Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[C:5](=[CH:10][C:11]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH:13]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CO.O>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=1[NH:25][C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])[C:3]([OH:36])=[O:2]
Reactant: COC(=O)c1cc(Nc2ccc(OC)cc2OC)c(Nc2ccc(OC)cc2OC)cc1C(=O)OC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2cc(C(=O)O)c(C(=O)O)cc2Nc2ccc(OC)cc2OC)c(OC)c1
Temperature: 25 °C

Procedure:
A steady stream of argon is passed through a suspension of 260 mg (0.6 mmol) of 4,5-bis(2,4-dimethoxy-anilino)phthalic acid dimethylester in 2 ml of methanol, and a solution of 101 mg (2.4 mmol, 4 eq) of lithium hydroxide monohydrate and 10 mg sodium ascorbate in 1 ml of water is added. The reaction mixture is heated to reflux for 10 hours, cooled to RT, and the methanol is removed by evaporation. The resulting mixture is poured onto 20 ml of 4N hydrochloric acid, the red suspension is filtered and the crystals are washed with washed with isopropanol/hexane 1:5 to yield the title compound in the form of red crystals, FAB-MS: 469 [M+ +H].
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([NH:21][C@H:22]([CH2:30][OH:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O.C(N(CC)CC)C>[CH2:11]([O:18][C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@H](CO)Cc1ccccc1)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
A solution of 24.5 ml of anhydrous dimethyl sulfoxide in 870 ml of anhydrous dichloromethane was cooled under N2 atmosphere to -60° C. and treated over a period of 15 min with 131 ml of a 2M solution of oxalyl chloride in dichloromethane in order that the internal temperature remained below -50° C. After addition, the solution was stirred at -60° C. for 15 min and treated over a period of 20 min with a solution of 50 g (0.175 mol) of N-(((benzyl)oxy)-carbonyl)-L-phenylalaninol in 200 ml of dichloromethane. The resulting solution was stirred at -60° C. for 1 h, then treated over a period of 15 min with 97 ml of triethylamine in order that the internal temperature remained below -50° C. After addition the solution was stirred at -60° C. for 15 min, then, with the cooling bath in place, was treated rapidly (over a period of 1 min) with a solution of 163 g of citric acid in 550 ml of water. The resulting slurry was stirred vigorously for 10 min, allowed to warm, diluted to 1 liter with water, and separated. The organic layer was washed with 700 ml of water followed by a mixture of 550 ml of water and 150 ml of saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo at 20° C. to give the crude desired compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(C(C)=O)C.[I-].[K+]>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 90.3 %

