Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[Br:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:15][CH2:16][C:17]([C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([Br:5])[CH:7]=2)[NH:12][CH:13]=1)=[O:18]
Reactant: O=C(Cl)CBr
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (338 mg, 2.54 mmol) in dichloromethane (10 mL) was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.507 mmol). After stirring for 30 min, bromoacetyl chloride (0.21 mL, 2.54 mmol) was added and the reaction mixture was stirred for 2 h, before quenching with MeOH at 0° C. The mixture was concentrated in vacuo, the pH was changed to 7 by addition of a saturated solution of aqueous sodium bicarbonate, and the aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO4 and filtered through a plug of silica gel. Solvent was evaporated to dryness to give 2-bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid (160 mg, quantitative). 1H NMR (500 MHz, DMSO-d6) δ 4.70 (s, 2H), 8.44 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.5 Hz, 1H), 8.68 (d, J=3.5 Hz, 1H), 12.9 (s, 1H). MS: m/z 316 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:28]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:28][C:8]=4[N:9]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)nc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2oc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)nc2c1
Reaction time: 4 h
Yield: 54.6 %

Procedure:
27 mg (0.0703 mmol) of 5-nitro-2-(4′-trifluoromethyl-[1,1′-biphenyl]-4-yl)benzo[d]oxazole was dissolved in methanol, and then, 10% Pd/C was added thereto to allow a catalytic reaction therebetween for 4 hours under hydrogen gas atmosphere. The reaction solution was diluted with ethyl acetate. Then, the diluted reaction solution was filtered with a celite pad, and then, was concentrated under reduced pressure. Afterwards, the filtered reaction solution was purified by using a silica gel column chromatography (ethyl acetate/normal-hexane at a volume ratio of 1:1) to obtain 13.6 mg (54.6%) of 2-(4′-trifluoromethyl-[1,1′-biphenyl]-4-yl)benzo[d]oxazole-5-amine (Derivative #8).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[NH4+].[Zn]>[CH2:1]([C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Product: O=C(O)c1ccc(Cl)cc1Cc1ccccc1

Procedure:
To a solution of 5.0 g of cupric sulfate in 3 liters of concentrated ammonium hydroxide solution were added 300 g (4.6 mol) of activated zinc dust and 100 g (0.42 mol) of 2-benzoyl-4-chlorobenzoic acid. The mixture was refluxed for 3 days, during which the volume was maintained by the addition of concentrated ammonium hydroxide solution. The mixture was cooled, and the excess zinc was removed by filtration. The filtrate was acidified by the addition of concentrated hydrochloric acid to a pH of 3. The resulting precipitate was collected by filtration and dried to constant weight to give a white solid, mp 142°-144° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].I[CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH3:12]
Reactant: CCI
Reactant: Oc1cccc(F)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cccc(F)c1Br
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-bromo-3-fluorophenol (5.000 g; 26.20 mmol), iodoethane (8.166 g; 52.40 mmol), and K2CO3 (4.342 g; 31.40 mmol) in anh. DMF (100 ml) was heated to 80° C., under nitrogen, for 1.5 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-bromo-1-ethoxy-3-fluorobenzene as a yellow oil. LC-MS (conditions A): tR=0.88 min.; no ionisation.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1>N1C=CC=CC=1>[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:2]=4[Cl:1])=[CH:8][CH:9]=3)=[O:12])[CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1)c1ccc(Cl)cc1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d] [1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]([OH:17])=O)(O)=[O:2].[NH4+:18].[OH-]>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][C:8]=1[O:10][CH3:11])[C:1](=[O:2])[NH:18][C:15](=[O:17])[CH2:14]2
Reactant: [NH4+]
Reactant: COc1cc(CC(=O)O)c(C(=O)O)cc1OC
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(cc1OC)C(=O)NC(=O)C2

