Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1.[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.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>[CH3:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:17]([F:24])=[CH:18][C:19]([F:23])=[CH:20][C:21]=2[F:22])=[N:4][CH:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1ccc2c(Br)cnc(-c3c(F)cc(F)cc3F)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnc(-c2c(F)cc(F)cc2F)c2cc(C(=O)O)ccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 4-bromo-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (160 mg), trimethylboroxin (117 mg), tetrakis(triphenylphosphine)palladium (23 mg), 2M aqueous sodium carbonate solution (1 mL), and 1,4-dioxane (5 mL) was heated under stirring in an oil bath at 100° C. for 4 hours. The reaction mixture was returned to room temperature and diluted with ethyl acetate, and then the insoluble materials were separated by filtration through Celite. The filtrate was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain 4-methyl-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylic acid (95 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14][C:15]=1[F:16]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:17][Br:1]
Reactant: Cc1ccc(F)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1Cl
Yield: 97.9 %

Procedure:
0.05 g of dibenzoyl peroxide and then 6.1 g of N-bromosuccinimide are added to a mixture of 5 g of 3-chloro-4-fluorotoluene and 100 ml of CCl4 and the reaction mixture is refluxed for 12 hours. The insoluble material is filtered off and washed with CCl4. The filtrate is washed with water and with saturated NaCl solution, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum to give 7.5 g of the expected product in the form of an oil, which is used as such.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:32][NH:31][CH2:30][CH2:29][C:5]=2[N:6]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:28])=[CH:12][N:13]3[S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:8]=1.[CH3:33][CH:34]([CH3:42])[C:35](=[O:41])[CH2:36][C:37](OC)=[O:38]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.ClCCl.O>[CH3:1][O:2][C:3]1[C:4]2[CH2:32][N:31]([C:37](=[O:38])[CH2:36][C:35](=[O:41])[CH:34]([CH3:42])[CH3:33])[CH2:30][CH2:29][C:5]=2[N:6]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:28])=[CH:12][N:13]3[S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:8]=1
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CNCC2
Reactant: COC(=O)CC(=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(C(=O)CC(=O)C(C)C)CC2
Temperature: 150 °C

Procedure:
To a solution of 4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, prepared as described in Example 17, (300 mg, 0.67 mmol) in toluene (3 mL), in a 2-5 mL microwave vial, was added methyl 4-methyl-3-oxopentanoate (0.28 mL, 2 mmol) followed by DMAP (25 mg, 0.2 mmol). The reaction vessel was then sealed and heated via microwave irradiation at 150° C. for 35 min. The reaction mixture was then cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the organic layer was dried by passing through a phase separator and then concentrated. The resulting residue was purified via silica gel flash chromatography (45-90% ethyl acetate/heptanes) to furnish 1-(4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpentane-1,3-dione. MS (ESI+) m/z 561.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl.Cl.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@@H:37]([N:39]2[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]2)[CH3:38])[CH2:32][CH2:31]1>>[OH:45][CH:42]1[CH2:41][CH2:40][N:39]([C@@H:37]([CH3:38])[CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:35][CH2:34]2)[CH2:44][CH2:43]1
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CCC(O)CC6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 122 (see example 94) and amine 50.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[C:26]1([C:32]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35][NH:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:26]1([C:32]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35][N:34]([C:15](=[O:17])[CH2:14][N:10]3[CH2:11][CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[C:9]3=[O:18])[CH2:33]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid (Example 90D, 0.345 g, 1.0 mmol) in dichloromethane (20 mL) under nitrogen was added 3,3-diphenylpyrrolidine (Example 17A, 0.223 g, 1.0 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.383 g, 2.0 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 200 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (Analogix®, Burlington, Wis.) eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.32-7.15 (m, 14H), 6.98 (t, J=8.7, 4H), 4.22 (d, J=3.0, 2H), 4.09 (d, J=3.5, 2H), 3.62-3.45 (m, 4H), 2.67-2.49 (m, 4H), 1.84 (d, J=5.6, 2H); MS (DCI) m/z 551.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[O:16][C:17]([Sn](CCCC)(CCCC)CCCC)=[CH:18][CH:19]=1)CCC>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:17]2[O:16][C:15]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)=[CH:19][CH:18]=2)=[N:3][CH:4]=1)#[N:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([Sn](CCCC)(CCCC)CCCC)o1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)cn3)o2)nc1
Yield: 85 %

