Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]1=2)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH:20]1[C:29](=[O:30])[C:28]2[NH:27][CH:26]=[N:25][C:24]=2[N:23]=[C:21]1[NH2:22]>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]2=3)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:22]1[C:21]1[NH:20][C:29](=[O:30])[C:28]2[NH:27][CH:26]=[N:25][C:24]=2[N:23]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=CC(CO)OC(C=O)n1cnc2c(=O)[nH]cnc21
Solvent: O
Solvent: CO
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2nc3nc[nH]c3c(=O)[nH]2)C1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.5 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (inosinedialdehyde), (1.33 g) was dissolved in a mixture of methanol (300 ml) and water (300 ml). To the solution was added guanine (0.76 g). The mixture was stirred at ambient temperature for three days and filtered. The filtrate was evaporated in vacuo at 35° C. The residue was triturated with acetone to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-hypoxanthinyl)morpholin-2-yl]hypoxanthine (2.20 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(#N)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2)CC1
Reaction time: 5 h
Yield: 125.8 %

Procedure:
To a stirring solution of 1-Boc-piperidine-4-carboxaldehyde (2.4 g, 11.3 mmol) in THF (60 mL) and acetonitrile (15 mL) was added piperazine (4.85 g, 56.3 mmol). After stirring for 5 h, sodium triacetoxyborohydride (2.87 g, 13.5 mmol) was added and the reaction was allowed to stir overnight. The next morning, the solvents were removed by rotary evaporation and the residue was dissolved in ethyl acetate, washed twice with satd aq. NaHCO3, followed by water, then dried over MgSO4, filtered and concentrated in vacuo. The residue was then chromatographed over silica gel, eluting with a step gradient of 2% through 15% (2 N ammonia/methanol) in dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 4.03 g (48%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:12])=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:13]#[N:14].[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[S:18][C:17]=1[C:31]#[N:32]>>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[C:10]2[C:2]3[N:1]=[N:15][N:14]=[CH:13][C:3]=3[S:4][C:5]=2[N:6]=1.[C:25]1([C:21]2[CH:22]=[CH:23][C:24]3[C:16]4[N:15]=[N:1][N:32]=[CH:31][C:17]=4[S:18][C:19]=3[N:20]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(C)c2c(N)c(C#N)sc2n1
Reactant: N#Cc1sc2nc(-c3ccccc3)ccc2c1N
Product: Cc1cc(C)c2c(n1)sc1cnnnc12
Product: c1ccc(-c2ccc3c(n2)sc2cnnnc23)cc1

Procedure:
In the same way as described in EXAMPLES 5, 6 and 11, 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine and 3-amino-2-cyano-6-phenylthieno[2,3-b]pyridine give 7,9-dimethylpyrido-[3',2':4,5]thieno[3,2-d]-1,2,3-triazine and 7-phenylpyrido-[3',2':4,5]thieno[3,2-d]-1,2,3-triazine, respectively.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[N:4][N:3]=1.[Cl-].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1>C1COCC1>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)=[N:3][N:4]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: Clc1nnc(Cl)c2c1CCCC2
Agent: [Cl-]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2nnc(Cl)c3c2CCCC3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 1,4-dichloro-5,6,7,8-tetrahydro-phthalazine (compound 41, 0.50 g, 2.46 mmol) in THF (5 mL) are added 4-fluoro-benzyl zincchloride (0.5M in THF) (6.40 mL, 3.20 mmol) and palladium tetrakis triphenylphosphine (0.36 g, 0.31 mmol). The mixture is degassed and stirred at 50° C. overnight. Then the reaction mixture is cooled down to room temperature, sat. NaHCO3 and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by chromatography (EtOAc/heptane: 10%˜40%) to give 1-chloro-4-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-phthalazine (46) (0.51 g, 30%).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.Br[CH2:9][C:10]([O:12]CC)=[O:11].Cl>O.CS(C)=O>[N:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[nH]c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cn1cccc1
Reaction time: 1 h

Procedure:
