Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][C:21]([O:24][C:25](=[O:43])[NH:26][CH:27]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:28](=[O:35])[NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:23])[CH3:22].C(N(CC)CC)C>C(#N)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:32]4[CH2:33][CH2:34][CH:30]([NH:29][C:28](=[O:35])[CH:27]([NH:26][C:25]([O:24][C:21]([CH3:22])([CH3:20])[CH3:23])=[O:43])[CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH2:31]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
A suspension of 14.1 g (50 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 18.3 g (55 mmol) of [R-(R*,S*)]-[1-phenylmethyl-2-oxo-2-[(3-pyrrolidinyl)amino]ethyl]carbamic acid 1,1-dimethylethyl ester, 15.2 g (0.15 mol) of triethylamine and 200 ml of acetonitrile was heated at reflux for four hours. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with 100 ml of cold 1.0M hydrochloric acid and then water. After drying (MgSO4) and filtering, the solvent was removed in vacuo to give 26.2 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([N+]([O-])=O)=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH3:31][O-:32].[K+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([O:32][CH3:31])=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A slurry of 50 mg (0.126 mmol) 2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine (synthesis see example 6) in 1 ml methanol was treated with 26.5 mg (3.0 mmol) potassium methylate. The mixture was stirred at 60° C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature. The solid was filtered off, washed with little methanol and dried under vacuum yielding 2-(2-fluoro-phenyl)-4-(8-methoxy-isoquinolin-5-yl)-[1,8]naphthyridine as colourless solid; HPLC/MS: 1.74 min, [M+H] 382.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[N:26]1([S:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([S:31]([N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)(=[O:33])=[O:32])=[CH:35][CH:36]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc(Nc4ccc(S(=O)(=O)N5CCCC5)cc4)nc4c3CCC4)cc2)CCC1
Reaction time: 45 h
Yield: 51.1 %

Procedure:
1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]cyclobutanecarboxylic acid methyl ester (0.36 g, 1 mmol) was added to a solution of 4-(pyrrolidine-1-sulfonyl)-phenylamine (0.24 g, 1.06 mmol) in anhydrous isopropanol (10 mL) and the mixture was stirred at a temperature in the range of 60° C. to 110° C. for 40 to 50 hours. The reaction was cooled to a temperature in the range of 15° C. to 25° C. The precipitated solid was filtered, washed with ether, and dried in vacuo to afford the title compound as a white solid (0.28 g, 54% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)[CH:11]=2)[C:6]([Cl:13])=[CH:7][N:8]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1cnc(Cl)c2cc(Br)ccc12
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: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(Cl)cnc(Cl)c3c2)cc1
Yield: 48 %

