Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](O)=O)=[CH:5][C:4]([CH3:17])=[N:3]1.O=P(Cl)(Cl)[Cl:20].[NH4+].[OH-]>>[CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:9]([C:10]([Cl:20])=[C:5]2[C:4]([CH3:17])=[N:3]1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(C)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nn(C)c2nc3ccccc3c(Cl)c12
Temperature: 0 °C

Procedure:
A mixture of N-(1,3-dimethyl-pyrazol-5-yl) anthranilic acid (7 g, 0.03 mol) and POCl3 (40 ml) is heated on a steam bath for 3 hours. The reaction mixture is then poured into ice water (600 ml) and then basified with NH4OH. The mixture is extracted with ether (3×200 ml), and the combined ether layers are dried over MgSO4 and evaporated to afford 7.0 g of 1,3-dimethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline, m.p. 127°-129° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29](Cl)=[O:30]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29]([C:25]5[S:24][CH:28]=[CH:27][N:26]=5)=[O:30])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1nccs1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1nccs1
Yield: 64.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and 1,3-thiazole-2-carbonyl chloride (89 mg, 0.60 mmol), and in the same manner as in Example 162, the title compound (136 mg, yield 65%) was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:22]=[CH:21][C:20]([CH:23]([OH:27])[CH2:24][CH2:25][CH3:26])=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:27][CH:23]([C:20]1[CH:19]=[C:16]([C:17]#[N:18])[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:22][CH:21]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(O)c1ccc(Br)c(C#N)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C#N)c1
Temperature: 140 °C
Yield: 83.2 %

