Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:32]2C(=O)C3=CC=CC=C3C2=O)=[C:13]([CH:31]=1)[NH:14][C:15]([O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>NN.CO.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:31]=[C:13]([NH:14][C:15]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:16])[C:12]([NH2:32])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(NC(=O)OCC2CCN(c3ccncc3)CC2)c1
Agent: NN
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(NC(=O)OCC2CCN(c3ccncc3)CC2)c1
Yield: 85.5 %

Procedure:
A solution of 5-(tert-butyldimethylsilyloxy)-2-phthalimido-N-[[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl]aniline (1.34 g, 2.28 mmol) in 1 M hydrazine in methanol (6 mL) was stirred at ambient temperature for 40 h during which time a white precipitate formed. The mixture was further diluted with methylene chloride and cooled with an ice bath then filtered. The filtrate was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 890 mg (86%) of the title compound as a tan powder.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.[CH3:38][N:39]1[CH2:43][C@@H:42]2[NH:44][CH2:45][CH2:46][C@@H:41]2[CH2:40]1>FC(F)(F)CO>[CH3:38][N:39]1[CH2:40][C@@H:41]2[C@@H:42]([N:44]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=56)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:36][CH3:37])[CH:12]=3)[CH2:45][CH2:46]2)[CH2:43]1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 51.5 %

Procedure:
DIPEA (0.343 mL, 1.97 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-s nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 300 mg, 0.79 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 109 mg, 0.87 mmol) in 2,2,2-trifluoroethanol (5 mL) and the mixture was heated in a microwave at 140° C. for 1 h. After cooling, the mixture was part-purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were then concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (198 mg, 52%) as a slightly impure orange/red solid which was used without further purification; 1H NMR (CDCl3): 1.89 (1H, dd), 2.06-2.18 (1H, m), 2.21 (3H, s), 2.31 (1H, dd), 2.47 (2H, ddd), 2.65 (1H, t), 2.99-3.10 (1H, m), 3.26 (1H, t), 3.51-3.60 (1H, m), 3.98 (3H, s), 4.39-4.46 (1H, m), 6.46 (1H, s), 6.93 (1H, td), 7.04 (1H, d), 7.38 (1H, s), 7.43 (1H, ddd), 8.36 (1H, d), 8.46 (1H, s), 8.52 (1H, m), 8.58 (1H, m), 8.98 (1H, s); m/z: ES+ MH+ 487.15.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]1.CS(C)=O>CCOC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: COC(=O)C1CCNCC1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(C=O)cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 43.7 %

Procedure:
To a mixture of 4-chloro-3-nitrobenzaldehyde 57 (5.099 g, 27 mmol), cesium carbonate (9.48 g, 29 mmol), and methyl piperidine-4-carboxylate (4 mL, 27 mmol) was added DMSO (27 mL). The reaction mixture was heated to 100° C. for 30 min and diluted with EtOAc. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 30% to 50% EtOAc in hexanes) gave methyl 1-(4-formyl-2-nitrophenyl)piperidine-4-carboxylate 58 (3.45 g, 43% yield) as a yellow oil. Mass spectrum: calculated for C14H16N2O5 292.1. found 293.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[C:8]([CH3:12])[N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[CH:7]=[C:8]([CH3:12])[N:9]=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:20][CH:21]=3)[C:5]2=[N:4][CH:3]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cn2c(Br)cnc2c(Cl)n1
Agent: Cl
Solvent: CC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn2c(Br)cnc2c(NCc2ccc(S(N)(=O)=O)cc2)n1
Temperature: 108 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of 3-bromo-8-chloro-6-methyl-imidazo[1,2-a]pyrazine (350 mg, 1.42 mmol) in iBuOH (3 mL) is added 4-aminomethyl-benzenesulfonamide hydrochloride (334 mg, 1.42 mmol) and DIPEA (0.49 mL, 2.82 mmol). The reaction is stirred at 108° C. for 16 h. After this time the solution is allowed to cool, resulting in a thick precipitate that is filtered and washed with diethyl ether to give 4-[(3-bromo-6-methyl-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide as a beige solid (420 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]([O:38]C(C)(C)C)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=2)[C:18]([CH3:43])=[C:17]3[CH3:44])=[O:13])[CH3:10])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(CC)(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]([OH:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=2)[C:18]([CH3:43])=[C:17]3[CH3:44])=[O:13])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)cc1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-tert-butyl 4′-((5-(1-(4-methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate (58.9 mg, 0.1 mmol) and 2,6-lutidine (0.13 mL, 1.15 mmol) in DCM (1 mL) at 0° C. was added TESOTf (0.17 mL, 0.75 mmol). The reaction mixture was stirred at rt for 2 h. The completion of the reaction was monitored by anal. HPLC. The mixture was evaporated in vacuo to obtain the crude which was purified by prep. HPLC (MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS (m/z): 533 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([CH2:13][CH:14]=[CH2:15])[CH:5]=1.[CH3:17]I>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:17])=[C:6]([CH2:13][CH:14]=[CH2:15])[CH:5]=1
Reactant: C=CCc1cc(C(=O)OC)cc(OC)c1O
Reactant: CI
Product: C=CCc1cc(C(=O)OC)cc(OC)c1OC
Reaction time: 16 h
Yield: 96 %

