Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[CH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[C:16][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C#CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccccn1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CC#Cc2ccccn2)CCN(C)C1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole[(p-tolylhydrazine hydrochloride (600 mg, 3.7 mmol), propargyl bromide (80 wt % solution in toluene, 0.34 mL, 3.7 mmol), triethyl amine (1.5 mL, 11.3 mmol) and N-methyl-4-piperidone hydrochloride (316 mg, 2.1 mmol) were taken in ethanol (15 mL) to obtain 80 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with MeOH-DCM gradient) (150 mg, 0.6 mmol)], 2-bromopyridine (0.06 mL, 0.6 mmol), dichlorobis(triphenylphosphine) palladium (8 mg, 0.012 mmol), CuI (1 mg, 0.006 mmol), and triethylamine (0.01 mL 0.071 mmol) in acetonitrile (5 mL) was heated at 80° C. for 1.5 h to obtain 108 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL). 1H NMR (DMSO-d6, TFA salt) δ (ppm): 8.45-8.40 (d, 1H), 7.80-7.70 (t, 1H), 7.45-7.40 (m, 1H), 7.30-7.25 (t, 1H), 7.25 (s, 2H), 7.10-7.00 (d, 1H), 5.60 (s, 2H), 4.60-4.55 (d, 1H), 4.25-4.20 (d, 2H), 3.85-3.75 (d, 1H), 3.65-3.40 (m, 2H), 3.00 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH3:21])=[O:13])(OCC)=O)C.[CH3:22][C:23]1[C:24]2[N:25]([N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH:32]=O)[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:22][C:23]1[C:24]2[N:25]([N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH:32]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH3:21])=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOP(=O)(CC(=O)N1CCCCC1CC)OCC
Reactant: Cc1cccn2nc(-c3ccccc3)c(C=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2cccc(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Sodium hydride (60%, 110 mg) was added to a solution of 1-(2-diethoxyphosphorylacetyl)-2-ethylpiperidine (0.80 g) in tetrahydrofuran (5 ml) at 7° C. under nitrogen atmosphere. A solution of 4-methyl-2-phenylpyrazolo-[1,5-a]pyridine-3-carbaldehyde (0.50 g) in tetrahydrofuran (5 ml) was added dropwise to the above solution at 10° C., and then stirred at room temperature for 1 hour. After evaporating the solvent, in vacuo saturated sodium chloride aqueous solution (20 ml) was added to the residue and extracted with ethyl acetate (20 ml×2). Combined extracts were washed with saturated sodium chloride aqueous solution (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(4-methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine (trans isomer) (788 mg) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH2:7])([O-:3])=[O:2].[Br:15]Br>CC(O)=O>[Br:15][C:8]1[CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[NH2:7]
Reactant: BrBr
Reactant: Nc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: Nc1cc([N+](=O)[O-])c(C(F)(F)F)cc1Br
Temperature: 20 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a solution of 3-nitro-4-(trifluoromethyl)aniline (31.0 g, 150.4 mmol) in HOAc (200 mL) was added bromine (9.3 mL, 180.5 mmol) at 0° C. under an atmosphere of N2. The cooling bath was removed and the mixture was stirred at 20° C. for 1 h. The solvent was removed in vacuo to afford the crude product 2-bromo-5-nitro-4-(trifluoromethyl)aniline (40.0 g, 93%), which was used directly in the next step.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:5]=12.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:33]=[C:32]([CH:34]3[CH2:36][CH2:35]3)[NH:31][N:30]=2)[CH:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(C(O)C(C)C)C>[CH:34]1([C:32]2[NH:31][N:30]=[C:29]([NH:28][C:26]3[CH:25]=[CH:24][N:23]=[C:22]([N:2]([CH3:1])[CH2:3][C:4]4[CH:9]=[N:8][CH:7]=[C:6]5[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:5]=45)[N:27]=3)[CH:33]=2)[CH2:36][CH2:35]1
Reactant: CNCc1cncc2c1ccn2COCC[Si](C)(C)C
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cncc2c1ccn2COCC[Si](C)(C)C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 140 °C
Yield: 57.9 %

Procedure:
A mixture of N-methyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine (110 mg, 0.38 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (107 mg, 0.454 mmol), DIPEA (146 mg, 1.134 mmol) in 2,4-dimethylpentan-3-ol (2.0 mL) in a sealed tube was heated at 140° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with DCM/MeOH (10:1) to afford 108 mg of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methyl-N2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methyl)pyrimidine-2,4-diamine as a yellow solid. MS (ESI): m/z=491.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][CH2:29]O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.[ClH:31]>>[Cl:31][CH2:29][CH2:28][CH2:27][NH:26][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5]([OH:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:25]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCCO)c2n1
Reactant: Cl
Product: O=C(NCCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Temperature: 85 °C
Yield: 106 %

Procedure:
A mixture of (R)-5-(2-(5-fluoro-2-methoxy pyridin-3-yl)pyrrolidin-1-yl)-N-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.0483 mmol) in HCl (4 N dioxane, 1.2 mL, 4.83 mmol) was heated at 85° C. overnight. The reaction mixture was concentrated, triturated with ether, and filtered, to provide the crude product as a beige solid, which was directly used in the next step without further purification (22 mg, 106% yield). MS (apci) m/z=419.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12](=O)N(C)C)=[C:7]([Cl:17])[CH:6]=1.C[O-].[Na+].BrC[CH2:24][CH2:25][O:26][C:27]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]2[C:30]([C:31]([CH2:41][CH3:42])=[CH:32][C:33](=[O:40])[O:34]2)=[CH:29][CH:28]=1>CO>[Cl:17][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[CH:10]=[CH:9][C:8]=1[S:11][CH2:12][CH2:24][CH2:25][O:26][C:27]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]2[C:30]([C:31]([CH2:41][CH3:42])=[CH:32][C:33](=[O:40])[O:34]2)=[CH:29][CH:28]=1
Reactant: CCCc1c(OCCCBr)ccc2c(CC)cc(=O)oc12
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2c(CC)cc(=O)oc12
Temperature: 70 °C

Procedure:
To a solution of 3-chloro-4-dimethylcarbamoylthiophenylacetic acid methyl ester (129 mg, 0.3991 mmol) in 0.75 mL methanol was added a 0.5M solution of sodium methoxide in methanol. This mixture was heated to 70° C. for 90 minutes. After cooling to ambient temperature, a solution of 7-(3-bromopropoxy)-4-ethyl-8-propylcoumarin (Step D) in 1.2 mL methanol was added dropwise. The mixture was heated to 70° C. for 16 hours. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic mixture was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][N:15]3[CH3:18])=[CH:11][C:10]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=2[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.C([O-])=O.[NH4+]>[Pd].CCOC(C)=O>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[NH:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:15]([CH3:18])[N:14]=[CH:13]3)=[C:21]([F:29])[CH:22]=1
Reactant: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cc3F)c(N=C(c3ccccc3)c3ccccc3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1ncc2cc(Oc3ccc(N)cc3F)c(NC(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a 100 mL round bottom flask is added N-(diphenylmethylene)-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-amine (424 mg, 909 μmol) and EtOH (35 mL, 601 mmol). To the mixture is added ammonium formate (1000 mg, 15.9 mmol) followed by the addition of 10% Pd/C (300 mg, 141 μmol) and the reaction mixture is stirred at RT for 1 hour and heated at 45° C. for 15 min. The solvent is removed and the residue is dissolved in DCM (150 mL) and distilled water (100 mL). The organic layer is washed with distilled water (1 x 100 mL), and the combined aqueous layers are extracted with DCM (1 x 50 mL). The combined organic solution is dried with Na2SO4, filtered, and concentrated. The crude is purified on a silica gel column eluting with hexanes (A) and EtOAc (B), gradient from 90% (A)10% (B) to 40% (A):60% (B) over 90 min to give an off-white solid material as the title compound (204 mg, 51% yield). MS (m/z): 438.8 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:21]2[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(C)cc(=O)n(CCN3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 5 mL of chloroform, (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde was dissolved, thereto were added 135 mg of tert-butyl piperazine-1-carboxylate and 43.6 mg of acetic acid, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 231 mg of sodium triacetoxyborohydride, and stirred for 1 hour. Thereto was added an aqueous saturated sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60N manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate] to obtain 173 mg of a yellow oily substance, tert-butyl 4-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1([C:15](O)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[CH2:43]([O:50][C:51](=[O:57])[C@@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:43]([O:50][C:51](=[O:57])[C@@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[C:15]([C:2]1([OH:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 9-hydroxy-9-fluorene carboxylic acid (5.04 g, 22.3 mmol) in N,N-dimethylformamide (30 mL), cooled to 0° C. under nitrogen, was added (O-7-azabenzotriazol-1-y)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), (9.32 g, 24.5 mmol), L-proline-benzyl ester hydrochloride (5.93 g, 24.5 mmol), and N,N-diisopropylethylamine (8.5 mL, 48.8 mmol). The mixture was stirred at 0° C. for 3 hours, then concentrated and purified on silica gel (ethyl acetate-hexane, 1:2) to give 9-hydroxy-9-fluorenylcarbonyl-L-proline benzyl ester. HPLC=96%, R.T.=3.7 min; Mass spec.(electrospray) M+1=414.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[CH2:21][O:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1cccc(CCCCc2ccccc2O)c1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(CCCCc2ccccc2OCC2CO2)c1
Yield: 78.1 %

Procedure:
Following a procedure similar to that described in Example 1(a), 1.90 g of 2-[4-(3-methylphenyl)butyl]phenol (prepared as described in Preparation 10), 0.89 g of potassium t-butoxide and 1.08 g of epibromohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 1.83 g (yield 78%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.N.O.[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH2:21])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)c1
Reaction time: 6 h

Procedure:
A suspension of (4′-cyano-biphenyl-3-yl)-carbamic acid tert-butyl ester (7.6 g, 26 mmol) and Raney Ni (1 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under 50 psi of H2 at 50° C. for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give (4′-aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester, which was used directly in next step.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]1)=[O:16])=O)(C)(C)C.[F:38][C:39]1[C:44]([O:45][CH2:46][CH3:47])=[CH:43][CH:42]=[C:41]([F:48])[C:40]=1B(O)O.C(O)(C(F)(F)F)=O>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(#N)C>[NH2:8][C:9]1[S:13][C:12]([C:40]2[C:41]([F:48])=[CH:42][CH:43]=[C:44]([O:45][CH2:46][CH3:47])[C:39]=2[F:38])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CCOc1ccc(F)c(B(O)O)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(F)c(-c2nc(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
A septum sealed microwave tube was charged with (S)-tert-butyl 1-(3-(5-(tert-butoxycarbonylamino)-2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (50 mg, 0.084 mmol), 2,6-difluoro-3-ethoxyphenyl-boronic acid (169 mg, 0.84 mmol), Pd(dppf)Cl2 (13.6 mg, 0.016 mmol) 1M Na2CO3 (0.6 mL, 14.1 mmol) and acetonitrile (3 mL). The mixture was irradiated for 30 min at 120 C. Upon completion of the reaction, the solvent was distilled off and the crude material was dissolved in CH2Cl2 (5 mL) and transferred to a scintillation vial. TFA (0.77 g, 6.7 mmol) was added and the mixture was stirred at room temperature for 30 min. The solvent was distilled off and the crude product was purified via reverse phase HPLC 40% to 80% MeOH in water with 0.1% NH4OH to afford (S)-5-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-2-(3-ethoxy-2,6-difluorophenyl)thiazole-4-carboxamide as a white solid (4.8 mg, 12%). 1H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 8.27-8.16 (m, 1H), 7.66 (s, 2H), 7.28 (td, J=9.2, 5.1, 1H), 7.23-7.09 (m, 2H), 4.15 (q, J=7.0, 2H), 3.06 (dd, J=41.9, 10.8, 5H), 2.65 (dd, J=15.7, 5.1, 1H), 1.89 (d, J=10.1, 1H), 1.82-1.67 (m, 2H), 1.36 (t, J=7.0, 3H). ESIMS m/z=475.1 (M+1).
