Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+].CCOC(C)=O>COCCOC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][Br:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (1.855 g, 5.23 mmol) in DME (19 mL) was added phosphorus tribromide (0.74 mL, 7.85 mmol), and the reaction was stirred at room temperature for 1.5 hours. The mixture was cooled to 0° C., and saturated aqueous NaHCO3 and EtOAc were added. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1>[Cu]I>[C:20]1([C:17]2[S:16][C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])=[N:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Brc1nnc(-c2ccccc2)s1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1nnc(-c2ccccc2)s1

Procedure:
The compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-bromo-5-phenyl-1,3,4-thiadiazole using 5 equivalents of copper (I) iodide. The title compound (180 mg) was obtained as a yellow solid, m/z 343 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].[CH3:30][N:31](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.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:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([C:30]#[N:31])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1nc2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c2c(C)c1Cc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1nc2c(Cl)ccc(C#N)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 125 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-3-(4-chlorobenzyl)-2,4-dimethyl-quinolin-5-yl ester (0.29 g), zinc cyanide (0.036 g), tetrakis(triphenylphosphine)palladium(0), (0.071 g) in N,N-dimethylformamide (8.0 mL) was heated by microwave irradiation at 125° C. for 10 minutes. The mixture was diluted with water and the resulting precipitate collected by filtration and then purified by column chromatography on silica gel, eluting with a mixture of cyclohexane, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:20:1 by volume) to afford title compound as a white solid, 0.17 g.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH:22][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Reactant: CCS(=O)(=O)Cl
Product: CCC1(c2c[nH]c3c(NS(=O)(=O)CC)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine and ethanesulfonyl chloride, the title compound is prepared as in example 15. 0.18 g (35%). LC-MS m/z 387.1 (M++1).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH:7]([C:15]([CH3:17])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O>CN(C=O)C>[C:1]([O:4][CH:7]([C:15]([CH3:17])=[O:16])[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium acetate (30.76 g, 375 mmol) in DMF (250 mL) was added dropwise tert-Butyl 2-bromo-acetoacetate (59.27 g, 250 mmol). After stirring at ambient temperature for 90 minutes, water (415 mL) was added, followed by extraction with ethyl acetate (3×325 mL). The combined organic layers were washed with water (3×325 mL) and brine (325 mL), dried over Na2SO4 and after filtration, the solvent was removed in vacuo. The resulting oil was purified by distillation (12 mbar, 128°)
Reaction SMILES: [CH2:1]([N:5]1[C:10]([OH:11])=[CH:9][C:8]([CH3:12])=[C:7]([C:13]#[N:14])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].CC1C=CC=CC=1N(C)N=[O:21]>>[CH2:1]([N:5]1[C:6](=[O:15])[C:7]([C:13]#[N:14])=[C:8]([CH3:12])[C:9](=[O:21])[C:10]1=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(O)cc(C)c(C#N)c1=O
Reactant: Cc1ccccc1N(C)N=O
Product: CCCCN1C(=O)C(=O)C(C)=C(C#N)C1=O

Procedure:
Prepared using the method of Example 2, with 1.03 g of 1-butyl-3-cyano-6-hydroxy-4-methylpyrid-2-one and 0.76 g of dimethyl-nitrosoaniline. Recrystallised from petrol/ethyl acetate, yield 0.54 g, m.p. 134°-135° C. This is the compound of formula (5).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH2:46][CH2:47][CH2:48][CH2:49][N:50]1[C:62]2[C:61]3[CH:60]=[CH:59][C:58]([C:63]4[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=4)=[CH:57][C:56]=3[N:55]=[C:54]([NH2:69])[C:53]=2[N:52]=[C:51]1[CH2:70][O:71][CH2:72][CH3:73]>C(Cl)(Cl)Cl.CC(N(C)C)=O>[NH2:69][C:54]1[C:53]2[N:52]=[C:51]([CH2:70][O:71][CH2:72][CH3:73])[N:50]([CH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([CH:6]([O:5][CH2:4][CH2:3][N:2]([CH3:22])[CH3:1])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:15][CH:14]=3)[C:62]=2[C:61]2[CH:60]=[CH:59][C:58]([C:63]3[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=3)=[CH:57][C:56]=2[N:55]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCN
Reactant: CN(C)CCOC(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A mixture of 4-[(2-dimethylaminoethoxy)phenylmethyl]benzoic acid (0.433 g) and 1-hydroxybenzotriazole (0.196 g) in chloroform (7 mL) was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.277 g) was added in small portions over a 2 minute period. The mixture was stirred for 1 hour and then added dropwise to a chilled (0° C.) solution of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1 H-imidazo[4,5-c]quinolin-4-amine (0.400 g) in anhydrous dimethylacetamide (7 mL). The cooling bath was removed and the reaction was stirred for an additional 16 hours. Water was added and the mixture was made acidic by the addition of 4N hydrochloric acid. The aqueous fraction was extracted with diethyl ether (3×) to remove the dimethylacetamide. Sodium hydroxide (10% in water) was added to make the aqueous fraction basic and the aqueous fraction was subsequently extracted with multiple portions of dichloromethane. The organic fractions were combined, washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of CMA/chloroform as the eluent. A final recrystallization from acetonitrile provided 0.426 g of N-[4-(4-amino-2-ethoxymethyl-7-(pyridin-3-yl)imidazo[4,5-c]quinolin-1-yl)butyl]-4-[(2-dimethylaminoethoxy)phenylmethyl]benzamide as a white crystalline solid, mp 157.0–161.0° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:26]([CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:31][CH2:30][CH2:29][C:28]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(OC)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22]Br)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31].O>CS(C)=O>[CH2:1]([C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:32]([CH2:5][CH2:1][CH2:2][CH3:3])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCCCc1nc2ccccc2n1S(=O)(=O)c1ccc(OCCCBr)cc1
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc2ccccc2n1S(=O)(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reaction time: 17 h

Procedure:
To a solution of 0.0017 mol of 2-n-butyl-1-(4-bromopropoxy-benzenesulphonyl) benzimidazole in 15 ml of dimethylsulphoxide was added 0.0034 mol of n-butylamine. The reaction medium was allowed to stand for 17 hours at room-temperature and then poured into 50 ml of water. After extraction, the ethereal phase was dried and evaporated to dryness. The residue so obtained was purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate) to obtain an oil which was the desired product in the form of the free base (yield: 50%). The oxalate of the base so provided was formed by dissolving the base in question into ethyl ether and adding an ethereal solution of oxalic acid.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O>>[C:1]1([N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1
Agent: O=P(O)(O)O
Product: O=C1C=CC(=O)N1c1ccccc1
Temperature: 210 °C

Procedure:
The slurry containing the N-phenyl maleinamic acid and 10 g of ortho-phosphoric acid added thereto were heated at 210° C. for three hours. The resultant reaction mixture was cooled to 30° C., washed with water, and distilled under a vacuum to expel tetrahydronaphthalene and obtain 78 g of N-phenyl maleimide crystals. By liquid chromatography, the crystals were found to have purity of 87.3% by weight, indicating the yield thereof to be 73.2 mol%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:27]([C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[Cl:24])=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added o-chlorobenzaldehyde (81.8 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (200 