Procedure:
3-Allyl-4,5-dimethoxybenzoic acid methyl ester was prepared from 3-allyl-4-hydroxy-5-methoxybenzoic acid methyl ester (Example 1, Step 2) by following Method C using methyl iodide as alkylating agent. The reaction was conducted at room temperature for 16 h and crude product was purified by flash column chromatography (96% yield).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[C:18]([C:19]2[CH:23]=[CH:22][O:21][C:20]=2[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:17][CH:16]=[C:15]([NH2:33])[C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[NH2:8][C:9]1[C:18]([C:19]2[CH:23]=[CH:22][O:21][C:20]=2[CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:27])[CH3:28])=[CH:17][CH:16]=[C:15]([NH:33][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1c(N)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
Pivaloyl chloride (0.353 g) was added to a stirred, cooled mixture of methyl 2,6-diamino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]benzoate (Intermediate 36, 1.0 g) and sodium bicarbonate (0.268 g) in ethyl acetate (20 mL) and water (7 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 1.5 hours. Further pivaloyl chloride (0.048 g) was added and the mixture was stirred for 1 hour. Ethyl acetate was added and the layers were separated. The organic layer was washed with aqueous sodium bicarbonate solution dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-20% to give methyl 2-amino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]-6-(2,2-dimethylpropionylamino)benzoate (0.744 g) as an oil.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:5][CH2:4]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][NH:17][C:16](=[O:28])[C:15]=2[C:29]#[N:30])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][N:17]([CH2:2][CH:3]3[CH2:5][CH2:4]3)[C:16](=[O:28])[C:15]=2[C:29]#[N:30])=[CH:10][CH:9]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn(CC3CC3)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 71.5 %

Procedure:
(Chloromethyl)cyclopropane (0.6 ml, 6.36 mmol) was added to a solution of 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one (1.71 g, 5.10 mmol) and potassium carbonate (2.02 g, 14.62 mmol) in N,N-dimethylformamide (5 ml), followed by stirring at a bath temperature of 80° C. for 6 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate (300 ml). The organic layer was washed with water and a saturated aqueous solution of sodium chloride (brine), successively, and was then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby the title compound (1.413 g, 71.5%) was obtained as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH2:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:24][C:25]1[CH:26]=[C:27](/[N:28]=[C:18](/[C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[NH:10][C:11]=3[CH:17]=2)\[C:19]([F:22])([F:20])[F:21])[CH:29]=[CH:30][C:31]=1[CH3:32]
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)C(F)(F)F)cc2[nH]1
Reactant: Cc1ccc(N)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(/N=C(/c2ccc3nc(-c4c(C)cccc4C)[nH]c3c2)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-2,2,2-trifluoro-ethanone (710 mg), 3,4-dimethylaniline (150 mg) and diisopropylethylamine (150 mg) in methylene chloride (15 mL) was added dropwise 1.1 mL of a 1.0M solution of TiCl4 in methylene chloride. The mixture was stirred at ambient temperature for 10 min then was washed with NaHCO3 solution. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using 10% EtOAc/methylene chloride as eluent to give (3,4-dimethyl-phenyl)-[1-[2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-2,2,2-trifluoroeth-(Z)-ylidene]-amine as an oil. This was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1/[C:25](=[CH:20]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])/[C:26](=[O:32])[NH:27]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 60.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 4-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 49 (40 mg, yield 60.5%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][CH:13]1[CH2:18][NH:17][CH2:16][CH:15]([CH3:19])[NH:14]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:17]1[CH2:16][CH:15]([CH3:19])[NH:14][CH:13]([CH3:12])[CH2:18]1)(=[O:10])=[O:9]
Reactant: CC1CNCC(C)N1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(S(=O)(=O)c2ccccc2Br)CC(C)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (100 mg, 0.39 mmol), 2,6-dimethylpiperazine (56 mg, 0.49 mmol), and diisopropylethyl amine (0.202 mL, 1.17 mmol) in CH2Cl2 (2.5 mL) was allowed to stir for 15 min at rt. The reaction mixture was then directly subjected to FCC purification to give the title compound (0.105 g, 81%). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 1H), 7.43-7.37 (m, 1H), 3.70-3.66 (m, 2H), 2.97-2.91 (m, 2H), 2.38-2.33 (m, 2H), 1.06-1.04 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>ClCCl>[CH3:41][S:42]([O:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])(=[O:44])=[O:43]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.7 g) in dichloromethane (100 ml) were added methanesulfonyl chloride (1.44 ml) and triethylamine (3.06 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue The residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (40:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.39 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20](C)[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4)(=[O:3])[CH3:2].Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>C1C=CC=CC=1.CCOCC.C(=O)([O-])[O-].[K+].[K+]>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:26][O:25][C:23]([N:20]1[CH2:19][CH2:18][C@@:15]23[C:16]4[CH:17]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[CH2:8][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:24]
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C)CC3
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCC(Cl)(Cl)Cl)CC3
Yield: 66.1 %

