Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([Si](C)(C)C)[S:4][C:3]=1[C:11]1[S:12][C:13]([Si](C)(C)C)=[CH:14][C:15]=1Br.C([Li])CCC.Cl[Si:27](Cl)([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>O1CCCC1.CCCCCC>[CH2:38]([Si:27]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:11]2[S:12][CH:13]=[CH:14][C:15]1=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: C[Si](C)(C)c1cc(Br)c(-c2sc([Si](C)(C)C)cc2Br)s1
Reactant: CCCCCCCCCC[Si](Cl)(Cl)CCCCCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCCCC[Si]1(CCCCCCCCCC)c2ccsc2-c2sccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
3,3′-dibromo-5,5′-bis(trimethylsilyl)-2,2′-bithiophene (Compound E4, synthesized in accordance with WO 2010/136353, 5.0 g) was placed in a 200 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (75 mL). This was cooled to −78° C., and a solution of n-butyl lithium in hexane (KANTO CHEMICAL CO., INC., 1.64 M, 13.7 mL) was added dropwise. After about 30 minutes of agitation, the dichlorodi-n-decylsilane (Compound E21) (4.89 g) synthesized in Synthesis Example A19 was added dropwise. The temperature was gradually raised to room temperature over the course of about 2 hours, after which water was added, and the product was extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, and concentrated by filtration. The resulting yellow-orange oily substance was dissolved in hexane (50 mL) and chloroform (25 mL), trifluoroacetic acid (2.2 mL) was added with the internal temperature at 2° C., and after 10 minutes of agitation water was added, and the organic layer was washed, dried with anhydrous sodium sulfate and then and concentrated by filtration. Heptane (32 mL) was added to the reaction solution, which was then concentrated under reduced pressure. The resulting yellow-green oily substance was dissolved in hexane, and subjected to silica gel column chromatography (solvent: hexane) to obtain the target 4,4-di-n-decyl-dithieno[3,2-b:2′,3′-d]silole (Compound E22, 4.46 g, yield 88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[CH:4][C:5]([Cl:17])=[C:6]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)[CH:7]=1.[N:19]([O-])=O.[Na+]>Cl.O>[ClH:17].[Cl:18][C:3]1[CH:4]=[C:5]([Cl:17])[C:6]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[CH:7][C:2]=1[NH:1][NH2:19]
Reactant: CC1(C)CON(Cc2cc(N)c(Cl)cc2Cl)C1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CON(Cc2cc(NN)c(Cl)cc2Cl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
A solution of 2-[(5-amino-2,4-dichlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (16.3 g, 0.564 mole) in concentrated hydrochloric acid (75 ml) was cooled to 0° C., and a solution of sodium nitrite (3.9 g, 0.564 mole) in water (50 ml) was added dropwise with the tip of the addition funnel below the surface of the solution. The reaction mixture temperature was kept below 2° C. during the addition. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes, and then stannous chloride (28 g, 0.124 mole) in concentrated hydrochloric acid (50 ml) was added dropwise maintaining the temperature below 2° C. The reaction mixture was stirred for one hour at 0° C., and then a tan solid was removed by filtration to yield 10.0 g of [2,4-dichloro-5-[(4,4-dimethyl-3-oxoisoxazolidin-2-yl)methyl]phenyl]hydrazine hydrochloride; m.p. 202°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([NH:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:16]=1>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18]([C:19](=[O:21])[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[C:12](=[O:13])[N:24]2[CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(Cl)cc1NCc1cccnc1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=c1c2ccc(Cl)cc2n(Cc2cccnc2)c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 16.6 %

