Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (410 mg, 1.62 mmol) and 1-bromoheptadecane (2.07 g, 6.47 mmol), alcohol 44 was obtained as a colorless oil (427 mg, 53% yield).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cu]I>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[S:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Brc1csc2ccccc12
Reactant: COc1ccc(O)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(Oc2csc3ccccc23)cc1
Temperature: 140 °C

Procedure:
A mixture of 4.00 g (19.7 mmol) of 3-bromobenzo[b]thiophene, 4.96 g (40 mmol) of 4-methoxyphenol, 5.52 g (40 mmol) of K2CO3, and 0.20 g (1.0 mmol) of CuI was heated to 140° C. and sonicated at this temperature for 2 h. The reaction was allowed to cool, taken up in CH2Cl2, and the mixture was washed several times with 0.5 N NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo to an oil that was subjected to chromatography (SiO2; gradient of 0-5% EtOAc in hexanes). The fractions containing the desired product were combined, evaporated in vacuo, and the residue was recrystallized from hexanes to afford 500 mg (1.95 mmol; 10%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br>C(#N)C>[O:1]1[CH2:20][CH2:19][N:6]2[N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=[C:2]12
Reactant: CCOC(=O)c1cc(O)[nH]n1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CCO2
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 ml of acetonitrile was added 13.68 g of 1,2-dibromoethane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 5.80 g of the desired product was obtained (48%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:18][S:19]([O:14][C:12]1[CH:11]=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:13]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)nc1NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc([N+](=O)[O-])c(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(Cyclohexylamino)-5-nitropyridin-2-ol (1.35 g, 5.69 mmol) was dissolved in DCM (1150 mL). Methanesulfonyl chloride (0.782 g, 6.83 mmol) and triethylamine (1.152 g, 11.38 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, acidified with 1 M HCl and extracted with DCM. The organic layers were combined, washed with water, dried over Na2SO4, and concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=316.30 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH3:23]>C1COCC1>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([N:22]([CH3:23])[CH3:21])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
The product from Example 181c (1.0 g, 3.4 mmol) was added to THF (25 mL) and dimethylamine (0.31 g, g, 6.8 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction was poured onto ice/water and extracted with ethyl acetate. The organic phase was washed with 5% HCl, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (0.90 g, 87%).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].Cl.Cl[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:12]=1)=[O:10]>CO>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:9]([NH:5][C:4]([NH2:6])=[NH:3])=[O:10])=[CH:12]2)=[CH:21][CH:22]=1
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2ncccc12
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2ccnc3ccccc23)c2ncccc12
Yield: 40 %