Procedure:
To a mixture of 2.7 g of (-)-3-acetyl-N-methylmorphinan, 50 ml of benzene and 20 mg of potassium carbonate, was added dropwise 2.11 g of 2,2,2-trichloroethyl chloroformate in 10 ml of benzene. The reaction mixture was stirred at reflux temperature for 48 hours and after cooling it was diluted with 100 ml ether. The ether solution was extracted with 1 N hydrochloric acid (2×30 ml) and dried over magnesium sulfate. Removal of the solvent gave 2.8 g (66%) of crude (-)-3-acetylmorphinan-17-carboxylic acid (trichloroethyl)ester. For analysis, a sample of this compound was distilled, bp 230°-240° (0.1 mm), [α]25D-127.21° (c 1.11, MeOH).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29][C@H:28]1[CH3:33])[CH3:26]
Reactant: CCN1CCNC[C@H]1C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (m, J=7.20, 7.20 Hz, 6H) 2.36 (s, 3H) 2.39 (br. s., 1H) 2.45-2.52 (m, 1H) 2.53-2.68 (m, 1H) 2.71-2.90 (m, 2H) 2.99 (br. s., 1H) 3.41-3.66 (m, 1H) 3.97 (br. s., 1H) 7.53 (d, J=7.83 Hz, 1H) 7.60 (s, 1H) 7.84 (d, J=8.08 Hz, 1H) 7.94 (d, J=7.79 Hz, 1H) 7.99 (s, 1H) 8.36 (d, J=8.59 Hz, 1H) 8.44 (d, J=1.77 Hz, 1H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:43]4[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 77.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (44 mg, 0.21 mmol), sodium carbonate (22 mg, 0.21 mmols) and bis(triphenylphosphine)palladium(II) dichloride (6 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 37 mg (74% yield) of the title compound. Purity 100%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (22 mg, 0.045 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at RT for 1 h and then directly loaded onto an SCX cartridge (2 g, pre-wet using DCM). Impurities were removed by eluting with MeOH:DCM (1:1) and product eluted using NH3 solution (2M in MeOH):DCM (1:1) to give the title compound (14 mg, 82%). LCMS (Method F): RT=9.03 min, [M+H]+=386. 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J=8.3 and 3.2 Hz, 1H), 7.55 (dd, J=9.5 and 4.7 Hz, 1H), 7.47-7.32 (m, 6H), 7.29 (d, J=7.9 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 2.61-2.50 (m, 2H), 2.22-2.00 (m, 3H), 1.82-1.69 (m, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[CH:15][CH:14]=2)[N:3]=1.[C:26]([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[CH:15][CH:14]=3)[N:3]=2)=[N:31]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(N)nn1C(C)(C)C
Reactant: Cc1ccccc1-c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Product: Cc1ccccc1-c1ccc(-n2nc(Nc3cc(C)n(C(C)(C)C)n3)c3ccccc3c2=O)cc1
Yield: 31 %

Procedure:
4-Bromo-2-(2′-methyl-biphenyl-4-yl)-2H-phtalazin-1-one (prepared from the appropriate starting materials in analogy to Method Q-1) was coupled with 1-tert-butyl-5-methyl-1H-pyrazol-3-ylamine in a Buchwald reaction as described in Method O to give the title compound (0.049 g, 31% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.44 (1H, s), 8.40 (1H, d), 8.33 (1H, d), 8.05 (1 H, t), 7.97 (1H, t), 7.62 (2H, d), 7.40 (2H, d), 7.30 (2H, d), 7.24 (2H, d), 6.00 (1H, s), 2.28 (3H, s), 2.12 (3H, s), 1.57 (9H, s); MS (ESI+)=464.36 (M+H)+.