Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: OB(O)c1ccc(F)c(F)c1F
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(F)c(F)c1F
Temperature: 95 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of 2,3,4-trifluorophenylboronic acid (4.70 g, 26.7 mmol), methyl 2-bromo-5-nitrobenzoate (9.02 g, 34.7 mmol), sodium carbonate (8.49 g, 80.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.55 g, 1.34 mmol) was suspended in a mixture of toluene (160 mL)-ethanol (40 mL)-water (80 mL), and then the mixture was stirred under nitrogen atmosphere at 95° C. overnight. After cooling down, ethyl acetate (200 mL) and water (200 mL) were added thereto, and then separated. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (4.37 g) as a brown oil. (Yield 53%)
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:2].[BH4-].[Na+]>C1COCC1>[OH:2][CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of 0.434 g of 4-formyl-piperidine-1-carboxylic acid, tert-butyl ester (from Step A) in 15 ml THF was added sodium borohydrid at 0° C. and stirred at 0° C. for 20 mn. The reaction was warmed to rt and stirred at rt for 14 hours. After quenching with CH3OH, the reaction mixture was concentrated, then partitioned between EtOAc and H2O. The aqueous layer was extracted with 2×20 mL of EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 50% EtOAc in hexane, then 100% EtOA to give 390 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([C:29]#N)[CH:3]=1.CC(C[AlH]CC(C)C)C.CC[O:42]C(C)=O.O>C1COCC1>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([CH:29]=[O:42])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(Br)c2nc(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Br)c2nc(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Temperature: -40 °C
Reaction time: 10 h
Yield: 43 %

Procedure:
To a solution of (S)-7-Bromo-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzimidazole-5-carbonitrile (150 mg, 0.31 mmol) in THF (50 mL) was added DIBAL-H (1 M toluene solution, 1.55 mL, 1.55 mmol) at −78° C. The reaction mixture was stirred at −40° C. for 10 h and cooled to −78° C. EtOAc (0.5 mL) was added. The reaction mixture was stirred for 30 min at −78° C. before water (1 mL) was added. The reaction mixture was warmed to room temperature and concentrated. The residue was passed through a small pad of celite. The filtrate was concentrated and purified by prep. HPLC to give the titled compound (67 mg, 43%). 1H NMR (400 MHz, CD3OD) δ 9.45 (1H, s), 7.62 (1H, s), 7.56 (1H, narrow d, J=1.6 Hz), 7.44 (1H, narrow d, J=1.0 Hz), 7.32–7.42(2H, m), 7.24–7.30 (3H, m), 6.24 (1H, d, J=7.6 Hz), 5.01 (1H, m), 3.65–3.76 (2H, m). LCMS (M+H)+ m/z 487 (t=1.76 min.).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]([O:26]C)=[O:25])=[CH:21]3)=[CH:16][C:15]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH2:9][CH2:8][CH2:7]2>CO.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21]3)=[CH:16][C:15]=1[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)[CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(F)cc3)c(N3CCCc4cc(Br)ccc43)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2cc(-c3ccc(F)cc3)c(N3CCCc4cc(Br)ccc43)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Sodium hydroxide (39 mg, 0.97 mmol) was added to a solution of methyl 7-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-6-(4-fluorophenyl)naphthalene-2-carboxylate (120 mg, 0.24 mmol) in methanol (30 ml) and water (2 ml). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (20 ml) and adjusted to pH 4 with hydrochloric acid (3 N) to give the precipitation, which was collected by filtration to afford 7-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-6-(4-fluorophenyl)naphthalene-2-carboxylic acid as a yellow solid (80 mg, 69%).
Reaction SMILES: C(S)CCCCCCC.C([Li])CCC.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([CH2:32][O:33][C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=3)([OH:31])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1)#[N:16]>CCCCCC.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][C:28]([CH2:32][O:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:42][CH:43]=3)([OH:31])[CH2:29][CH2:30]2)=[CH:21][CH:22]=1)#[N:16]
Reactant: COC(=O)c1ccc(OCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: CCCCCCCCS
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(C(=O)O)cc3)CC2)cc1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
To a solution of n-octanethiol (2.04 g) in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous hexamethylphosphoric triamide (HMPA) (5 mL), a 1.59 M solution of n-butyl lithium in hexane (8.74 mL) was added dropwise under cooling with ice-water under nitrogen atmosphere. After stirring at the same temperature for fifteen minutes, a solution of the compound (2.50 g) obtained in Example 13 in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous HMPA (5 mL) was added dropwise thereto over ten minutes, followed by stirring at the same temperature for thirty minutes and further stirring at room temperature for seventeen hours. After the completion of reaction, the reaction mixture was mixed with an ice water (20 mL) under cooling with ice-water and was washed with ethyl acetate (25 mL×2). Small portions of 3 N hydrochloric acid were gradually added to the aqueous layer with stirring under cooling with ice-water, to adjust the pH of the mixture to 5.6. The precipitated crystals were collected by filtration and were sequentially washed with water and ethanol. The resulting crystals were suspended in a mixture of methanol (50 mL) and water (10 mL), followed by heating under reflux for thirty minutes. After standing to cool, the crystals were collected by filtration and were washed with methanol, and dried under reduced pressure to yield the titled compound (1.83 g) as crystals.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[Cl:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][C:1]([CH2:13][Cl:14])=[CH:2][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(-c2ccccn2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc(-c2ccccn2)cc1
Yield: 53.8 %