Procedure:
1.5 g (65 mmol) of sodium (washed beforehand in toluene) were added gradually to 100 cm3 of methanol at a temperature in the region of 20° C. under an argon atmosphere. After dissolving with stirring, 6.5 g (68 mmol) of guanidine hydrochloride were added and the mixture was stirred at a temperature in the region of 20° C. for 2 h. The reaction mixture was subsequently concentrated to dryness under reduced pressure (2.7 kPa) and the residue was twice in succession taken up in 70 cm3 of dichloromethane (stabilized over amylene) and concentrated to dryness under reduced pressure (2.7 kPa). The residue was subsequently taken up in a mixture of 50 cm3 of tetrahydrofuran and 50 cm3 of dichloromethane under an argon atmosphere at a temperature in the region of 20° C. and then 11.8 mmol of 3-chlorocarbonyl-1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride were added thereto with stirring. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The solid residue was taken up in 70 cm3 of 0.1N sodium hydroxide and the insoluble material was filtered off and then dissolved in 200 cm3 of dichloromethane. After separation by settling, the organic phase was dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with a dichloromethane/methanol/triethylamine (88/10/2 by volume) mixture. The fractions comprising the expected product were combined and concentrated to dryness under reduced pressure (2.7 kPa) and the solid residue was taken up in a mixture of 60 cm3 of pentane, 10 cm3 of diethyl ether and 0.1 cm3 of methanol which was brought to reflux for 10 minutes. After returning to a temperature in the region of 20° C., filtering and washing with 10 cm3 of pentane, the solid was dried at a temperature in the region of 40° C. under reduced pressure (2.7 kPa). 1.56 g of N-[1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine were thus obtained in the form of a cream solid melting at 230° C. (the product was partially salified with 3.7% of hydrochloric acid, the base form melts at 164° C.). Mass spectrum: DCI: m/z=331 MH+ base peak.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][O:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[CH2:22]([O:21][CH2:20][C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:23]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: OB(O)c1ccsc1
Product: CCOCc1nc2c(N)nc3cc(-c4ccsc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by purification on silica gel (5% methanol in CH2Cl2 to 7% methanol in CH2Cl2 gradient) afforded 2-ethoxymethyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 187-189° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]1=[O:14].[C:15]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[C:21]([CH2:31][CH2:32][CH3:33])[N:20]=1)([CH3:18])([CH3:17])[CH3:16].[Br-].[Na+].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CN1CCCC1=O>[C:15]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]3=[O:14])[CH2:27][CH2:26]2)[CH:22]=[C:21]([CH2:31][CH2:32][CH3:33])[N:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Reactant: COc1cccn(CCCCCl)c1=O
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCc1cc(N2CCN(CCCCn3cccc(OC)c3=O)CC2)nc(C(C)(C)C)n1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
A mixture of 1-(4-chlorobutyl)-3-methoxy-1H-pyridin-2-one (0.93 mmol, 0.20 g) from Example 5.1, 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.93 mmol, 0.24 g; prepared as described in DE 19735410), sodium bromide (4.64 mmol, 0.48 g), ethyldiisopropylamine (9.09 mmol, 1.17 g) and N-methylpyrrolidinone (0.5 ml) was heated at 120° C. for 6 hours. The resulting suspension was filtered with suction and the filtrate was concentrated. The residue obtained in this way was taken up in ethyl acetate/water. The aqueous mixture was adjusted to pH 5.5 with sodium bicarbonate and the aqueous mixture was extracted several times with diethyl ether. The organic phase was then dried, the desiccant was removed by filtration, and the organic phase was concentrated under reduced pressure. Chromatography of the residue on silica gel (eluent: CH2Cl2/CH3OH (0-2%) afforded 0.24 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=O.[NH2:13][C:14]([CH:18]([F:20])[F:19])=[CH:15][C:16]#[N:17]>C(O)(=O)C.C1COCC1>[F:19][CH:18]([F:20])[C:14]1[NH:13][C:14]([CH:18]([F:20])[F:19])=[C:15]([C:16]#[N:17])[CH:11]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[CH:6]3)[C:15]=1[C:16]#[N:17]
Reactant: O=Cc1cc2cn[nH]c2cc1F
Reactant: N#CC=C(N)C(F)F
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CC1=C(C(F)F)NC(C(F)F)=C(C#N)C1c1cc2cn[nH]c2cc1F

Procedure:
A solution of 150 mg (0.55 mmol) 6-fluoro-1H-indazole-5-carbaldehyde (Example 5A) and 142 mg (1.21 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in acetic acid (0.5 ml) containing powdered 4 Å molecular sieve was heated to reflux temperature for 5 h. After cooling, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 147 mg (72% of th.) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][C:20]1[N:21]=[C:22]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:23][C:24]=1[C:25]([F:28])([F:27])[F:26]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:32]1[CH2:33][CH2:34][N:29]([C:22]2[S:23][C:24]([C:25]([F:28])([F:26])[F:27])=[C:20]([CH3:19])[N:21]=2)[CH2:30][CH2:31]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1nc(N2CCNCC2)sc1C(F)(F)F
Agent: Cl
Product: Cc1nc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)sc1C(F)(F)F
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white foam (yield 52%). MS (m/e): 492.0 (M+H+, 100%).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][CH:4]=1)[CH3:2].C(O[CH2:14][C:15]1[NH:19][C:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[C:17]([CH3:30])[C:16]=1[CH2:31][CH3:32])(=O)C>>[CH2:23]([O:22][C:20]([C:18]1[NH:19][C:15]([CH2:14][C:4]2[NH:5][C:6]([CH2:14][C:15]3[NH:19][C:18]([C:20]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[C:17]([CH3:30])[C:16]=3[CH2:31][CH3:32])=[C:7]([CH2:8][CH3:9])[C:3]=2[CH2:1][CH3:2])=[C:16]([CH2:31][CH3:32])[C:17]=1[CH3:30])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1c(COC(C)=O)[nH]c(C(=O)OCc2ccccc2)c1C
Reactant: CCc1c[nH]cc1CC
Product: CCc1c(Cc2[nH]c(Cc3[nH]c(C(=O)OCc4ccccc4)c(C)c3CC)c(CC)c2CC)[nH]c(C(=O)OCc2ccccc2)c1C

