Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH:11]=[N:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1.[Li+].[Cl-].[F-].[Cs+]>[Cu]I.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>[CH3:24][N:25]1[CH2:26][CH2:27][N:28]([C:31]2[N:32]=[C:33]([C:2]3[C:10]4[N:9]5[CH:11]=[N:12][N:13]=[C:8]5[CH:7]=[N:6][C:5]=4[N:4]([S:14]([C:17]4[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=4)(=[O:16])=[O:15])[CH:3]=3)[CH:34]=[CH:35][N:36]=2)[CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c2ncc2nncn23)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(N2CCN(C)CC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccnc(N4CCN(C)CC4)n3)c3c2ncc2nncn23)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
A vial containing 8-bromo-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.030 g, 0.076 mmol, prepared using D from Preparation #BBBBB.1 and NaOH, GGG.1 with NBS, K.1 with TsCl and NaH), 2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine (0.054 g, 0.12 mmol, Preparation #39), LiCl (0.010 g, 0.24 mmol), CuI (0.003 g, 0.02 mmol), CsF (0.017 g, 0.12 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) under nitrogen was evacuated and then back-filled with nitrogen. 1,4-Dioxane (0.5 mL) was added and nitrogen was bubbled through the mixture for about 30 min. The reaction vessel was sealed and the mixture was warmed to about 80° C. After about 4 h, the mixture was allowed to cool to ambient temperature. The mixture was diluted with water (5 mL) and EtOAc (5 mL) and then filtered through a syringe filter. The layers were separated and the aqueous phase was extracted with EtOAc (5 mL). The combined organics were concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM over 40 min to afford 8-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.026 g, 69%): LC/MS (Table 1, Method n) Rt=0.56 min; MS m/z 490 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5]C[O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18].FC(F)(F)C(O)=O>>[F:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8](=[O:18])[N:7]2[CH2:6][CH:2]([OH:3])[O:1][CH3:5])=[N:12][CH:13]=1
Reactant: O=c1ccc2ncc(F)cc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: COC(O)Cn1c(=O)ccc2ncc(F)cc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To 2.2 g of 1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one, 20 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at 80 to 90° C. for 3 hours. Thereto was added 10 mL of an 80% aqueous trifluoroacetic acid solution, and the mixture was stirred at 80 to 90° C. for 2 hours, then, 10 mL of an 80% aqueous trifluoroacetic acid solution was further added, and the mixture was stirred at the same temperature for 9 hours. The reaction mixture was cooled to room temperature, and the solvent was then distilled off under reduced pressure. To the resultant residue, a 2 mol/L aqueous sodium hydroxide solution was added and adjusted to pH 8.0, and chloroform and methanol were added thereto. The organic layer was separated, and the aqueous layer was extracted with a mixed solution of chloroform and methanol twice. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether and hexane were added to the resultant residue, and the solid was filtered off to obtain 1.5 g of 7-fluoro-1-(2-hydroxy-2-methoxyethyl)-1,5-naphthyridin-2(1H)-one as a light brown solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16](Cl)=[O:17]>>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1c(Cl)cccc1Cl
Yield: 45.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 47 mg of 2,6-dichloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 45%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:25])=[CH:34][CH:35]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCN(CC)CCOC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Product: CCN(CC)CCOC(=O)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1

Procedure:
2850 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 2440 mg of the product obtained in step 1 above are added. 30 mg of the expected product are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>C(Cl)Cl>[C:27]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:30])[CH:28]=[CH2:29]