Procedure:
580 mg (2.68 mmol) of 4-chlorobenzenesulfonylisocyanate and 600 mg (2.28 mmol) of 4-chloro-2-(3-pyridylmethyl)aminobenzoic acid were treated in the same way as in Example 1 to obtain 175 mg of the above-identified compound (yield 16.6%). Properties: colorless crystal, Melting point: >190° C. (decomposition), PMR (δppm, DMSO-d6):5.29 (2H,s), 7.3-7.4 (2H,m), 7.39 (1H,s), 7.68 (1H,d), 7.79 (2H,d), 7.97 (1H,d), 8.20 (2H,d), 8.46 (1H,d), 8.57 (1H,d).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([NH:6][C@@H:7]1[C:13]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=2[C:11]2[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:10]=2[CH2:9][CH2:8]1)(=[O:5])=[O:4].Cl[C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C>C(#N)C>[C:31](=[O:32])([O:33][CH3:34])[O:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11]3[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:6][S:3]([N:2]([CH3:1])[CH3:29])(=[O:5])=[O:4])[C:13]=2[CH:14]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1[C@@H](NS(=O)(=O)N(C)C)CC2
Reactant: COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc2c(c1)[C@@H](NS(=O)(=O)N(C)C)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 32 %

Procedure:
A solution of (5S)-5-{[(dimethylamino)sulphonyl]amino}-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ol (1) (0.9; 0.71 mmol), methyl chloroformate (0.061 ml; 0.782 mmol) and triethylamine (0.109 ml; 0.782 mmol) in acetonitrile (8 ml) was stirred under argon atmosphere at 40° C. for 4 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with ethanol/dichloromethane (2/98) to give (5S)-5-{[(dimethylamino)sulphonyl]amino}-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl methyl carbonate.
Reaction SMILES: [ClH:1].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(N[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[NH:20])=[CH:14][CH:13]=1)=O)(C)C.NC1C=CC([C:41]([NH:43][NH:44][C:45]([NH:47][C:48]2[CH:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51]([OH:58])=[C:50]([C:59]([CH3:62])([CH3:61])[CH3:60])[CH:49]=2)=[O:46])=[O:42])=CC=1.CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NC1C=CC(N)=CC=1)=O)(C)C>>[ClH:1].[CH3:57][C:54]([C:52]1[CH:53]=[C:48]([NH:47][C:45]([NH:44][NH:43][C:41]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[NH:20])=[CH:14][CH:13]=2)=[O:42])=[O:46])[CH:49]=[C:50]([C:59]([CH3:60])([CH3:61])[CH3:62])[C:51]=1[OH:58])([CH3:55])[CH3:56]
Reactant: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc(NC(=N)c3cccs3)cc2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C(=O)Nc2ccc(N)cc2)cc(C(C)(C)C)c1O
Agent: Cl
Product: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc(NC(=N)c3cccs3)cc2)cc(C(C)(C)C)c1O
Yield: 58 %

Procedure:
The experimental protocol used is the same as that described for compound 1, with N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. The free base is purified on a silica column (eluant: heptane/ethyl acetate: 1/1). The pure fractions are collected and concentrated under reduced pressure. The evaporation residue is diluted in 15 ml of acetone and salified with a molar solution of HCl in anhydrous ether, as described previously. 0.40 g (58%) of a yellow powder is obtained. Melting point: 254-255° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:17]([Li])CCC.[C:22]([Si:26]([CH3:56])([CH3:55])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[C:32]3[C:45](=[O:46])[O:44][C:43]4[CH:42]=[C:41]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:40]=[CH:39][C:38]=4[C:33]=3[CH2:34][O:35][C:36]=2[CH:37]=1)([CH3:25])([CH3:24])[CH3:23].C[Mg]Br>C1COCC1>[C:51]([Si:48]([CH3:50])([CH3:49])[O:47][C:41]1[CH:40]=[CH:39][C:38]([C:33]2[CH2:34][O:35][C:36]3[C:31]([C:32]=2[C:45]([OH:46])([C:2]2[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=2)[CH3:17])=[CH:30][CH:29]=[C:28]([O:27][Si:26]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:55])[CH3:56])[CH:37]=3)=[C:43]([OH:44])[CH:42]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCc1c-2c(=O)oc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Reactant: [Li]CCCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O)COc2cc(O[Si](C)(C)C(C)(C)C)ccc21)c1ccc(OCCN2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(4-bromophenoxy)-ethyl]-piperidine (360 mg, 1.27 mmol) in THF (7.5 mL) at −78° C., was added n-butyl lithium (1.6 M in hexane, 773 μL, 1.24 mmol). The reaction mixture was stirred at −78° C. for 0.5 hours. To the reaction mixture was then added 2,8-bis-(tert-butyl-dimethyl-silyloxy)-11H-chromeno[4,3-c]chromen-5-one, prepared as in Example 22, (158 mg, 0.31 mmol) in THF (3 mL) and the mixture was stirred at −78° C. for 1.5 hours. To the reaction mixture was then added methyl magnesium bromide (3 M in diethyl ether, 1 mL, 3 mmol) at −78° C. and the reaction stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The organic layer was concentrated to yield the crude title product as a yellow oil, which was carried into the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:16]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:25]1[CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21

