Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 3-(trifluoromethyl)-phenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C=CC(=O)O)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
3-methoxy-4-hydroxy-cinnamic acid (8 g, 41.2 mmol) and imidazole (8.4 g, 123.6 mmol) were charged in a 500 mL round-bottom flask and dissolved in 30 mL of dimethylformamide. Tert-butyldimethylsilyl chloride (13.04 g, 86.5 mmol) was added thereto at 0° C., followed by stirring for 30 minutes. The reaction liquid was concentrated by distillation under reduced pressure and dichloromethane (200 mL) was added thereto, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated and dissolved in tetrahydrofuran (180 mL)/methanol (500 mL), and a 0.00035M potassium carbonate aqueous solution (175 mL) was added thereto, followed by stirring for 1 hour. After being concentrated by distillation under reduced pressure, the resulting solid was filtered, washed with water, and dried under vacuum to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13](CNC2N=C(C3C=NC=CN=3)C=CN=2)=[CH:12][CH:11]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43]C3C=CC(C(O)=O)=CC=3)[N:38]=2)[CH:32]=1>>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:13]3[CH:12]=[CH:11][C:10]([C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH2:1])=[O:30])=[CH:15][CH:14]=3)[N:38]=2)[CH:32]=1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Product: Nc1ccccc1NC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
Title compound was obtained in 54% yield according to the procedure described for the synthesis of compound 26a (scheme 6, step 4) replacing acid 25a by the acid 343. Characterization of the title compound is provided in the Table 12.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:6][CH:5]=1>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][C:11]([OH:1])=[O:12])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: O=CCCc1ccc(Cl)s1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Silver nitrate (117 mg, 0.69 mmol) in 1 mL of H2O is added to 1.36 mL of 1N NaOH at 0° C. and stirred for 5 minutes. To the brown suspension is added 3-(5-chloro-thiophen-2-yl)-propionaldehyde (60 mg, 0.34 mmol) and the resulting mixture is allowed to warm to room temperature over 2 hours. The precipitate is filtered and washed with hot water (2×). The combined aqueous layers are acidified with 6 N HCl and extracted with EtOAc (2×). The combined organic layers are washed with water (2×), then dried over MgSO4, filtered and concentrated in vacuo to give the title compound (50 mg, 0.26 mmol) as a beige solid. The crude material can be used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ6.72 (d, 1H), 6.60 (d, 1H), 3.07 (t, 2H), 2.71 (t, 2H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=O.Cl.[NH2:24][OH:25].[OH-].[Na+].O>CO>[N:24](=[C:14]1[CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]34[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]2[CH2:20][C:7]2[CH:8]=[CH:9][C:10]([OH:22])=[C:11]([O:12][C@@H:13]13)[C:6]4=2)[OH:25]
Reactant: NO
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=NO)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of oxymorphone (1.2 g, 4 mmol) and hydroxylamine hydrochloride (0.35 g, 5 mmol) in 20 mL of methanol was treated with 2 mL of 10% aqueous NaOH and stirred at room temperature for 15 h. The reaction mixture was poured into water and extracted with 150 mL CHCl3 (3×50 mL). The CHCl3 extract was dried (MgSO4), and evaporated. The residue was recrystallized from THF-petroleum ether yielding 600 mg (47.4%), mp 270°-71° C. IR: (KBr): No C=O absorption at 1720 cm-1. H NMR (d6DMSO) δ 4.83 (s, C5H), Rf: silica gel EtOAc-EtOH-NH4OH (100:1:1) 0.18. Anal. Calcd for C17H20N2O4C, 64.54; H, 6.37; N, 8.86. Found C, 64.76; H, 6.5; N, 8.58.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])=[N:8][CH:9]=1)[CH3:24]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ccc(C(=O)O)cn1
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)nc1
Yield: 68 %

Procedure:
In a manner identical to Example 15, 6-prenyloxynicotinic acid (0.70 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.90 g, thereby yielding 0.73 g (68%) of the aimed compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH3:12])[N:6]=[CH:5]2.C([Li])CCC.CON(C)[C:21]([C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][N:24]=1)=[O:22].C(=O)([O-])O.[Na+]>C1COCC1>[Cl:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]([C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=2)[N:7]([CH3:12])[N:6]=[CH:5]3)=[O:22])[CH:28]=1
Reactant: CON(C)C(=O)c1cc(Cl)ncn1
Reactant: Cc1cc(Br)cc2cnn(C)c12
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(C)c12
