperature it was stirred for an additional 24 hours. 3 l. of water were then added and the resulting precipitate of 3-methylthio-4-nitroveratrole formed in the above reaction was separated by filtration. The filter cake was recrystallized from a benzene-ethanol solvent mixture to yield yellow crystals melting at 137°-140° C. (weight=22.8 g)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([O:35][C:36](Cl)=[O:37])[CH2:33][CH3:34]>>[CH2:32]([O:35][C:36]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:37])[CH2:33][CH3:34]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 17 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propylchloroformate (Aldrich), to afford 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid propyl ester. HRMS, observed: 414.2140; Calcd for (M+H)+: 414.2136.
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(#N)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:31][C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][C@H:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH2:11]2)=[CH:23][CH:22]=1)=[O:21]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc(N2CC[C@H](NC(=O)c3cccnc3)C2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](NC(=O)c3cccnc3)C2)cc1
Yield: 19.9 %

Procedure:
A solution of 399 (93 mg, 0.3 mmol), phenylene diamine (65 mg, 0.6 mmol), EDC (86 mg, 0.45 mmol), HOBT (53 mg, 0.33 mmol) and Et3N (125 μL, 91 mg, 0.9 mmol) in acetonitrile (2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography using the gradient 5-20% MeOH in DCM as an eluent to afford the title compound (24 mg, 16% yield). 1H NMR (CDCl3) δ 8.97 (s, 1H), 8.66 (d, J=4.9 Hz, 1H), 8.21 (d, J=3.9 Hz, 1H), 7.87 (d, 2H, J=8.8 Hz), 7.52 (dd, J=5.1 Hz, J=8.0 Hz, 1H), 7.15 (d, 1H, J=7.9 Hz), 7.05 (t, J=8.1 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.76 (t, J=7.3 Hz, 1H), 6.66 (d, J=9.0 Hz, 2H), 4.78 (m, 1H), 3.80 (dd, J=6.7 Hz, J=10.2 Hz, 1H), 3.61 (m, 1H), 3.49 (m, 1H), 3.41 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H). LRMS: (calc) 401.2; (found) 402.2 (M+H1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C.Cl>O1CCCC1>[C:18]1([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([B:29]([OH:32])[OH:30])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a 300 mL three-necked flask was placed 5.0 g (13 mmol) of 2-(4-bromophenyl)-3-phenylquinoxaline, and the atmosphere in the flask was replaced with nitrogen. There was added 40 mL of tetrahydrofuran, and the mixture was cooled to −78° C. under nitrogen stream. After cooling, 10 mL (16 mmol) of 1.6 M n-butyllithium was dripped thereinto, and the mixture was stirred at the same temperature for 1 hour. After a predetermined time, there was added 3.1 mL (27 mmol) of trimethyl borate, and the temperature of the solution was raised to room temperature, and then, the solution was stirred for 10 hours. After a predetermined time, the solution was cooled to 0° C., to which 100 mL of 0.1 M hydrochloric acid was added, and the solution was stirred for 1 hour. After a predetermined time, an organic substance was extracted with ethyl acetate from the aqueous layer. The extract was washed with a saturated aqueous sodium chloride solution together with the organic layer and then dried over magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The obtained filtrate was condensed to obtain a solid. The solid was recrystallized with ethyl acetate/hexane; thus, 3.0 g of target pale-yellow powder was obtained with a yield of 66%.
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[F:23]>C1COCC1.CCOC(C)=O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]2[C:18](=[O:20])[O:19][CH2:2][C:16]=2[C:15]=1[F:23]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1OCc2c1ccc(Br)c2F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-BuLi (40 mL, 100 mmol) was added dropwise to a solution of diisopropylamine (10.6 g, 105 mmol) in 150 mL of THF at −70° C. The mixture was stirred at 0° C. for 15 minutes and then cooled to −70° C. again. A solution of 4-bromo-3-fluorobenzoic acid (10 g, 45.7 mmol, in 50 mL of THF) was added dropwise. The resulting mixture was stirred at −70° C. for 1 hour then CH2O gas (generated by heating 5.1 g of Para formaldehyde to 200° C.) was bubbled into the mixture. The resulting mixture was stirred at −70° C. for 1 hour then allowed to warm to room temperature and stirred for another 2 hours. HCl gas was bubbled into the suspension for 15 minutes to give a clear solution. The mixture was diluted with 1 L of EtOAc and washed subsequently with water, saturated Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give 5-bromo-4-fluoro-2-benzofuran-1(3H)-one as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C(=O)O)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccnc(C(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 4-tert-butoxycarbonylamino-pyridine-2-carboxylic acid (43) (800 mg, 3.2 mmol) in CHCl3 was added morpholine (0.4 mL, 3.8 mmol), HOBT (857 mg, 6.3 mmol), EDC.HCl (1.2 g, 6.3 mmol) and DIPEA (0.8 mL, 4.8 mmol), and stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with 10% MeOH/CHCl3. The organic layer was washed with water, dried over Na2SO4 and evaporated to give compound 44 (920 mg, 92%) as a white solid; (m/z): 308 [MH]+; 1H NMR (400 MHz, CDCl3): δ 8.40 (1H, d, J=5.6 Hz), 7.57 (1H, d, J=2.0 Hz), 7.54 (1H, d, J=5.6 Hz), 6.98 (1H, br s), 3.79 (4H, m), 3.67-3.66 (4H, m), 1.53 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Br:11]Br.O>CC(O)=O>[Br:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: BrBr
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cc(O)c(O)c(Br)c1
Yield: 47.9 %