Procedure:
Proceeding in the same manner as that described in part A of Example 6 above, 14.3 g (0.05 mole) of tetrachlorophthalic anhydride, 16.0 g (0.052 mole) of 76.5 percent active 1-n-octyl-2-methylindole and 13.3 g (0.10 mole) of aluminum chloride were interacted to obtain 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: R°=R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =(CH2)7CH3 ; Y1 =H), a pale orange solid melting at 132°-134° C. The infrared spectrum, showing a maximum at 1745 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum was in accord with the structure.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[OH2:10].[CH:11]1[C:16](N)=[CH:15][CH:14]=[C:13](N)[CH:12]=1.[CH3:19][C:20]([CH3:22])=[O:21]>>[CH:13]1[C:22]2[C:20](=[O:21])[C:19]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:11](=[O:10])[C:15]=2[CH:16]=[CH:11][CH:12]=1
Reactant: Nc1ccc(N)cc1
Reactant: CC(C)=O
Reactant: O
Agent: Clc1nc(Cl)nc(Cl)n1
Product: O=C1c2ccccc2C(=O)c2ccccc21
Reaction time: 0.55 h

Procedure:
1-18.4 g of cyanuric chloride was placed into a beaker. A small amount of crushed ice and water were added for pulping for 0.1-1 h; during which, 1-17.4 g of 1-nitro-4-amino-6-anthraquinone in 200 ml of acetone was added with the cyanuric chloride, and condensed for 4-5 h. The temperature was increased to 40° C. p-phenylene diamine was added and condensed for 4-5 h, to obtain an anthraquinone dye comprising triazinyl group and amino group.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](O)[C:5]=1N.C(OC([O:20][CH2:21]C)OCC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+:34]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:20][CH:21]=[N:34][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1cccc(O)c1N
Reactant: CCOC(OCC)OCC
Reactant: c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc2ncoc12
Yield: 477.6 %

Procedure:
A solution of 0.22 g (1.32 mmol) of methyl-2-amino-3-hydroxybenzoate, 0.77 mL (4.6 mmol) of triethylorthoformate and 0.066 g (0.26 mmol) of pyridinium p-toluene sulfonate in 15 mL of xylene was heated at reflux for 18 h. The reaction mixture was concentrated and purified by chromatograph (silica, hexanes:EtOAc, 6:1) to give 0.22 g of the title compound.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][CH:33]=1>>[C:34]1([C:31]2[CH:30]=[CH:29][C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)=[CH:33][N:32]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1ccc(-c2ccccc2)nc1
Product: FC(F)(F)c1ccn2c(-c3ccc(-c4ccccc4)nc3)cnc2n1