Procedure:
A mixture of 7-bromo-1,4-dichloroisoquinoline (276 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (60 mg, 5 mol %), 4-methyphenylboronic acid (137 mg, 1.00 mmol), and aqueous Na2CO3 (2.0 mL, 1.0 M, 2.0 mmol) in DME (6 mL) was heated at reflux under N2 for 20 h. The mixture was diluted with EtOAc (100 mL), washed with water (30 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexanes-EtOAc (99:1 to 97:3) as eluant to give 1,4-dichloro-7-(4-methylphenyl)isoquinoline (139 mg, 0.48 mmol) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1
Reactant: Cn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-methyl-1H-pyrazole.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:13]1[CH:14]=[C:15]2[C:19](=[N:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>CN(C)C=O.[Cu]Br>[N:1]1([CH2:7][CH2:8][O:9][C:13]2[CH:14]=[C:15]3[CH:16]=[CH:17][NH:18][C:19]3=[N:20][CH:21]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: OCCN1CCOCC1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc2cc(OCCN3CCOCC3)cnc2[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To 4-morpholineethanol (30 mL, 0.2 mol) in N,N-dimethylformamide (30 mL) was slowly added sodium hydride (7 g, 60% dispersion in mineral oil, 0.2 mol). After the solution turned clear, a solution of 5-bromo-7-azaindole (44, 1.0 g, 0.0051 mol) in N,N-dimethylformamide (5 mL) and copper(I) bromide (1.4 g, 0.0098 mol) were added. The reaction mixture was stirred at 120° C. under nitrogen for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was collected, washed with a solution of ammonium chloride and ammonium hydroxide (4:1), brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (79, 0.62 g, 50%). MS (ESI) [M+H+]+=248.25.
Reaction SMILES: O[NH:2][C:3](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][N:10]=1)[C:4]([CH3:7])([CH3:6])[CH3:5].N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:4]([C:3]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][N:10]2[N:2]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=Nc1ccc(I)cn1)NO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc2ccc(I)cn2n1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
N-Hydroxy-N′-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamidine (example 39, step 3) (2.8 g, 8.77 mmol) was suspended in 15 ml of toluene and pyridine (2.8 ml, 35.1 mmol, 4 equiv.). The mixture was cooled to 0-5° C. and p-toluenesulfonyl chloride (6.7 g, 35.1 mmol, 4 equiv.) was added. The reaction mixture was stirred for 1 hour at 0-5° C. and 4 hours at room temperature. The reaction mixture was extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0->0:100. The desired 2-tert-butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (2 g, 76% yield) was obtained as a light yellow oil, MS: m/e=302.1 (M+H+).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[C:20]1([N:26]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO>C(COC)OC>[C:20]1([N:26]([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][C:10]#[N:11])=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: N#CCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: -55 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A solution of 68.3 g (0.35 mol) of (p-toluenesulfonyl)methyl isocyanide (TOSMIC) in 300 ml of dimethoxyethane was added dropwise to a stirred suspension of 78 g (0.70 mol) of potassium tert-butoxide in 300 ml of dimethoxyethane at −30° C. under nitrogen. After the solution had been cooled to −55° C., a solution of 92 g (0.34 mol) of 4-(N,N-diphenylamino)benzaldehyde in 100 ml of dimethoxyethane was added dropwise. After stirring at −55° C. for 1 hour, methanol was added. The reaction solution was heated to boiling under reflux for 30 min. After the solution had been concentrated to dryness, the residue was taken up with 600 ml of water and 30 ml of acetic acid. The aqueous solution was extracted with methylene chloride. The combined organic phases were washed with a saturated sodium carbonate solution, dried over magnesium sulfate and concentrated to dryness. 75 g (79% of theory) of the desired nitrile were obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].[Cl:7][C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([I:17])=[CH:15][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12]=2[N:13]=1>C1COCC1>[Cl:7][C:8]1[N:9]=[C:10]([O:6][CH:4]([CH3:5])[CH3:3])[C:11]2[C:16]([I:17])=[CH:15][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12]=2[N:13]=1
Reactant: CC(C)O
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1nc(Cl)nc2c1c(I)cn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a suspension of sodium hydride (1 equiv, 60% in mineral oil) in dry THF (0.9 M) under nitrogen atmosphere was added propan-2-ol (0.52 equiv). The reaction mixture was stirred at room temperature for 30 min before a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.5 equiv) in dry THF (0.45 M) was added. The mixture was stirred at room temperature for 1 h. The reaction was monitored by thin layer chromatography. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (0-10% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (81% yield). MS (ESI) m/z 468.2 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.I.[NH2:33][C:34]1[C:35]([C:42]([NH:44][C:45](=[NH:48])SC)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1>C(O)C>[NH2:33][C:34]1[C:35]([C:42]([N:44]=[C:45]([NH2:48])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([S:12]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18])(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCN)cc1)C(N)=O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)C(N)=O
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of (2S)-[4-(4-aminobutyl)benzenesulfonylamino]-3-methylbutyramide 15 (156 mg, 0.47 mmol), diisopropylethylamine (0.60 mL, 3.0 mmol), and 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (230 mg, 0.61 mmol) in absolute ethanol (8 mL) was stirred at 70° C. for 5 h and then cooled to room temperature. The reaction mixture was concentrated by rotary evaporation. The crude residue was washed with water, filtered and the crude solid product was purified by flash silica gel column chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (5:1:0.1, v/v) to give the desired product as a yellow solid (137 mg, 54% yield). Part of the solid (86 mg) was further purified by semi-preparative HPLC (acetonitrile/water/0.1% TFA) to give the analytical pure sample which was then co-evaporated with 5% aqueous HCl to give the hydrochloride salt 16. mp 154-156° C. (decomposed). 1H NMR (300 MHz, CD3OD) δ 0.85 (d, 3H), 0.86 (d, 3H), 1.70 (m, 4H), 1.90 (m, 1H), 2.75 (m, 2H), 3.32 (m, 2H), 3.52 (d, 1H), 7.35 (d, 2H), 7.75 (d, 2H). m/z (ESI): 540 [C21H30ClN9O4S+H]+. [α]D25+5.2° (c 0.50, MeOH).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51]S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:74])[CH3:2].[N-:75]=[N+:76]=[N-:77].[Na+].O>CN(C=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:75]=[N+:76]=[N-:77])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 40.9 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-[4"-(2"'-nitrobenzenesulfonyloxy)-3"-hydroxycyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (105 mg, Example 64, compound A) in dry DMF (1 ml) with sodium azide (22 mg) was heated to 50° C. for 3 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and purified by column chromatography on silica gel (2:1 ethyl acetate/hexane) to gave 32 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. This material (30 mg) and triphenylphosphine (15 mg) in 1 ml of wet benzene was refluxed for 6.5 h. The solvent was removed in vacuo and the residue was purified on silica gel (eluted first with 5% MeOH/CH2Cl2, then 1% NH4OH in 5% MeOH/CH2Cl2) to give 12 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O>O1CCOCC1>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:24])=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 134.5 %

