Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[CH3:18][O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105.6 %

Procedure:
To a solution of tert-butyl (R)-3-hydroxymethylpiperidine-1-carboxylate (11.50 g, 53.7 mmol) in N,N-dimethylformamide (110 ml) was added sodium hydride (3.22 g, 80.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added methyl iodide (4.35 ml, 69.9 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give tert-butyl (R)-3-methoxymethylpiperidine-1-carboxylate (13.00 g, yield 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]1[CH2:10][C@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1([CH2:17][N+:14]([O-:16])=[O:15])[CH2:7][C@@H:8]([CH3:12])[C@H:9]([CH3:11])[CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C=C1C[C@@H](C)[C@@H](C)C1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
The unsaturated ester (2) (1.384 g, 7.60 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 70° C. with nitromethane (0.82 mL, 15.2 mmol) and tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 11.4 mL, 11.4 mmol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with 2N HCl (30 mL) followed by brine (50 mL). The organic phase was collected, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 5:95) to give 0.837 g (45%) of a clear oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2].O1CCOCC1.[OH-].[Na+].Cl>O>[CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)OCC)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Temperature: 20 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 850 mg of ethyl 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate, 10 ml of dioxane, 40 ml of distilled water and 5.8 ml of 1N sodium hydroxide solution is stirred under a stream of argon at a temperature in the region of 20° C overnight. The reaction mixture is cooled to a temperature in the region of 0° C. and neutralized with 5.8 ml of 1N hydrochloric acid. The precipitate obtained is filtered, washed with distilled water a number of times and dried in an oven. 695 mg of 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid are obtained in the form of a brown solid melting above 300° C. (1H NMR spectrum in d6-DMSO, T=300 K, δ in ppm (300 MHz): 1.05 (3H, t, J=6 Hz, CH3), 3.10 (2H, m, NCH2), 3.47 (2H, s, CH2CO), 4.02 (2H, s, CH2), 7.30 (1H, d, J=8 Hz, arom. CH), 7.48 (1H, 8, arom. CH), 7.82 (1H, d, J=8 Hz, arom. CH), 8.08 (1H, t, J=5 Hz, NH), 8.52 (1H, s, imidazole H)).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:19][C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=3)[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[CH2:3][CH2:2]1.Br[C:28]1[S:32][C:31]([C@@:33]2([OH:45])[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[C:35]([CH3:44])([CH3:43])[CH2:34]2)=[N:30][CH:29]=1.O1CCOCC1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH:1]1([C:4]2[CH:9]=[C:8]([C:28]3[S:32][C:31]([C@@:33]4([OH:45])[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[C:35]([CH3:43])([CH3:44])[CH2:34]4)=[N:30][CH:29]=3)[CH:7]=[C:6]([NH:19][C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(Br)s2)CC1(C)C
Reactant: Cc1ccnc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cc(C3CC3)c2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(Nc4nccc(C)n4)cc(C4CC4)c3)s2)CC1(C)C
Yield: 49.1 %

Procedure:
A reaction mixture containing N-[3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylpyrimidin-2-amine (60 mg, 0.171 mmol), methyl(1S,4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (62.5 mg, 0.179 mmol), PdCl2(dppf)-CH2Cl2 adduct (27.9 mg, 0.034 mmol), 1,4-dioxane (1.2 mL), water (0.1 mL), and aqueous sodium bicarbonate solution (2 M, 0.171 mL, 0.342 mmol) was irradiated in the microwave for 15 minutes at 160° C. The reaction mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (25-50% ethyl acetate/hexanes) to afford methyl(1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (41.3 mg, 0.084 mmol, 49% yield) as an off-white, solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[N:5]=[C:4]([N:23]([CH3:25])[CH3:24])[N:3]=1.[OH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:22][O:21][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([N:23]([CH3:25])[CH3:24])[N:3]=[C:2]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:34])([F:35])[F:36])[N:7]=2)[CH:14]=[CH:13][C:12]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)C)n2)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(Nc2nc(Oc3ccccc3C(F)(F)F)nc(N(C)C)n2)ccc1-n1cnc(C)c1
Yield: 15.4 %

