Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[S:13](=[O:16])(=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:21])CCC>O1CCCC1.CCCCCC>[Li:21][C:1]1[C:14]2[S:13](=[O:15])(=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: O=S1(=O)c2ccccc2Oc2ccccc21
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]c1cccc2c1S(=O)(=O)c1ccccc1O2
Temperature: -40 °C

Procedure:
A mixture of phenoxathiin 10,10-dioxide (50.5 g) in dry tetrahydrofuran (500 mL) under nitrogen was cooled in an acetone/dry ice bath. To this slurry was added a 1.6 M solution of n-butyllithium in hexane (144 mL) at a rate which maintained the reaction temperature at -40° C., resulting after 30-45 min. in an orange solution of 1-lithiophenoxathiin 10,10-dioxide. To this solution was added ethyl iodide (35 mL), after which the reaction mixture was allowed to warm to room temperature. After about 3-4 hr the yellow solution was partially evaporated under reduced pressure and was then partitioned between methylene chloride and water. The methylene chloride phase was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to a yellow residue which was purified by column chromatography on Silica Gel 60 (E. Merck, Darmstadt, Germany) eluting with toluene. The desired fractions were combined and evaporated, and the residue was crystallized from ethyl acetate/pentane to give 1-ethylphenoxathiin 10,10-dioxide, mp. 112°-114° C. (del. 102°-104° C.).
Reaction SMILES: [CH3:1][NH2:2].CO.CO.Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C>[CH3:1][NH:2][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CN
Solvent: CO
Solvent: CCN(CC)CC
Product: CNCc1cccc2ccccc12
Temperature: 0 °C
Yield: 91.9 %

Procedure:
1.14 g (11.3 mmol), of triethylamine was mixed with a 40% methylamine-methanol solution and 5 ml of the methanol containing 2.00 g (11.3 mmol), of 1-chloromethylnaphthalene was dropped while stirring in an ice bath. After dropping, the reaction mixture was taken out of the ice bath and stirred at room temperature for 60 hours. The solvent was distilled off under reduced pressure and extracted with ether-2N hydrochloric acid. The organic extract was washed with saturated saline and dried with sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 1.78 g (yield: 91.9%), of the target compound as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.CN(C)C=O.C(NC(C)C)(C)C.[CH:35]([NH:38][CH2:39][CH2:40][OH:41])([CH3:37])[CH3:36]>>[OH:41][CH2:40][CH2:39][N:38]([CH:35]([CH3:37])[CH3:36])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: CC(C)NCCO
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Temperature: 50 °C
Yield: 15.1 %

Procedure:
To a solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (363.8 mg, 1.161 mmol) in N,N-dimethylformamide (39-60 equiv.) and N,N-Diisopropylamine (1.5 equiv.) was added 2-(isopropylamino)ethanol (133.1 mg, 1.29 mmol) followed by the addition of N,N,N′N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (1.1 equiv.). The reaction mixture was heated at 50° C. for 2 hrs to 24 hours depending on when complete by LCMS. Reaction mixture was concentrated on the genevac and purified by HPLC or diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated in vacuo prior to purification by HPLC to give 103 (70 mg, 15% yield, M+1 399.1)
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH3:22])[CH:8]([CH3:21])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:20])=[N:12]1.Br.Br[CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH3:22][N:7]([CH3:6])[CH:8]([CH3:21])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[N:12]1
Reactant: CCN(CC)CCCBr
Reactant: CC(CCn1nc(N)c2ccccc21)N(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1nn(CCC(C)N(C)C)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.4 %

Procedure:
To 60 ml of anhydrous N, N-dimethylformamide were added 7.50 g of the 1-(3-dimethylaminobutyl)-3-aminoindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 6.18 g of 1-(3-dimethylaminobutyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 52%.
Reaction SMILES: [C:1]12([CH2:11][N:12]3[C:21]4[C:16](=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=4)[CH:15]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:14][C:13]3=[O:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mn]([O-])(=O)(=O)=O.[K+].C(O)=O>O1CCOCC1.O>[C:1]12([CH2:11][N:12]3[C:21]4[C:16](=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=4)[C:15]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:14][C:13]3=[O:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C1NC(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1CC12CC3CC(CC(C3)C1)C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Solvent: C1COCCO1
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.8 g of 1-(1-adamantylmethyl)-4-phenyl-6-nitro-3,4-dihydro-2(1H)-quinazolinone in 70 ml of dioxane was added a suspension of 1.5 g of potassium permanganate in 10 ml of water and the mixture was stirred at room temperature for 3 hours. Then, 7 ml of formic acid was added and stirring was continued for 30 minutes. The brown precipitate was filtered off and the filtrate was diluted with water. The resulting mixture was extracted with chloroform. The chloroform extract was washed, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from a mixture of ethanol and chloroform to give 1-(1-adamantylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 228°- 231°C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+].O>C(O)(C)C.C1COCC1>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([C:25]([CH3:27])([CH3:26])[C:28]#[N:29])=[CH:23][CH:24]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(C)(C)C#N)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C#N)cn2)c1=O
Yield: 16.8 %