Procedure:
3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was reacted with 5-bromo-2-phenylpyridine (prepared according to the procedure of Tilley and Zawoiski, J. Org. Chem., 1988, 53(2), 386-90) by the method of Example 1 to afford 3-(2-phenylpyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 7.30 (1H, d, J 7), 7.47-7.56 (3H, m), 7.96 (2H, m), 8.09 (2H, dd, J 8 and 1), 8.19 (1H, s), 8.83 (1H, d, J 7), 8.93 (1H, d, J 2); m/z (ES+) 340 (M++H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:16]([Cl:17])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)[CH:7]=1.[S-:19][C:20]#[N:21].[NH4+].BrBr.O.[C:26](O)(=O)C>>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([F:18])[C:6]([N:8]3[C:16]([Cl:17])=[C:15]4[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]4)=[N:9]3)=[CH:7][C:2]=2[CH:26]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Reactant: CC(=O)O
Agent: BrBr
Agent: [NH4+]
Solvent: O
Product: Nc1cc2cc(-n3nc4c(c3Cl)CCCC4)c(F)cc2s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
2-(5-Amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (22.97 g) was dissolved in 95% aqueous acetic acid (79.53 g), and ammonium thiocyanate (15.92 g) was added thereto at room temperature (ca. 20° C.). To the resultant mixture, a solution of bromine (15.89 g) in, acetic acid (23.77 g) was dropwise added in 105 minutes. After being allowed to stand overnight, the mixture was heated to 100° C., and hot water (173 ml) was added thereto, followed by filtration. The filtrate was cooled and neutralized with sodium carbonate. The precipitated crystals were collected by filtration and dried to give 2-(2-amino-6-fluorobenzothiaol-5-yl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (8.77 g). m.p., 212.4° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([C:20]([O:22]C)=[O:21])[CH:11]=1)#[N:2].C(O)C.O1CCOCC1.[OH-].[Na+]>O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A round-bottom flask was charged with dimethyl 2′-cyano-4′-methylbiphenyl-3,5-dicarboxylate (1.5 g, 4.4 mmol), ethanol (100 mL), 1,4-dioxane (20 mL), and a solution of sodium hydroxide (0.17 g, 4.4 mmol) in water (10 mL). The mixture was stirred at room temperature for 3 h. The volatiles were removed under reduced pressure, and the residue was acidified with 1N aq. HCl to pH=4 and extracted with CH2Cl2. The combined organic layers were dried and concentrated. The residue was purified via flash chromatography to afford the desired product 2′-cyano-5-(methoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): 13.58 (br, 1H), 8.56 (t, J=1.3 Hz, 1H), 8.34-8.31 (m, 2H), 7.85 (s, 1H), 7.65 (d, J=2.6 Hz, 2H), 3.92 (s, 3H), 2.42 (s, 3H). 3-Ethyl 5-methyl 2′-cyano-4′-methylbiphenyl-3,5-dicarboxylate was also isolated as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:13]([Si](C)(C)C)#[CH:14]>>[C:13]([C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1)#[CH:14]
Reactant: Nc1cccc2c(Br)cncc12
Reactant: C#C[Si](C)(C)C
Product: C#Cc1cncc2c(N)cccc12

Procedure:
The title compound can be synthesized from 4-ethynylisoquinolin-8-amine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 1. 4-ethynylisoquinolin-8-amine is prepared from 4-bromoisoquinolin-8-amine and ethynyitrimethylsilane according to the 2 steps procedure described in example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Mg]Br)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]2([OH:26])[CH2:24][CH2:25][N:21]([CH2:20][C:19]3[CH:27]=[CH:28][CH:29]=[C:17]([O:16][CH3:15])[CH:18]=3)[CH2:22]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(I)cc1Cl
Reactant: COc1cccc(CN2CCC(=O)C2)c1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 3,4-dichloro-1-iodobenzene (1.33 g, 4.90 mmol) in tetrahydrofuran (10 mL) at room temperature, was added isopropylmagnesium bromide (2.4 mL of a 2.0 M solution in THF, 4.9 mmol) dropwise. After 2 h, a solution of 1-(3-methoxybenzyl)pyrrolidin-3-one (500 mg, 2.43 mmol) from Step B above in tetrahydrofuran (3 mL) was added dropwise at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride (5 mL). The mixture was diluted with ethyl acetate (100 mL) and washed with saturated ammonium chloride (20 mL), water (20 mL), and brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (5% ethyl acetate/methylene chloride to 80% ethyl acetate/methylene chloride) gave 3-(3,4-dichlorophenyl)-1-(3-methoxybenzyl)pyrrolidin-3-ol (500 mg, 58%) as a yellow oil: ESI MS (m/z) 352 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](#N)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH2:21]([C:22]1[NH:3][CH2:2][CH2:1][N:4]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5]
Reactant: NCCN
Reactant: CCCCCCCCCCCCCCCCCC#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC1=NCCN1
Temperature: 210 °C
Yield: 86.7 %

