Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.[Cl:21][CH2:22][CH2:23][CH2:24]O>C1(C)C=CC=CC=1>[Cl:21][CH2:22][CH2:23][CH2:24][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OCCCCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C(OCCCCl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a mixture of 106.0 g of 2,4-dinitrobenzoic acid in 200 ml of toluene were added 10.0 g of concentrated sulfuric acid and 95.0 g of 3-chloropropanol. The mixture was refluxed for 4 hrs and the resulting water removed by azeotropic distillation. After this period the mixture was cooled to room temperature and washed with 250 ml of an aqueous 5% NaHCO3 solution followed by two 200 ml water washings. The toluene was removed at reduced pressure to yield 146 g of (3-chloropropyl)-2,4-dinitrobenzoate, mp 40° C.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.CC(N=NC(C#N)(C)C)([C:15]#[N:16])C.C1C(=O)N(Br)C(=O)C1.C[Si](C#N)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[C:9]([CH2:10][C:15]#[N:16])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: Cc1cc(C#N)c(F)cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CCc1cc(C#N)c(F)cc1Br
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 4-bromo-2-fluoro-5-methylbenzonitrile, AIBN (0.1 eq.) and NBS (1 eq.) in CCl4 (0.14 M) was stirred at 80° C. for 18 h. After cooling to RT the mixture was quenched with 1N aq. NaS2O3 and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness under reduced pressure. The residue was dissolved in MeCN (0.2 M), then trimethylsilyl cyanide (1 eq.) was added, followed by TBAF (1M in THF, 1 eq.). The mixture was stirred for 2 h at RT, and then water was added and the solvents were removed under reduced pressure. The residue was diluted with DCM, washed with brine, dried (Na2SO4), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 5-50% EtOAc/petroleum ether to afford the product as a white solid. 1H-NMR (300 MHz, CDCl3) δ: 7.78 (1H, d, J=6.3 Hz), 7.55 (1H, d, J=7.8 Hz), 3.82 (2H, s). MS (ES) C9H4BrFN2 requires: 238/240, found: 237/239 (M−H)−.
Reaction SMILES: B.O1CCCC1.C([O:11][C:12](=[O:34])[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][C:26](=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:19][CH:18]=1)([CH3:15])[CH3:14])(C)(C)C.Cl>O1CCCC1>[CH2:26]([NH:25][CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:13]([CH3:14])([CH3:15])[C:12]([OH:34])=[O:11])=[CH:22][CH:21]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCC(=O)NCCc1ccc(NC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCNCCc1ccc(NC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
1H NMR (400 MHz, CDCl3) δ6.98 (d, 2H), 6.59 (d, 2H), 5.38 (s, 1H), 4.03 (s, 1H), 3.47 (m, 2H), 2.70 (t, 2H), 2.11 (t, 2H), 1.65−1.40 (m, 3H), 1.53 (s, 6H), 1.39 (s, 9H), 1.29 (m, 5H), 0.89 (t, 3H). Borane-tetrahydrofuran complex (1.0M in THF; 6.96 mL, 6.96 mmol) was added to a solution of 2-[4-(2-heptanoylamino-ethyl)-phenylamino]-2-methyl-propionic acid tert-butyl ester (1.36 g, 3.48 mmol) and tetrahydrofuran (25 mL) and the resulting mixture stirred at ambient temperature for 18 h. Additional borane-tetrahydrofuran complex (3.5 mL, 3.5 mmol) was added and the resulting mixture stirred 24 h at ambient temperature before acidifying with 1N aqueous hydrochloric acid. The resulting mixture was then refluxed for 2 h, cooled to ambient temperature and the tetrahydrofuran removed under reduced pressure. The resulting residue was neutralized with saturated aqueous sodium bicarbonate, concentrated under reduced pressure, azeotroped with ethyl acetate and purified by flash column chromatography (10% methanol/1% concentrated ammonium hydroxide/chloroform→15% methanol/1% concentrated ammonium hydroxide/chloroform) to provide 417 mg (38%) of 2-[4-(2-heptylamino-ethyl)-phenylamino]-2-methyl-propionic acid as a white solid.
Reaction SMILES: [C:1]([O:12]C)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-])=[O:7])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16].Cl>CO>[C:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][NH2:16])=[O:7])=[CH:4][CH:3]=1)([OH:12])=[O:11]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(C(=O)O)cc1