Procedure:
A sealed flask was charged with the (4-(trifluoromethyl)phenyl)boronic acid (1.09 g, 5.76 mmol), 2-bromo-5-(1-hydroxybutyl)benzonitrile (1.33 g, 5.23 mmol) and acetonitrile (17 mL). Once everything get into solution, 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (115 mg, 157 μmol) was added followed by the sodium carbonate 2M aq. (6.54 mL, 13.1 mmol). Flask sealed and heated at 140° C. for 1 hour. Organic solvent removed under reduced pressure and ethyl acetate added. Organics washed with water (1×), with brine (1×), dried over sodium sulfate, filtered and concentrated to provide the crude material. Purification by silica gel flash chromatography (Ethyl Acetate/Heptane) provide the title compound as a colorless oil (1.39 g, 83.2%). 1H NMR (400 MHz, DMSO-d6) δ 0.87-0.93 (m, 3 H) 1.25-1.45 (m, 2 H) 1.57-1.67 (m, 2 H) 4.64-4.70 (m, 1 H) 5.41 (d, J=4.68 Hz, 1 H) 7.64 (d, J=8.00 Hz, 1 H) 7.75-7.79 (m, 1 H) 7.82 (d, J=8.00 Hz, 2 H) 7.88-7.94 (m, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[C:22]([CH3:23])=[CH:21][C:6]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=4)[NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1)[CH3:2].C(=O)([O-])[O-:25].[Na+].[Na+].[ClH:30]>C(O)(=O)C>[ClH:30].[ClH:30].[CH2:1]([C:3]1[C:22]([CH3:23])=[CH:21][C:6]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:20])=[O:25])[CH:17]=4)[NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2nc(-c3n[nH]c4ccc(C#N)cc34)[nH]c2cc1C
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc2nc(-c3n[nH]c4ccc(C(N)=O)cc34)[nH]c2cc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile [100 mg, Example 235(an)] in acetic acid (1 ml) and concentrated hydrochloric acid (1 ml) was heated at 80° C. for 30 minutes and then at 100° C. for 4 hours. The reaction was cooled to ambient temperature and stirred for 16 hours. The reaction was then heated at 80° C. for 2.5 hours and then at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and neutralized with aqueous sodium carbonate solution. The resulting white precipitate was collected by filtration and the aqueous layer was extracted with ethyl acetate, combined with the precipitate and concentrated in vacuo. The residue was taken up in methanol, transferred to a solid phase cartridge containing MP-carbonate resin (100 mg) and shaken for 16 hours. The reaction was then filtered, the resin washed with methanol and the combined organic layers concentrated in vacuo. The residue was triturated with diethyl ether, taken up in methanol and acidified with 4M hydrogen chloride in 1,4-dioxane. The solvent was removed in vacuo to give 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid amide dihydrochloride (58 mg) as a pale brown solid. LC-MS (METHOD M): RT=9.40 minutes, 320(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]=[C:11]2[C:16](=[O:17])OC(C)(C)OC2=O)[CH:6]=[CH:7][CH:8]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:16]([OH:17])=[CH:11][CH:10]=[N:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(NC=C2C(=O)OC(C)(C)OC2=O)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2c(O)ccnc2c1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
5-{[(3-Methoxyphenyl)amino]methylene}-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 11, 43.5 g, 157 mmol) was added in small portions to phenylether (200 mL) at 225-260° C. under stirring. The reaction mixture was stirred for an additional 5 minutes, until the evolution of gas had stopped. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration and washed with hexanes. Purification by recrystallization from methanol gave 12.4 g (45% yield) of product as a green solid, mp 210° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.[Li+].[BH4-].C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: CC(C)c1cc(Br)cc2c1NC(=O)C2=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc(Br)cc2cc[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
To a stirred solution of 5-bromo-7-isopropylindoline-2,3-dione (45.1 g, 0.17 mol) in THF (275 ml) at room temperature under a nitrogen atmosphere, was added, via syringe, 2.0 M solution of LiBH4/THF (215 ml) over 30 min. The reaction mixture was stirred at 90° C. for 1 hr, cooled, quenched with distilled water and 5% HCl, and extracted with EtOAc. The extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by elution from a silica gel column with hexane/EtOAc (9:1) to give (14.5 g, 36%) of the product. 1H NMR (300 MHz, CDCl3) δ 8.18 (b, NH), 7.62 (d, 1H), 7.21 (t, 1H), 7.16 (d, 1H), 6.51 (dd, 1H), 3.20 (m, 1H), 1.38 (d, 6H); ESI (+) MS m/e=239 (MH+), ESI (−) MS m/e=237 (MH−).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[OH:15][C:16]1[CH:27]=[CH:26][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>>[N:21]1([CH2:20][C:19]2[CH:26]=[CH:27][C:16]([O:15][CH2:2][C:3]3[CH:14]=[CH:13][C:6]([CH2:7][N:8]4[CH:12]=[CH:11][CH:10]=[CH:9]4)=[CH:5][CH:4]=3)=[CH:17][CH:18]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ClCc1ccc(Cn2cccc2)cc1
Reactant: Oc1ccc(CN2CCCC2)cc1
Product: c1ccn(Cc2ccc(COc3ccc(CN4CCCC4)cc3)cc2)c1

Procedure:
The title compound was prepared starting from 1-(4-chloromethyl-benzyl)-pyrrole and 4-hydroxybenzyl-pyrrolidine by the same method described in Example 19. 1H NMR (400 MHz, MeOD-d4)δ7.18 (m, 2 H), 6.99 (m, 2 H), 6.59 (t, J=2.1 Hz, 2 H), 5.97 (t, J=2.1 Hz, 2 H), 4.99 (s, 2 H), 3.55 (s, 2 H), 2.41 (m, 4 H), 1.70 (m, 4 H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-])=O)[CH:6]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH2:15])[CH:8]=[C:9]([C:11]([F:12])([F:14])[F:13])[CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1cc(N)cc(C(F)(F)F)c1

