Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:44])[CH2:19][C:20]([NH:22][CH2:23][C:24]2[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]3=[N:28][C:29]=2[CH2:30][CH3:31])=[O:21])=[CH:4][CH:3]=1.[NH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(O)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:44])[CH2:19][C:20]([NH:22][CH2:23][C:24]2[C:25]([NH:37][CH:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[C:26]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]3=[N:28][C:29]=2[CH2:30][CH3:31])=[O:21])=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(-c2cccc(C=O)c2)c1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(-c2cccc(CN3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.3 %

Procedure:
N-[(6-chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (37.0 mg, 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing piperazine (0.18 mmol) and acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirring at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and purification was completed using reversed phase HPLC (acidic conditions) via a Gilson. The product after HPLC purification was dissolved in 3 mL of MeOH and was passed through a 0.5 g amine column (washed with 8 mL of MeOH) to afford 12.1 mg of the title compound (29.3%). LC-MS m/z 687 (M+H)+, 1.88 min (ret time).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)[C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc([N+](=O)[O-])cc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(c2oc3ccc([N+](=O)[O-])cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a mixture of cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methanone (3.00 g) synthesized above, methyl 4-aminobenzoate (1.57 g), triethylamine (11.6 mL) and methylene chloride (40 mL) was added titanium (IV) chloride (1.37 mL), and the mixture was stirred overnight under argon atmosphere at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (40 mL) of the obtained oil in tetrahydrofuran were added acetic acid (2.98 mL) and sodium cyanoborohydride (1.31 g), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give the title object compound (2.66 g, 61%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:39]([C:36]5[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=5)=[O:40])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: COc1ncc(C(=O)O)cn1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)n1
Product: COc1ncc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)cnc43)CC2)cn1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 55) was coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 562.2 (M−H−, 1Cl).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:37](C(OC(C)(C)C)=O)[CH:38]=[CH:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:37][CH:38]=[CH:39][CH:40]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)n1cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc[nH]2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 100 mg, 0.224 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (131 mg, 0.448 mmol), Pd(PPh3)2Cl2 (15.73 mg, 0.022 mmol), Na2CO3 (95 mg, 0.896 mmol), DME (951 μL), water (272 μL) and EtOH (136 μL) in a MW vial was sealed, evacuated/purged 3 times with argon and stirred at 80° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW irradiation at 150° C. for 5 min, diluted with DME (3 mL) and treated with Si-Thiol (Silicycle, 1.44 mmol/g, 93 mg, 0.134 mmol) overnight. The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) to afford the title compound as a grey solid. UPLC-MS (Condition 3) tR 1.02 min, m/z=433.4 [M+H]+, m/z=477.3 [M+formic acid-H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.77 (m, 1H) 1.77-1.88 (m, 1H) 2.97 (d, J=11.80 Hz, 1H) 3.23-3.32 (m, 2H) 3.39-3.49 (m, 1H) 4.15-4.24 (m, 1H) 4.79-4.89 (m, 1H) 6.06-6.13 (m, 2H) 6.76-6.84 (m, 1H) 7.34 (d, J=8.28 Hz, 2H) 7.82-7.92 (m, 2H) 8.02 (d, J=2.51 Hz, 1H) 8.69 (d, J=2.51 Hz, 1H) 10.17 (s, 1H) 11.14 (d, J=1.76 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.[Pd]>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=c1ccc(Br)cn1CCO
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1ccc(-c2cccc(F)c2)cn1CCO
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
5-Bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one (100.7 mg, 462 μmol), 3-fluorophenylboronic acid (121.5 mg, 868 μmol), palladium fibercat catalyst (4.11%, 14.1 mg), and sodium carbonate (0.48 ml, 2.0 M in water, 960 μmol) were put in a microwave vial, and then 1,4-dioxane (0.69 ml) was added. The microwave vial was sealed and heated in the CEM microwave at 120° C. and 50 Watts for a 5 minute ramp time and then a 20-minute run time. The reaction was then cooled to room temperature, diluted with water, and extracted with 3:1 CH2Cl2/MeOH. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and dried under vacuum. The material was used for the next step. MS (ESI pos. ion) m/z (MH+): 234. Calc'd exact mass for C13H12FNO2: 233.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[C:30]([O:34][C:35](=[O:41])[C@@H:36]([NH2:40])[CH:37]([CH3:39])[CH3:38])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([O:34][C:35](=[O:41])[C@@H:36]([NH:40][C:27]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[C@H:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]1)=[O:28])[CH:37]([CH3:38])[CH3:39])([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1)C(=O)OC(C)(C)C
Yield: 32.4 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (215.7 mg, 0.50 mmol) prepared in Example 1d was reacted with (S)-2-amino-3-methyl-butyric acid tert-butyl ester (125.4 mg, 0.60 mmol), HATU (210.1.0 mg, 0.60 mmol) and iPr2NEt (129.3 mg, 1.00 mmol) in CH2Cl2 (5 mL) at rt overnight to give (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (95.0 mg, 32.4%) after column separation. HRMS (ES+) m/z Calcd for C32H41Cl2N3O3+H [(M+H)+]: 586.2602. found: 586.2598.
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([CH3:18])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8][CH2:7]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:18][C@:6]1([CH2:5][OH:4])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8][CH2:7]1
Reactant: CC(=O)OC[C@]1(C)CCn2cc([N+](=O)[O-])nc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@@]1(CO)CCn2cc([N+](=O)[O-])nc2O1
Yield: 96.3 %