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 0.450 g (2.00 mmol) 5-bromo-1,7-dimethyl-1H-indazole in 25 mL THF were cooled to −75° C., combined with 1.40 mL (2.24 mmol) of a 1.6 molar n-butyllithium solution and stirred for 1 h at −75° C. Then 0.480 g (2.14 mmol) 6-chloro-pyrimidine-4-carboxylic acid methoxy-methyl-amide were added dropwise. The mixture was brought to 0° C. and stirred for a further hour. Then saturated sodium hydrogen carbonate solution was stirred in, the mixture was extracted with EtOAc, the organic phase was dried and evaporated down i. vac. The residue was triturated with DIPE, suction filtered and dried. The precipitate was purified by flash chromatography (Alox).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1Cl
Reactant: CNC
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-Chloro-3-nitrobenzenesulfonyl chloride (235 mg, 0.918 mmol) was treated with a 2 M solution of dimethylamine in methanol (0.55 mL, 1.10 mmol), and triethylamine (0.13 mL, 0.918 mmol) in methanol (1 mL), and the suspension was stirred at room temperature for 2.5 h. The volatiles were removed in vacuo, and the residue was purified by column chromatography using heptane/ethyl acetate, 70:30-50:50 as an eluent, affording 2-chloro-N,N-dimethyl-3-nitrobenzenesulfonamide, 202 mg (83%) as a white solid. MS (ESI) m/z 265 [M+H]. 1H NMR (400 MHz, CDCl3) δ ppm 2.95 (s, 6 H); 7.56 (t, J=8.0 Hz, 1H), 7.88 (dd, J=8.1, 1.5 Hz, 1H), 8.31 (dd, J=8.1, 1.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]([CH3:29])=[C:2]([C:35]4[CH:36]=[N:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: COc1ccc(B(O)O)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cn1
Yield: 48 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (6-methoxypyridin-3-yl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 48%. Melting point: 120-123° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22]C=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[CH:25]=[CH:24][S:48][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCCc3sccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2sccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.39, 7.12, 6.99, 5.45, 4.64, 2.90, 2.65, 2.51, 2.20, 1.99, 1.27, 1.20; 13C NMR (100 MHz, CDCl3) δ 151.51, 150.78, 140.47, 139.15, 137.82, 137.21, 135.35, 134.47, 132.93, 128.78, 127.51, 127.37, 123.01, 117.71, 46.74, 29.97, 27.62, 26.36, 25.53, 21.37, 12.32, 11.63; HRMS (FAB) calcd for C22H23Cl2N3S+H 432.1068, found 432.1073.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=1.OO.[O-:32]Cl=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>CC#N>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:15][CH2:14]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:27]([OH:32])=[O:28])=[O:29]
Reactant: [O-][Cl+][O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C(=O)O)c2)c1N
Yield: 36.8 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-formylbenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (900 mg) in CH3CN (25 mL) were added NaH2PO4 (55 mg in 2 mL water) and H2O2 (1.3g, 30% solution in water) followed by the dropwise addition of an aqueous solution of NaClO2 (365 mg) at 10° C. The mixture was stirred at this temperature for 4h before Na2SO3 was added. Solvent was removed and residue was dissolved in EtOAc, the organic layer was washed with water and brine and concentrated. The crude product was purified by column chromatography on silica gel eluted with EtOAc followed by EtOAC: AcOH=100 :1), to provide the desired intermediate as a beige foam (345 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][NH:23][C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: NCC1CC1
Product: Cc1c(-c2ccc(C(=O)NCC3CC3)s2)noc1C(F)(F)F
Yield: 67 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and cyclopropylmethylamine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, triturated and filtered with the aid of water, then washed with an aqueous 1 N hydrochloric acid solution followed by water. The crude solid was then triturated with a 25% EtOAc/hexanes solution (3×1 mL) and air dried to afford product as a colorless solid (110 mg, 67%). 1H NMR (CDCl3) 0.27-0.32 (m, 2 H), 0.55-0.61 (m, 2 H), 1.03-1.12 (m, 1 H), 2.37 (d, J=0.9, 3 H), 3.31 (d, J=5.7, 1 H), 3.33 (d, J=5.7, 1 H), 6.23 (br s, 1 H), 7.50 (d, J=4.0, 1 H), 7.56 (d, J=4.0, 1 H). 19F NMR −63.1. LC/MS 6.5 min, [M+1]+ 331.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br.Br[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].[H-].[Na+].O>CN(C=O)C>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(-c2ncc[nH]2)c1
Reactant: CN(C)CCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCn1ccnc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