Procedure:
A mixture of 4-hydroxyacetophenone (30 g), potassium carbonate (33.4 g), potassium iodide (1 g) and benzyl bromide (41.4 g) in methyl ethyl ketone (500 mL) is heated at reflux for 18 hours. The cooled reaction mixture is filtered and the filtrate evaporated. The residue is crystallised from cyclohexane to give 4-benzyloxyacetophenone (45 g, 90%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH4-].[Na+]>C(O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To 1-Boc-4-piperidone (10 g) in ethanol stirring at 0° C. was added sodium borohydride (9.45 g) portionwise. The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was then quenched with water and extracted with chloroform. The combined organic were washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 9.2 g of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][NH:14][CH3:15].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:13][CH3:12])[CH3:15])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CNOC
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
A mixture of 4-bromo-3-methyl-benzoic acid (15 g, 0.069 mol), O,N-dimethyl hydroxylamine (6.5 g, 0.1 mol) HATU (38 g, 0.1 mol), and triethylamine (20 g, 0.2 mol) dissolved in DMF (50 mL) was stirred at RT for 12 h, concentrated, and purified by silica gel chromatography (1:1 EtOAc:petroleum ether) to provide the title intermediate (11 g, 61% yield) 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.52 (m, 2H), 7.32 (m, 1H), 3.50 (s, 3H), 3.29 (m, 3H), 2.38 (s, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([CH3:18])[CH:6]=1)(=O)C.C[O-].[Na+]>CO>[OH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([CH3:18])[CH:6]=1
Reactant: CCOC(=O)COc1ccc(OC(C)=O)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)COc1ccc(O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of ethyl 2-(4-acetoxy-2-methylphenoxy)acetate (684) (6.79 g, 27 mmol) in dry methanol (150 mL) was added sodium methoxide (1.1 eq.) and the reaction was stirred at room temperature under N2 for 3 hours. The reaction was quenched with 1M HCl and the volatiles were removed in vacuo. The oil was dissolved in ethyl acetate (100 mL) and washed with water (2×100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afforded ethyl 2-(4-hydroxy-2-methylphenoxy)acetate (685) as a white solid (77%).
Reaction SMILES: [OH-].[Na+].[Br-].[C:4]([CH2:9][P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:6][CH2:7][CH3:8])=[O:5].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1>O.C(Cl)(Cl)Cl>[C:4]([CH:9]=[P:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Ethyl bromoacetate (14.4 g, 0.094 mol) was added dropwise over 30 min to a stirred solution of 26.2 g (0.1 mol) of triphenylphosphine in 120 ml of benzene maintained at 35 38° C. After stirring for additional 12 h at room temperature the precipitate was filtered and washed twice with hexane to give 34.7 g (86%) of (carboethoxymethyl)-triphenylphosphonium bromide, m.p. 159 160° C. 115 ml of 10% aqueous sodium hydroxide was added dropwise with cooling at 5° C. to a stirred suspension of 118.4 g (0.276 mol) of the bromide in 500 ml of water and 200 ml of chloroform containing a small amount of phenolphthalein. Stirring was continued over 30 min. period without external cooling followed by adding 500 ml of chloroform to give clear layers. The aqueous layer was extracted three times with 100 ml of chloroform and the combined chloroform fractions were dried over sodium sulfate and concentrated in vacuo. Crystallization of the residue from 180 ml of 1:1 mixture of benzene and hexane gave 86.2 g (90%) of pure (carboethoxymethylene)triphenylphosphorane, m.p. 119 120° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.38 h
Yield: 66.1 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.30 g, 1.6 mmol) in anhydrous N,N-dimethylformamide (5.5 mL) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (82.5 mg, 2.06 mmol) under nitrogen. The reaction was stirred at 0° C. for 20-25 min. At this time, the reaction was treated with (2-(chloromethoxy)ethyl)trimethylsilane (340 μL, 1.92 mmol) and was purged with nitrogen. The ice/water bath was removed, and the reaction was stirred at room temperature over 3 nights. At this time, the reaction was diluted with water (50 mL) and was extracted with ethyl acetate (2×50 mL). The combined organics were washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and rinsed with ethyl acetate, and concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 1-30% ethyl acetate/hexanes) afforded 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a viscous yellow oil (336.5 mg, 66.3%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.18-−0.01 (m, 9H) 0.74-0.94 (m, 2H) 3.43-3.62 (m, 2H) 5.60 (s, 2H) 6.78 (d, J=3.77 Hz, 1H) 7.90 (d, J=3.77 Hz, 1H). LC-MS calcd. for C12H18Cl2N3OSi [(M+H)+] 318, obsd. 317.9.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C(C)=CC=CC=1>[CH:6]1([NH:12][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[S:1](=[O:3])(=[O:2])([OH:5])[OH:4]
Reactant: NC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
In a Meyer's flask having an inner volume of 300 ml, 100 g of orthoxylene and 60 g of sulfuric acid were dispersed. Then the Meyer's flask was kept cooled in a water bath, 122 g of cyclohexylamine was added dropwise thereto to obtain a xylene slurry of white crystals of dicyclohexylamine salt of sulfuric acid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12](=O)[NH:11][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:9][C:8]=1[C:17]([OH:19])=[O:18].N>C(#N)C>[Cl:6][C:7]1[C:8]([C:17]([OH:19])=[O:18])=[N:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:11][C:12]=1[Cl:3]
Reactant: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: CC#N
Product: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 85 °C