Procedure:
To a solution of 3,4-dihydroxy benzaldehyde (15.48 g, 112 mmol) in 500 ml AcOH was added bromine (6.1 ml, 118 mmol) drop-wise in 50 ml AcOH over 10 min. After 4 h the mixture was poured into cold H2O. The precipitate was filtered, washed with cold H2O and dried in vacuum to give 3-bromo-4,5-dihydroxy-benzaldehyde (11.64 g, 48%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[C:11](=[O:14])[CH2:12][CH2:13][C:7]=3[C:6]=2[CH:5]=[C:4]([Cl:15])[CH:3]=1.[C:16]([O-:19])([O-])=O.[K+].[K+].CN([CH:25]=[O:26])C>O>[C:16]([O:26][CH2:25][N:9]1[C:10]2[C:2]([Cl:1])=[CH:3][C:4]([Cl:15])=[CH:5][C:6]=2[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[C:8]1=2)(=[O:19])[C:6]([CH3:7])([CH3:10])[CH3:5]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2c1[nH]c1c(Cl)cc(Cl)cc21
Agent: [K+]
Solvent: O
Product: CC(C)(C)C(=O)OCn1c2c(c3cc(Cl)cc(Cl)c31)CCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 5,7-dichloro-1,2-dihydrocyclopenta[b]indol-3(4H)-one (0.1 g, 0.41 mmol) in anhydrous DMF (5 mL), K2CO3 (80 mg, 0.62 mmol) was added followed by chloro methyl pivalate (0.07 mL, 0.51 mmol) and the resulting mixture stirred at room temperature for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (3:17) as eluant] to provide the title compound as a yellow solid (0.10 g, 68%). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.61 (s, 1H), 7.41 (s, 1H), 6.56 (s, 2H), 3.04 (s, 4H), 1.14 (s, 9H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([O:35][CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:37][S:38]([OH:41])(=[O:40])=[O:39]>>[CH3:37][S:38]([O-:41])(=[O:40])=[O:39].[CH3:36][O:35][C:29]1[CH:34]=[CH:33][C:32]([S+:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)O
Reactant: O=S(c1ccc(Oc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1
Reactant: COc1ccccc1
Product: COc1ccc([S+](c2ccc(Oc3ccccc3)cc2)c2ccc(Oc3ccccc3)cc2)cc1
Product: CS(=O)(=O)[O-]
Temperature: 100 °C
Yield: 90.8 %

Procedure:
A mixture of 50.24 g of bis-(4-phenoxyphenyl)sulfoxide, 140.58 g of anisole and 124.93 g of methane sulfonic acid was heated at 100° C. for 24 hours. The mixture was poured into 700 g of ice water and worked up substantially according to the previously described procedure to give 67.6 g of 4-methoxyphenyl-bis-(4-phenoxyphenyl)sulfonium methane sulfonate (91 percent yield).