To a mixture of potassium hydroxide (16.7 g) and dry DMSO (150 mL), pyrrole (5 g) was added dropwise at 20-25° C., with stirring under nitrogen atmosphere. Stirring was continued for 1 hr at 20-25° C. Ethyl bromoacetate (24.5 g) was added dropwise at 20-25° C. and stirring was continued for 2 hr. In the reaction mixture (150 mL) DM water was added and pH was made acidic (pH=3) with 20% HCl (50 mL). The reaction mixture was extracted with diethyl ether (2×100 mL). The combined organic extract was washed with DM water (100 mL), saturated brine (100 mL) and dried over Na2SO4. The solvent was evaporated to obtain pyrrol-1-yl-acetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.C1COCC1.C([Li])CCC.Cl[P:34]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:34]([CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]2)[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:11])=[CH:5][CH:4]=1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: CC(Br)=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1)P(C1CCCCC1)C1CCCCC1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
Into a reactor were introduced 1.44 g (4.00 mmol) of the 1,1-bis(4-dimethylaminophenyl)-2-bromopropene obtained in Example 4 (2) and 14 mL of THF under a nitrogen atmosphere. The contents were cooled to −60° C. Thereto was gradually added dropwise 2.8 mL (4.4 mmol; 1.6 M hexane solution) of butyllithium. The resultant mixture was stirred at that temperature for 1 hour. Thereafter, 0.97 mL (4.4 mmol) of chlorodicyclohexylphosphine was added thereto, and this mixture was stirred for 30 minutes, subsequently heated to room temperature, and then further stirred for 17 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and hexane to obtain 0.44 g (23%) of the target compound as white crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[C-:13]#[N:14].[K+]>CN(C=O)C.O>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][C:13]#[N:14])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc(CBr)ccc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 5-(bromomethyl)-2-chlorobenzoic acid [WO 2001044170] (1.75 g) in DMF (20 mL) was treated with a solution of potassium cyanide (0.91 g) in water (7 mL) and the resulting solution was stirred at room temperature over 3 days. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was carefully acidified with concentrated hydrochloric acid (5 mL), venting any liberated HCN through bleach solution via a stream of nitrogen. After being stirred for 20 minutes, the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled compound as a brown solid. Yield 1.25 g.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35]C[CH2:33][CH2:32]1.C([N:40](C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:40]([CH2:21][CH2:20][CH2:19][C:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH:18]=2)[CH2:33][CH2:32]1
Reactant: Clc1ccccc1N1CCCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=CCCc1cc(-c2cccc(Oc3ccccc3)c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccccc1N1CCN(CCCc2cc(-c3cccc(Oc4ccccc4)c3)no2)CC1
Yield: 92.7 %

Procedure:
About 2 min after dissolving 3-[3-(3-phenoxyphenyl)isoxazol-5-yl]propanal (40.8 mg, 0.14 mmol), (2-chlorophenyl)piperidine HCl (27.0 mg, 0.12 mmol), and diisopropylethyl amine (20.2, 0.12 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (73.8 mg, 0.35 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22 hr and followed the same processes as in Example 1 to obtain 52.7 mg (95.6%) of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:20][CH2:19]1>CN1C(=O)CCC1.O>[N:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:20][CH2:19]3)[N:7]=2)[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: Clc1nccc(-c2cnc3ccccn23)n1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)NC1CCC(Nc2nccc(-c3cnc4ccccn34)n2)CC1
Temperature: 105 °C
Reaction time: 10 h
Yield: 2.8 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.125 g), N-(4-amino-cyclohexyl)-methanesulfonamide (0.372 g), and TEA (0.38 mL) in NMP (3 mL) was stirred at 105° C. for 10 h. The reaction mixture was cooled to RT, diluted with water, and the resulting solid filtered, washed with water, and dried. The product was purified by ISCO using 100% DCM to 15% MeOH/DCM, the pure fractions combined and concentrated, then titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide N-[4-(4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide (compound 10, 5.8 mg).
