Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:27]1[C@H:29]([C:30]([O:32]CC)=[O:31])[C:28]1([CH3:36])[CH3:35].[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[F:47]>>[F:40][C:41]1[CH:42]=[C:43]([C:2]2[CH:39]=[CH:38][CH:37]=[C:4]([CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]5[CH:26]=[CH:25][C:24]6[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=6)[N:18]=5)=[CH:14][C:9]=4[N:8]=[C:7]3[C@@H:27]3[C@H:29]([C:30]([OH:32])=[O:31])[C:28]3([CH3:36])[CH3:35])[CH:3]=2)[CH:44]=[CH:45][C:46]=1[F:47]
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccc(F)c(F)c3)c2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 3,4-difluorophenylboronic acid in Step A. MS (ESI): mass calcd. for C36H29F2N3O3, 589.22; m/z found, 590.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.5, 1H), 8.11 (d, J=8.4, 1H), 7.87-7.83 (m, 1H), 7.79-7.73 (m, 1H), 7.70 (d, J=8.5, 1H), 7.60-7.54 (m, 1H), 7.51-7.47 (m, 1H), 7.45-7.40 (m, 1H), 7.34-7.29 (m, 2H), 7.27-7.25 (m, 2H), 7.24-7.18 (m, 2H), 7.16-7.11 (m, 1H), 7.02-6.97 (m, 1H), 5.52-5.35 (m, 4H), 2.29 (d, J=8.2, 1H), 2.11 (d, J=8.2, 1H), 1.17 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[CH2:32][CH2:31][CH2:30][CH2:29][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)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>[C:1]([N:5]1[CH2:32][CH2:31][CH2:30][CH2:29][C:8]2[C:9]([C:37]3[CH2:38][CH2:39][O:34][CH2:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: CN(C)C=O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(C3=CCOCC3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 125 °C

Procedure:
A mixture of 75 mg of 25b, 37 mg of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane, 41 mg of K2CO3 and 17 mg of tetrakis(triphenylphosphine)palladium(0) in 3 ml of degassed DMF was heated under N2 atmosphere at 125° C. for 2 hr. The reaction was cooled and diluted with 15 ml of water. The product was extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated. The remainder was chromatographed over silcagel (using a gradient of heptane/acetone as eluent). The product isolated was triturated with diethyl ether, providing 57 mg of white crystalline 25c; Mp 208-210° C. LC-MS-ESI: [M+1] 512.13. NMR (CDCl3) δ 8.70, 8.58, 7.88, and 7.37 (4×m, 4, pyridine-H), 7.68 and 6.87 (2×s, 2, Ar—H), 1.60 (s, 9, tertC4H9), 3.87 (s, 3, OCH3), 5.75 (m, 1, CH), 4.30 (m, 2, CH2O), 4.70 (bm, 1, CH2), 3.55 (bm, 1, CH), 3.85 (bm, 4, 2×CH2) 3.00 and 3.20 (2×bm, 2, CH2), 2.63 (bm, 2, CH2), 2.35 (m, 2, CH2), 1.70-2.05 (bm, 4, 2×CH2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[N:31]([CH3:36])[N:30]=[CH:29]3)=[O:25])[CH:19]=1>CN(C=O)C>[CH3:36][N:31]1[C:32]2[C:28](=[CH:27][C:26]([C:24]([C:20]3[N:21]=[CH:22][N:23]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:19]=3)=[O:25])=[CH:34][C:33]=2[CH3:35])[CH:29]=[N:30]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(C)c12
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2cnn(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
25 mg (0.12 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 35 mg (0.10 mmol) (6-chloro-pyrimidin-4-yl)-(1,7-dimethyl-1H-indazol-5-yl)-methanone and 25 μL (0.18 mmol) TEA were combined in 1 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and evaporated down to approx. 5 mL. This residue was neutralised with saturated sodium hydrogen carbonate solution, the precipitate formed was suction filtered and dried.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:20][OH:21].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:21][NH:20][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(CCN)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: NCCN1CCN(c2ncc(C(=O)NO)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15d (125 mg, 0.462 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (321 mg, 4.62 mmol) and a freshly prepared solution of sodium methoxide in methanol (159 mg, 6.91 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethylacetate (5 mL) and the combined organic layers were dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16d.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15](C(OC)=O)[CH2:14][C@@H:13]1[CH3:22])=[O:10].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[CH3:22])=[O:10]
Reactant: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](C)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1[nH]c(C(=O)N[C@@H]2CCNC[C@@H]2C)c(Cl)c1Cl
Yield: 63.4 %

Procedure:
A solution of methyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate (Intermediate 40, 3.4 g, 9.79 mmol), potassium hydroxide (3.84 g, 68.58 mmol), and hydrazine hydrate (3.6 mL, 68.58 mmol) in ethylene glycol (180 mL) was stirred for 60 h at 120° C. The reaction mixture was poured in to water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to yield the crude product, which was triturated with water (150 mL) to afford 3,4-dichloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide 1.8 g, (63%) as solid.