Procedure:
In 1 l of methanol was dissolved 180 g of monomethyl terephthalate, and the solution was slowly added dropwise to 500 ml of hydrazine hydrate (50%) at room temperature while stirring. After the drop-wise addition, the mixture was heat-refluxed for 5 hours while stirring. A hydrochloric acid aqueous solution was slowly added to the reaction mixture to adjust to a pH of about 1 to thereby precipitate white crystals. Two liters of water was added to the system, followed by stirring for a while. The formed crystals were collected by filtration under reduced pressure, washed twice with 200 ml of water, and dried to obtain 160 g of p-carboxybenzhydrazide (melting point: 235-236° C.).
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13]([O:19][CH2:20][CH:21]=[CH2:22])([CH2:17][CH3:18])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([C:4]1[C:12]([C:13]([CH2:17][CH3:18])([O:19][CH2:20][CH2:21][CH3:22])[CH:14]([CH3:15])[CH3:16])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=CCOC(CC)(c1c(C(C)C)nn2ccccc12)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCOC(CC)(c1c(C(C)C)nn2ccccc12)C(C)C
Yield: 70 %

Procedure:
A solution of 500 ml of 2-isopropyl-3-(1-allyloxy-1-ethyl-2-methylpropyl)pyrazolo[1,5-a]pyridine (Example 31) in 20 ml of ethanol was stirred in a hydrogen atmosphere at atmospheric pressure and room temperature in the presence of 20 mg of 10% palladium-on-charcoal. Absorption ceased after an hour. The solution was filtered and concentrated to dryness in vacuo. The residue was applied to silica gel column chromatography, eluted with dichloromethane, to give 350 mg (70%) of the desired compound as pale yellow oil.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Cc1ccnc(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccnc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 22.4 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 65° and 72° C., to a solution of 2-amino-4-methylpyridine (2.15 g) and triethylamine (4.05 g) in dioxane (100 cc) which is heated to a temperature in the vicinity of 65° C., in the course of 20 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 5 hours and 45 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (250 cc). The solution obtained is washed with distilled water (100 cc) and then with an aqueous 4N sodium hydroxide solution (100 cc) and 3 times with distilled water (450 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (4.8 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(4-methyl-2-pyridyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (1.5 g) in the form of cream-coloured crystals, m.p. 163° C., is thereby obtained.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][C:12](=[S:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21]I>C1C=CC=CC=1>[CH3:21][S:14][C:12]1[CH2:13][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[N:11]=1
Reactant: CI
Reactant: S=C1CC(c2ccccc2)=Nc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CSC1=Nc2ccccc2N=C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
12.6 parts of 2,3-dihydro-4-phenyl-1H-1,5-benzodiazepine-2-thione is suspended in 1000 parts by volume of dry benzene. To this suspension is added 3 parts of 57% sodium hydride and the resultant mixture is stirred for about 2 hours at reflux temperature. 10 Parts of methyl iodide is then added to the reaction mixture and stirring is continued at reflux temperature overnight. The reaction mixture is then cooled to room temperature, filtered and the filtrate concentrated under reduced pressure to afford 2-methylthio-4-phenyl-3H-1,5-benzodiazepine, as an oil. This compound has the formula ##STR15##
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH2:36]([NH2:38])[CH3:37].CO.[BH4-].[Na+]>O.CC#N.CC#N.O.C(Cl)Cl.CO>[CH2:36]([NH:38][CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH3:37]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CCNC[C@@H]1CNC[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C