Procedure:
condensing 3,4-diethylpyrrole with two molecular equivalents of benzyl 5-(acetoxymethyl)-4-ethyl-3-methylpyrrole-2-carboxylate to produce 2,5-bis(5-benzyloxycarbonyl-3-ethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccccc1F
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-fluoroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH2:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:4]=1.[H-].[Na+].[C:25]([C:29]1[C:30]([Cl:38])=[C:31]([C:35](O)=[O:36])[N:32]([CH3:34])[N:33]=1)([CH3:28])([CH3:27])[CH3:26].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH:12][C:35]([C:31]2[N:32]([CH3:34])[N:33]=[C:29]([C:25]([CH3:27])([CH3:26])[CH3:28])[C:30]=2[Cl:38])=[O:36])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[N:4]=1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Reactant: COc1nc(-c2ccccc2C(F)(F)F)cc(N)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2C(F)(F)F)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of 2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (162 mg, 0.517 mmol, prepared as described in Example 5, Step B above) in THF (10 mL) was treated with NaH (62.1 mg, 1.55 mmol, 60% dispersion in oil) at room temperature, and the mixture was allowed to stir for 1 h. Simultaneously, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (168 mg, 0.776 mmol, prepared as described in Example B above) in anhydrous DCM (10 mL) was treated with oxalyl chloride (67.7 μL, 0.776 mmol) and DMF (2 drops), and the mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 3:17 over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as a white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C22H21N5O4ClF3: 512.1 (M+H). Measured: 512.1.
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10](B4OC(C)(C)C(C)(C)O4)=[CH:11][CH:12]=3)[C@@:7]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:6]=2[CH:5]=[C:4]([O:30][CH3:31])[CH:3]=1.Cl[C:33]1[CH:38]=[N:37][CH:36]=[C:35]([C:39]#[C:40][CH3:41])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>O.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>[F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:33]4[CH:38]=[N:37][CH:36]=[C:35]([C:39]#[C:40][CH3:41])[N:34]=4)=[CH:11][CH:12]=3)[C@@:7]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:6]=2[CH:5]=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1O2
Reactant: CC#Cc1cncc(Cl)n1
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: O
Solvent: CCOC(C)=O
Product: CC#Cc1cncc(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(OC)cc(F)c2O3)n1
Temperature: 110 °C
Yield: 30.6 %

Procedure:
Combined tetrakis(triphenylphosphine)palladium (54.2 mg, 0.047 mmol), (S)-4′-fluoro-2′-methoxy-7′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (200 mg, 0.47 mmol, prepared as described in Method BB40) and 2-chloro-6-(prop-1-ynyl)pyrazine (93 mg, 0.61 mmol) in a sealable tube and potassium carbonate (1.5 M) (1.6 mL, 2.35 mmol) was added. The tube was sealed and heated at 110° C. in a microwave for 8 min. The reaction solution was diluted with water and extractd by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc again. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by chromatography through a gold Redi-Sep pre-packed silica gel column using a gradient of 25% to 50% to 80% DCM: MeOH: NH4OH (90:10:1) in 40% EtOAc in hexane to provide (S)-4′-fluoro-2′-methoxy-7′-(6-(prop-1-ynyl)pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (60 mg, 0.144 mmol, 30.7% yield) as white solid.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[NH2:8][C:9]([NH2:11])=[O:10].[ClH:12]>C(O)C>[ClH:12].[CH3:2][C:1]1[CH:4]=[C:5]([CH3:6])[NH:11][C:9](=[O:10])[N:8]=1
Reactant: NC(N)=O
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)[nH]c(=O)n1
Temperature: 0 °C
Yield: 55 %

