Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][S:15][CH2:16][C:17]([F:31])([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=2)[C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[O:1]([C:8]1[N:13]=[C:12]([CH2:14][S:15]([CH2:16][C:17]([F:31])([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=2)[C:18]([F:21])([F:19])[F:20])=[O:40])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc(C(F)(CSCc2cccc(Oc3ccccc3)n2)C(F)(F)F)cc1
Solvent: ClCCl
Product: CCOc1ccc(C(F)(CS(=O)Cc2cccc(Oc3ccccc3)n2)C(F)(F)F)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A solution of 1,1,1,2-tetrafluoro-2-(4-ethoxyphenyl)prop-3-yl 6-phenoxy-2-pyridylmethyl sulphide (0.1 g) in dichloromethane (7 cm3) was cooled to -30° C. and meta-chloroperbenzoic acid (0.078 g) was added. The solution was allowed to warm to -20° C., and was stirred at this temperature for 30 minutes. Silical gel (3 g) was added to the reaction mixture and the solvent was then evaporated under reduced pressure. The residue was applied to a silica gel column, and eluted with diethyl ether containing 30% petroleum ether. Evaporation of the major product containing fraction gave 1,1,1,2-tetrafluoro-2-(4-ethoxyphenyl)prop-3-yl 6-phenoxy-2-pyridylmethyl sulphoxide as a colourless oil (0.095 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[CH:20]=[CH:21][CH2:22][OH:23])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[CH:20]=[CH:21][CH2:22][OH:23])=[CH:25][CH:26]=1)[CH:11]=[N:10]2
Reactant: CC(C=CCO)Oc1ccc(O)cc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.99 g (10 mmol) of 2,6-dichloroquinoxaline, 2.13 g (11 mmol) of 4-(4-hydroxyphenoxy)-2-penten-1-ol, 1.73 g (12.5 mmol) of powdered, anhydrous potassium carbonate and 50 ml of dry acetonitrile was warmed at reflux under nitrogen for a period of 3 hours. The mixture was cooled to room temperature, and the solid filtered off and washed well with ether. The filtrates were combined and evaporated to dryness, and the residue partitioned between ether and 2 percent aqueous sodium hydroxide. The aqueous layer was separated and extracted again with ether. The combined organic layers were washed with water, dried over MgSO4 and evaporated to dryness. The residual solid was purified by preparative scale HPLC, eluting with 7:3 hexane:ethyl acetate, to give a solid which was recrystallized from toluene. This gave 2.60 g (73%) of the desired pentenol as pale yellow crystals, having a melting point (m.p.) of 124°-126° C. (Compound C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: Cc1ccc(S(=O)(=O)N2C(=O)C(=O)c3cc(Cl)ccc32)cc1

Procedure:
5-chloro-N-(p-tolylsulfonyl)-isatin was prepared by the method of Example 3, Step B from 5-chloroisatin and p-tolylsulfonyl chloride.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:7]1[C:12](=O)[C:11](Cl)=[C:10](Cl)[C:9](=O)[C:8]=1Cl>C1(C)C=CC=CC=1>[C:7]1([C:2]2[O:1][C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]3[C:3]=2[CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:2]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccoc1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3c(-c4ccccc4)oc(-c4ccccc4)c3cc2-c2ccccc2)cc1