Procedure:
6-Chloro-N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′,N′-dimethyl-[1,3,5]triazine-2,4-diamine (200 mg, 0.56 mmol) in 7 ml acetonitrile was treated with 2-hydroxy-benzotrifluoride (95 mg, 0.59 mmol) and potassium carbonate (85 mg, 0.62 mmol). The resulting mixture was stirred under reflux for 5 days. The mixture was then diluted with 25 ml of water and extracted with ethyl acetate. Chromatography on silica gel using ethyl acetate as a solvent and subsequent crystallization from methanol gave the title compound as colorless solid (42 mg, 16%).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=O)[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].N1CCCCC1.C(O)(=O)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:33]([O:41][CH2:42][CH3:43])=[O:40])[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:31][CH:32]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of 1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.60 g), diethyl malonate (0.69 g), piperidine (0.12 ml), benzoic acid (0.09 g), and toluene (50 ml) was subjected to azeotropic dehydration for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). Sodium borohydride (105 mg) was added to a mixture of the obtained colorless oily substance, ethanol (20 ml), and tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain diethyl [1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (1.76 g, yield: 83%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]#[N:13])=[CH:5][NH:6]2.[H-].[Na+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>O1CCCC1>[CH3:16][N:17]([CH3:21])[C:18]([N:6]1[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:11][C:12]#[N:13])=[CH:5]1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: N#CCc1c[nH]c2cccc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1cc(CC#N)c2c(Cl)cccc21
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of (4-chloro-1H-indol-3-yl)-acetonitrile (200 mg, 1.05 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) at 0° C. was added sodium hydride (63 mg, 1.57 mmol, 60% dispersion in mineral oil). After 20 minutes at 0° C., the ice bath was removed and dimethyl carbamyl chloride (0.12 mL, 1.26 mmol) was slowly added. After one hour, the reaction was partitioned between ethyl acetate (100 mL) and saturated sodium chloride solution (2.5 mL). The ethyl acetate extract was dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. The resulting material was purified by flash column chromatography over silica gel eluting with 40% ethyl acetate in hexane to give 4-Chloro-3-cyanomethyl-indole-1-carboxylic acid dimethylamide as a white solid (239 mg, 87%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](O)=[O:21])=[O:17])=[CH:10]2>>[CH2:23]([CH:19]([NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17])[C:20](=[O:21])[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: C1CCNC1
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Pyrrolidine (0.35 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.31 mmol) were coupled according to procedure A (0-25° C. reaction temperature, 140 hour reaction time) and the crude product triturated with ether: Yield 89 mg, 71%; HPLC (70/30) 7.57 minutes (98%); PBMS 396/398 (MH+, 100/80%);
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6]C.N.CO.C(=O)=O.[Na].[Cl-].[NH4+].[C:20]1([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6][C:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN[C@@H](CCSC)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Agent: O=C=O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN[C@@H](CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
7.5 g (0.046 mol) of N-methyl-L-methionine is introduced, and 200 ml of ammonia is condensed while being cooled with MeOH/dry ice. At −35° C., 5.2 g (0.23 mol) of sodium is added in portions over one hour and stirred for two more hours. Then, 9.7 g (0.18 mol) of ammonium chloride is added in portions, the cooling is withdrawn, and the ammonia is driven off overnight with nitrogen. 14.0 g (0.054 mol) of triphenylmethanol is added. While being cooled with ice, 50 ml of dichloromethane and 90 ml of trifluoroacetic acid are then added. It is stirred for one hour at room temperature and evaporated to the dry state. The residue is suspended in 200 ml of water and brought to pH 13 with sodium hydroxide solution. After one more hour of stirring, it is suctioned off, and the solid is suspended in 500 ml of water. By adding citric acid, it is set at pH 4. 600 ml of MTBE is added and stirred for 30 minutes. It is suctioned off and washed twice with 100 ml each of MTBE. The residue is mixed with 100 ml of dichloromethane, 20 ml of ethanol is added, and then 500 ml of MTBE is added in drops. It is stirred for one more hour, suctioned off, washed with MTBE. After drying, 12.6 g (0.032 mol, 70% of theory) of a colorless solid is obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35](O)=[O:36])[C:29]=2[O:28][CH2:27][CH2:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:34]2[C:29]3[O:28][CH2:27][CH2:26][N:25]([CH3:24])[C:30]=3[CH:31]=[CH:32][CH:33]=2)=[O:36])=[O:10])[N:12]=1
Reactant: CN1CCOc2c(C(=O)O)cccc21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCN3C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=503.1.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=4)[C:12]3=[N:11][CH:10]=2)=[CH:5][C:4]=1[CH3:30].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][CH:25]=4)[C:12]3=[N:11][CH:10]=2)=[CH:5][C:4]=1[CH3:30]
Reactant: COc1ccc(-c2cnc3c(NCc4ccc(S(N)(=O)=O)cc4)nccn23)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cnc3c(NCc4ccc(S(N)(=O)=O)cc4)nccn23)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 4-{[3-(4-Methoxy-3-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide (0.167 g, 0.39 mmol) in dichloromethane (5 mL) at −78° C. was added boron tribromide (3.9 ml, 3.9 mmol, 1 M solution in dichloromethane). The reaction was allowed to warm gradually to ambient temperature then quenched with saturated aqueous sodium bicarbonate solution (30 mL). The reaction mixture was extracted with ethyl acetate (3×30 ml), the organic layers were combined and dried with magnesium sulphate, filtered and concentrated in vaccuo. The residue was taken up in DMSO and purified by prep HPLC. The product, 4-{[3-(4-Hydroxy-3-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide, is obtained as a white solid (25 mg, 16%) (LC-MS m/z 410 [M+H]+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH:31]1([NH2:34])[CH2:33][CH2:32]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:31]1([NH:34][C:2]2[CH:10]=[CH:9][C:8]3[N:7](/[CH:11]=[C:12](/[C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)\[CH3:13])[C:6]4[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=4[C:4]=3[CH:3]=2)[CH2:33][CH2:32]1
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Reactant: NC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: C/C(=C\n1c2c(c3cc(NC4CC4)ccc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C
Yield: 3.1 %