Procedure:
To a solution of 2-(p-tolyl)pyridine (1.7 g) and N-chlorosuccinimide (1.5 g) in carbon tetrachloride (30 mL) was added α,α-azobisisobutyronitrile (0.033 g), and the mixture was heated under reflux for 5 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1-3/1) to give 4-(pyridin-2-yl)benzyl chloride (1.1 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450 mg) and 3-methoxybenzaldehyde (352 uL) in CH2Cl2 (4.5 mL) was added sodium triacetoxyborohydride (922 mg), which was stirred at room temperature for 2 hours. To the resultant was added sat. NaHCO3 aq., which was stirred for 20 min. The mixture was extracted with CH2Cl2. The organic phase was washed with brine and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]carbamate (744 mg) as a off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>C(O)C>[CH2:8]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN1CCNCC1
Reaction time: 8 h
Yield: 29.2 %

Procedure:
Anhydrous piperazine (19.5 g) was dissolved in ethanol (100 ml), and a solution of 1-bromobutane (24.8 g) in ethanol (50 ml) was added dropwise over a period of 20 minutes at room temperature. After stirring overnight, the reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure. To the residue obtained was added a 40% aqueous solution of sodium hydroxide, and extracted with ether three times. The ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol:aqueous ammonia=90:10:0.5) to give the title compound (7.53 g) as a yellow oily substance. Yield=29%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:5][CH:6]=O.Cl.[NH2:17][C@H:18]1[C:27]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:26]2[CH:25]=[C:24]([C:32]([NH2:34])=[O:33])[CH:23]=[CH:22][C:21]=2[CH2:20][C@@H:19]1[O:35][CH3:36].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.CO>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:5][CH2:6][NH:17][C@@H:18]1[C@@H:19]([O:35][CH3:36])[CH2:20][C:21]2[C:26](=[CH:25][C:24]([C:32](=[O:33])[NH2:34])=[CH:23][CH:22]=2)[C:27]1([CH2:30][CH3:31])[CH2:28][CH3:29]
Reactant: COC(=O)[C@H](CC=O)CC1CCCCC1
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCC[C@H](CC1CCCCC1)C(=O)OC
Reaction time: 3 h