Procedure:
Referring now to Scheme 4, a mixture of 6-chloronicotinonitrile (1.38 g, 10 mmol), 2,5-bis(tri-n-butylstannyl)furan (3.2 g, 5 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (125 mg) in dry 1,4-dioxane (40 mL) was heated under nitrogen at reflux (100–110° C.) for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and the solution was passed through CELITE® matrix (available from Word Minerals Corporation of Santa Barbara, Calif., United States of America) to remove Pd. The solution was evaporated, filtered and the precipitate was washed with hexanes to afford 21 in 85% yield, mp 311–312° C. (DMF). 1H nmr (DMSO-d6); δ 7.55 (s, 2H), 8.20 (d, J=8.4 Hz, 2H), 8.44 (dd, J=8.4, 2.1 Hz, 2H). 9.06 (d, J=2.1 Hz, 2H). 13C nmr; δ 153.5, 152.8, 150.0, 141.0, 118.8, 117.1, 114.8, 107.3. Calcd. for C16H8N4O: C, 70.58; H, 2.96; N, 20.57. Found. C, 70.35; H, 3.04; N, 20.35.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8](SC)=[CH:7][CH:6]=1)=[O:4].O[O:16][S:17]([O-:19])=O.[K+].[C:21](O)(C)(C)C>C(Cl)Cl.O.CCOC(C)=O>[OH:1][C:2]([CH3:13])([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:17]([CH3:21])(=[O:19])=[O:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Reactant: O=S([O-])OO
Reactant: CC(C)(C)O
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (4° C.) solution of 2-hydroxy-2-methyl-1 -(4-(methylthio) phenyl)propan-1-one (45.0 g, 214 mmol, Step 2) in t-butanol (500 mL) and CH2Cl2 (500 mL) was added a solution of OXONE™ (194 g, 316 mmol) in water (1.4 L). The resulting suspension was stirred at r.t. for 18 h. The reaction was diluted with EtOAc (400 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was dissolved in diethyl ether (250 mL), hexane was added (150 mL) and the product was swished for 2 h. The product was collected by filtration to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[CH:7]=O)[CH:2]=[CH2:3].[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])[CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)cc(CC=C)c1O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCc1cc(C=C2SC(=S)NC2=O)cc(CC=C)c1O
Temperature: 0 °C
Yield: 94.6 %

Procedure:
3,5-di-(2-propenyl)-4-hydroxybenzaldehyde (50.5 g), 36.6 g of rhodanine and 164 g of sodium acetate were heated together at reflux temperature in 1.25 liter of acetic acid for 14.5 hours. The resultant solution was cooled, poured into 2 l of ice water to yield, upon separation, about 75 g of 5-[(3,5-di-2-propenyl-4-hydroxyphenyl)methylene]-2-thioxo-4-thiazolidinone, m.p. 157°-160° C.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C-:9]#[N:10].[K+].[S:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>O>[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:15]2([C:9]#[N:10])[CH2:16][CH2:17][S:12][CH2:13][CH2:14]2)[CH2:4]1
Reactant: [C-]#N
Reactant: O=C1CCSCC1
Reactant: OC1CCCNC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(N2CCCC(O)C2)CCSCC1
Reaction time: 24 h