Reaction SMILES: C([O:8][C@@H:9]([CH2:38][O:39]CC1C=CC=CC=1)[CH2:10][C:11]1([S:14]([NH:17][C:18]2[C:26]3[O:25][CH:24]=[CH:23][C:22]=3[C:21]([F:27])=[C:20]([F:28])[C:19]=2[NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])(=[O:16])=[O:15])[CH2:13][CH2:12]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.Cl.CCCCCCC>C(Cl)Cl.C(OCC(C)C)(=O)C>[F:27][C:21]1[C:22]2[CH:23]=[CH:24][O:25][C:26]=2[C:18]([NH:17][S:14]([C:11]2([CH2:10][C@@H:9]([OH:8])[CH2:38][OH:39])[CH2:12][CH2:13]2)(=[O:15])=[O:16])=[C:19]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:20]=1[F:28]
Reactant: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CC(=O)OCC(C)C
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1(C[C@@H](O)CO)CC1
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of (R)-1-(2,3-bis(benzyloxy)propyl)-N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)cyclopropane-1-sulfonamide (140 g, 183.6 mmol) in DCM (700 mL) was added 1M BCl3 solution in DCM (1.8 L, 1.84 mol) at −65-70° C. The mixture was stirred at −65˜−70° C. for 30 minutes until HPLC analysis showed the reaction had gone to completion. The cold solution was added to 1N HCl solution (1.8 L) at below 15° C., stirred for 15 mins and separated. The DCM layer was washed with water (2 L), the brine (1.5 L). DCM layer was concentrated to ˜250 mL and filtered to give white solid. The solid was dissolved in isobutyl acetate (240 mL) and heptane (500 mL) was added. The suspension was stirred overnight, filtered and dried to give 70 g of (R)—N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide with 98.4% purity (65.5% yield, ee>99%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](Br)=[O:25].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:23][C:24]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:36])[C:24](OC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH2:37]([NH2:45])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:36])[C:24]([NH:45][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OCC
Reactant: NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)NCCc3ccccc3)c2)cc1)OCC
Yield: 49.4 %

Procedure:
A solution of 1.75 g (3 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate, 0.46 mL (3.7 mmol) of phenethylamine, in 20 mL of dimethylformamide is heated at 80° C. for 2 hours. After addition of water, the reaction medium is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 0.7 g (50%) of ethyl (Z)-2-ethoxy-3-[3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]acrylate is obtained.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6]2[C:10](=[C:11]3[C:23]4=[CH:24][N:25]([CH3:28])[C:26](=[O:27])[C:22]4=[C:21]4[C:13]([NH:14][C:15]5[CH:16]=[CH:17][C:18](=[O:29])[CH2:19][C:20]=54)=[C:12]3[CH:30]=1)[N:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>CN(C=O)C.CCOC(C)=O>[Br:51][CH2:2][CH2:3][CH2:4][C:5]1[C:6]2[C:10](=[C:11]3[C:23]4=[CH:24][N:25]([CH3:28])[C:26](=[O:27])[C:22]4=[C:21]4[C:13]([NH:14][C:15]5[CH:16]=[CH:17][C:18](=[O:29])[CH2:19][C:20]=54)=[C:12]3[CH:30]=1)[N:9]=[CH:8][CH:7]=2
Reactant: BrC(Br)(Br)Br
Reactant: CN1C=c2c(c3c4c([nH]c3c3cc(CCCO)c5c(c23)N=CC=5)C=CC(=O)C4)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C=c2c(c3c4c([nH]c3c3cc(CCCBr)c5c(c23)N=CC=5)C=CC(=O)C4)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 13-(3-hydroxypropyl)-5-methyl-7H-indolo[6,7-a]pyrrolo[3,4-c]-carbazole-6,8-dione (1.18 g, 2.97 mmol) in DMF (45 mL) was added triphenylphosphine (1.17 g, 4.45 mmol) followed by carbon tetrabromide (1.48 g, 4.45 mmol). The resulting solution was allowed to stir at room temperature for 30 min. The solution was diluted with EtOAc (200 mL) and washed with water (2×200 mL) and brine (200 mL). The combined aqueous layers were washed with EtOAc (100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to a red-orange solid. Flash chromatography (SiO2, 20% EtOAc/hexanes) gave the title compound (1.05 g, 77%) as an orange solid, mp 238 C. 1H NMR (DMSO-d6)11.15 (s, 1H), 9.16 (d, J=7.5 Hz, 1H), 8.36 (d, J=9 Hz, 