Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][CH2:17][C:18](Cl)=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:18](=[O:19])[CH2:17][Cl:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)CCl)C1
Reaction time: 8 h

Procedure:
3-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester 1c (5.0 g, 23.4 mmol) in 20 mL CH2Cl2 was added dropwise to a cold (−10→0° C.) solution of chloroacetylchloride (2.8 mL, 35 mmol, 1.5 equiv) and diisopropylethylamine (6.1 mL, 35 mmol, 1.5 equiv) in 60 mL CH2Cl2 under N2. After being left overnight (−10° C.→rt), the mixture was diluted with ethyl acetate and washed briefly with water and brine, dried (Na2SO4), and concentrated to give 3-[(2-chloroacetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester 1d as a dark brown oil. The crude product was used without further purification.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[S:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:7]2=1.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[S:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:7]2=1
Reactant: COC(=O)c1cc2c3cc(Cl)ccc3n(C)c2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1c2ccc(Cl)cc2c2cc(C(=O)O)sc21
Yield: 92.6 %

Procedure:
KOH (0.57 g) was dissolved in methanol-water (1/1) (10 ml). (49) (0.50 g) was added and the mixture refluxed for 13/4 h. After cooling the mixture was acidified with 1M HCl to pH=1. The precipitate was filtered off, washed with water and dried to give 0.44 g (93%) of (54). M.p. 259°-262° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C1CCCCC1)C1CCCCC1)CCC.C1(C)C(C)=CC=CC=1>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 85 %

Procedure:
A 100-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 7.536 g (48 mmol) of bromobenzene, 6.769 g (40 mmol) of diphenylamine, 4.613 g (48 mmol) of sodium-tert-butoxide, 0.090 g (0.40 mmol) of palladium (II) acetate and 5 ml of xylene were weighed in the flask, followed by stirring. Further, 0.690 g (1.20 mmol) of n-butyldicyclohexylphosphonium tetraphenylborate obtained in Example B-47 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 125° C. for 4 hours. After the completion of the reaction, 45 ml of xylene and 50 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 8.345 g of triphenylamine (yield: 85 mol % based on diphenylamine). The melting point was 125-126° C.
Reaction SMILES: P.C1(P(C2C=CC=CC=2)(C2C=CC3CCCCC=3C=2C2C3CCCCC=3C=CC=2P(C2C=CC=CC=2)(C2C=CC=CC=2)=O)=O)C=CC=CC=1.[Br:50][C:51]1[CH:60]=[CH:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]=1[C:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH:64]=[CH:63][C:62]=1[Br:71]>[Ru]>[Br:50][C:51]1[CH:60]=[CH:59][C:58]2[CH2:57][CH2:56][CH2:55][CH2:54][C:53]=2[C:52]=1[C:61]1[C:70]2[CH2:69][CH2:68][CH2:67][CH2:66][C:65]=2[CH:64]=[CH:63][C:62]=1[Br:71]
Reactant: Brc1ccc2ccccc2c1-c1c(Br)ccc2ccccc12
Agent: [Ru]
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(c1-c1c(P(=O)(c3ccccc3)c3ccccc3)ccc3c1CCCC3)CCCC2
Agent: P
Product: Brc1ccc2c(c1-c1c(Br)ccc3c1CCCC3)CCCC2