Procedure:
The title compound is prepared from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.52 mmol), 2N solution of ethylamine in MeOH (3.805 mL, 7.61 mmol) and NaBH4 (0.115 g, 3.04 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4, then CH2Cl2/MeOH (10% NH3 conc.) gradient from 9:1 to 8:2) to give a colorless oil. MS: 522.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.47 min.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:3][CH2:4]1
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[CH:5][CH:4]=1.Br[C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[CH:5][CH:4]=1
Reactant: CCCn1c(C)c(-c2ccc(OC)cc2)c2cc(O)ccc21
Reactant: CC(C)(Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(C)c(-c2ccc(OC)cc2)c2cc(OC(C)(C)C(=O)O)ccc21

Procedure:
A mixture of 5.9 g (0.02 mole) of 3-(4-methoxyphenyl)-2-methyl-1-propyl-1H-indole-5-ol, 5.1 g (0.03 mole) of 2-bromo-2-methyl-propanoic acid, and 15 g of potassium carbonate was refluxed in 100 ml of acetone for 48 hours. The acetone was removed in vacuo, and the residue was acidified with 2N hydrochloric acid. After extraction with ethyl acetate, the extracts were dried over sodium sulfate and evaporated. The residue obtained was purified by chromatography on silicagel (eluant: chloroform/methanol (9:1)).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17]Cl)=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[I-:24].[Na+]>CC(C)=O>[F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][I:24])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1
Reactant: [I-]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CCl)c1CC(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CI)c1CC(C)C

Procedure:
Reaction of methyl 2-(difluoromethyl)-5-(chloromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (U.S. Pat. No. 5,169,432 example 3) with sodium iodide in refluxing acetone according to the procedure known to those in the art yielded the product.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14](I)[N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=1)=[O:5].[CH3:38][N:39]1[C:47]2[C:42](=[CH:43][C:44](B(O)O)=[CH:45][CH:46]=2)[CH:41]=[CH:40]1.C([O-])([O-])=O.[K+].[K+].CC#N.O>CCOC(C)=O.O.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>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:44]3[CH:43]=[C:42]4[C:47](=[CH:46][CH:45]=3)[N:39]([CH3:38])[CH:40]=[CH:41]4)[N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(-c2ccc4c(ccn4C)c2)n3S(=O)(=O)c2ccccc2)c1F
Temperature: 160 °C
Yield: 70 %

Procedure:
A mixture of 2,6-difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (27 mg, 40 mmol, 1.0 eq.), 1-methyl-1H-indol-5-ylboronic acid (1.5 eq.), K2CO3 (20 eq.) and Pd(PPh3)4 (0.05 eq.) were taken up in 4:1 MeCN/water (0.7 mL) and heated to 160° C. for 15 minutes under microwave irradiation. The mixture was diluted with 1:1 EtOAc/water (6 mL), filtered through GF/F paper, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated to afford 2,6-difluoro-N-(2-(1-methyl-1H-indol-5-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (19 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N:11][N:10]=1.OO.[OH-].[Na+].C(OCC)(=[O:33])C.C(OCC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N+:11]([O-:33])[N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3cncn3)c2c1
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[n+]([O-])c(-n3cncn3)c2c1
Reaction time: 48 h
Yield: 41 %