Procedure:
3-hydroxy-piperidine hydrochloride (6.5 g, 47.3 mmoles) in 30 ml of water is introduced into a 100 ml two-necked flask. Potassium cyanide (1.85 g, 35.5 mmoles) is added and tetrahydro-4H-thiopyran-4-one (2.7 g, 23.6 mmoles) is introduced dropwise. The pH of the medium is adjusted to 11 with a few drops of soda (10%). After 24 hours under agitation at ambient temperature, extraction with ether (3×80 ml) is carried out, the combined organic phases are washed with water (100 ml), dried over Na2SO4, filtered and concentrated to dryness. In this way, a colourless oil is obtained (3.9 g, 17.2 mmoles).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([NH2:22])[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:30][N:31]=[C:32]=[O:33].C(Cl)Cl.C(OCC)(=O)C>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([NH:22][C:32]([NH:31][CH3:30])=[O:33])[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1ccccc12
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)NC1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a mixture of the intermediate obtained in Step A (263 mg, 0.865 mmol) and triethylamine (0.145 ml, 1.03 mmol) in methylene chloride was added methylisocyanate (0.061 ml, 1.03 mmol). The reaction mixture was stirred overnight and then applied to a flash chromatography column. Flash chromatography (silica gel, methylene chloride/ethyl acetate 1:1) provided the title compound (206 mg, 0.57 mmol).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]([OH:22])[CH2:13][NH:14][C:15](=O)[O:16]C(C)(C)C)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[O:22][C:15](=[O:16])[NH:14][CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C(O)CNC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C1CNC(=O)O1
Temperature: 70 °C

Procedure:
To a solution of tert-butyl [2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]carbamate (140 mg, 0.40 mmol) (Peak 1, single enantiomer from step 2, Example 324) in tetrahydrofuran (2.5 mL), N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) and N,N-carbonyldiimidazole (130 mg, 0.80 mmol). The reaction was refluxed at 70° C. for 10 minutes. The reaction was evaporated to dryness. Purification on silica gel using (0-50%) ethyl acetate in hexane gave the desired compound as a single enantiomer, 78 mg, 69%. LCMS calculated for C13H15ClNO4 (M+H)+: m/z=284.1; found: 284.1.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:11]=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)[CH2:3][CH2:4]OS(C)(=O)=O.[H-].[Na+].CN(C)C=O>O>[CH3:1][N:2]1[C:10]2[CH:11]=[CH:12][C:13]([C:24]([F:25])([F:26])[F:27])=[C:14]3[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]([C:18]=23)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(N(C)CCOS(C)(=O)=O)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc3c2n1CCN3C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 7-[N-methyl-N-(2-methanesulfonyloxyethyl) amino]-4-trifluoromethyl-1H-indole-2-carboxylate (3.15 g, 7.71 mmol), 60% sodium hydride (0.31 g, 7.71 mmol) and N,N-dimethylformamide (200 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into cold water and extracted with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was recrystallized from isopropanol to obtain ethyl 2,3-dihydro-1-methyl-7-trifluoromethyl-1H-pyrrolo [1,2,3-de]quinoxaline-5-carboxylate. M.p. 91°-92° C.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11](=[CH:12]2)[C:10]2([C:26]4[C:18]([C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:17][CH:16]=[CH:15]2)[C:9](Br)=[C:8](Br)[C:7]=3Br)=[C:4](Br)[C:3]=1Br.B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:37][CH:38]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[C:2]1[CH:14]=[C:13]([C:12]2[CH:25]=[CH:26][CH:18]=[CH:17][C:11]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:6]3[C:15](=[CH:10][C:9]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[C:36]4[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=4)=[CH:8][CH:7]=3)[C:16]3([C:17]4[CH:18]=[C:26]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH:25]=[C:24]([C:23]5[CH:22]=[CH:21][CH:20]=[CH:16][C:15]=5[C:10]5[CH:11]=[CH:6][CH:7]=[CH:8][CH:9]=5)[C:19]=4[C:42]4[C:41]3=[CH:40][C:39]([C:36]3[CH:37]=[CH:38][CH:33]=[CH:34][C:35]=3[C:13]3[CH:14]=[CH:2][CH:3]=[CH:4][CH:5]=3)=[CH:44][CH:43]=4)[C:4]=2[CH:3]=1
Reactant: BrC1=C2C(=Cc3cc(Br)c(Br)c(Br)c32)C2(C=CC=C3C2=Cc2ccccc23)C(Br)=C1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2-c2ccc3c(c2)C2(c4cc(-c5ccccc5-c5ccccc5)ccc4-c4c(-c5ccccc5-c5ccccc5)cc(-c5ccccc5-c5ccccc5)cc42)c2cc(-c4ccccc4-c4ccccc4)cc(-c4ccccc4-c4ccccc4)c2-3)cc1