Procedure:
Of the starting optically active phosphine compounds L1, the optically active compound of formula (III), i.e., 2,2'-bis(diphenylphosphinyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (hereinafter abbreviated as OcH-BINAP) can be synthesized, for example, as follows. 2,2'-Dibromo-1,1'-binaphthyl synthesized by the process disclosed in H. Takaya, et al., J. Orc. Chem., Vol. 51, p. 629 (1986) is hydrogenated in the presence of a ruthenium-on-carbon catalyst to obtain 2,2'-dibromo-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (2,2'-dibromo-1,1'-bitetrahydronaphthalene), which is then reacted with metallic magnesium to form a Grignard reagent. The resulting Grignard reagent is condensed with diphenylphosphinyl chloride to synthesize racemic OcH-BINAP. The racemate is optically resolved by recrystallization from a mixed solvent of chloroform and ethyl acetate in the presence of optically active dibenzoyltartaric acid as a resolving agent, and the precipitated crystal collected by filtration is treated with 1N sodium hydroxide to obtain a phosphine oxide. The optical purity of the phosphine oxide is determined by high performance liquid chromatography using an optically active column, and the above recrystallization operation is repeated until the product becomes optically pure. The thus obtained optically active phosphine oxide is then reduced by using trichlorosilane to obtain optically active OcH-BINAP.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=1B(O)O>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][C:17]=1[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc3[nH]ncc23)c(F)c1
Temperature: 140 °C

Procedure:
A vial was charged with a mixture of 4-bromo-6-(trifluoromethyl)-1H-indazole (0.402 g, 1.515 mmol), (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (0.3 g, 1.515 mmol) and PdCl2(dppf) (0.055 g, 0.076 mmol) in dioxane (10 mL) and aqueous saturated NaHCO3 (3 mL). The resulting light yellow suspension was heated at 140° C. for 45 minutes in a microwave reactor. The reaction mixture was subsequently concentrated. The crude residue was diluted with EtOAc and washed with water, dried over Na2SO4, and the volatiles were removed via rotary evaporation to give the title compound, which was used without further purification (0.4 g, 78%). ESI-MS m/z [M+H]+ calc'd for C16H10F4N2O2, 339.1. found 339.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[CH:11]=1>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: Oc1ccc2c(c1)C=CCO2
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Oc1ccc2c(c1)CCCO2
Reaction time: 0.67 h
Yield: 92.1 %

Procedure:
The 6-hydroxybenzopyran (1.5 g; 10 mM) was dissolved in 100 ml of anhydrous benzene along with Wilkinson's catalyst (280 mgs; 0.30 mM). This hydrogenation bottle containing this reaction mixture was first flushed with nitrogen and then with hydrogen. The bottle was pressurized to 40 psi in a Parr shaker and agitated for 40 minutes at which time the pressure in the bottle (400 ml dead volume) had dropeed to 30 psi and was dropping no further. The bottle was then flushed with nitrogen and the solvent was removed in vacuo. The residue was taken up in ether and filtered through a pad of celite. The solvent was removed and the oil was purified by flash chromtography on a 30 mm×6" column of silica gel eluted with 600 ml of 20% ethyl acetate in hexane. This purification produced 1.40 g (93%) of 2,3-dihydro-6-hydroxybenzopyran as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH:27]([F:29])[F:28]>O>[F:28][CH:27]([F:29])[O:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: FC(F)Cl
Reactant: COc1cc2sc(C#N)cc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2sc(C#N)cc2cc1OC(F)F
Temperature: 40 °C