Procedure:
Under N2 at 0° C. a solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-4-[1,2,4]triazol-1-yl-phthalazine (5.1 g, 13.2 mmoles), prepared as described in example 51, in trifluoroacetic acid (25 ml), was dropwise added with H2O2 (1.35 ml, 13.5 mmoles). The temperature was left to rise to the room value and, after 48 hours, the pH was adjusted with NaOH. After further 24 hours under stirring, the mixture was dried, taken up in CH2Cl2. The organic phase was washed with water, anhydrified and dried to give a foam which was flash chromatographed (eluent: ethyl acetate/ethyl ether 6:4, then 8:2) to give 2.2 g of the title compound (yield: 41%). m.p.: 218-220° C. (dec.).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(OCC)=O)C.CC(C)([O-])C.[K+].[Cl:18][C:19]1[N:20]=[C:21]([CH2:46][CH3:47])[NH:22][C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40]([CH:42]=O)[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]>C1COCC1>[Cl:18][C:19]1[N:20]=[C:21]([CH2:46][CH3:47])[NH:22][C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40](/[CH:42]=[CH:9]/[C:10]#[N:11])[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]
Reactant: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C=O)c3)c2F)[nH]1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(/C=C/C#N)c3)c2F)[nH]1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
A solution of diethylphosphonoacetonitrile (15 μL, 0.094 mmol) in THF (1 mL) was cooled to 5° C. in an ice bath and potassium t-butoxide (1 M in THF, 94 μL, 0.094 mmol) was added dropwise. The reaction was stirred at 5° C. for 30 min and a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-2-ethyl-1H-imidazole-5-carboxamide (40 mg, 0.085 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at 5° C. for 30 min, warmed to room temperature and stirred for an additional 60 min. The reaction was quenched with water (1 mL) and concentrated to a yellow oil. The crude material was purified by column chromatography (10% to 100% EtOAc/hexanes gradient) to afford the title compound (32 mg, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.69 (s, 1H), 8.05 (t, 1H), 7.58 (d, 1H), 7.53 (s, 1H), 7.47-7.44 (m, 1H), 7.31 (t, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 6.58 (d, 1H), 4.49 (d, 2H), 2.55 (q, 2H), 1.13 (t, 3H). MS: m/z 493, 495 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:7][C:6]2[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: COC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 35.5 %

Procedure:
A mixture of (R)-2-[4-(4-chloro-benzyl)-phenoxymethyl]-pyrrolidine hydrochloride (1.37 g, 4 mmol), methyl 4-bromobutyrate (916 mg, 5 mmol), and potassium carbonate (1.12 g, 8 mmol) in DMF (15 mL) was stirred for 60 h at rt. The solvent was removed in vacuo to obtain the crude mixture. The mixture was diluted with 30 mL of water and extracted with ethylacetate (130 mL). The aqueous layer was re-extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (570 mg, 35%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>CC#N>[CH:26]1([CH2:25][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1CC1CC1
Temperature: 90 °C
Yield: 68.4 %

Procedure:
To a suspension of commercially available ethyl 5-nitro-1H-indole-2-carboxylate (0.5 g, 2.13 mmol) in MeCN (7 mL) was added Cs2CO3 (1.39 g, 4.27 mmol) and (bromomethyl)cyclopropane (0.58 g, 4.27 mmol). The mixture was heated at 90° C., under N2, for 5 h. Upon cooling, the mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-30% EtOAc-hexanes gradient). The product slowly crystallized from CH2Cl2-hexanes to afford the title compound as a light yellow solid (0.42 g, 68% yield): MS (ES) m/z 289 (M+1).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1.CCOC(C)=O.[Cl-].[Na+].O.O>[F:8][C:7]1[C:2]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: NCC1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(F)c(NCC2CCOCC2)n1
Temperature: 70 °C

Procedure:
A mixture of 2,3,6-trifluoropyridine (3 g, 22.54 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (3.89 g, 33.8 mmol) and triethylamine (7.86 mL, 56.4 mmol) in NMP (60 mL) was heated at about 70° C. for about 1 hr. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (˜100 mL), brine (˜50 mL) and water (˜50 mL). The separated organic layer was washed with brine (1×), 0.3N aqueous HCl (2×), saturated aqueous NaHCO3 solution (1×), brine (1×), dried over Na2SO4, filtered off and concentrated in vacuo providing crude 3,6-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine, which was directly used in the next reaction without further purification. Yield: 3.5 g. LCMS (m/z): 229.1 [M+H]+; Retention time=0.79 min.