Reaction SMILES: Cl[CH:2]([O:8][CH3:9])[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([CH:19]([F:21])[F:20])[NH:16][C:15]=2[CH:22]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([CH:19]([F:20])[F:21])[N:16]([CH2:9][O:8][CH2:2][CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[C:15]=2[CH:22]=1
Reactant: FC(F)c1nc2ccc(Br)cc2[nH]1
Reactant: COC(Cl)C[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(C(F)F)nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2-Chloro-methoxy-ethyl)-trimethyl-silane (1.1 ml, 6.4 mmol, 1.5 eq.) was added to an anhydrous dichloromethane solution (22 ml) of 6-bromo-2-difluoromethyl-1H-benzimidazol (1.0 g, 4.27 mmol) and N,N-diisopropyl ethyl amine (1.9 ml, 10.6 mmol, 2.5 eq.). This was stirred at room temperature for 18 hours. The reaction mixture was concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 6-bromo-2-difluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole was obtained as a yellow solid (1.37 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: Fc1ccc2c(C3CCNCC3)c[nH]c2c1

Procedure:
A mixture of platinum oxide (1.0 g) in ethanol (37.5 ml) and glacial acetic acid (12.5 ml) were mixed under nitrogen with 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (20 g, 0.0926 mol) in ethanol (187.5 ml) and glacial acetic acid (62.5 ml). The reaction mixture was then hydrogenated at 60 psi until the reaction was complete by tlc. The catalyst was removed by fitration and the solvent evaporated in vacuo to give a yellow solid which was dried at 60° C. in vacuo (EP 722941).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O.CC(C)=O.[Cu]>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Cc1ccc(O)cn1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cu]
Agent: [K]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cccc(C(F)(F)F)c2)cn1

Procedure:
3.68 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylformamide, and 5.65 g of m-bromobenzotrifluoride and 300 mg of copper powders were added to the suspension, followed by allowing the mixture to react in a nitrogen stream at 120° C. for 15 hours while stirring. After cooling, the reaction mixture was diluted with 40 ml of acetone and filtered. The filtrate was immediately dried to solidify, and 100 ml of chloroform and 50 ml of water were added thereto. The mixture was adjusted to a pH of 9 with 5 N sodium hydroxide, and any insoluble matter was again separated by filtration. The resulting chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.1 g of oily 5-(m-trifluoromethylphenoxy)-2-methylpyridine.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:20](Cl)([Cl:22])[Cl:21]>>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][CH2:9][CH:10]([O:13][P:20]([Cl:22])[Cl:21])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClP(Cl)Cl
Reactant: OC1CCC(c2ccccc2)(c2ccccc2)CC1
Product: ClP(Cl)OC1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
reacting 4,4-diphenylcyclohexanol with PCl3 to obtain 4,4-diphenylcyclohexyloxy dichlorophosphine having the formula: ##STR16## (b) coupling the 4,4-diphenylcyclohexyloxy-dichlorophosphine formed in step (a) with an amine base to obtain 4,4-diphenylcyclohexyloxydiaminophosphine having the formula: ##STR17## (c) coupling of the 4,4-diphenylcyclohexyloxy-diaminophosphine formed in step (b) with hydroxymethyl-DTPA penta tert-butyl ester to obtain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA -oxy, penta tert-butyl ester)amino-phosphine having the formula: ##STR18## (d) hydrolysis and oxidation of the 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA oxy, penta tert butyl ester) aminophosphine formed in step (c) with dilute HCl and an oxidant to form (4,4-diphenylcyclohexyl)phosphonooxymethyl diethylene triamine, penta t-butyl ester having the formula: ##STR19##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH:21]1[CH2:30][NH2:31]>>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH:21]1[CH2:30][NH:31][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: NCC1COc2ccccc2O1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(NCC2COc3ccccc3O2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 22.49 min.; purity: 87.6%; MS (m/e): 411.01 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a 250 mL round bottom flask charged with 4-cyanobenzoic acid (19.36 g, 0.13 mol) in abs. ethanol (100 mL) was added