Procedure:
A mixture of 5-hydroxy-6-methoxy-benzo[b]thiophene-2-carbonitrile (10.30 g) and anhydrous potassium carbonate (7.63 g) was treated with a solution of dry dimethylformamide (110 ml) which has been previously saturated with chlorodifluoromethane gas. The mixture was then sealed in an autoclave, stirred, and heated to 40° C. After 3 days the reaction mixture was cooled and poured into water (700 ml). The resultant precipitate was iiltered off, dried, and extracted with hot dichloromethane (300 ml). The organic extract was concentrated then poured through a column of fine silica (200 g). The appropiate fractions were combined and evaporated to dryness to give 5-difluoromethyloxy-6-methoxy-benzo[b]thiophene-2-carbonitrile as an off-white solid (5.49 g), m.p. 99°-101° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:49][C@@H:50]2[CH2:54][O:53][C:52](=[O:55])[NH:51]2)(=O)=O)=CC=1>C(#N)C.O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:49][C@H:50]4[CH2:54][O:53][C:52](=[O:55])[NH:51]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(=O)N2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2COC(=O)N2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
A solution of N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.5 g) in acetonitrile (10 mL) was treated with potassium carbonate (0.495 g) and (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (0.324 g) under nitrogen. The resulting mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water, and extracted with DCM. The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle compound as a solid (0.6 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.COB(OC)OC.[CH2:33]([C@H:35]1[C@@H:39]([C:40]2[N:44]3[C:45]4[C:51](I)=[CH:50][N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:46]=4[N:47]=[CH:48][C:43]3=[N:42][N:41]=2)[CH2:38][C@@H:37]([N:61]([CH2:68][O:69][CH2:70][CH2:71][Si:72]([CH3:75])([CH3:74])[CH3:73])[S:62]([CH:65]2[CH2:67][CH2:66]2)(=[O:64])=[O:63])[CH2:36]1)[CH3:34]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:33]([C@H:35]1[C@@H:39]([C:40]2[N:44]3[C:45]4[C:51]([CH3:1])=[CH:50][N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:46]=4[N:47]=[CH:48][C:43]3=[N:42][N:41]=2)[CH2:38][C@@H:37]([N:61]([CH2:68][O:69][CH2:70][CH2:71][Si:72]([CH3:75])([CH3:74])[CH3:73])[S:62]([CH:65]2[CH2:67][CH2:66]2)(=[O:64])=[O:63])[CH2:36]1)[CH3:34]
Reactant: CC[C@@H]1C[C@H](N(COCC[Si](C)(C)C)S(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3c(c(I)cn3COCC[Si](C)(C)C)n12
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: COB(OC)OC
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](N(COCC[Si](C)(C)C)S(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3c(c(C)cn3COCC[Si](C)(C)C)n12
Temperature: 85 °C
Yield: 76.9 %

Procedure:
Cesium carbonate (0.274 g, 0.841 mmol), tricyclohexylphosphine (20 wt % solution in toluene, 0.094 g, 0.067 mmol), Pd2(dba)3 (0.039 g, 0.042 mmol) and trimethylborate (0.069 g, 0.547 mmol) were added to a solution of N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-((2-(trimethylsilyl)ethoxy)methyl)cyclopropanesulfonamide (0.32 g, 0.421 mmol, prepared using KK from Preparation #GGG.1) in 1,4-dioxane (8 mL). The mixture was degassed and heated at about 85° C. for about 2 h. The solvent was removed and the residue was partitioned between EtOAc and water (20 mL each). The organic phase was washed with brine (15 mL), dried over anhydrous MgSO4, filtered and concd. The resulting mixture was purified by silica gel flash chromatography (40 to 100% of EtOAc in heptane) to yield N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-((2-(trimethylsilyl)ethoxy)methyl)cyclopropanesulfonamide (0.21 g, 77%) as a yellow amorphous solid. LC/MS (Table 1, Method a) Rt=3.39 min; MS m/z: 650 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Nc3ccccc3)cc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A vessel containing 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.35 mmol), aniline (64 μL, 0.71 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (19 mg, 0.035 mmol), Pd2(dba)3 (16 mg, 0.018 mmol) and NaOtBu (51 mg, 0.53 mmol) in toluene (2 mL) was evacuated and flushed with nitrogen. The mixture was stirred at 110° C. overnight, then was allowed to cool and then partitioned between EtOAc and water. The organic extract was washed with brine, dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2; gradient elution with 50-100% EtOAc in petrol) gave the title compound (60 mg, 50%) as a colourless solid. MS: [M+H]+=340.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>C(#N)C.O>[OH:25][C:24]1[C:4]2[O:3][C:2]([NH:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[C:6]([C:7]([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)=[O:20])[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: Nc1cccnc1
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)c2c(Nc3cccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 6 h
Yield: 24.4 %