Procedure:
To a mixture of acetyl acetone (4.0 g, 40.0 mmol) and urea (2.0 g, 33.3 mmol) in ethanol (40 mL) was added concentrated HCl (10 mL) and stirred at reflux for 3 h. The reaction mixture was cooled to 0° C. and filtered; the colourless solid was washed thoroughly with ice cold ethanol then ether and dried under vacuum to afford 4,6-dimethyl-1H-pyrimidin-2-one hydrochloride (3.5 g, 55%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH-:8].[N+:9]([C:12]1[CH:24]=[C:23]2[C:15]([C:16]3[C:17]([C:26](O)=O)=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]2=[O:25])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:26]1[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:24][C:23]=1[C:22]2=[O:25]
Reactant: O=C(O)c1cccc2c1-c1ccc([N+](=O)[O-])cc1C2=O
Reactant: [NH-]c1ccccc1N
Solvent: CC(=O)O
Product: O=C1c2cc([N+](=O)[O-])ccc2-c2c1cccc2-c1nc2ccccc2[nH]1
Temperature: 130 °C

Procedure:
The procedure used in Example 68 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, heat, at 130° C. for 4 hours, a suspension of 1.6 g of (2-aminophenyl)amide of 7-nitro-9-oxo-9H -fluorene-4-carboxylic acid, obtained in the previous stage, in 30 ml of acetic acid. After cooling, the insoluble material that formed is filtered off, and washed successively with water, with a saturated aqueous solution of sodium hydrogen carbonate and then with water. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and 7N ammoniacal methanol (9/1 by volume), then formation of a paste in diisopropyl ether, in this way we obtain 550 mg of 5-(1H-benzimidazol-2-yl)-2-nitro-9H-fluoren-9-one, in the form of a yellow powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a stirred solution of 6-bromo-3H-imidazo[4,5-b]pyridine (506 mg, 2.55 mmol) from Step 1 of this Example in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt, then stirred for a further 15 h. To the reaction mixture was added water and the mixture was extracted with EtOAc. The organic layer was separated and the aq layer extracted with additional EtOAc. The combined organic layers were washed with water then brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (460 mg, 48%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.40 (d, J=1.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 375 and 377 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[N:7]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17])[CH2:6][CH2:5]2>CN(C)C=O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[N:7]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17])[CH2:6][CH2:5]2
Reactant: NC(=O)c1ccccc1N1CCc2cc(Cl)cc([N+](=O)[O-])c21
Solvent: CN(C)C=O
Solvent: CCO
Product: NC(=O)c1ccccc1N1CCc2cc(Cl)cc(N)c21
Reaction time: 2 h
Yield: 119.3 %

Procedure:
To the solution of 2-(5-chloro-7-nitroindolin-1-yl)benzamide of Example 1b (10 gm, 26.5 mmoles) in dimethylformamide (DMF) [100 ml] and ethanol (100 ml) was added 1% Pt/carbon (2.0 gm). The mixture was shaken under hydrogen (59 psi) for 41/2 hours. The mixture was then filtered under nitrogen and concentrated to remove solvent at 55° C. and high vacuum to give a solid (9.1 gm). Recrystallization from chloroform twice afforded 2-(5-chloro-7-aminoindolin-1-yl)benzamide, (4.3 gm, 47.3%), m.p. 199°-201° C. dec.