Procedure:
8-Chloro-2-methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.100 g, 0.245 mmol), sodium tertbutoxide (0.283 g, 2.948 mmol), palladium acetate (0.010 g, 0.049 mmol) and 2-di-tertbutylphosphino-2′-4′-6′-triisopropylbiphenyl (0.031 g, 0.0735 mmol) were charged in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Dry toluene (2 mL) was added under nitrogen atmosphere. Finally, cyclopropylamine (24.3 mg, 0.343 mmol) was added to the reaction mixture and the contents heated to 100° C. overnight. The reaction mixture was filtered and precipitate washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and purified by reverse phase chromatography to yield 2.74 mg of compound as the oxalate salt. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.60 (d, 2H), 7.82 (d, 2H), 7.44 (s, 1H), 7.10 (d, 1H), 7.04 (s, 1H), 6.90 (d, 1H), 4.60 (m, 2H), 3.70 (m, 2H), 3.18 (m, 2H), 3.10 (s, 3H), 2.50 (m, 1H), 2.05 (s, 3H), 0.78 (m, 2H), 0.58 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:32]=1)[C:18]1[CH:17]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)[C:15]([F:25])=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:26]#[C:27][C:28]([CH3:31])([OH:30])[CH3:29])=[CH:9][CH:10]=1>CO.[Pd]>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:32]=1)[C:18]1[CH:17]=[C:16]([C:19]3[CH:24]=[N:23][CH:22]=[N:21][CH:20]=3)[C:15]([F:25])=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([CH2:26][CH2:27][C:28]([CH3:29])([OH:30])[CH3:31])=[CH:9][CH:10]=1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)c(F)cc1O2
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)CCc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)c(F)cc1O2

Procedure:
A vial charged with (R)-4-(2-amino-3′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbut-3-yn-2-ol (0.050 g, 0.116 mmol) and 10% Pd/C (1.236 mg, 0.012 mmol) was taken up in 5 mL MeOH thoroughly degassed then placed under 50 psi H2 overnight. The reaction mixture was filtered through celite and concentrated in vacuo to provide an off white solid. Purification of the crude residue by column chromatography [0-80% (9:1:0.1—CH2Cl2:MeOH:NH4OH)/CH2Cl2] gave (R)-4-(2-amino-3′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbutan-2-ol. MS m/z=435.0 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[C:21]([CH3:22])=[C:20]([N:23]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[O:25])[N:19]3[N:40]=[CH:41][C:42]([C:43]([O:45]CC)=[O:44])=[C:18]3[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CC(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[C:21]([CH3:22])=[C:20]([N:23]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[C:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[CH:30][CH:31]=3)=[O:25])[N:19]3[N:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[C:18]3[N:17]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cnn2c(N(OC(C)(C)C)C(=O)c3ccc(OCC)cc3)c(C)c(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOc1ccc(C(=O)N(OC(C)(C)C)c2c(C)c(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c(C(=O)O)cnn23)cc1
Temperature: 50 °C
Reaction time: 40 h

Procedure:
To a stirred suspension of ethyl 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (5.55 g) in 2-propanol (136 mL) was added 2 mol/L aqueous NaOH (34 mL). The resulting mixture was stirred at 50° C. for 40 h, and then at 80° C. for 4 h. The mixture was acidified (pH 4) with 1 mol/L aqueous HCl and concentrated in vacuo. The residue was suspended in water (150 mL) and slowly stirred for 1 h. The precipitate was filtered and dried in vacuo to give the title compound (5.35 g, yield 78%) as a white solid. The 1H-NMR and ESI/MS data for this compound are shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:22][N:23]([CH3:33])[C:24]([C:26]1[CH:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][N:23]([CH3:33])[C:24]([C:26]1[CH:31]=[C:30]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH:29]=[CH:28][N:27]=1)=[O:25]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CN(C)C(=O)c1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Oc2ccc(N)c([N+](=O)[O-])c2)ccn1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture containing 4-amino-3-nitrophenol (1 eq) and potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added 4-Chloro-pyridine-2-carboxylic acid dimethylamide (1 eq) and potassium carbonate (1.2 eq) and then it was stirred at 90° C. for 3 days. The reaction mixture was then concentrated before partitioning between ethyl acetate and water. The organic layer was separated, washed with brine, dried, filtered and concentrated in vacuum to give brown solid. Purification by flash chromatography with ethyl acetate and hexane (1:1) gave the desired product as a yellow syrup. HPLC, 1.69 min; MS: MH+=303.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.Cl.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[CH:24])[C:18]1=[O:25]>>[O:25]=[C:18]1[C@@H:17]([NH:16][S:10]([C:8]2[S:7][C:6]3[CH:14]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:21][CH2:20][N:19]1[CH2:22][C:23]#[CH:24]
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: C#CCN1CC[C@H](N)C1=O
Agent: Cl
Product: C#CCN1CC[C@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)C1=O

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and 3-(S)-amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride as starting material. The crude product is isolated as a beige foam and used in the subsequent step without further purification.