1H), 8.04 (d, J=9 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.60–7.67 (m, 2H), 7.44 (dd, J=7.5, 7.5 Hz, 1H), 6.85 (d, J=3 Hz, 2H), 5.03 (t, J=7 Hz, 2H), 3.85 (s, 3H), 3.72 (t, J=7 Hz, 2H), 2.50 (m, 2H, partially buried under DMSO signal). MS (atmospheric pressure chemical ionization, m/z) 460, 462 [C24H18BrN3O2+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][OH:50])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][OH:50])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of Intermediate 5c (109 mg, 0.300 mmol) and Intermediate 33a (126 mg, 0.300 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 μL, 0.45 mmol) was stirred at 80° C. for 3 h, and then at 95° C. for 2 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (95 mg, 50%). LCMS (Method 5): Rt 3.26 min, m/z 635.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.81-2.26 (11H, m), 2.31-2.40 (1H, m) 3.10-3.17 (1H, m), 3.99 (1H, br t, J 8.1), 4.56 (2H, d, J 5.6), 4.78-4.87 (1H, m), 5.29 (1H, t, J 5.7), 5.37-5.42 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J 8.7), 7.24-7.47 (9H, m), 7.75 (1H, d, J 9.7), 8.07 (1H, s), 8.24 (1H, br d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:33])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:30](O)[CH3:31])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=[O:10].C([SiH](CC)CC)C.B(F)(F)F>ClCCl>[Cl:33][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:30][CH3:31])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:13][CH:12]=1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(C)O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Product: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
A stirred solution of N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide [0.06 g, Example 16(a)] in dichloromethane (2 ml), under nitrogen and at 0° C., was treated with triethylsilane (0.028 g,) and boron trifluoride dietherate (0.015 ml). The mixture was allowed to warm to room temperature and then stirred at this temperature for 3 hours. The solution was partitioned between ethyl acetate (15 ml) and saturated sodium bicarbonate solution (15 ml). The organic layer was dried over sodium sulphate then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (gradient elution, 1:3 to 2:1, v/v) to give the title compound (22 mg) as a white solid, m.p. 147-149° C. [Elemental analysis:—C, 56.69; H, 4.04; N, 8.15%. Calculated for C23H19Cl2N3O3S:—C, 56.56; H, 3.92; N, 8.60%].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36].O1CCOCC1>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.O>[C:35]([C:37]1[CH:42]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[C:18]([C:28]([NH:29][CH3:30])=[O:31])[C:17]=3[CH:32]=2)[CH:40]=[CH:39][CH:38]=1)#[N:36]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: N#Cc1cccc(B(O)O)c1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Temperature: 90 °C

Procedure:
Cesium carbonate (187 mg, 0.575 mmol) was added to Pd(Ph3P)4 (22 mg, 0.019 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (160 mg, 0.383 mmol), 3-cyanophenylboronic acid (85 mg, 0.575 mmol). Dioxane (3 mL) and water (600 μL) was added at rt. The reaction was degassed 3× and heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was taken up in DCM. A white precipitate formed which was filtered to give the titled compound. The filtrate was purified on silica gel (Biotage, EtOAc/hexanes gradient, Rf˜0.4:50% EtOAc/Hex, fraction collection at λ=254 nm) to give the titled compound which was combined with the previously collected precipitate (85 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.46-8.53 (1H, m), 8.24 (1H, s), 8.09 (1H, d, J=7.93 Hz), 7.99-8.05 (2H, m), 7.96 (1H, d, J=1.53 Hz), 7.85 (1H, d, J=7.63 Hz), 7.74-7.82 (2H, m), 7.70 (1H, t, J=7.78 Hz), 7.40 (2H, t, J=8.85 Hz), 2.87 (3H, d, J=4.58 Hz). LC-MS retention time: 2.17 min; m/z (MH+): 371. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=13.59 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.29 min, purity=99%.