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50 mg, 0.10 mmol) and 3-amino-pyridine (30 mg, 0.30 mmol) in a mixture of solvent acetonitrile:water (8:2, 5 mL) was refluxed with stirring for 6 hours. The solvent was distilled under vacuum and the residue was purified over silica gel column to afford the title compound as yellow solid (11 mg, 23%); 1H NMR (300 MHz, CDCl3) δ 11.22(s, 1H), 8.77(b, 1H), 8.42(b, 1H), 8.01(bd, 1H), 7.28(b, 1H), 7.03(s, 2H, benzoyl Hs), 6.71(d, 1H, J=8.82 Hz), 6.63(d, 1H, J=8.37 Hz), 3.94(s, 3H, OMe), 3.90(s, 3H, OMe), 3.86(s, 6H, 2×OMe).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[CH3:23])[CH2:18][NH2:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][C:22]([CH3:23])=[C:15]([CH3:14])[CH:16]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: Cc1ccc(CN)cc1C
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)cc1C
Yield: 11.6 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 3,4-dimethylbenzylamine (0.09 mL, 0.636 mmol), Pd2(dba)3 (58 mg, 0.063 mmol), rac-BINAP (104 mg, 0.167 mmol) and NaOtBu (155 mg, 1.613 mmol) in DMA (6 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,4-dimethyl-benzylamino)-2H-phthalazin-1-one (21 mg) as a white solid, 1H (400 MHz, d6-DMSO) δ: 2.15 (d, 6H), 4.25 (d, 2H), 6.79 (s, 1H), 7.05 (s, 2H), 7.10 (m, 2H), 7.57 (t, 1H), 7.87 (d, 1H), 12.30 (s, 1H) ppm; m/z (M+1) 313.99.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].[NH2:14][CH2:15][C@@H:16]([OH:33])[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[Cl:31])[O:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][C@H:16]([OH:33])[CH2:15][NH:14][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:23][CH2:22]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1C(=O)NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Yield: 35 %

Procedure:
A mixture of 2-(methylsulphonyl)benzoic acid (0.063 g), (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and N,N-diisopropylethylamine (0.1 ml) in dry dimethylformamide (3 ml) was cooled to 0° C. with stirring. 2-(1H-9-Azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.13 g) was added and the mixture was stirred at 0° C. for 1-2 h. Saturated sodium bicarbonate solution (10 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulphate. The mixture was filtered and the solvent was evaporated. The resulting oil was purified by normal phase chromatography using methanol/dichloromethane as eluent, and by reverse phase HPLC using acetonitrile and 0.1% aqueous ammonium acetate as eluent, to give the title compound as a white solid (0.055 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[CH:27]=[C:26]([CH3:28])[N:25]([CH3:29])[C:22]4=[N:23][CH:24]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[CH:27]=[C:26]([CH3:28])[N:25]([CH3:29])[C:22]4=[N:23][CH:24]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(c3)cc(C)n4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3cnc4c(c3)cc(C)n4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: (49 mg, 0.09 mmol) in THF/CH3OH (1.0 mL/1.0 mL) was added 2N NaOH (0.44 mL, 0.9 mmol). The reaction mixture was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C29H28ClN3O3S: 534.2 (M+H+); Found: 534.2 (M+H+); 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=1.6 Hz, 1H), 8.41 (d, J=2 Hz, 1H), 7.82 (s, 1H), 7.70-7.58 (m, 5H), 5.25 (s, 1H), 3.80 (s, 3H), 2.61 (s, 3H), 2.49 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>O1CCOCC1.C(OCC)C.O>[C:18]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccn1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 54 mg (0.10 mmol) of (t-Bu)2PCl)2PdCl2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.65 g (5.33 mmol) of PhB(OH)2 and 0.40 g (7.13 mmol) of KOH in 2 mL of 1,4-dioxane. The reaction mixture was refluxed for 7 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-phenylpyridine. LC-MS Found: 156.2 (M++1).