Procedure:
In a 500 ml SUS 316L stainless steel autoclave were charged 60 g of ethylene diamine, 267 g of stearonitrile and 2.5 g of titanium tetraisopropoxide. After addition of 1 g of water, the mixture was heated up to 210° C. with stirring and maintained at that temperature for 4 hours while removing ammonia produced in situ to maintain the pressure within the autoclave at 8-9 kg/cm2G. The resulting mixture was then subjected to vacuum distillation at 0.6 mmHg and at 230°-235° C. to obtain 267 g of 2-heptadecyl-2-imidazoline with a yield of 86%.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([O:24][CH2:25][C:26](Cl)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][CH2:25][C:26]([NH:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=1)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1cc(Br)cnc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COCc1ccccc1)Nc1cc(Br)cnc1Br
Temperature: 0 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To the solution of 2,5-Dibromo-pyridin-3-ylamine (8.6 g, 34.12 mmol) in 50 ml of DCM was added triethylamine (5.3 ml, 37.53 mmol). Cooled the reaction mixture to 0° C. To this added the solution of 2-benzyloxy acetyl chloride (7.45 g, 40.95 mmol) in 35 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (10:90) as the eluent to provide the title compound (3.2 g, 24.17%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14][CH:15]3CO3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-]#[N:19].[Na+].[Cl-].[NH4+].O.[CH2:24]([OH:26])[CH3:25]>>[OH:26][CH:24]([CH:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)[CH3:15])[C:25]#[N:19]
Reactant: c1cc(CC2CO2)cc(CN2CCCCC2)c1
Reactant: CCO
Reactant: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CC(c1cccc(CN2CCCCC2)c1)C(O)C#N

Procedure:
0.74 g (3.2 mmol) of 2-[3-(1-piperidylmethyl)phenyl]methyl-oxirane, 0.294 g (6 mmol) of sodium cyanide and 0.107 g (2 mmol) of ammonium chloride are boiled in 5 ml of ethanol/5 ml of water for 6 hours. After extensive concentration of the mother liquor by evaporation under vacuum, the residue is taken up with 10 ml of water, and the solution is adjusted to pH 12 with potassium carbonate and extracted with 3×20 ml of methylene chloride. After dehydration and concentration under vacuum, the organic phase yields 0.82 g of a brown oil.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[NH:22]N.CS(O)(=O)=O>C(O)C>[N:1]1([CH:7]2[CH2:12][C:11]3[C:17]4[C:16](=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=4)[NH:22][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(N2CCCCC2)CC1
Reactant: NNc1ccc(F)cc1F
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Fc1cc(F)c2[nH]c3c(c2c1)CC(N1CCCCC1)CC3

Procedure:
A solution of 10.2 g. of 4-(1-piperidyl)-cyclohexanone, 8.1 g. of 2,4-difluorophenylhydrazine, and 11 g. of methanesulfonic acid in 100 ml. of absolute ethyl alcohol was heated under reflux for 12 hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was treated in ether with 10% potassium hydroxide solution and the ether extract was washed with water, dried, and treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided). The resulting gummy precipitate was separated by decantation and suspended in boiling isopropyl alcohol. The hot mixture was filtered to give, after recrystallization from absolute ethyl alcohol, 4.5 g. of 3-(1-piperidyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. > 290° C.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[C:10]([Cl:11])[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[O:22][CH3:23].[Cu][C:25]#[N:26].O.C(OCC)(=O)C>CN(C)C=O>[Cl:11][C:10]1[C:6]2[CH:5]=[C:4]([O:20][CH3:21])[C:3]([O:22][CH3:23])=[C:2]([C:25]#[N:26])[C:7]=2[S:8][C:9]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]
Reactant: N#C[Cu]
Reactant: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1OC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(C#N)c1OC

Procedure:
(7-Bromo-3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (0.7 g) and copper(I) cyanide (2.3 g) in N,N-dimethylformamide were irradiated in a microwave oven at 180° C. for 1.5 hours. To the mixture water (40 ml) and ethyl acetate (40 ml) were added. The solid was filtered and the organic phase was evaporated and dried in vacuum. The product was purified by flash chromatography using heptane-ethyl acetate as an eluent.