Procedure:
Next, the dihydro-compound of furan and tetrachloro-p-benzoquinone (chloranyl) in toluene were heated under reflux to effect dehydrogenation, yielding 1,3,5,6-tetraphenylisobenzofuran.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][OH:5].[OH-].[K+].Cl[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)=[O:17].Cl>CN1CCCC1=O>[CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][O:5][CH2:15][C:16]([C:18]1[CH:19]=[C:20]([CH:28]([CH3:30])[CH3:29])[C:21]([OH:27])=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1)=[O:17]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)=CCC/C(C)=C/COCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of 86.4 g (560 mmol) of (E)-3,7-dimethyl-octa-2,6-dien-1-ol and 64.5 g (1150 mmol) of potassium hydroxide in 150 ml of N-methylpyrrolidone a solution of 58.59 g (230 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-iso-propylphenyl)-ethanone in 100 ml of N-methylpyrrolidone is added dropwise at room temperature and under inert atmosphere. After the addition is completed stirring is continued for additional 16 hours. Then the reaction mixture is acidified with 1N HCl and extracted with ethyl acetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 45.3 g of compound 108, m.p. 70-71° C.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:39][C:40]([CH3:42])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([CH:40]([CH3:42])[CH3:39])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a stirred solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 149) (115 mg, 0.279 mmol) in anhydrous DMF (2 ml) was added triethylamine (780, 0.558 mmol) and anhydrous acetone (100 μL). The reaction was stirred at RT for 30 minutes after which time sodium triacetoxyborohydride (118 mg, 0.558 mmol) was added and the reaction was stirred for a further 2 hours at RT. The reaction was then partitioned between H2O and DCM and the aqueous phase was extracted into DCM. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at high pH to yield the title compound (16 mg, 13%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.C(Cl)(Cl)Cl.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.[Fe]>[F:1][C:2]([F:6])([F:5])[S:3][C:12]1[CH:13]=[C:14]([S:3][C:2]([F:6])([F:5])[F:1])[CH:15]=[C:16]([S:3][C:2]([F:6])([F:5])[F:1])[C:11]=1[OH:17]
Reactant: FC(F)(F)SCl
Reactant: Oc1ccccc1
Agent: [Fe]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Oc1c(SC(F)(F)F)cc(SC(F)(F)F)cc1SC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Condensed 32.5 g of trifluoromethylsulphenyl chloride was placed in a pressured bottle in a dry ice bath. 60 ml of chilled chloroform was added under nitrogen, followed by the addition of 5.6 g of phenol in 16 g of pyridine and 0.8 g of iron powder. The mixture was stirred in a closed bottle at room temperature for two days. The solution was then washed with water and diluted with hydrochloric acid. After removal of the solvent, the crude product was distilled with a column. The yield was 10 g. The b.p. was 51° C./0.1 mm. NMR (CDCl3), δ 8.1 (s) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:18][O:19][CH3:20])[CH2:9][CH2:8][N:7]([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]([C:5]1([CH2:18][O:19][CH3:20])[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6]1)=[O:4]
Reactant: COCC1(C(=O)OC)CCN(CC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: COCC1(C(=O)OC)CCN(CC(=O)O)C1
Reaction time: 0.33 h

Procedure:
The 1-tert-butoxycarbonylmethyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (118 mg) was treated with trifluoroacetic acid (2 ml), stirred for 20 minutes and evaporated to a residue that was exchanged with hydrochloric acid (1 ml, 4N) and lyophilized overnight to a gummy title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:11](=[O:22])[NH:12][CH2:13][CH:14]=[C:15]([CH2:16][C:17]([N:19]=[N+]=[N-])=[O:18])[C:5]2=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]N>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:19][C:17](=[O:18])[CH:16]=[C:15]1[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]=2[C:11](=[O:22])[NH:12][CH2:13][CH2:14]1
Reactant: CN(C)CCN
Reactant: [N-]=[N+]=NC(=O)CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)C=C1CCNC(=O)c2[nH]c3ccc(F)cc3c21
Temperature: 110 °C

Procedure:
A suspension of (7-Fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetyl azide, prepared as in reference 17, (10 mg, 0.33 mmol) and N,N-dimethylethylene-diamine (15 mg, 0.17 mmol) in dry toluene (1 mL) is heated at 110° C. for 1 hour. Toluene is removed in vacuum and the residue is purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.5% TFA) to afford N-(2-dimethylamino-ethyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide; 1H NMR (DMSO-d6) δ 2.85 (s, 6H), 3.19-3.22 (m, 2H), 3.25-3.30 (m, 2H), 3.44-3.48 (m, 2H), 3.49 (q, 2H, J=6.8 Hz), 6.34 (s, 1H), 7.18 (dt, 1H, J1=2.8 Hz, J2=8.8 Hz), 7.50 (dd, 1H, J1=4.4 Hz, J2=8.8 Hz), 7.74 (dd, 1H, J1=2.8 Hz, J2=10.4 Hz), 8.39-8.44 (m, 2H), 9.36 (bs, 1H), 12.12 (s, 1H); m/z [M++1] 345.1.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5]>CC1C=CC(C)=CC=1>[C:4]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)/C=C\C(=O)OCC

