Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([N:35]3[CH2:46][C:45]4[N:44]5[C:39]([CH2:40][CH2:41][CH2:42][CH2:43]5)=[CH:38][C:37]=4[C:36]3=O)[N:30]=[CH:29][CH:28]=2)=[CH:3]1.[BH4-].[Na+].C[OH:51]>>[OH:34][CH2:33][C:32]1[C:31]([N:35]2[C:46](=[O:51])[C:45]3[N:44]4[C:39]([CH2:40][CH2:41][CH2:42][CH2:43]4)=[CH:38][C:37]=3[CH2:36]2)=[N:30][CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CO
Reactant: CC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4Cc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4Cc5cc6n(c5C4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 238f (90 mg, 1.0 eq., 0.14 mmol), NaBH4 (23 mg, 5 eq., 0.60 mmol), and methanol (5 mL). The resulting mixture was stirred at room temperature for 20 minutes and quenched with water. It was then concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 238 (60 mg, 66%) as a white solid. MS-ESI: [M+H]+ 637.3. 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=1.5 Hz, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.86 (s, 1H), 7.36-7.31 (m, 2H), 6.83 (d, J=9.0 Hz, 1H), 6.15 (s, 1H), 5.71 (t, J=6.5 Hz, 1H), 4.96 (s, 2H), 4.72-4.63 (m, 4H), 4.52-4.51 (m, 2H), 3.97-3.95 (m, 2H), 3.75 (s, 3H), 3.55-3.53 (m, 1H), 3.48-3.46 (m, 1H), 3.10-3.08 (m, 2H), 2.91-2.89 (m, 2H), 2.58-2.56 (m, 1H), 2.49-2.48 (m, 2H), 2.23-2.19 (m, 1H), 2.08-2.02 (m, 2H), 1.93-1.89 (m, 2H), 1.00 (d, J=6.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:6]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(F)cc23)CC1

Procedure:
(22.6 mg, 58%) from 5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5c, 25 mg, 0.1 mmol) and 4-fluorophenylsulfonyl chloride (29.2 mg, 0.15 mmol), HRMS- FAB+ for C20H20N2O2SF2, calculated MH+ : 391.12918; found: 391.12926.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:15].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([F:15])=[O:12])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with N-BOC-glycine, 24a, (175.2 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes, with reaction progress indicated by the gradual formation of a precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The product crystallized upon storage at 0° C., affording 145.6 mg of 25a as white crystals. FTIR (neat) 1859 cm−1.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:29]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[N:30]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:29]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([C:39]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[N:30]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Clc1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(Cn6cccn6)cc5)nc34)CC2)cc1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-bromo-4-[4-(4-chloro-benzyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.043 g, 0.10 mmol) and EtOH (4.0 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.024 g, 0.13 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 2%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.023 g, 40%); 1H-NMR (500 MHz, DMSO-d6) 2.66 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2C6H4Cl), 3.66 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=1.9 Hz, 1H, pyrazole 4-H), 7.35 (d, J=7.6 Hz, 2H) and 8.14 (d, J=8.3 Hz, 2H) (3,5-C6H4CH2N and 2,6-C6H4CH2N), 7.40 (m, 4H, C6H4Cl), 7.49 (d, J=1.5 Hz, 1H, pyrazole-H), 7.86 (d, J=1.8 Hz, 1H, pyrazole-H), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.54 (br s, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=O.[C:16](Br)(Br)([Br:18])[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][C:16]([Br:18])=[CH:9][C:8]1[CH:11]=[C:4]([O:3][CH:2]([F:15])[F:1])[CH:5]=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=Cc1cc(OC(F)F)ccc1[N+](=O)[O-]
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1C=C(Br)Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 131.1 %