Procedure:
Phosphorus oxychloride (14 mL, 23 g, 0.15 mol) and 5-chloro-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step B1 or B2) (75 g, 300 mmol) were combined and heated at 85° C. for 3 h. The reaction mixture was cooled to 30° C. and added over 30 minutes to a mixture of acetonitrile (50 mL) and ice water (80 mL), with the temperature maintained at 5-10° C. and the pH maintained in the range 1-3 by co-feeding aqueous ammonia (28%). The pH was adjusted to about 2, the mixture was concentrated at 25° C. with a rotary evaporator to remove acetonitrile, and the precipitated product was isolated by filtration and washed with water (2×25 mL). The solid was dried in a vacuum oven to afford the title compound (ca. 7.0 g).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:10][CH2:9][CH2:8][N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCN1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
Add NaH (3.2 g, 80 mmol) portionwise to a 0° C. solution of 2-pyrrolidin-1-yl-ethanol (9.4 mL, 80 mmol) in DMF (180 mL). Stir the reaction 15-20 min until gas evolution ceases. Add a solution of 1-chloro-2-methoxy-4-nitro-benzene (15.0 g, 80 mmol) in DMF (100 mL) via cannula. Warm the reaction to 130° C. and stir for approximately 18 h. Cool to RT and dilute with EtOAc (300 mL). Wash with water (2×100 mL). Extract the organic layer with 1 N HCl (3×150 mL). Wash this acidic layer with EtOAc (100 mL) then basify by adding 1 N NaOH (500 mL) until pH=8-9. Extract the now basic aqueous layer with CH2Cl2 (3×150 mL). Dry the organic layer over Na2SO4 and concentrate to provide 8.5 g (40%) of the desired product as an orange solid. MS/ES m/z 267.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.II.[F:17]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:17][C:7]1[N:6]=[C:5]2[C:14](=[C:13]3[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:1]=[CH:2][CH:3]=[CH:4]2
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: FF
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Product: Fc1nc2ccccc2c2ccccc12
Yield: 8.1 %

Procedure:
A solution containing phenanthridine (1.0 g, 5.6 mmol) and iodine (1.4 g, 5.6 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to an orange oil (0.91 g). GC/MS analysis showed a 17% conversion of starting material. Column chromatography on silica get with dichloromethane as eluant gave 6-fluoro-phenanthridine (0.09 g, 48%); RF 0.78 (CH2Cl2); δH (400 MHz, CDCl3, Me4Si) 7.61 ppm (1H, d d d, JH1,H2 =JH2,H3 =7.8, JH2,H4 1.2, H-2), 7.69 (2H, m, H-3 and H-9), 7.88 (1H, d d d, JH7,H8 8.4, JH8,H9 7.2, JH8,H10 1.4, H-8), 7.97 (1H, d d, JH3,H4 8.0, JH2,H4 1.2, H-4), 8.21 (1H, d d, JH9,H10 8.0, JH8,H10 1.4, H-10 8.45 (1H, d d, JH1,H2 8.0, JH1,H3 0.8, H-1), 8.52 (1H, d d, JH7,H8 8.4, JH7,H9 1.2, H-7); δF (376 MHz. CDCl3, CFCl3) -68.2 ppm (s); δC (100 MHz, CDCl3, Me4Sl) 117.3 ppm (d, J 35.1,C-6a), 122.2 (d, 3J 3.8, C-7), 122.2 (s, C-1), 123.9 (d, 4J 1.9, C-10b), 124.2 (s, C-10), 126.5 (d, 6J 2.3, C-2), 127.9 (s, C-9), 128.7 (d, 4J 1.6, C-4), 129.4 (s, C-3), 132.1 (s, C-8), 136.5 (d, 3J 7.2, C-10a), 141.5 (d, 3J 17.9, C-4a), 158.1 (d, 1J 248.7, C-6); m/z (E1+) 197 (M+, 100%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][NH:16][CH:17]=O)[CH:11]=[CH:12][CH:13]=1>CCCCCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[CH:17]=[N:16][CH2:15][CH2:14]2
Reactant: COc1cccc(CCNC=O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCN=C2
Temperature: 25 °C
Yield: 67.5 %

Procedure:
Phosphorus oxychloride (80 mL, 0.85 mol) was added dropwise to N-[2-(3-methoxy-phenyl)-ethyl]-formamide (41.1 g, 0.24 mol) and refluxed for 1 hour. The reaction mixture was cooled to room temperature, and hexane (3×500 mL) was added and decanted off three times. To the dark oily solution was added slowly water (200 mL) while stirring. The mixture was basified with NaOH to pH>13, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford the desired product (26.1 g, 67%). MS: 162.1 (M+1+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:13]2=[N:14][CH:15]=1.C1CCCCC=1>[Pd].C1(C)C=C(C)C=C(C)C=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:16][C:13]2=[N:14][CH:15]=1
Reactant: COc1ccc(F)c(-c2cnc3[nH]c4c(c3n2)CCCC4)c1
Agent: [Pd]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C1=CCCCC1
Product: COc1ccc(F)c(-c2cnc3[nH]c4ccccc4c3n2)c1
Temperature: 200 °C