Procedure:
In a 500 ml four-necked flask were charged 305 mmol (52.5 g) of diethyl fumarate obtained by isomerization of diethyl maleate and 400 ml of p-xylene. The flask was provided with a thermometer, a dropping funnel and a condenser, and put in an oil bath. While maintaining the temperature at 135° C. under stirring with a magnetic stirrer and refluxing under a flow of nitrogen, a solution of 35 mmol (5.8 g) of AIBN (2,2-azobisisobutyronitrile) in p-xylene was added dropwise over 11 hours. The heating and refluxing were continued for further 19 hours. The solvent and unreacted reactant were then distilled off under reduced pressure to obtain 49 g of a reaction product with a yield of 94%.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:22]([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN>ClCCl>[CH3:22][NH:24][C:19](=[O:21])[CH2:18][C:17]1[C:9]2[O:8][C:7]([C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=3)=[CH:12][C:11](=[O:13])[C:10]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Agent: CN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CNC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (568 mg) and triethylamine (0.34 ml) were added to dichloromethane (6 ml) and to the mixture was added dropwise diphenylphosphoryl azide (0.52 ml) with stirring at room temperature. After stirring for 30 minutes, 30% aqueous methylamine solution (5 ml) was added and stirring was continued for additional 2 hours. The solvent was distilled off under reduced pressure and n-hexane was added to the residue. Crystals deposited were filtered. The crude crystals were recrystallized from methanol to obtain the title compound as prisms, yield 380 mg (64%), m.p. 213°-214° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:16])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: Cc1cc(-c2ccc(F)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (46 mg, 79%), MS (ISP) m/z=313.4 [(M+H)+], mp 249.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 10) (52 mg, 0.186 mmol) and commercially available 3,4-difluoro-phenylboronic acid (38.2 mg, 0.24 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)#[CH:25].CO>C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C#Cc2cc3ncc(C#N)c(Nc4cc(OC)c(Cl)cc4Cl)c3s2)cc1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (134 mg, 0.28 mmol), 1-ethynyl-4-methoxybenzene (50 μL, 0.39 mmol), 3 mg of tetrakis(triphenylphosphine)palladium(0) and 5 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 24 hours. An additional 1 mL of triethylamine and 4 mL of benzene are added and the reaction is heated at reflux for 6 hours. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of ethyl acetate. The insoluble material is removed by filtration, washing with ethyl acetate. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 4:1 hexane:ethyl acetate to provide 92 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 249-250° C.; 1H NMR (DMSO-d6) δ 3.81 (s, 3H), 3.86 (s, 3H), 7.01 (d, J=7 Hz, 2H), 7.40 (s, 1H), 7.55 (d, J=7 Hz, 2H), 7.70 (s, 1H), 7.79 (s, 1H), 8.65 (s, 1H), 9.81 (s, 1H); MS 477.9, 479.9 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[C:18](Cl)[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([F:24])([F:25])[F:23])=[C:16]([Cl:15])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Temperature: 25 °C

Procedure:
A stirred mixture of D7 (5.0 g, 25 mmol), 2,6-dichloro-3-trifluoromethyl-pyridine (5.4 g, 25 mmol) and cesium carbonate (12.22 g, 37.5 mmol) in 1,4-dioxane (75 mL) was heated at reflux under argon for 64 h. To the mixture, which was cooled to ambient temperature, was added water (250 mL) and DCM (250 mL) with shaking and the layers were separated. The aqueous phase was further extracted with DCM (250 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo to an oil. This material was purified by chromatography over silica gel eluting with a gradient of ethyl acetate/hexane to afford the title compounds
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:28]=[C:29]([CH2:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=1>>[O:36]=[C:34]([CH3:35])[CH2:33][C:29]1[CH:28]=[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)Cc1cccc(Br)c1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Product: CC(=O)Cc1cccc(-c2ccc3c(c2)CC(NS(=O)(=O)C(C)C)C3)c1