mg, 96% yield) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:27]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:1][CH2:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](C)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (R)-(−)-3-hydroxy-2-methylpropionate (0.82 g, 6.92 mmol) (Aldrich) was dissolved in dichloromethane (8 mL, dried over molecular sieves). Imidazole (0.67 g, 9.68 mmol) (Aldrich) was added. When all had dissolved, tert-butyldiphenysilyl chloride (1.80 mL, 6.92 mmol) (Aldrich) was added and the mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with additional dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give methyl (R)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionate as an oil. (Yield 2.42 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:12][NH2:13]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:13][CH3:12])=[O:11])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Nc1cc(Br)cnc1C(=O)O
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3-Amino-5-bromopyridine-2-carboxylic acid (500 mg, 2.30 mmol) and N′,N-carbonyldiimidazole (410 mg, 2.53 mmol) were stirred in DMF (5 mL) at 40° C. for 2 hours. After cooled to room temperature, methylamine (2.0 M in THF, 2.3 mL) was added thereto and further stirred at room temperature for 1 hour. The solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1 to 4/1) to obtain the intended compound (4.99 g, 94%) as a milky white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[CH:4][CH:3]=1.[C:16]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:19])[CH:17]=[CH2:18].C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C=O)C>[CH3:9][O:8][C:6]1[N:7]=[C:2](/[CH:18]=[CH:17]/[C:16]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: C=CC(=O)NNC(=O)OC(C)(C)C
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1nc(/C=C/C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
DMF (52 mL) was added to the 6-Bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (13.0 g, 48.5 mmol) and the tert-Butyl 2-acryloylhydrazinecarboxylate (9.9 g, 53.3 mmol) at room temperature under nitrogen atmosphere, And the mixture was stirred at 50° C. for 10 minutes. Tri(o-tolyl)phosphine (885 mg, 2.90 mmol), Palladium (II) acetate (327 mg, 1.45 mmol) and N,N-diisopropylethylamine (12.7 mL, 72.7 mmol) were added to the mixture, and the reaction mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and filtrated through Celite. The residue was washed twice with DMF (6 mL). Water (104 mL) was added dropwise to the filtrate at room temperature over 10 minutes. The mixture was stirred at room temperature for 15 hours. After the mixture was filtrated, the residue was washed with water/DMF=2:1 (30 mL) and MTBE (30 mL). The obtained solid was suspended in MTBE (50 mL) at room temperature for 2 hours, filtrated and dried under the reduced pressure to obtain the title compound (15.8 g, 87% yield).
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][C@@H:4]([NH2:18])[CH2:3][C@@H:2]([F:1])[CH2:8]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)C[C@@H](F)C1

Procedure:
Following the procedure for Example 101, starting with Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 126 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.80 (s, 1H), 7.37-7.28 (m, 2H), 7.08-6.98 (m, 3H), 6.13 (s, 2H), 4.83-4.78 and 4.72-4.68 (2 m, 1H), 3.79-3.72 (m, 3H), 3.54-3.30 (m, 3H), 3.24-3.12 (m, 2H), 2.31-2.22 (m, 1H), 2.18-2.07 (m, 1H), 1.93-1.76 (m, 2H). LCMS (ES+) m/z 466 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].Cl>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:13]=[CH:12]/[C:11]([OH:15])=[O:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1Br
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC#N