Reactant: CC(C)(C)OC(=O)NCc1cc([N+](=O)[O-])ccc1N
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc([N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of tert-butyl 2-amino-5-nitrobenzylcarbamate (200 mg, 0.75 mmol) and triethylamine (76 mg, 0.75 mmol) in DCM was added acryloyl chloride (102 mg, 1.12 mmol). The mixture was stirred at rt for 48 h, and purified with column chromatography to give tert-butyl 2-acrylamido-5-nitrobenzylcarbamate. The tert-butyl 2-acrylamido-5-nitrobenzylcarbamate was dissolved in EtOH/HCl and stirred at rt for 1 h. Diethyl ether was then added and the solid formed was collected by filtration to yield the HCl salt of N-(2-(aminomethyl)-4-nitrophenyl)acrylamide (46 mg, 0.18 mmol).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:21])[C:19]=1[OH:20])[CH:15]=O>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:15][C:14]2[CH:17]=[C:18]([CH3:21])[C:19]([OH:20])=[C:12]([CH3:11])[CH:13]=2)=[CH:5][CH:6]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(=O)c1ccc(Cl)cc1
Product: Cc1cc(C=CC(=O)c2ccc(Cl)cc2)cc(C)c1O

Procedure:
This compound was synthesized from 4-chloroacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described hereinabove.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:22](/[CH:23]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)[CH:21]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: O=[N+]([O-])c1ccc(/C=C/c2cccc(Cl)c2)cc1

Procedure:
In an analogous manner to that described in Example 36a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 3-chlorobenzaldehyde yields the (E)-1-chloro-3-[2-(4-nitrophenyl)ethenyl]-benzene as an orange crystalline solid; MS: m/e=259 (M)+.
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:30](Cl)(=[O:35])[CH2:31][C:32](Cl)=[O:33]>C1COCC1>[O:33]=[C:32]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:30](=[O:35])[CH2:31]1
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To 100 mL of THF at 0° C. is added dropwise over 20 min simultaneously a solution of 8.0 g (20.5 mmol) of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Intermediate 43, in 100 mL of THF and 2.40 mL (24.6 mmol, 1.2 equiv) of malonyl dichloride in 100 mL of THF. The resulting solution is stirred at RT for 20 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash column chromatography afforded 7.5 g of the title compound as a light tan solid: 1H NMR (CDCl3, 300 MHz) δ7.44-6.86 (m, 13H), 5.02 (m, 1H), 4.38 (d, 1H, J=16.6), 4.04 (d, 1H, J=16.6), 3.84 (s, 3H), 2.55 (m, 2H), 1.10 (d, 6H, J=6.8); Rf =0.15 in hexane/EtOAc 1/1.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH2:23])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:10]1[CH:11]=[C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH2:23])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ncnc3sc(N)nc23)cc1-c1ccc(Cl)cc1Cl
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: CC(=O)O
Solvent: ClCCl
Product: Nc1nc2c(-c3cc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)ncnc2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A mixture of 7-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl][1,3]thiazolo[5,4-d]pyrimidin-2-amine (28.0 mg, 0.058 mmol), acetic acid (2.0 mL) and DCM (6.0 mL) was degassed with vacuum and then the atmosphere was replaced with nitrogen. To the mixture, were added tetrakis(triphenylphosphine)palladium(0) (7.03 mg, 0.00608 mmol) and phenylsilane (0.10 mL, 0.81 mmol). The resulting mixture was stirred at 40° C. for 30 min. The mixture was allowed to cool to rt followed by adding sat. NaHCO3 and DCM. After being stirred for 10 min, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (15.1 mg, 59%) as a pale yellow solid. LCMS: (AA) ES+445, 447. 1H NMR (400 MHz, d6-DMSO) δ: 11.82 (bs, 1H), 8.64 (s, 1H), 8.39-8.37 (m, 2H), 7.73 (d, J=2.0 Hz, 1H), 7.64-7.42 (m, 3H), 7.12 (bs, 1H), 6.95 (bs, 1H).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]1([CH2:22][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:26]1([C:24]2([CH2:23][CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:25][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CCc1ccccc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=CCC(CCc2ccccc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of 3-phenylpropiophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 130°-130.55,° C.). 1H NMR (CDCl3) δ 2.2-2.4 (m, 2 H), 2.4-2.6 (m, 1 H), 2.6-2.8 (m, 1 H), 2.9 (d, 1 H), 3.0 (d, 1 H), 3.3 (d, 1 H), 3.4 (d, 1 H), 7.0-7.5 (m, 15 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](O)=[O:9])[CH:5]=[N:6][CH:7]=1.CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCOCC1