Procedure:
A sealed tube containing 2-(2-Fluoro-5-methoxyphenyl)-6,7,8,9-tetrahydro-indolo[2,3-b]pyrazine (46 mg, 0.155 mmol), cyclohexene (10 equiv., 0.157 mL, 1.55 mmol), Pd black (35 mg) and mesitylene (10 mL) was heated to 200° C. in an oil bath and the contents stirred via a magnetic stir bar. The progress of the reaction was monitored by intermittently opening the cooled tube and taking out an aliquot for TLC analysis (30% ethyl acetate/hexanes eluent; the aromatized product has a slightly larger Rf value than that of the starting material). Upon completion of the reaction, the mixture was filtered through celite and the mesitylene removed using a high vacuum rotary evaporator. Recrystallization from hexanes/ethyl acetate afforded 2-(2-Fluoro-5-methoxyphenyl)-5H-indolo[2,3-b]pyrazine (Compound 2) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[C-:10]#[N:11].[Na+]>CS(C)=O.C(OCC)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: BrCc1cccc(Br)n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1cccc(Br)n1
Temperature: 50 °C

Procedure:
A solution of 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (5 g, 19.9 mmol) in dimethylsulfoxide (50 mL) was charged with sodium cyanide (2.93 g, 59.8 mmol). The reaction was heated to 50° C. overnight. Upon completion, the reaction was diluted with ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The organic layer was then dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (hexane:ethyl acetate 7:3) followed by purification by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to afford the title compound.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([CH2:10][Br:1])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccccc2)c(F)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1-c1ccccc1

Procedure:
In a similar experiment 0.8 equivalent of Br2 was added dropwise to a refluxing solution of 2-fluoro-4-methylbiphenyl (2) and CCl4. NMR analysis showed the ratio of starting material:monobromide:dibromide to be 31:61:8.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]([O:26][CH3:27])[O:24][CH3:25].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:21]4[CH:20]=[N:19][CH:18]=[CH:17][C:22]=4[CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: COC(OC)c1ccncc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(OC)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 51 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 590 mg, 2.7 mmol) was reacted with 3-bromo-4-dimethoxymethyl-pyridine (I-149a: 690 mg, 2.97 mmol), 1,4-dioxane (50 mL), copper iodide (51.46 mg, 0.27 mmol), trans-1,2-diamino cyclohexane (93 mg, 0.81 mmol) and potassium phosphate (1.72 g, 8.1 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 510 mg of the product (51.2% yield).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH:9]=[N:8]1.[OH-].[Li+]>C1COCC1.CO.O>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)c1
Yield: 511.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperidin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (170 mg, 0.026 mmol) was hydrolyzed by lithium hydroxide (12 mg, 0.264 mmol) in THF/methanol/water (10/5/2.5 ml) to yield 60 mg (40% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.54 (s, 2H), 8.229-8.227 (d, 1H), 7.959-7.957 (d, 1H), 7.73-7.70 (m, 3H), 7.44-7.41 (d, 2H), 7.38-7.23 (m, 1H), 7.12-7.09 (d, 1H), 7.08-7.00 (m, 2H), 5.43 (s, 2H), 3.55-3.50 (d, 2H), 3.21-3.13 (m, 2H), 3.05-2.93 (m, 1H), 2.16-2.11 (d, 2H), 2.02-1.89 (m, 2H). MS: m/z=452.5 (M+1), HPLC: 96.75% in method A.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(F)C=3)C=2)=[O:7])=[CH:4][N:3]=1.CC1CNCC(C)N1>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:26]=[CH:27][CH:2]=[N:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(F)c2)c1)c1ccc(Cl)nc1
Agent: CC1CNCC(C)N1
Product: NC(=O)c1cccnc1

Procedure:
6-chloro-N-(4-chloro-3-(3-fluorobenzamido)phenyl)nicotinamide (0.117 mmol) was used in general procedure 3 with 2,6-dimethylpiperazine (0.35 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-fluorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)nicotinamide. MS (Q1) 482.1 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O.[NH2:10][NH2:11]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: NN
Reactant: Clc1cccc(Cl)n1
Solvent: O
Product: NNc1cccc(Cl)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
The title compound was prepared according to the method described in U.S. Pat. No. 4,260,767 (1981). A mixture of 2,6-dichloropyridine (25.0 g, 169 mmol) and hydrazine monohydrate (60 mL, 1.24 mol) was heated and stirred at 100° C. for 4 hours. The solution was ice cooled, and the resulting crude crystals were collected by filtration. The crystals were washed with cold water and air dried. The crystals thus obtained were recrystallized from chloroform/hexane to give the title compound (15.8 g, 65% yield).