Procedure:
A mixture of 156e (191 mg, 0.30 mmol) and lithium hydroxide.1water (126 mg, 3.0 mmol) in i-propanol/THF (1:1, 8 mL) and water (2 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated under reduced pressure and diluted with water (10 mL). It was then extracted with dichloromethane (3×20 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 156 (30 mg, 17%) as a pale yellow solid. MS-ESI: [M+H]+ 594.3. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.59 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.91 (s, 1H), 7.79-7.74 (m, 2H), 7.57-7.53 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 4.92 (bs, 1H), 4.43 (s, 2H), 3.62 (s, 3H), 1.67 (s, 6H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](OC(C)(C)C)=O.ClC1[N:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:24]=1[C:25]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:26]>>[Cl:45][C:42]1[CH:43]=[N:44][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[CH2:6][O:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=2)=[C:24]([CH:41]=1)[C:25]([NH:27][C:28]1([C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc(F)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC[C@H]3COc3cccc(F)c3)CC2)cc1
Yield: 100.5 %

Procedure:
The title compound (D202) (89 mg) was prepared according to the experimental procedure described in Description 160 starting from (S)-tert-butyl 2-((3-fluorophenoxy)methyl)pyrrolidine-1-carboxylate (D44) (100 mg, 0.338 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (61.8 mg, 0.169 mmol).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cc1ccc(C2CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
Methyl 2-(4-cyclopropylphenyl)acetate (3.10 g, 16.30 mmol) was dissolved in a mixture of THF/MeOH/water (2:2:1, 80 mL), and the solution was treated with lithium hydroxide hydrate (0.8548 g, 20.37 mmol). The mixture was then stirred at ambient temperature for 4 hours. The reaction mixture was neutralized to a pH of 4 with 3N HCl and concentrated in vacuo. The solids were re-dissolved in ethyl acetate and water. The pH was re-adjusted to a pH of about 3 to about 4 with 3N HCl. The layers were then separated. The aqueous layer was washed with ethyl acetate (2×). The combined organic layers were then washed with saturated NaCl, dried over Na2SO4 and concentrated to yield 2-(4-cyclopropylphenyl)acetic acid (2.82 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 7.16 (d, J=8.2, 2H), 7.03 (d, 2H), 3.60 (s, 2H), 1.92-1.83 (m, 1H), 098-0.91 (m, 2H), 0.70-0.64 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:29]1[C:24]([Cl:23])=[N:25][CH:26]=[CH:27][C:28]=1[C:31]([F:34])([F:33])[F:32]
Reactant: Oc1cc(Cl)cc(Br)c1
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reaction time: 1 h

Procedure:
To a round bottom flask charged with 3-bromo-5-chlorophenol (5.20 g, 25.1 mmol) and potassium carbonate (3.46 g, 25.1 mmol) was added N-methylpyrrolidinone (25 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (5.00 g, 25.1 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 60 minutes, the reaction mixture was allowed to cool to room temperature at which point, water (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic fractions were washed with brine (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 330 gram column, eluting with 0-75% CH2Cl2 in hexanes to yield the title compound. 1H NMR (CDCl3) δ 8.53 (d, J=5.0 Hz, 1H), 7.62 (d, J=5.0 Hz, 1H), 7.29-7.27 (m, 1H), 6.87-6.84 (m, 1H), 6.76-6.73 (m, 1H). FIRMS (M+1)=385.8957.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH2:24][C@@H:25]([C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([Br:42])[CH:36]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:24][C@@H:25]([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([Br:42])[CH:36]=3)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)c1cc(F)cc(Br)c1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (35 mg, 0.110 mmol) in DMF (368 μl) was added (S)-tert-butyl (2-amino-2-(3-bromo-5-fluorophenyl)ethyl)carbamate (40.8 mg, 0.110 mmol), aza-HOBt (22.52 mg, 0.165 mmol). EDC (31.7 mg, 0.165 mmol), and DIEA (57.8 μl, 0.331 mmol). The reaction mixture was stirred at room temperature for 3 h, and then partitioned between EtOAc and water. The organic was washed by NaHCO3, water and brine, dried over Na2SO4 and concentrated. The crude (S)-tert-butyl (2-(4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-bromo-5-fluorophenyl)ethyl)carbamate was used in next step reaction without further purification. LCMS (m/z): 632.1/634.1 (MH+), 0.97 min.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:25])[CH2:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:26]([O:28]C)=[O:27].[I-].[Li+].Cl>N1C=CC=CC=1.O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:25])[CH2:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(CCC1CCCC1)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
A mixture of methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (5.72 g) and anhydrous lithium iodide (14.3 g) in dry pyridine (59 ml) was stirred at 120° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a crystalline residue, which was suspended in water (100 ml). The suspension was adjusted to pH 1.7 with conc. hydrochloric acid to yield yellow crystals, which were separated by filtration, washed with water and dried. Recrystallization from N,N-dimethylformamide gave crystalline 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (4.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CC1(C)CNCC[C@@]1(O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)N1CC[C@@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 94.1 %