Procedure:
(S)-2-cyclohexylmethyl-4-oxo-butyric acid methyl ester (822 mg, 3.38 mmol), (6S,7S)-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid amide hydrochloride (1.01 g, 3.23 mmol) and triethylamine (326 mg, 3.23 mmol) were dissolved in dichloromethane (15 mL) and methanol (10 mL). Sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was added. Over 3 h, additional sodium triacetoxyborohydride (900 mg, 4.2 mol) and (S)-2-cyclohexylmethyl-4-oxo-butyric acid methyl ester (550 mg, 2.6 mmol) were added in two portions, and the reaction mixture was stirred for 1 h after the last addition. Saturated sodium bicarbonate (60 mL) was added, and the reaction mixture was extracted with dichloromethane (4×50 mL). The organic layer was dried with Na2SO4 and concentrated. The resulting oil was dissolved in methanol (50 mL) and concentrated. The crude product was purified by preparative HPLC. Fractions containing pure product were pooled and the acetonitrile was removed at reduced pressure. Sodium carbonate (1.3 g, 12.3 mmol) was added and the product extracted into dichloromethane (3×200 mL). An additional portion of sodium sulfate (15 g, 140 mmol) was added to the aqueous layer which was extracted with dichloromethane (3×200 mL). The organic extracts were combined, dried with Na2SO4 and concentrated to give the title compound as the free base (1.16 g, 76% yield).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>COCCOC>[F:26][C:22]1[C:23]([F:25])=[CH:24][C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][C:34]([F:33])([F:46])[F:45])=[C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH:21]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1cc(F)c(F)cc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1cc(F)c(F)cc1-c1ccccc1OC(F)(F)F
Yield: 68.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4,5-difluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/2M Na2CO3 (0.443 ml, 0.863 mmol) was treated with 2-trifluoromethoxybenzeneboronic acid (72 mg, 0.351 mmol) and Pd[PPh3]4 (54 mg, 0.046 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate in hexanes gradient to afford the product as a white, crystalline solid (81 mg, 68%). MS m/e 509.24 (M+H+)
Reaction SMILES: Br[CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH:9]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32]4)=[CH:27][CH:26]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:9]1([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][CH:33]([N:36]([CH3:37])[CH2:2][C@H:3]5[CH2:4][CH2:5][C:6](=[O:8])[NH:7]5)[CH2:32]4)=[CH:27][CH:26]=3)=[O:23])=[CH:19][CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CNC1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)cc3)cc2)C1
Reactant: O=C1CC[C@H](CBr)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CCC(=O)N1)C1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)cc3)cc2)C1
Reaction time: 2 h

Procedure:
(R)-5-Bromomethylpyrrolidin-2-one (15 mg) was added to a suspension of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methyaminopyrrolidin-1-yl)phenyl]urea (30 mg) and potassium carbonate (20 mg) in DMF (3 ml). After 2 hours, the reaction mixture was filtered and concentrated, and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 491.64 (C28H37N5O3); MS (ESI): 492 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:5]([F:20])=[CH:4][C:3]=1[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23].C(N(CC)CC)C.[CH3:34][C:35]1([O:38][C:39](ON2C(=O)CCC2=O)=[O:40])[CH2:37][CH2:36]1>ClCCl>[CH3:25][N:24]([CH3:26])[C:22](=[O:23])[CH2:21][C:3]1[C:2]([F:1])=[CH:7][C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:39]([O:38][C:35]3([CH3:34])[CH2:37][CH2:36]3)=[O:40])[CH2:18][CH2:19]2)=[C:5]([F:20])[CH:4]=1
Reactant: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Reactant: CC1(OC(=O)ON2C(=O)CCC2=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2,5-difluoro-4-{2-[(1S,2R)-2-piperidin-4 ylcyclopropyl]ethoxy}phenyl-)-N,N-dimethylacetamide (40.0 mg, 0.109 mmol) in 1 ml anhydrous dichloromethane at 0° C. was added triethylamine (0.0300 ml, 0.218 mmol) and 1-({[(1-methylcyclopropyl)oxy]carbonyl}oxy)pyrrolidine-2,5-dione (27.9 mg, 0.131 mmol). The reaction was stirred at RT for 2 hours. The solvent was evaporated, and the residue was purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 25-85% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 465.4 (M+H)+. Human EC50: 2.2 nM
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:21]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:28]1([CH3:31])[CH:27]=[CH:26][C:25]([S:22]([N:21]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=[C:13]2[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=3)[N:8]([CH3:12])[CH:7]=2)(=[O:24])=[O:23])=[CH:30][CH:29]=1
Reactant: COc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3cccnc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of 2-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [24.5 g, Reference Example 13(b)] in dichloromethane (500 mL), at 0° C. under an atmosphere of nitrogen, was added a solution of boron tribromide in dichloromethane (60 mL, 1.0M) and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was allowed to warm slowly to ambient temperature and stirring continued for 12 hours. A solution of sodium carbonate (1M, 250 mL) was added to the mixture and stirring was continued vigorously for 3 hours. The precipitated solid was collected by filtration, washed with dichloromethane (100 mL) and dried to give the title compound (18.75 g) as a colourless solid, m.p. 256-257° C. MS: 418 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.C(O)=O>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCOC(=O)CCc1ccc(C#N)cc1
Yield: 98.4 %