Product: OCc1cncc(Br)c1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
To a solution of 12 g (59.4 mmol) of 5-bromopyridine-3-carboxylic acid in 300 mL of anhydrous THF, under argon, are added, at −10° C., 6.6 mL of NMM and then 5.7 mL (59.4 mmol) of ethyl chloroformate. After stirring for 20 minutes at −10° C., 6.8 g (179.8 mmol) of sodium borohydride are added portionwise. The medium is then cooled to −70° C. and 400 mL of MeOH are added over 1 hour 30 minutes. The temperature is then allowed to rise to room temperature and stirring is continued for 12 hours. The medium is then concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 8.4 g of (5-bromopyridin-3-yl)methanol are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][C:31]#[N:32])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].[NH4+].[Cl-].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:36])=[CH:27][C:28]([O:29][CH2:30][C:31]4[NH:43][N:42]=[N:41][N:32]=4)=[CH:33][C:34]=3[F:35])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCC#N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCc4nnn[nH]4)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)acetonitrile (129 mg, 0.23 mmol), NH4Cl (124 mg, 2.3 mmol) and NaN3 (16.60 mg, 0.25 mmol) in DMF (1.5 mL) was heated 17 h at 90° C. The reaction mixture was partitioned in EtOAc and H2O. The organic layer was washed with H2O and brine, dried over Na2SO4 and purified by flash chromatography (20% MeOH/DCM) to give the title compound (93 mg, 67%). 1HNMR (400 MHz, DMSO-d6) δ7.23 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 6.96 (m, 2H), 6.82 (m, 2H), 6.57-6.45 (m, 4H), 5.30 (s, 2H), 3.95 (s, 2H), 3.68 (s, 3H), 1.46 (s, 6H); MS (EI) m/z 601.3 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:14]1[S:18][C:17]([S:19]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: CCCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Yield: 55 %

Procedure:
N-[5-(4-propylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 33C, from 4-propylphenyl boronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as a white solid in 55% yield, m.p. 106-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:27])[N:10]([CH2:11][C:12]3[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21]CC)[O:18]CC)=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([O:28][CH2:29][CH2:30][O:31][CH3:32])[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:27])[N:10]([CH2:11][C:12]3[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:18])([OH:21])[OH:24])=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([O:28][CH2:29][CH2:30][O:31][CH3:32])[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Cn2c(=O)[nH]c3c(N)nc(OCCOC)cc32)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COCCOc1cc2c([nH]c(=O)n2Cc2ccc(CP(=O)(O)O)cc2)c(N)n1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
To a solution of diethyl 4-((4-amino-6-(2-methoxyethoxy)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzylphosphonate (1 equiv.) in CH2Cl2 (0.10 M) at 0° C. was slowly added trimethylsilyl bromide (10 equiv.). After 1 h the ice-bath was removed and the reaction mixture was allowed to stir at 22° C. for 18 h. At this point the volatiles were removed in vacuo and the resulting residue was purified by Reverse Phase-HPLC using a 20-90% 0.5 mM NH4OAc (in MeCN) to 10 mM NH4OAc (in water) gradient to deliver the title compound (41%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:33]([CH3:34])[CH:8]2[CH2:9][C:10]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[CH:31][N:30]=[CH:29]5)=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])([CH3:12])[O:11][C:7]2=[C:6]([CH3:35])[C:5]=1[CH3:36])([O-])=O.C(O)C.C(O)(=O)C.[OH-].[Na+]>[C].[Pd].O>[NH2:1][C:4]1[CH:33]([CH3:34])[CH:8]2[CH2:9][C:10]([NH:13][C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[CH:31][N:30]=[CH:29]5)=[CH:24][CH:23]=4)[CH2:20][CH2:21]3)=[O:15])([CH3:12])[O:11][C:7]2=[C:6]([CH3:35])[C:5]=1[CH3:36]