Procedure:
A solution of 8.2 g (34.1 mmol) of 2-carboxy-4,5-dimethoxybenzeneacetic acid (Tetrahedron 1975, 31, 2607) in 17 ml of concentrated NH4OH is evaporated to dryness. This operation is repeated. The resulting tan solid ammonium salt is suspended in 34 ml of 1,2-dichlorobenzene. The stirred mixture is boiled in an oil bath at 2100 while collecting some distillate during 90 m. The cooled mixture is stirred in hexane and H2O, and the resulting solid is collected by filtration. The white solid is stirred in satd NaHCO3 for 15 m, filtered, washed with H2O, and dried to give 3.45 g (46%), mp 234-238°; MS (ES−) m/z 220.1 (M−H)−1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([F:14])[CH:11]=[C:12]([F:13])[C:5]=2[N:4]=1.[CH3:15][Si:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19]>>[F:13][C:12]1[C:5]2[N:4]=[C:3]([CH2:2][CH2:19][C:18]#[C:17][Si:16]([CH3:21])([CH3:20])[CH3:15])[N:7]([CH3:8])[C:6]=2[CH:9]=[C:10]([F:14])[CH:11]=1
Reactant: Cn1c(CCl)nc2c(F)cc(F)cc21
Reactant: CC#C[Si](C)(C)C
Product: Cn1c(CCC#C[Si](C)(C)C)nc2c(F)cc(F)cc21
Yield: 90.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from 2-(chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (440 mg, 2.03 mmol) and trimethyl(prop-1-ynyl)silane (274 mg, 2.44 mmol). 4,6-difluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (539 mg, Yield: 91%) was obtained as a brown oil which can be used in the next step without any purification.
Reaction SMILES: O[N:2]1[C:7]2=[CH:8][N:9]=[N:10][C:6]2=[CH:5][N:4]=[CH:3]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][N:2]1[C:7]2=[CH:8][N:9]=[N:10][C:6]2=[CH:5][N:4]=[CH:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: On1cncc2nncc1-2
Product: Cln1cncc2nncc1-2

Procedure:
The compounds of Formula (5) that are pyrazolopyrimidines of the structure ##STR38## where E is CR1 and X is NH2, Scheme 12, can be synthesized from the corresponding 4-hydroxypyrazolopyrimidine of Formula (25) and phosphoryl chloride to give the corresponding 4-chloropyrazolopyrimidine of Formula (27) which is then treated with ammonia to give compounds of Formula (28). ##STR39##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Yield: 98.1 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and diethylamine (0.26 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide (0.38 g, 98%) was provided after purification. MS (ESI) m/z 376. HPLC purity 100.0% at 210-370 nm, 10.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH2:19]O)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.P(Br)(Br)[Br:28]>C1(C)C=CC=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:19][Br:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(CO)cc1C12CC3CC(CC(C3)C1)C2
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(CBr)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.72 g (10 mmol) of the above benzyl alcohol (a), 30 ml of toluene and 800 μl (10 mmol) of pyridine were introduced into a three-necked flask. A solution of 940 μl (10 mmol) of phosphorus tribromide in 9 ml of toluene was added dropwise, at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction medium was evaporated to dryness and the residue was taken up in water and ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated from hexane, filtered and dried. 2.35 g (70%) of the expected benzyl bromide, having a melting point of 95°-9° C., were recovered.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[F:25][C:26]([F:53])([F:52])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:37]2[CH2:41][C:40]([CH:43]=O)([CH3:42])[C:39]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)=[N:38]2)=[O:36])=[CH:30][CH:29]=1>C(Cl)Cl.[Zn]>[F:53][C:26]([F:25])([F:52])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:37]2[CH2:41][C:40]([CH:42]=[C:20]([Br:24])[Br:21])([CH3:43])[C:39]([C:45]3[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=3)=[N:38]2)=[O:36])=[CH:30][CH:29]=1
Reactant: CC1(C=O)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C=C(Br)Br)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
To 1.5 g of zinc dust (23.8 mmole) and 5.2 g of triphenylphosphine (20 mmole) in 20 ml of methylene chloride was added 6.8 g of carbon tetrabromide (20 mmole) after stiring for 90 minutes a solution of 3 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-formyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide in 10 ml of MeCl2 is added and the mixture is stirred an additional 60 minutes. The reaction is partitioned between ether and aqueous sodium thiosulfate, dried, rotovaped and chromatographed (ether/hexane) to yield 2.0 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-(2,2-dibromovinyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide an oil. NMR data was consistent with the structure.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([OH:3])=[O:2].S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].[CH2:24](Cl)Cl>>[C:1]([CH2:4][S:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:24])=[O:10])([OH:3])=[O:2]
Reactant: ClCCl
Reactant: Cc1c(SCC(=O)O)cccc1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(SCC(=O)O)c1C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
14.3 g (0.06 mmol) of 3-carboxymethylthio-2-methylbenzoic acid are dissolved in 300 ml of methylene chloride and 13.1 g (0.11 mmol) of thionyl chloride are added dropwise. The mixture is refluxed for 1 hour and the solvent and excess thionyl chloride are then distilled off. The residue is taken up in 100 ml of methylene chloride and treated with 31.8 g (0.24 mmol) of aluminum trichloride. The reaction is stirred at about 20° C. for 1 hour. The mixture is then added to ice-water and the organic phase is separated off. After washing and drying the organic phase, the solvent is removed. The product is reacted further without purification.
Reaction SMILES: [BH4-].[Na+].[I-].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[CH2:19][CH2:18][N+:17]=2[CH3:30])[CH2:15][CH2:14][CH2:13]1)#[N:5].[OH-].[Na+].[C:33]([C:41]([C:56]([OH:58])=[O:57])([OH:55])[C:42]([C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([OH:46])[C:43]([OH:45])=[O:44])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(OCC)(=O)C.CCOCC.CC(O)C.CO>[C:47]([C:42]([C:43]([OH:45])=[O:44])([OH:46])[C:41]([C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([OH:55])[C:56]([OH:58])=[O:57])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([CH:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[CH2:19][CH2:18][N:17]2[CH3:30])[CH2:15][CH2:14][CH2:13]1)#[N:5]
Reactant: COc1cc2c(cc1OC)C(C1(c3ccccc3C#N)CCC1)=[N+](C)CC2
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Agent: [BH4-]
Agent: [I-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1OC)C(C1(c3ccccc3C#N)CCC1)N(C)CC2
Reaction time: 2 h