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=C)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:43].[Na+]>CC(C)=O.O>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=[O:43])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1C=O)O2
Reaction time: 2 h

Procedure:
To a solution of the product from Step 1 (30 mg, 0.053 mmol) in acetone (1 ml) and water (1 mL) was added potassium osmate dehydrate (19.61 mg, 0.053 mmol). The reaction was stirred at room temperature for 10 minutes after which sodium periodate (114 mg, 0.532 mmol) was added. After stirring for 2 hours, an additional 15 mg of potassium osmate and 115 mg of sodium periodate were added. After stirring 16 hours, the reaction was filtered and the solid was washed with acetone. The filtrate was concentrated, diluted with EtOAc and washed with Na2S2O3 and NaHCO3 aq. soln. Purification by PTLC (30% EtOAc-hexane) provided the desired aldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:22])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1COCC1.[Cl:33][Si:34](Cl)([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:22])[CH:8]2[Si:34]([Cl:33])([CH3:36])[CH3:35])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)=C2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 16.2 g (55.4 mmol) of 5-tert-butyl-6-methoxy-2-methyl-7-phenyl-1H-indene in 300 ml of toluene, 22.2 ml (55.5 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 2 h, and then 15 ml of THF was added. The formed suspension was stirred for 12 h at room temperature, ca. 2 h at 60° C., then cooled to −20° C., and 35.8 g (277 mmol) of dichlorodimethylsilane was added in one portion. The resulting solution was warmed to 60° C. and stirred for 1 h at this temperature. The resulting mixture was evaporated to ca. ½ of its volume, then filtered through glass frit (G3). The precipitate was additionally washed by 20 ml of toluene. The combined filtrate was evaporated to dryness to give 21.2 g (99%) of viscous yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([I:11])[N:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[I:11])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Nc1nc(I)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(I)nc(N)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a solution of 2-amino-6-iodo-purine (78.3 g, 0.3 mol) in DMF (1960 mL) was added ethyl bromoacetate (55.1 g, 0.33 mol) and potassium carbonate (82.9 g, 0.6 mol). The resulting reaction mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated to small volume (about 150 mL) in vacuo and the residue was dissolved in water. The solid was filtered off, washed with water and ethyl ether, and dried in vacuo to give the titled compound (98.4 g, 95%). 1H-NMR (50 MHz; DMSO-d6) δ 8.06 (s, 1H), 6.90 (br.s, 2H), 4.94 (s, 2H), 4.17 (q, 2H), 1.22 (t, 3H).
Reaction SMILES: Br[C:2]1[O:6][C:5]2[C:7](=[O:16])[C:8]3[C:13]([C:14](=[O:15])[C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(S)[CH2:18][S:19]([O-])(=O)=O.[Na+]>O1CCCC1.O>[CH3:18][S:19][C:2]1[O:6][C:5]2[C:7](=[O:16])[C:8]3[C:13]([C:14](=[O:15])[C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=S(=O)([O-])CCS
Reactant: O=C1c2ccccc2C(=O)c2oc(Br)cc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc2c(o1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To the solution of 0.7 gram (2.5 mmoles) of 2-bromo-naphtho[2,3-b]furan-4,9-dione in 20 mL of tetrahydrofuran at room temperature, 0.4 grams (5.0 mmoles) of MeSNa in 5 mL of water was added dropwise over 1 minute. The mixture was further stirred for 2 hours at room temperature, and then evaporated to remove tetrahydrofuran. To the residue, 20 mL of 1N hydrochloric acid was added, and the resulting mixture was filtered. The solid was washed with water, and then crystallized in ethanol/water. Pure crystal product was filtered and dried under vacuum. 0.55 grams of product (yield 90%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in CDCl3) δ 2.66 (s, 3H), 6.79 (s, 1H), 7.75-7.79 (m, 2H), 8.18-8.25 (m, 2H). Mass (M+H) is 245.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:10]([N+:24]([O-:26])=[O:25])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
In 13 ml of acetic anhydride was suspended 5.0 g of 3,4-diethoxycarbonyl-6-phenyl-2-pyridone; and the suspension was cooled to -10° C. Fuming nitric acid (1.32 ml; 2.0 eq.) was added dropwise over 1 hour, and the mixture was stirred for 45 minutes as it is. After 40 ml of water was added, the mixture was stirred at room temperature and left standing overnight. The resulting crystals were collected by filtration and dried. Yield: 4.61 g (80.7%). The crystals were recrystallized from ethanol, to give pale yellow needles.