Product: COc1cc(/C=C/C(=O)O)ccc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-iodo-2-methoxybenzene (L. A. Hasvold et al., US 2004/0254159) in MeCN (1.1 M) was added acrylic acid (1.24 eq.), TEA (2.5 eq.) and palladium acetate (0.03 eq). The reaction mixture was heated to 90° C. for 40 min, cooled to RT and poured into 1N HCl. After sting for 30 min, the solid was filtered, heated to reflux in EtOH (2.3 M), allowed to cool to RT and stirred overnight. The solid was filtered and washed with 1:1 EtOH:hexane to give the desired product 119. LRMS ESI+ (M+H)+ 257.0.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](=O)[CH2:32][CH2:33][CH3:34]>CO.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: CCCC=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (165 mg, 0.415 mmol) and butyraldehyde (50 mg, 0.69 mmol) in MeOH (4 mL) was heated at reflux for 30 minutes. The solution was allowed to cool to room temperature, 10% Pd/C (20 mg, 0.019 mmol) was added, and the mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 20 h. The mixture was filtered through Celite and the solvent from the filtrate was removed under reduced pressure. Purification of the crude material by column chromatography on silica gel (200:5:1 CH2Cl2/MeOH/NH4OH) afforded AMD9701 (16 mg, 8%) as a colourless foam. 1H NMR (CDCl3) δ0.87 (m, 3H), 1.24-1.49 (m, 4H), 1.68 (m, 1H), 2.02 (m, 2H), 2.26 (m, 1H), 2.56 (m, 2H), 2.79 (m, 2H), 3.68 (s, 2H), 3.73 (s, 2H), 3.97 (d, 1H, J=17 Hz), 4.08 (m, 1H), 4.17 (d, 1H, J=17 Hz), 7.18 (m, 5H), 7.35 (m, 2H), 7.42 (m, 1H), 7.58 (m, 2H), 8.69 (d, 1H, J=3.9 Hz); —C NMR (CDCl3) δ14.39, 20.84, 21.79, 23.77, 29.63, 32.57, 48.88, 49.53, 54.11, 60.58, 111.30, 119.11, 121.68, 122.04, 122.60, 128.47, 128.99, 135.09, 137.55, 138.30, 139.82, 147.33, 156.73, 157.89. ES-MS m/z 454 (M+H). Anal. Calcd. for C29H35N5.1.3H2O: C, 73.02; H, 7.94; N, 14.68. Found: C, 73.06; H, 7.70; N, 14.32.
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][N:5]2[C:4](=[O:18])[N:3]1[C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:22]1([C@@H:20]2[CH2:21][C@H:19]2[N:3]2[C:2](=[O:1])[CH:6]3[CH2:7][NH:8][CH2:9][CH2:10][N:5]3[C:4]2=[O:18])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N([C@@H]3C[C@H]3c3ccccc3)C(=O)C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C2CNCCN2C(=O)N1[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of A4 in DCM (0.5 M) was cooled to 0° C. (ice bath) and TFA (9 eq.) was added and the reaction was stirred at RT overnight. The solvent was removed under reduced pressure. The crude material was treated with Et2O (20 mL) and HCl (1N, 12 mL). The two layers were separated, and organic phase washed with water (2×15 mL). To the combined organic extracts was added solid K2CO3 in small portion until pH 9-10. The mixture was extracted with DCM and combined extracts were dried and evaporated under reduced pressure to yield (100%) the desired compound that was used crude in the next step. 1H NMR (400 MHz, DMSO-d6, 300K) δ 7.29-7.20 (5H, m), 3.90 (1H, m), 3.78 (1H, m), 3.15 (1H, m), 2.85 (3H, m), 2.65 (1H, m), 2.50-2.30 (3H, m), 1.5 (1H, m), 1.35 (1H, m). MS (ES+) C15H17N3O2 requires 271, found: 272 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([O:22]C)=O)[CH:17]=[C:16]([CH:24]=[CH2:25])[CH:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:26]>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([NH2:26])=[O:22])[CH:17]=[C:16]([CH:24]=[CH2:25])[CH:15]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: C=Cc1cc(C(=O)OC)nc(-c2ccc(-c3ccc(F)cc3)cc2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=Cc1cc(C(N)=O)nc(-c2ccc(-c3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 6-(4′-fluoro-[1,1′-biphenyl]-4-yl)-4-vinylpicolinate (600 mg, 1.8 mmol) was dissolved in 10 mL of methanol in a pressure tube. Into the tube was condensed about 10 mL ammonia at −20° C. to −30° C. The pressure tube was tightly closed and the resulting solution was stirred at room temperature for overnight. TLC (silica gel, 10% methanol in chloroform) showed the reaction had gone to completion. The ammonia was removed by nitrogen purge and the methanol was removed under reduced pressure to obtain 300 mg of 6-(4′-fluoro-[1,1′-biphenyl]-4-yl)-4-vinylpicolinamide which was pure enough to take to next step without purification.