Procedure:
1-methanesulfonyl-3-nitro-5-trifluoromethylbenzene (500 mg; 1.9 mmol) was dissolved in 100 mL methanol, 70 mg of Pd/C (10%) was added and the mixture was hydrogenated at 3 bar. The reaction mixture was filtrated and solvent removed under reduced pressure. 250 mg (1.04 mmol; 55% yield) of a colorless solid were obtained.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][C:15]([NH:14][S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])=[CH:16][CH:17]=1)=[O:20]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
A mixture of 2.00 g of 3-(chlorosulfonyl)benzoic acid, 1.37 g of methyl 4-aminobenzoate, and 20 mL of pyridine was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 665 mg of 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoic acid as a pink solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[OH:14][C:15]1[CH:19]=[C:18]([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:22]=[CH:21]2)[S:17][C:16]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:20]1([C:18]2[S:17][C:16]([C:29]([O:31][CH3:32])=[O:30])=[C:15]([O:14][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]([F:13])([F:12])[F:1])[CH:19]=2)[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[N:22]=[CH:21]1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Reactant: FC(F)(F)Oc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
110 mg of 2-(trifluoromethoxy)benzyl bromide is added to a mixture of 100 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 59.7 mg of potassium carbonate in 3 ml anhydrous DMF. The mixture is stirred for 14 h at room temperature. Ice water is added and the organic phase is extracted with dichloromethane. The organic phase is poured on a phase separator and the solvent is removed under vacuum. The residue is dissolved in 2 ml of dichloromethane and filtered through a short plug of silica gel (eluent: hexane/ethyl acetate 1/1 (v/v) to 0/100 (v/v)) to yield the title compound.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:6][O:5][C:4]1=[O:16].Cl.[N:18]([O-])=O.[Na+]>O>[ClH:1].[CH3:2][N:3]1[C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][NH2:18])=[CH:11][CH:10]=2)[CH2:6][O:5][C:4]1=[O:16]
Reactant: O=N[O-]
Reactant: CN1C(=O)OC[C@@H]1Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1C(=O)OC[C@@H]1Cc1ccc(NN)cc1
Reaction time: 0.5 h

Procedure:
A solution of the product from step (b) (4.1 g) in water (24 ml) was cooled to -5° C. and c.HCl (40 ml) added. A solution of sodium nitrite (1.2 g) in water (12 ml) was then added and stirring continued for 0.5 hour. The resulting solution was added dropwise at -5° C. to a stirred solution of stannous chloride dihydrate (18.8 g) in c.HCl (34 ml). The resulting mixture was stirred at 0° C. for 2.5 hours, then evaporated in vacuo. The residue was taken up in water, brought to pH 2.5 using 1 ON aqu. NaOH and filtered. The filtrate was evaporated in vacuo and the residue triturated with ethanol and filtered. The filtrate was evaporated in vacuo to give the desired product as a froth.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([NH:35][CH2:36][CH3:37])[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)ccc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (149 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.68 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided 35 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 49 as a yellow solid (14 mg, 4% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:41])[O:30][C:29]2[CH:31]=[CH:32][C:33]([C:35]3([C:38]([OH:40])=O)[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27]1.[NH2:42][C:43]1[CH:44]=[C:45]2[CH:51]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[N:49]([CH2:56][CH2:57][OH:58])[C:46]2=[CH:47][N:48]=1.C(N(CC)CC)C>CN(C=O)C>[C:52]([C:50]1[N:49]([CH2:56][CH2:57][OH:58])[C:46]2=[CH:47][N:48]=[C:43]([NH:42][C:38]([C:35]3([C:33]4[CH:32]=[CH:31][C:29]5[O:30][C:26]([F:25])([F:41])[O:27][C:28]=5[CH:34]=4)[CH2:36][CH2:37]3)=[O:40])[CH:44]=[C:45]2[CH:51]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)c1cc2cc(N)ncc2n1CCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ncc2n1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (38 mg, 0.10 mmol) was added to a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (24 mg, 0.10 mmol), 2-(5-amino-2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (23 mg, 0.10 mmol) and triethylamine (42 μL, 0.30 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was filtered and purified by reverse-phase HPLC (10-99% CH3CN—H2O with 0.035% TFA) to yield N-(2-tert-butyl-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 457.2, found 458.5 (M+1)+. Retention time 1.77 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (br s, 1H), 8.84 (s, 1H), 7.83 (s, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 6.67 (s, 1H), 4.58 (t, J=5.7 Hz, 2H), 3.76 (t, J=5.7 Hz, 2H), 1.58 (m, 2H), 1.46 (s, 9H), 1.28 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[CH:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and commercially available 6-amino-3-bromo-pyridine (87 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (19 mg, 9%). MS (ISP) 447.9 [(M+H)+]; mp 177° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[N:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:12]3[C:11]4[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:10]=4)[N:15]=[CH:14][N:13]=3)=[CH:31][N:30]=2)[CH:26]=[CH:27]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OCc1ccccc1
Yield: 60.6 %