Procedure:
To a solution of 5-difluoromethoxy-2-nitrobenzaldehyde (238 mg) and carbon tetrabromide (545 mg) in dichloromethane (5.4 mL) was added dropwise a solution of triphenylphosphine (863 mg) in dichloromethane (3.6 mL) under cooling with ice. The mixture was gradually warmed to room temperature and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in diethyl ether and this resulting mixture was stirred at room temperature for 16 hours. The precipitate was removed by filtration through celite (registered trademark) and washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain the title compound (536 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[C:10]([CH3:11])[C:2]=1[NH2:1]
Reactant: COc1ccc(C(=O)O)c(N)c1C
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OC)c(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of 2-amino-4-methoxy-3-methyl benzoic acid (3.1 g, 17.1 mmol) in dry DMF (40 ml) was added potassium carbonate (2.4 g, 17.1 mmol) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (3.1 g, 22 mmol) was added and the mixture was stirred for three hours at room temperature. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (2.75 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:54])[C@H:25]([NH:34][C:35]([C@@H:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][N:38]2C(OC(C)(C)C)=O)=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:20][CH2:19]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:54])[C@H:25]([NH:34][C:35]([C@@H:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][NH:38]2)=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy)carbonyl-amino]ethyl}-amino)phenyl]-piperidyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (386 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min) provided the title compound (TFA salt) as a white foam (162 mg). MS (ESI, pos. ion) m/z: 560 (M+1); (ESI, neg. ion) m/z: 558 (M−1). Calc'd for C32H38ClN5O2: 559.27. Anal. Calcd for C32H38ClN5O2-3C2HF3O2: C, 50.59; H, 4.58; N, 7.76. Found: C, 50.98; H, 4.87; N, 8.01.
Reaction SMILES: [F:1][CH2:2][C:3]([O-:5])=O.[Na+].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.Cl.[NH2:24][CH2:25][C:26]([C:28]12[CH2:35][N:32]([CH2:33][CH2:34]1)[CH2:31][CH2:30][CH2:29]2)=O>CN(C)C=O>[F:1][CH2:2][C:3]1[O:5][C:26]([C:28]23[CH2:35][N:32]([CH2:33][CH2:34]2)[CH2:31][CH2:30][CH2:29]3)=[CH:25][N:24]=1
Reactant: NCC(=O)C12CCCN(CC1)C2
Reactant: O=C([O-])CF
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: FCc1ncc(C23CCCN(CC2)C3)o1
Temperature: -15 °C
Reaction time: 0.04 h
Yield: 17.6 %

Procedure:
Sodium monofluoroacetate (110mg, 1.1 mmole) was dissolved in dry, distilled N,N-dimethylformamide (20ml), the solution cooled to -15° C., and N-methylmorpholine (0.114ml, 1.0 mmole) added, followed by isobutylchloroformate (0.176ml, 1.1 mmole). The resulting white suspension was stirred for 2-3 minutes. 5-(2-Aminoacetyl)-1-azabicyclo[3.2.1]octane dihydrochloride salt (D24A) (250mg, 1.0 mmol) was suspended in dry N,N-dimethylformamide (20ml) and N-methylmorpholine (0.228ml, 2.0 mmol) added. The resulting suspension was added immediately to the reaction mixture, the suspension stirred for 15-30 min and then allowed to warm to room temperature and stirred for 90 min. The reaction mixture was evaporated to dryness under reduced pressure and polyphosphoric acid (20g) added. The mixture was heated with stirring at 160° C. for 30 minutes and the warm syrup was then poured carefully onto a mixture of solid potassium carbonate and ice. The resulting aqueous solution was saturated with solid potassium carbonate and extracted with ethyl acetate (3×250ml) and chloroform (2×250ml). The organic extracts were dried (Na2SO4), filtered, combined and evaporated to dryness under reduced pressure. The resulting brown oil which was purified by column chromatography (basic alumina eluting with diethyl ether) to yield a pale yellow oil (37mg, 18%), which was converted into the hydrochloride salt m.p. 138°-141° C. (ethyl acetate).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C([Sn](CCCC)(CCCC)[C:37]1[N:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]2=[N:39][CH:38]=1)CCC>CN(C=O)C.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]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:37]4[N:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]5=[N:39][CH:38]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2ccccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc4ccccn34)nc12)C(=O)N1CC(C#N)C1
Temperature: 75 °C

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]amide (110 mg, 0.22 mmol) was combined with 3-tributylstannanyl-imidazo[1,2-a]pyridine (159 mg, 0.39 mmol) in DMF that had been sparged with nitrogen for 10 min. To this was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) and the mixture heated to 70-80° C. for 3 h. All solvent was removed by high vacuum evaporation and the product purified by silica gel chromatography to give 2-imidazo[1,2-a]pyridin-3-yl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. LCMS: (M+H)+=544.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])#[CH:2].Cl[C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[N:20]=1.F[B-](F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:4]1[C:5]([C:9]([F:11])([F:10])[F:12])=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:23]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:19][N:20]=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)=[CH:32][CH:31]=2)[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1cccc(C(F)(F)F)c1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Temperature: 110 °C

Procedure:
A mixture of methyl 2-(2-ethynyl-6-(trifluoromethyl)phenyl)acetate (A93) (0.113 g, 0.468 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.222 g, 0.487 mmol), copper(I) iodide (0.005 g, 0.03 mmol), PdCl2(PPh3)2 (0.021 g, 0.030 mmol) and t-Bu3PH.BF4 (0.011 g, 0.038 mmol) in DMF (2.0 mL) was degassed with nitrogen for several minutes before the addition of DIPEA (2.0 mL, 12 mmol) then further degassed with nitrogen for several minutes. The resulting mixture was heated under microwave irradiation 110° C. for 20 minutes and then a further 30 minutes. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound A94 (0.127 g, 41%); 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.47 (t, J=7.7 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8.5 Hz, 2H), 4.25 (m, 2H), 4.17 (s, 2H), 3.69 (s, 3H), 2.81 (t, J=12.5 Hz, 2H), 2.65 (m, 1H), 1.83 (d, J=12.6 Hz, 2H), 1.63 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.12 min; m/z 661.1 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=O)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH2:18][NH:33][CH2:32][CH2:31][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Reactant: NCCN1CCCC1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cc(CNCCN2CCCC2)no1
Yield: 53 %