Procedure:
Sodium borohydride (0.465 G) was added portionwise to a mixture of 1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-3,4-dihydroisoquinolinium iodide (6 g) and methanol (40 ml). The mixture was stirred for 2 hours then poured onto aqueous sodium hydroxide solution and the product extracted into ether. The solvent was removed from the extracts to give a gum which was dissolved in ethyl acetate and a little propan-2-ol. A 0.4M solution of (±)-dibenzoyltartaric acid in ether (35 ml) was added and the resulting suspension was concentrated in vacuo. The residual solid was washed with ether to give 1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (±)-dibenzoyltartrate (7.2 g), m.p. 109°-112° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(O)C=CC=CC=1.Br.CC(O)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCOC(c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CNCCO2)cc1
Temperature: 75 °C

Procedure:
A mixture of 2-(4-Nitrophenyl)-4-tosylmorpholine (I85) (430 mg, 1.19 mmol), phenol (670 mg, 7.12 mmol) and 33% HBr/AcOH (2.2 mL) was heated in a sealed tube (microwave tube, conventional heating) at 75° C. for twenty hours. The cooled mixture was concentrated and the residue loaded onto a 10 g SCX cartridge in methanol. The cartridge was washed with methanol (200 mL), then eluted with 1% methanolic methylamine (100 mL). The methylamine eluent was evaporated to give the title compound (I86) (204 mg, 83%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.27-8.18 (m, 2H), 7.57-7.51 (m, 2H), 4.63 (dd, J=10.3, 2.5 Hz, 1H), 4.13-4.04 (m, 1H), 3.82 (td, J=11.3, 3.1 Hz, 1H), 3.13 (dd, J=12.3, 2.5 Hz, 1H), 3.06-2.92 (m, 2H), 2.74 (dd, J=12.3, 10.3 Hz, 1H). LCMS Method C: rt 1.49, 1.58 min; m/z 209.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7])([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)=[O:7]
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Reaction time: 24 h
Yield: 70.6 %

Procedure:
0.5 g (0.00147 mol) of 1-benzyl-piperidin-4-yl 2-nitro-benzoate was dissolved in 20 ml of ethanol and treated with 0.05 g of Raney-nickel. The mixture was hydrogenated at room temperature under normal pressure for 24 hrs. The catalyst was filtered off and the solvent was removed completely. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.322 g (71%) of 1-benzyl-piperidin-4-yl 2-amino-benzoate was obtained as yellow crystals; m.p. 87°-88°.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([Cl:15])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[Cl-].[CH:71]1([C@@H:74]([NH3+:79])[C:75]([F:78])([F:77])[F:76])[CH2:73][CH2:72]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[Cl:15][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:2]([NH:79][C@H:74]([CH:71]4[CH2:73][CH2:72]4)[C:75]([F:78])([F:77])[F:76])=[N:3][CH:4]=[C:5]([C:16]#[N:17])[C:6]=3[NH:7][C:8]=2[CH:9]=1
Reactant: [NH3+][C@H](C1CC1)C(F)(F)F
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1cc(Cl)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: N#Cc1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(Cl)ccc12
Temperature: 85 °C