Procedure:
A solution of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.449 g, 1.49 mmol), (EP1153920 production examples 28-30), 5-hydroxy-7-azaindole (0.22 g, 1.64 mmol) and potassium carbonate (0.28 g, 2.02 mmol) in DMF (5 ml) was stirred at 95° C. for 3 hours. The mixture was filtered and the filtrate was evaporated and dried overnight under vacuum. The residue was triturated under methylene chloride and ethyl acetate and the solid was filtered and dried under vacuum to give 4-(7-azaindol-5-yloxy)-6-benzyloxy-7-methoxyquinazoline (0.36 g, 60%).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: Clc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)c1cccc(Cl)c1

Procedure:
1-Chloro-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-chloro-3-bromobenzene as the dihalo compound of formula (II).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)O)ncn2-c2cccc(Cl)c2C1=O

Procedure:
A mixture of 37.3 g (116.6 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 5.276 g (131.9 mmol) of sodium hydroxide, 150 ml of ethanol and 100 ml of water is heated to boiling under reflux for 15 minutes. The mixture is then neutralized by the addition of 132 ml of 1N hydrochloric acid, the ethanol is distilled off in vacuo and the residue is diluted with 100 ml of water. The mixture is cooled to about 0°, the product is filtered off under suction, rinsed with water and dried at 80° in a high vacuum. There is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 283°-284°.
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH2:16]=[O:17]>>[OH:17][CH2:16][NH:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: C=O
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCO)S1

Procedure:
A suspension of 5 g. of 2-(2-amino-5-thiadiazolyl)-1-methyl- 5-nitroimidazole in 200 ml. of 36% aqueous formaldehyde solution is stirred for 20 hours at room temperature. The suspension is cooled in ice, and the insoluble solid is collected by filtration and washed with acetone. The yield of the title compound is 6.15 g., melting point 177° C. with decomposition (rapid heating).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:10].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2[CH2:17][CH2:18][CH2:19][CH2:20][C:12]1=2>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[C:13]3[CH2:17][CH2:18][CH2:19][CH2:20][C:12]=3[C:11]2=[O:16])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Yield: 34.3 %

Procedure:
2-Chloro-4-fluoro-5-aminophenol (6.6 g) and 3,4,5,6-tetrahydrophthalic anhydride (6 g) were dissolved in acetic acid (20 ml) and refluxed for 2 hours. The resultant mixture was allowed to cool to room temperature and poured into ice-water, followed by extraction with ether. The ether extract was washed with a saturated sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate was concentrated. The residue was purified by silica gel chromatography to obtain 4.0 g of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 151° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[N:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.Br[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[N:11]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)nc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccc(=O)n(CCO[Si](C)(C)C(C)(C)C)c2)n1

Procedure:
To a solution of 5-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)pyridin-2-ol (1.10 g, 4.74 mmol) in MeCN (10.0 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (1.28 mL, 5.68 mmol) and K2CO3 (0.785 g, 5.68 mmol) and the mixture heated to reflux for 6 hr. The resulting mixture was cooled and was loaded directly onto silica and purified by flash column chromatography (SiO2, 40 g, 0-100% EtOAc in isohexane, gradient elution) to afford the title compound, Intermediate A15, as a pale yellow solid (1.11 g, 60%); Rt 2.61 min (Method 2, acidic); m/z 391 (M+H)+, (ES+).