concentrated sulfuric acid (3 mL). This mixture was heated to reflux for a period of 28 h, then allowed to cool to room temperature overnight. The solvent was removed via rotary evaporation and the resulting off-white residue was taken up in diethyl ether (500 mL). This was then washed with saturated sodium bicarbonate/water solution (5×100 mL), then brine (1×100 mL), and dried over magnesium sulfate. Filtration and concentration yielded an off-white solid. Recrystallization from 95% ethanol (50 mL) yielded product as white crystals (16.85 g, 73%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.14 (AA′XX′, J=8.6 Hz, 2H), 7.74 (AA′XX′, J=8.6 Hz, 2H), 4.42 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]([O:15][CH3:16])[N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=2)[CH:12]=1
Reactant: COc1c2cc(Cl)ccc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2cc(Cl)ccc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (57 mg, described in Example 107) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (96 mg, 95%). MS (ES): M/Z [M+H]=469. 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 4.19 (s, 3H), 4.77 (d, 1H), 4.90 (d, 1H), 7.16 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.4 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.92-8.01 (m, 3H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=O)C.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+:29](C)C.C(N(CC)C(C)C)(C)C.N>C(#N)C>[NH:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[NH:8][CH:7]=[C:6]([C:4]([NH2:29])=[O:3])[CH:10]=2)=[N:12]1
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Reactant: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (80 mg, 0.35 mmol) (from Example 11) and fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (92.7 mg, 0.35 mmol) (Aldrich, Milwaukee, Wis.) in acetonitrile (6 mL) at 0° C. was added N,N-diisopropylethylamine (DIPEA) (54.28 mg, 0.42 mmol). The mixture was allowed to warm up to room temperature and stirred for one hour. The mixture was then cooled in an ice-bath and charged with ammonia gas. After stirring at room temperature for overnight, the reaction was concentrated, diluted with water and extracted with DCM. The organic layer was concentrated and triturated with DCM to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[C:4]([F:10])[C:3]=1[CH3:11].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC#N>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([CH3:11])=[C:4]([F:10])[C:5]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cc(Br)c(O)c1F
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1c(Br)cc(Br)c(C)c1F
Temperature: 30 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a homogeneous CH3CN (200 mL) solution of 4,6-dibromo-2-fluoro-3-methylphenol (2, 28.4 g, 100 mmol) at rt, K2CO3 (16.59 g, 120 mmol) was added, followed by MeI (9.3 mL, 150 mmol). The cloudy solution was stirred at 30° C. overnight. The reaction went to completion monitored by LC and TLC. The mixture was cooled to rt, quenched by addition of H2O (100 mL) and sat. aq. NH4Cl (100 mL), two layers were mixed well and then separated, aqueous layer was extracted with EtOAc (50 mL), organic layers were combined, dried (MgSO4), filtered, solvent was removed in vacuo. The crude product, an oil, was dissolved in CH2Cl2 (˜80 mL) and the solution was passed through a silica gel pad (˜50 g of silica gel), washing with CH2Cl2 (˜100 mL). The filtrate was collected, and the solvent was removed in vacuo. 1,5-Dibromo-3-fluoro-2-methoxy-4-methylbenzene was obtained as a solid: 31.62 g (>99% yield); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=2.1, 1H), 3.92 (s, 3H), 2.29 (d, J=2.8, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:17])[C:14]=1[CH2:15][OH:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:17])[C:14]=1[CH2:15][O:16][S:26]([CH3:25])(=[O:28])=[O:27])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc(F)c(CO)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a stirred solution of tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (1.9 g, 7.78 mmol) in DCM was added Et3N (3.27 mL, 23.4 mmol, 3 eq) and methanesulfonylchloride (0.72 mL, 9.3 mmol, 1.2 eq) successively at 0° C. After the reaction was stirred for 30 min, it was extracted with CH2Cl2C and water. Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (2.25 g, 89% yield) as a ivory solid.