Procedure:
Hydrolysis of (S)-acetate 161 (426 mg, 1.67 mmol) with K2CO3 in MeOH/water as in Example 2EEE above, followed by chromatography of the product on silica gel, eluting with 0-1% MeOH/CH2Cl2 (forerun), and then with 1-2.5% MeOH/CH2Cl2, gave [(7S)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]methanol (162) (343 mg, 96%) as a pale yellow solid that was used directly in the next step; 1H NMR [(CD3)2SO] δ 8.03 (s, 1H), 5.22 (br t, J=5.7 Hz, 1H), 4.13 (dt, J=13.0, 6.0 Hz, 1H), 4.05 (ddd, J=12.9, 8.1, 5.6 Hz, 1H), 3.54 (dd, J=11.6, 5.4 Hz, 1H), 3.48 (dd, J=11.6, 5.7 Hz, 1H), 2.21 (ddd, J=14.4, 8.1, 5.9 Hz, 1H), 2.00 (dt, J=14.4, 5.8 Hz, 1H), 1.32 (s, 3H); [α]D27 18.0° (c 1.00, DMF).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[N:6]/[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1]
Reactant: NC(=O)c1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccc(F)cc1F
Temperature: 120 °C
Yield: 91 %

Procedure:
A suspension of 2,4-difluorobenzamide (5 g, 32 mmol) in DMF-DMA (10 mL) was heated at 120° C. for 2.5 h, allowed to cool down to RT and filtered to afford the title compound as a white solid (6.16 g, 91%). 1H NMR (CDCl3): 8.60 (1H, s), 8.19-8.12 (1H, m), 6.91-6.79 (2H, m), 3.19 (6H, m).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)(=O)=O.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[Br:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][N:20]1[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]2[C:16]1=[O:26]
Reactant: CS(=O)(=O)OCCOc1cccc(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 78.2 %