Procedure:
In a 250 ml two-necked flask fitted with reflux condenser and precision glass stirrer, 1.6 g of hexabromospirobifluorene and 3 g of biphenylboronic acid are slurried in a mixture of 50 ml of toluene and 50 ml of 1 M potassium carbonate solution. The mixture is refluxed under nitrogen and 115 mg of tetrakis(triphenylphosphine)palladium in 5 ml of toluene are added. The mixture is boiled under reflux for 7 hours while stirring. After the reaction is complete, the cooled solution is filtered and the filtrate is extracted twice by shaking with water (to improve the phase separation, chloroform is added). The organic phase is dried over sodium sulfate, filtered through a short column of silica gel and subsequently evaporated on a rotary evaporator. The product is further purified by recrystallization from dichloromethane/pentane. This gives 2 g (80%) of colorless crystals which fluoresce blue under UV illumination.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1[NH:49][CH3:50])[C:42]([O:44][CH3:45])=[O:43]>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1[N:49]([C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][N:7]1[CH2:8][CH2:9][C@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]1)[CH3:50])[C:42]([O:44][CH3:45])=[O:43]
Reactant: CNc1ccc(C(=O)OC)cc1OC
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2OC)C1
Yield: 60 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 3-methoxy-4-methylaminobenzoate in 60% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[S:6][CH:5]=[CH:4][C:3]1=2.C(Br)=C.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[S:6]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:2](=[CH:1][C:24]3[CH:25]=[C:20]([NH2:19])[CH:21]=[CH:22][CH:23]=3)[C:3]=2[CH:4]=[CH:5]1
Reactant: Nc1cccc(B(O)O)c1
Reactant: C=C1c2ccccc2CCc2sccc21
Agent: C=CBr
Product: Nc1cccc(C=C2c3ccccc3CCc3sccc32)c1

Procedure:
4-Methylene-9,10-dihydro-4H-1-thia-benzo[f]azulene is converted to the vinyl bromide as in Preparation 24 and the vinyl bromide coupled with 3-aminophenylboronic acid using the procedures essentially as described in Example 219.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](Cl)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2].[CH3:18][NH:19][NH2:20]>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([N:19]([CH3:18])[NH2:20])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CNN
Solvent: CO
Product: CCOC(=O)c1c(C)nc(N(C)N)c([N+](=O)[O-])c1Cl
Reaction time: 0.5 h

Procedure:
27.9 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) are dissolved in about 100 ml. methanol. At 50° C., 9.2 g. of methylhydrazine are dropped in and the mixture is stirred for 30 minutes. On cooling 4-chloro-6-(1-methyl)hydrazine-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester precipitates. Yield 18 g. (62.2%), m.p. 159°-161° (methanol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:7]([OH:9])[CH:8]=1.C(N(CC)CC)C.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[NH:31][C:30](=[O:37])/[C:29]/2=[CH:38]/OC.O>CN(C)C=O>[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[NH:31][C:30](=[O:37])/[C:29]/2=[CH:38]\[NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:7]([OH:9])[CH:8]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1ccc(OCCN2CCCC2)c(O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(OCCN2CCCC2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
An amount of 33.5 mg (0.142 mmol) of 5-Aminomethyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenol, is dissolved in N,N-dimethylformamide (2 ML). 30 μl (0.213 mmol) of triethylamine is added followed by 20 mg (0.071 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, water (2 mL) is added and the reaction mixture is stirred for 60 min. The precipitate is filtered and washed several times with anhydrous ether. The crude solid is then purified by high performance liquid chromatography to give 23 mg of a yellow solid. MS (ESI) m/z 486.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:36]=[C:37]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]2)[CH:38]=[CH:39][C:40]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:34][C:35]1[CH:36]=[C:37]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]2)[CH:38]=[CH:39][C:40]=1[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4F)cnc32)cc1
Yield: 83.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (130 g, 0.248 mmol) was coupled with tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69B) (151 mg, 0.372 mmol) using sodium carbonate (79 mg, 0.714 mmol) and Pd(PPh3)2Cl2 (9 mg, 0.124 mmol) in DME/water (5/2 mL). This afforded 150 mg (83.3% yield) after purification by column (Silica gel 60/120) using 50% ethyl acetate in hexane as eluent. MS: m/z=725.3 (M+1).