Reactant: CC1=C2OC(C)(NC(=O)N3CCN(c4ccc(-n5ccnc5)cc4)CC3)CC2C(C)C([N+](=O)[O-])=C1C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(N)C(C)C2CC(C)(NC(=O)N3CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
In an autoclave, 0.88 g of (±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-[4-(4-imidazol-1-ylphenyl)-piperazin-1-yl]carboxamide and 0.5 g of 10% palladium carbon, 10 ml of ethanol and 5 ml of acetic acid were added, followed by stirring overnight under a hydrogen pressure of 10 kg/cm2. The reaction solution was poured into water, neutralized with a 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol=10:1) to obtain 0.56 g of the objective product (melting point: 189-191° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([OH:12])=O)[C:6]=1[CH3:7].[Br:44][C:45]1[CH:46]=[N:47][C:48]2[CH2:49][CH2:50][NH:51][CH2:52][C:53]=2[CH:54]=1>>[Br:44][C:45]1[CH:46]=[N:47][C:48]2[CH2:49][CH2:50][N:51]([C:10]([C:9]3[CH:13]=[C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[CH:15]=[CH:16][C:8]=3[N:5]3[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:33]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:39][CH2:40][CH2:41][CH3:42])=[O:43])=[N:4]3)=[O:12])[CH2:52][C:53]=2[CH:54]=1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Reactant: Brc1cnc2c(c1)CNCC2
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ncc(Br)cc3C2)c(C)c1Cl
Yield: 48.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 93B, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 25 mg, 0.040 mmol) and 3-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine (D-L Chiral, 9 mg, 0.044 mmol) were converted to the title compound (16 mg, 45%) following purification by preparative HPLC. 1H NMR (1:1 CD3OD:CDCl3, 1.5:1 mixture of amide rotamers) δ ppm 8.69-8.65 (m, 1H), 8.47-8.41 (m, 1H), 8.21-8.16 (m, 1H), 8.09-8.05 (m, 2H), 8.04-8.00 (m, 1H), 7.99-7.95 (m, 1.5H), 7.94-7.90 (m, 1H), 7.78-7.74 (m, 0.5H), 7.66-7.57 (m, 1.5H), 7.53-7.43 (m, 1.5H), 4.79-4.73 (m, 1H), 4.57-4.51 (m, 1H), 3.71-3.61 (m, 1.5H), 3.58-3.39 (m, 1H), 3.31-2.85 (m, 5.5H), 2.31 (s, 1.5H), 2.28 (s, 1.5H), 1.57-1.02 (m, 8H), 0.93 (dt, J=14.4, 7.4 Hz, 3H), 0.79 (t, J=7.4 Hz, 1.5H), 0.74 (t, J=7.4 Hz, 1.5H); MS(ESI+) m/z 821.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[C:25]([O:29][C:30](=[O:38])[N:31]([CH3:37])[CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>CN1C(=O)CCC1.CC(OC)(C)C>[C:25]([O:29][C:30](=[O:38])[N:31]([CH:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][C:21]=4[F:22])[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH2:33]1)[CH3:37])([CH3:28])([CH3:26])[CH3:27]
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: [F-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN1CCCC1=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 150 mg, 0.474 mmol), KF (139 mg, 2.372 mmol) and (rac)-methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (285 mg, 1.423 mmol) were suspended in NMP (1.5 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with TBME and washed with water (3×). The aqueous phases were further extracted with TBME (1×). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized in Et2O to afford the title compound as a beige solid (tR 3.91 min (conditions 13), MH+=477).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:11]=2)=[CH:15][CH:16]=1
Reactant: C1COCCN1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(N3CCOCC3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and morpholine (30 μL) by a procedure similar to Example 10 and was isolated as white powder (10 mg, 66%). 1H NMR (CDCl3): 7.46 (d, J=8.4 Hz, 1H), 7.35 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.13-7.07 (m, 2H), 6.91-6.85 (m, 3H), 6.67 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.85-3.81 (m, 7H), 3.52 (s, 3H).