Procedure:
1,7-Dichloro-5H-pyrido[4,3-b]indole-4-carbonitrile (5.0 g, 19 mmol), Pd2(dba)3 (0.873 g, 0.954 mmol), BINAP (1.782 g, 2.86 mmol), and sodium tert-butoxide (9.17 g, 95 mmol) were added to a flask. DME (125 ml) was added immediately followed by the addition of (1R)-1-cyclopropyl-2,2,2-trifluoroethanaminium chloride (5.02 g, 28.6 mmol). The reaction mixture was purged with nitrogen for 10 min, and heated at 85° C. overnight. The reaction was diluted with EtOAc, washed with water and brine, dried (magnesium sulfate), concentrated, and purified by flash chromatography to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 12.63 (s, 1H); 8.56 (d, 1H); 8.40 (s, 1H); 7.54 (d, 1H); 7.47 (d, 1H); 7.36 (dd, 1H); 4.78 (m, 1H); 1.56 (m, 1H); 0.73 (m, 1H); 0.62 (m, 1H); 0.52 (m, 1H); 0.37 (m, 1H). LRMS (APCI) calc'd for (C17H12ClF3N4) [M+H]+, 365.1. found 365.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]=12.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][OH:27])=[CH:23][CH:22]=1>>[ClH:2].[Cl:16][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:17][CH2:18][CH2:19][C:4]3=[C:3]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][OH:27])=[CH:23][CH:22]=3)[CH:8]=2)[CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: Clc1cc(Cl)cc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3cc(Cl)cc(Cl)c3)nc3c2CCC3)cc1
Yield: 45.2 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 4-aminophenethyl alcohol (0.055 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.065 g, 65%) as a light yellow solid. MW=435.77. 1H NMR (DMSO-d6, 300 MHz) δ 14.15 (s, 1H), 9.69 (s, 1H), 7.88 (d, J=1.8 Hz, 2H), 7.87-7.83 (m, 1H), 7.33 (s, 4H), 7.07 (s, 1H), 3.64 (t, J=6.9, 2H), 3.13 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.28-2.17 (m, 2H); APCI MS m/z 399 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10](OC)OC)=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: COC(CSc1ccc(Cl)cc1)OC
Solvent: Clc1ccccc1
Product: Clc1ccc2sccc2c1
Yield: 31.8 %

Procedure:
A mixture of polyphosphoric acid (11.2 g) in chlorobenzene (290 mL) was heated to reflux and added, under nitrogen, dropwise in about one hour 1-chloro-4-(2,2-dimethoxy-ethylsulfanyl)-benzene (compound PRE9; 9.12 g, 39.2 mmol). The reaction mixture was then heated for one night until reaction is complete, cooled, quenched with water (150 mL) and extracted into methylene chloride (200 mL). Combined organic layer was dried over Na2SO4 and concentrated to give a crude residue that was purified by flash chromatography (silica, eluting solvent: petroleum ether) to give 2.1 g of 5-chloro-benzo[b]thiophene (limpid oil) (Yield=32%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:24]([NH2:26])=[O:25])[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:27].[Na+]>[Ag]=O>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:24]([NH2:26])=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:27])=[O:21])=[CH:22][CH:23]=2)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=O)cc1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
The above compound was prepared from 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzaldehyde by heating with silver oxide in the presence of 1N sodium hydroxide solution for 20 minutes in a steam bath, subsequent acidification with 2N sulfuric acid at a pH of 5, extraction with ethyl acetate, and purification by column chromatography on silica gel (toluene/acetone=1:1).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:8]1)(=O)=O.[CH3:24][C:25]1([CH3:37])[C:29]([CH3:31])([CH3:30])[O:28][B:27]([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)[O:26]1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[CH2:8][CH:7]([CH2:6][N:35]2[CH:36]=[C:32]([B:27]3[O:26][C:25]([CH3:37])([CH3:24])[C:29]([CH3:31])([CH3:30])[O:28]3)[CH:33]=[N:34]2)[CH2:11][C:10]1=[O:12]
Reactant: COc1ccc(CN2CC(COS(C)(=O)=O)CC2=O)c(OC)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CC(Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)CC2=O)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of [1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-3-yl]methyl methanesulfonate (1.5 g, 4.2 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.0 mmol), NaI (64.0 mg, 0.04 mmol) and K2CO3 (1.2 g, 8.4 mmol) in DMF (15 mL) was stirred at 80° C. for 8 hours. The mixture was diluted with water and extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford racemic 1-(2,4-dimethoxybenzyl)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}pyrrolidin-2-one which was used in next step without purification. MS ESI calc'd. for C23H33BN3O5 [M+H]+ 442. found 442.