Procedure:
From 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde and 2-pyrrolidin-1-yl-ethylamine according to procedure 24. Yield 53%.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH:38]3[CH2:40][CH2:39]3)[C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[C:24]([O:41][CH3:42])[CH:23]=2)[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:13]=[C:8]2[N:7]=1)C.[OH-].[K+]>C(O)CCC.O>[CH:38]1([CH:29]([C:30]2[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH2:21][N:20]3[C:9]4=[N:10][CH:11]=[C:12]([C:14]5[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=5)[CH:13]=[C:8]4[N:7]=[C:6]3[NH2:5])=[CH:23][C:24]=2[O:41][CH3:42])[CH2:40][CH2:39]1
Reactant: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OC(c2ccc(OC)nc2)C2CC2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(C(Oc2ccc(Cn3c(N)nc4cc(-c5cnn(C)c5)cnc43)cc2OC)C2CC2)cn1
Temperature: 130 °C
Reaction time: 16 h
Yield: 15.1 %

Procedure:
To a stirred solution of ethyl(3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.44 g, 0.75 mmol) in n-butanol (4 mL) and water (4 mL) was added potassium hydroxide (0.42 g, 7.49 mmol). The mixture was heated to 130° C. After 16 h, the mixture was allowed to cool to room temperature and was diluted with water (15 mL). The mixture was extracted with ethyl acetate (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified via prep-HPLC to provide 0.058 g (15%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=1.5 Hz, 1H), 8.09 (d, J=3.0 Hz, 1H), 7.78 (s, 1H), 7.70-7.68 (m, 2H), 7.64 (s, 1H), 6.78-6.23 (m, 4H), 5.21 (s, 2H), 4.85 (s, 2H), 4.50 (d, J=8.5 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.79 (s, 3H), 1.45-1.40 (m, 1H), 0.75-0.70 (m, 1H), 0.61-0.50 (m, 2H), 0.38-0.34 (m, 1H) ppm; (M+1)=512.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([CH:39]5[CH2:41][CH2:40]5)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnn2c(C3CCN(C4CC4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 29.2 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.244 mmol) was dissolved in methanol (3.5 mL). Acetic acid (140 uL, 2.44 mmol) was added followed by a small scoop of activated molecular sieves. [(1-ethoxycyclopropyl)oxy](trimethyl)silane (255 mg, 1.47 mmol) was added to the flask via syringe. Solid sodium cyanoborohydride was added (61 mg, 0.977 mmol) to the reaction which was then heated under nitrogen overnight. The mixture was partitioned between ethyl acetate (100 mL) and sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine and then dried with sodium sulfate. The product was purified using column chromatography, eluent 2-3% (7N NH3 in Methanol)/dichloromethane to afford 32 mg (29%) of desired product. 1H NMR (300 MHz, dichloromethane-d2) δ 8.04 (s, 1 H), 7.89 (s, 1 H), 7.78-7.73 (m, 3 H), 7.60-7.40 (m, 4 H), 7.25 (d, 1 H), 6.63 (s, 1H), 5.62 (s, 2 H), 5.52 (bs, 2 H), 3.90 (m, 1H), 3.40 (m, 1H), 2.80 (m, 3 H), 2.40 (m, 1 H), 1.95 (m, 1 H), 1.75 (m, 1 H), 1.40-0.90 (m, 3 H); ES-MS m/z 450.2 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH:8]([N:21]1[CH2:24][CH:23](OS(C)(=O)=O)[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.C(OCC)(=O)C>[CH:8]([N:21]1[CH2:24][CH:23]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:22]1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CC(n3ccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A solution of 3.20 g of imidazole in 25 ml of dimethylformamide was added to 2.10 g of a suspension of sodium hydride (as a 55% w/w dispersion in mineral oil) in 25 ml of dimethylformamide, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour. A solution of 5.00 g of 1-benzhydryl-3-methanesulfonyloxyazetidine in 50 ml of dimethylformamide was then added to the mixture, after which the mixture was stirred at 70° C. for 17 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was then dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 2.88 g of the title compound, as a powder, from the fraction obtained by elution with a 95:5 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c2c1C
Reaction time: 2 h

Procedure:
To a solution of 5,6-dimethyl-1,4dihydro-quinoxaline-2,3-dione (28.5 g, 150 mmol) in concentrated H2SO4 (50 mL) was added KNO3 (15.15 g, 150 mmol) portionwise keeping temperature below 5° C. Reaction mixture was stirred for 2 hours and poured over ice. Yellow precipitate was filtered, washed, and air dried.