Procedure:
4-{[4-(Trifluoromethyl)phenyl]carbonyl}benzoic acid (200 mg, 0.68 mmol) was stirred in dioxane (5 mL) and thionyl chloride (0.496 mL, 6.8 mmol) added. The reaction mixture was heated at reflux for 1 h. Further thionyl chloride (0.496 mL, 6.8 mmol) was added and heating continued for 3 h. On cooling, the reaction mixture was concentrated in vacuo to give 4-{[4-(trifluoromethyl)phenyl]carbonyl}benzoyl chloride as an oily white liquid (0.286 g) which was used directly in step 2. Step 2: The acid chloride from step 1 was taken up in DCM (2 mL) and added drop-wise to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.170 g, 0.53 mmol) and triethylamine (0.11 mL) in DCM (2 mL). The reaction mixture was stirred at room temperature under argon overnight then diluted with water (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL) and the combined organic layers were dried, concentrated and purified by column chromatography. Elution with 0-30% EtOAc/pentane gave the title compound as a colourless oil (0.244 g). MS (ES): MH+ 596.2. Description 124
Reaction SMILES: [OH:1][CH:2]1[C:23](=[O:24])[N:5]2[CH2:6][CH2:7][N:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)(=[O:12])=[O:11])[CH2:9][CH:4]2[CH2:3]1.[H-].[Na+].Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>CN(C)C=O>[F:20][C:19]([F:21])([F:22])[C:15]1[CH:14]=[C:13]([S:10]([N:8]2[CH2:7][CH2:6][N:5]3[C:23](=[O:24])[CH:2]([O:1][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=4)[CH2:3][CH:4]3[CH2:9]2)(=[O:12])=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: O=C1C(O)CC2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CCN12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(Oc2ccc(C(F)(F)F)cn2)CC2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CCN12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the product from Example 217B (23 mg, 0.063 mmol) in anhydrous N,N-dimethylformamide (0.6 mL) at 0° C. was added sodium hydride (60% suspension in mineral oil, 2.78 mg, 0.069 mmol). The resulting mixture was stirred at 0° C. for 10 minutes, and 2-bromo-5-(trifluoromethyl)pyridine (21 mg, 0.095 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was partitioned between water and ethyl acetate (3×), and the combined organic layers were concentrated in vacuo and purified on C18 silica gel using a solvent gradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid). The title compound was obtained as a colorless solid (22 mg, 68%). 1H NMR (300 MHz, CDCl3) δ ppm 1.58-1.68 (m, 0.5H) 2.03-2.49 (m, 3H) 2.88-3.21 (m, 1.5H) 3.72-4.08 (m, 3H) 4.21 (dd, J=13.39, 3.22 Hz, 1H) 5.50-5.74 (m, 1H) 6.88 (t, J=8.82 Hz, 1H) 7.69-7.85 (m, 2H) 7.88-8.00 (m, 2H) 8.02 (s, 1H) 8.26-8.43 (m, 1H); MS (ESI) m/z 510 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1)[NH2:24]
Reactant: Cn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-(4-nitro-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].F[C:24]1[CH:37]=[CH:36][C:27]2[C:28](=[O:35])[N:29]([CH3:34])[C:30]([CH3:33])([CH3:32])[O:31][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:22][C@H:18]([O:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([O:1][C:24]2[CH:37]=[CH:36][C:27]3[C:28](=[O:35])[N:29]([CH3:34])[C:30]([CH3:33])([CH3:32])[O:31][C:26]=3[CH:25]=2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6])[CH2:19][O:20][CH3:21]
Reactant: CN1C(=O)c2ccc(F)cc2OC1(C)C
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OC(C)(C)N(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 12 h
Yield: 30.1 %

Procedure:
A mixture of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.25 g, 0.82 mmol), 7-fluoro-2,2,3-trimethyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (172 mg, 0.82 mmol) and potassium carbonate (226 mg, 1.64 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 12 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 0-10% methanol in DCM, to give the desired compound as a white foam (122 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:17]([Cl:18])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:4][C:3]=1[OH:19].Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CS(C)=O>[Cl:18][C:17]1[C:9]([C:5]2[CH:4]=[C:3]([O:19][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:2]([Cl:1])=[CH:7][C:6]=2[F:8])=[N:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=12
Reactant: Oc1cc(-c2nn3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CS(C)=O
Product: Fc1cc(Cl)c(Oc2ncccn2)cc1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of 2-chloro-5-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-4-fluorophenol (0.5 g) and 2-chloropyrimidine (0.25 g), in a mixed solvent of 2-butanone:dimethylsulfoxide (1:4) (50 ml) was added potassium carbonate (0.35 g) at room temperature. After addition, the mixture was heated at reflux for 12 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and partitioned between ethyl acetate and brine. The organic phase was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluent, ethyl acetate:hexane, 2:1) to give the desired compound (0.47 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10](N)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[I-:21].[K+]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([I:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: COc1cc(N)cc(-c2cccc(F)c2)c1
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Product: COc1cc(I)cc(-c2cccc(F)c2)c1
Yield: 77.6 %

Procedure:
A similar procedure as described in Example 12, step 5 was used, starting from 3′-fluoro-5-methoxy-biphenyl-3-ylamine (940 mg, 4.32 mmol), sodium nitrite (545 mg, 7.79 mmol), and potassium iodide (1.44 mg, 8.65 mmol) to afford 3′-fluoro-3-iodo-5-methoxy-biphenyl (1.1 g, 78%) as an amorphous light yellow oil: ES(+)-HRMS m/e calculated for C13H10FIO (M+H)+ 329.1190, found 329.1192.