Procedure:
A solution of (R)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (1.96 g, 8.18 mmol) in Pyridine (20 mL) was cooled to 0° C., then treated with the dropwise addition of ethyl chloroformate (0.942 mL, 9.81 mmol), causing a color change to orange. The mixture was allowed to come to room temperature and stirred over night. The reaction was concentrated in-vacuo, and the residue was taken up in ethyl acetate, washed 3× with 1M NaOH, 3× with 1M HCl, once with brine, dried over sodium sulfate, and concentrated in-vacuo to yield the title compound (2.4 g, 7.70 mmol, 94% yield). The residue was used as-is in the next step. MS (ESI+)=334, (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:33][CH2:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>O1CCOCC1.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([CH2:34][OH:33])[CH:40]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Temperature: 160 °C
Yield: 45.8 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20.0 mg, 0.048 mmol), K3PO4 (21.0 mg, 0.096 mmol) and [3-(hydroxymethyl)phenyl]boronic acid (30.0 mg, 0.193 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (9.7 mg, 46%).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[O:25]1[CH:29]=[C:28]([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[N:27]=[CH:26]1>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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:33]#[C:32][C:30]([C:28]4[N:27]=[CH:26][O:25][CH:29]=4)([OH:34])[CH3:31])[CH:10]=3)[C:6]([CH3:18])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Reactant: C#CC(C)(O)c1cocn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3cocn3)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a vial was added 4-(6-iodo-3-methylindazol-1-yl)pyrimidin-2-amine (150 mg, 0.43 mmol), piperidine (1.5 mL), tetrakis(triphenylphosphine)palladium (49.36 mg, 0.04 mmol), copper(I) iodide (8.14 mg, 0.04 mmol) and 2-(1,3-oxazol-4-yl)but-3-yn-2-ol (87.87 mg, 0.64 mmol). The mixture was stirred at RT for 20 mins. Reaction mixture was concentrated in vacuo. DCM (5 mL) added and mixture was concentrated in vacuo. This was repeated twice. The crude material was purified by column chromatography (Biotage, 98:2 to 88:12 DCM: methanol gradient). Further purification by flash column chromatography gave the title compound: 1H (500 MHz, DMSO) delta 1.81 (3H, s), 2.58 (3H, s), 6.26 (1H, s), 6.99 (2H, s), 7.04 (1H, d, J=5.5 Hz), 7.39 (1H, dd, J=8.2, 1.1 Hz), 7.85 (1H, d, J=8.1 Hz), 8.13 (1H, s), 8.26 (1H, d, J=5.5 Hz), 8.36 (1H, s), 8.87 (1H, s); LC-MS: m/z=+361.05 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].C(N(CC)CC)C.[CH3:21][N:22]1[C:26](=[O:27])[CH2:25][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:23]1>C(O)C>[NH2:12][C:11]1[O:27][C:26]2[N:22]([CH3:21])[N:23]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:25]=2[CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:9]#[N:13]
Reactant: O=Cc1ccccc1
Reactant: N#CCC#N
Reactant: CN1N=C(c2ccccc2)CC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1nc(-c2ccccc2)c2c1OC(N)=C(C#N)C2c1ccccc1
Reaction time: 0.02 h
Yield: 299 %

Procedure:
A mixture consisting of benzaldehyde (290 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 1-methyl-3-phenyl-1H-pyrazol-5(4H)-one (500 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 21 h and washed with ethanol and hexanes; re-crystallized from ethanol, and washed with hexanes and ethanol to give 6-amino-1-methyl-3,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (282 mg, 8.58 mmol, 30%) as a white solid. 1H-NMR (400 MHz) DMSO: 7.41-7.38 (m, 2H), 7.28-7.24 (m, 2H), 7.21-7.18 (m, 6H), 4.88 (s, 1H), 4.77 (s, 2 H), 3.83 (s, 3H), 13C-NMR (100 MHz) DMSO: 158.1, 146.0, 144.8, 144.6, 133.2, 128.7, 128.5, 127.9, 127.8, 127.1, 126.4, 120.5, 95.7, 59.9, 38.2, 34.5; LC/MS-MS: 329.1-263.1 m/z; GS1 and GS2 at 30, DP=71, CE=31, CXP=18, tR=4.00 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([OH:22])=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH:16]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:30])([F:29])[S:25](O)(=[O:27])=[O:26].N1C=CC=CC=1>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:15]([CH:16]=[O:17])[C:14]=1[O:22][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)c(O)c1OCCCOCc1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1OCCCOCc1ccccc1

Procedure:
Synthesized according to the methods of general procedure 6 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-Benzyloxy-propoxy)-2-hydroxy-4-methyl-benzaldehyde (0.3 g, 1.0 mmol), trifluoromethanesulfonic acid (0.34 mL, 2.0 mmol), pyridine (0.25 mL, 3.1 mmol), dichloromethane (15 mL). Purification: flash column chromatography (10-15% EtOAc/hexane): yield 0.25 g (59%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.14 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.42-7.29 (m, 6H), 4.53 (s, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.71 (t, J=6.1 Hz, 2H), 2.40 (s, 3H), 2.07-2.22 (m, 2H). 19F NMR (400 MHz, CDCl3) δ (ppm): −73.63 (s).