Procedure:
Pd/C (5 g, 10%) was added to a solution of 3-(4-cyanophenyl)acrylic acid ethyl ester (50 g, 0.25 mol; see step (i) above) in dry ethyl acetate (500 mL) under a nitrogen atmosphere, followed by triethylamine (50.3 g, 0.5 mol) and formic acid (57.2 g, 1.24 mol). The mixture was refluxed overnight under a nitrogen atmosphere. After the completion of the reaction (monitored by TLC), the mixture was filtered and the filtrate then washed with water, 5% NaHCO3 solution and brine, before being dried over sodium sulfate. Solvent evaporation under reduced pressure yielded 50 g (99%) of the sub-title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:11][C:12]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH2:11][C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cc1cc(O)ncc1Br
Reactant: COC(=O)C1(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(COc2cc(C)c(Br)cn2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
In tetrahydrofuran (26 mL) was dissolved 5-bromo-4-methylpyridin-2-ol (1.3 g), methyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.08 g) and triphenylphosphine (2.72 g), and 40% diethyl azodicarboxylate-toluene solution (4.72 mL) was added dropwise to the solution at 0° C. The mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added to the mixture, and the organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1 to 99:5) to obtain methyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]-methyl}cyclopropanecarboxylate (2.08 g).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.Cl.CN(C)CC(O)=O>[Cu]I.O1CCOCC1>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: Ic1cnccn1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(Oc2cnccn2)cc1
Temperature: 90 °C
Yield: 86.7 %

Procedure:
2-Iodopyrazine (2.00 g, 9.42 mmol), copper(I) iodide (366 mg, 1.88 mmol), cesium carbonate (6.14 g, 18.84 mmol), 4-hydroxybenzonitrile (1.68 g, 14.13 mmol) and N,N-dimethylglycine hydrochloride (398 mg, 2.83 mmol) were dried and placed under nitrogen and then degassed 1,4-dioxane (25.0 mL) was added. The whole mixture was heated at 90° C. for 138 hours. The cooled mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with brine (50 mL) and dried with Na2SO4 and concentrated in vacuo. The crude solid was placed on a silica gel column and purified (EtOAc/Hex 1:8) to give the product as an off white solid (1.61 g, 87%). 1H NMR (300 MHz, CDCL3) δ(ppm): 7.31 (2H, d, J=9.1 Hz), 7.74 (2H, d, J=9.1 Hz), 8.14 (1H, dd, J=2.4, 1.4 Hz), 8.37 (1H, d, J=2.4 Hz), 8.51 (1H, s). 13C NMR (75 MHz, CDCL3) δ(ppm): 109.0, 118.5, 122.0 (CH), 134.1 (CH), 136.4 (CH), 139.8 (CH), 141.1 (CH), 156.7, 159.1. MS (FAB+): 198 (MH+). HRMS for C11H7N3O (MH+): calculated: 198.0667; found 198.0661.