Procedure:
The title compound was prepared from N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide and 1-(3-bromophenyl)-2-propanone in a similar manner to Example 1.
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C([Mg]Cl)(C)C.C(C(CC=C)CO[SiH2]C1C=CC([Mg]Cl)=CC=1)C=C.[CH3:41][Sn:42](Cl)([CH3:44])[CH3:43]>O.C1COCC1>[CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn:42]([CH3:44])([CH3:43])[CH3:41])=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C[Sn](C)(C)Cl
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Agent: C=CCC(CC=C)CO[SiH2]c1ccc([Mg]Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(CC=C)CO[SiH2]c1ccc([Sn](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 96 %

Procedure:
At first, a THF solution (2 mL) of the 4-(diallylethoxysilyl)iodobenzene (202 mg, 0.56 mmol) obtained in Example 2 was added dropwise with 2 mol/L of i-PrMgCl (0.59 mL (solvent: THF), 1.18 mmol) at −30° C. Then, the resultant solution was stirred under a nitrogen atmosphere at −30° C. for 1.5 hours to obtain a THF solution containing 4-(diallylethoxysilyl)phenylmagnesium chloride (Grignrad solution). Subsequently, the obtained Grignrad solution was added dropwise with 1 mol/L of trimethyl tin chloride (Me3SnCl: 1.18 mL (solvent: THF), 1.18 mmol) at −30° C. to obtain a reaction mixture. Thereafter, the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 13 hours, and added with distilled water to terminate the reaction. After that, the organic layer was separated from the reaction mixture, and the aqueous layer was extracted with ether to collect the organic layer. Subsequently, the organic layer thus collected was washed with sat.NaHCO3 and sat.NaCl, dried with MgSO4, filtered, and concentrated to obtain a crude product. Thereafter, the crude product thus obtained was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1), and thereby 4-(diallylethoxysilyl)phenyl-trimethyltin was obtained (214 mg, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:23])[CH:21]=[CH2:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[Li]OC(C)=O.O.O.[Li+].[Cl-].I[C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:23])[CH2:21][CH2:22][C:34]4[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=4[C:36]([O:38][CH3:39])=[O:37])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: COC(=O)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A degassed suspension of the product of Step 1 (50.3 g, 156 mmol), n-Bu4NCl (86.0 g, 312 mmol), LiOAc.2H2O (41.2 g, 390 mmol), LiCl (6.84 g, 156 mmol), Pd(OAc)2 (1.00 g, 4.7 mmol), and methyl 2-iodobenzoate (41.00 g, 156 mmol) in DMF (300 mL) was stirred for 3 hours at 90° C. The dark red solution was then cooled to r.t. and poured into 2 L of ice cold H2O. The product was extracted with hot EtOAc, dried over Na2SO4, filtered and concentrated to dryness. It was dissolved in 600 ml of hot toluene and filtered through a small silica pad (1 L). The title product was finally recrystallized from EtOAc:hexane 1:1 (1.2 L). The title product was finally recrystallized from EtOAc:hexane 1:1 (1.2 L). Recrystallization of the mother liquors in EtOAc:hexane 1:3 ( 400 mL) afforded a second crop of the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:39][CH3:40])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:22]>C(O)C.N1CCCCC1>[CH2:39]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide as a yellow solid (72.6 mg, 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH2:23]([N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: O=C1CN(CCc2ccccc2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 38.2 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (370 mg, 1.01 mmol) and 4-phenethylpiperazin-2-one (197 mg, 0.965 mmol) were reacted according to Example 2 (step f) to provide the title compound (180 mg, 39%) as a yellow powder: 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 1H), 7.35-7.28 (m, 2H), 7.27-7.18 (m, 4H), 6.99-6.97 (dd, J=8.3, 1.8 Hz, 1H), 4.61 (br s, 2H), 3.74 (br s, 4H), 3.60 (s, 3H), 3.45 (br s, 2H), 2.91 (br s, 4H), 2.74 (br s, 4H), 1.50 (s, 9H).