Procedure:
To a solution of mesylate 16 (24.05 g, 81.5 mmol) in anhydrous DMF (160 ml) was added potassium phthalimide (15.53 g, 83.8 mmol) and the reaction mixture was stirred at 60° C. for 14 h. The mixture was concentrated under reduced pressure and the residue was partitioned between hexane-EtOAc (7:1) and water. A precipitate formed which was collected by filtration, washed excessively with water and hexane, then dried in vacuum to give N-(2-(3-Bromophenoxy)ethyl)phthalimide (17) as white fluffy crystals (22.05 g). To collect a second batch of crystals, the organic layer of the filtrate was concentrated under reduced pressure. The residue was suspended in 10% EtOAc-hexanes. The solution was washed with water and the precipitate collected by filtration, washed excessively with water, then hexane and dried in vacuum to give phthalimide 17 (5.65 g). Combined yield (21.18 g, 98%). 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.73 (m, 2H), 7.03-7.12 (m, 3H), 6.80 (ddd, J=8.0, 2.5, 1.4 Hz, 1H), 4.21 (t, J=6.9 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:2]1([CH2:1][N:8]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@@H:10]([CH2:19][N:30]3[CH2:31][CH2:32][CH:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: c1ccc(CN2C[C@H](CN3CCC(c4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.68 g (10 mmol) of 1-benzyl-3-(R)-formyl-4-(S)-phenylpyrrolidine in 10 mL of 1,2-dichlorethane was added 2.0 g (12 mmol) of 4-phenylpiperidine. To this was added 3.2 g (15 mmol) of sodium triacetoxyborohydride and the solution was stirred at room temperature for 1 h. The reaction was poured into 50 mL of saturated NaHCO3 solution and the mixture was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel using ethyl acetate-hexane (1:1) to afford the title compound. 1H NMR (CDCl3) δ 1.6-1.85 (m, 4H), 1.98 (dq, J=7 Hz, J=2 Hz, 2H), 2.4-2.56 (m, 4H), 2.62 (m, 1H), 2.72 (m, 1H), 2.83 (m, 1H), 3.04 (m, 4H), 3.69 (d, AB, J=7 Hz, 1H), 3.77 (d, AB, J=7 Hz, 1H), 7.2-7.6 (m, 15H); Mass Spectrum (ESI) m/e 411 (M+1); [α]D =+26.0 (c.=1.56, CHCl3)
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].C(Cl)Cl.C(N)CN>C(O)(C(F)(F)F)=O>[OH:1][CH2:2][C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CO)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide (35 mg, 0.068 mol) was dissolved in a 4:6 solution of TFA:DCM (10 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure. The crude material was then dissolved in dichloromethane and treated with ethylenediamine (41 mg, 0.68 mmol). After stirring at room temperature overnight, the precipitate was collected by filtration to afford 15 mg (57%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide as a yellow solid. MS: (M+H)+=385; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.97 (d, J=2.64 Hz, 1H) 8.66 (d, J=8.69 Hz, 1H) 8.36 (s, 1H) 8.15 (d, J=7.93 Hz, 1H) 7.92 (s, 1H) 7.26 (d, J=8.31 Hz, 1H) 3.96-4.39 (m, 3H) 3.31-3.68 (m, 1H) 1.25 (d, J=6.80 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[NH:51][S:52]([CH3:55])(=[O:54])=[O:53].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[C:37]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NS(C)(=O)=O
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 51.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example 9) (100 mg, 0.19 mmol) was coupled with N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65C) (62 mg, 0.19 mmol) using potassium carbonate (60 mg, 0.57 mmol) and Pd(PPh3)4 (11 mg, 0.0095 mmol) in toluene/ethanol/water (2/2/1 mL). This afforded 63 mg (51.4% yield) after purification by preparative TLC (silicagel-1000 micron) using 40% ethyl acetate in hexane as eluent. MS: m/z=646.2 (M+1).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([CH:21]([OH:29])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=1.O>CN(C)C=O>[Si:6]([O:29][CH:21]([C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CCC(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC(O[Si](C)(C)C(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
Imidazole (5.4 g) and tert-butyldimethylsilyl chloride (3.98 g) were added to a solution of ethyl 4-(5-chloro-2-nitrophenyl)-4-hydroxybutanoate (3.8 g) in anhydrous dimethylformamide (25 mL), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water three times and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1) to obtain 5.3 g of ethyl 4-(tert-butyldimethylsilyloxy)-4-(5-chloro-2-nitrophenyl)butanoate with a quantitive yield.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([S:15][CH3:16])=[CH:7][CH:6]=1.C(OO)(=[O:20])C>C(OCC)(=O)C.CCCCCCC>[CH3:1][NH:2][C:3](=[O:17])[O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([S:15]([CH3:16])=[O:20])=[CH:7][CH:6]=1
Reactant: CNC(=O)Oc1ccc(SC)c2c1CCCC2
Reactant: CC(=O)OO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1ccc(S(C)=O)c2c1CCCC2
Yield: 90 %

Procedure:
This compound was prepared in 90% yield by allowing a solution of 4-methylmercapto-5,6,7,8-tetrahydro-1-naphthyl N-methylcarbamate in ethyl acetate to slowly react at 35°-40° with one equivalent of peracetic acid in ethyl acetate. An ice bath was required to maintain the reaction temperature in the proper range. At the conclusion of the reaction, the solution was diluted with heptane and the resulting precipitate collected by filtration and washed thoroughly with heptane. After drying, the product melted at 135°-138°.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11]O)=[CH:8][C:7]=1[O:15][CH3:16]>ClCCl>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Cl:3])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CCO)ccc1O
Solvent: ClCCl
Product: COc1cc(CCCl)ccc1O
Temperature: 25 °C

Procedure:
Thionyl chloride (0.5 ml) was added, dropwise, to a! stirred solution of 4-hydroxy-3-methoxyphenethyl alcohol (0.83 g--commercially available) in dichloromethane (50 ml). When the addition was complete, the mixture was heated under reflux for 3 hours. On cooling to room temperature, the mixture was concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.36 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1.[O-:11][Mn](=O)(=O)=O.[K+:16]>CC(C)=O>[K+:16].[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(CO)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(C(=O)[O-])n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 127.7 %

Procedure:
To a solution of (4-bromo-6-methyl-pyridin-2-yl)-methanol (3.13 g, 15.5 mmol) in acetone (400 mL), KMnO4 (6.24 g, 39.5 mmol) is added portionwise. The resulting mixture is stirred at rt for 18 h before it is filtered over a glass-filter. The filter cake is washed with water and acetone and the filtrate is concentrated and dried under HV to give crude 4-bromo-6-methyl-pyridine-2-carboxylic acid potassium salt (5.03 g) as a white solid; 1H NMR (D2O): δ 2.47 (s, 3H), 7.58 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: OCCNCCO
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CCO)CCO

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and diethanolamine.