Reaction SMILES: [C:1]([C:3](=[C:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)S([Cl:45])(=O)=O.Cl>C(OCC)(=O)C.C1COCC1>[F:15][CH:14]([F:16])[C:7]1[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:4]([C:3](=[C:25]2[CH:29]([Cl:45])[CH2:28][CH2:27][O:26]2)[C:1]#[N:2])=[C:9]([C:10]([F:12])([F:11])[F:13])[N:8]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1CC(C)C
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2OCCC2Cl)c1CC(C)C
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
A 100 mL round-bottomed flask was charged with 1.2 g (2.9 mmol) of the compound of Example 2 and 30 mL anhydrous THF and cooled to -70° C. Then 2.9 mL sodium bis(trimethylsilyl)amide (1.0 M solution in THF) was added. After 5 minutes, 0.48 g (2.9 mmol) trifluoromethanesulfonyl chloride was added. To the reaction mixture was added 0.25 g additional trifluoromethanesulfonyl chloride. The reaction mixture was poured into dilute HCl and extracted with ethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 1.3 g of crude product. Chromatography using 15% ethyl acetate in hexanes yielded 0.34 g of the desired product, as a yellow oil, a 27% yield. nD25 1.4860.
Reaction SMILES: [OH:1][CH:2]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]1[OH:33].[C:34](N1C=CN=C1)(N1C=CN=C1)=[S:35]>O1CCCC1>[S:35]=[C:34]1[O:33][CH:3]2[C:4]3[C:5]([N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:25][CH:2]2[O:1]1)=[N:6][C:7]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[N:9]=3
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(O)C3O)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC2OC(=S)OC32)cc1
Temperature: 25 °C

Procedure:
tert-Butyl 7,8-di hydroxy-2,3-d i-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 2) (1.28 g, 2.86 mmol) was dissolved in tetrahydrofuran (50 ml). 1,1′-Thiocarbonyl diimidazole (1.019 g, 5.72 mmol) was added and the solution heated at reflux for 3 h. The reaction mixture was cooled to room temperature and evaporated to dryness. Water and DCM (300 ml) were added. The organic layer was separated and evaporated to dryness. Ethyl acetate (5 ml) was added to the dark residue and the resulting solid filtered off. The solid was washed twice with EtOAc (5 ml) to afford the titled compound;
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:28][CH:27]2[CH:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1>CN(C)C=O>[CH3:20][N:21]1[CH2:28][CH:27]2[CH:23]([CH2:24][N:25]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:26]2)[CH2:22]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN1CC2CNCC2C1
Solvent: CN(C)C=O
Product: CN1CC2CN(C(=O)N3c4ccccc4C(=O)Nc4cccnc43)CC2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4.9 g (18 mmoles) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2.3 g of 3- methyl-3,7-diazabicyclo[3.3.0]octane in 75 ml of dry dimethylformamide was stirred for 20 hours at ambient temperature. The reaction mixture was concentrated in vacuo, the residue was divided between 1N hydrochloric acid and methylene chloride. The organic phase was washed two further times using 1N hydrochloric acid and once using water. The combined aqueous phases were rendered basic using potassium carbonate and extracted using methylene chloride (3×150 ml). The combined methylene chloride phases were dried over magnesium sulphate, concentrated and the crude material was recrystallised from acetonitrile. 2.9 g (41% of theory) of colourless crystals of m.p. 157°-159° C. were obtained.