At rt and under N2, to a solution of 2-(3-nitrophenyl)-1H-imidazole (0.189 g, 1.00 mmol) and (2-bromoethyl)dimethylamine hydrobromide (0.280 g, 1.20 mmol) in anhydrous DMF (5 mL) was added NaH (60% in mineral oil, 160 mg, 4.0 mmol) in two portions with caution. The mixture was stirred at rt for 15 h. Water (0.3 mL) was added cautiously to quench the reaction. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography (5% MeOH in dichloromethane) to afford the title compound. 1H-NMR (CDCl3, 400 MHz): δ=2.24 (s, 6H), 2.69 (t, J=7.2 Hz, 2H), 4.13 (d, J=6.8 Hz, 2H), 7.17 (d, J=1.2 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 8.04(dt, J=0.8, 8.0 Hz, 1H), 8.28 (dq, J=1.2, 8.4 Hz, 1H), 8.56 (t, J=1.6 Hz, 1H). MS (ES+): m/z 261.17 [MH+]. HPLC: tR=0.46 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:27]([CH:28]=[O:29])=[CH:26][C:8]2[C:9]3[N:13]([CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)[CH:12]=[C:11]([C:17]1[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=1)[N:10]=3>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[F:4][C:5]1[C:27]([CH:28]([OH:29])[CH3:1])=[CH:26][C:8]2[C:9]3[N:13]([CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)[CH:12]=[C:11]([C:17]1[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=1)[N:10]=3
Reactant: C[Mg]Br
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C=O)c(F)cc2OCC3)n(C(C)C)n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Methylmagnesium bromide (10.1 mL of a 1.4 M solution in THF/PhMe) was added to a solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-carbaldehyde (968 mg, 2.83 mmol) in THF (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched by addition of sat. NH4Cl (10 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined organics were washed (brine), dried (Na2SO4) and concentrated in vacuo. Compound purified by column chromatography (Si-PPC, gradient 0-5% MeOH in DCM) to give the title compound (361 mg, 0.97 mmol, 34%) as a pale brown solid. LCMS (Method J): RT=2.53 min, [M+H]+=372
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([NH:27]C(=O)C)[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:16][C:10]([NH:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:12]([F:13])([F:14])[F:15])=[C:2]([F:1])[CH:7]=1)=[O:11])[CH:26]=[CH:25][CH:24]=2
Reactant: CC(=O)Nc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Nc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-Fluoro-4-(isocyanatomethyl)-1-(trifluoromethyl)benzene (2.59 mmol) in toluene (10 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (400 mg, 1.99 mmol) and DIEA (1.8 mL). The mixture was heated at 80° C. for 5 hours, cooled to room temperature, and filtered. The solid was triturated with 97:3 CH2Cl2:CH3OH and stirred as a suspension in 48% aqueous HBr (8 mL) at 60° C. for 2 hours. After cooling to room temperature, the mixture was poured into concentrated NH4OH (20 mL). The solid was washed with water and air-dried to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.68 (s, 1H), 7.94 (s, 1H), 7.76 (t, 1H, J=7.9 Hz), 7.35-7.49 (m, 3H), 7.26 (s, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 6.84 (t, 1H, J=6.0 Hz), 6.62 (s, 1H), 4.41 (d, 2H, J=6.1 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C)C=O>[N:17]([C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To 5-chloro-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (4.0 g, 16.87 mmol) in dimethylformamide was added sodium azide (1.56 g, 23.9 mmol) and the reaction mixture was heated at 80° C. for 8 hrs. Cooled the reaction mixture, added water and white precipitate filtered and dried to yield 5-azido-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (2.95 g, 75% yield). LCMS (M+1=244)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12.Cl.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1.[OH-].[Na+]>CCO.CC#N>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=4)[N:30]=3)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2ccnc(Cl)c21
Reactant: N=C(N)Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: CCn1cc(-c2ccnc(Nc3ccc(O)cc3)n2)c2ccnc(Cl)c21
Temperature: 150 °C

Procedure:
A mixture of (E)-1-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (0.5 mmol), 1-(4-hydroxyphenyl)guanidine hydrochloride (0.5 mmol) and NaOH (2 mmol) in a mixture of EtOH-MeCN (1:2, v/v, 3 mL) was heated in a microwave at 150° C. for 25 minutes. The residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to yield 4-(4-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-ylamino)phenol as white solid. 1H-NMR (DMSO-d6) δ: 1.43 (m, 3H, CH3), 4.49 (m, 2H, CH2), 6.74 (m, 2H, Ph-H), 7.11 (d, 1T-F=5.6 Hz, Pyrimidin-H), 7.52 (m, 2H, Ph-H), 7.74 (d, 1H, J=5.6 Hz, Ar—H), 8.10 (d, 1H, J=5.2 Hz, Ar—H), 8.29 (d, 1H J=5.6 Hz, Pyrimidin-H), 8.37 (s, 1H, Ar—H), 9.04 (s, 1H, OH), 9.09 (s, 1H, NH). MS (ESI+) m/z 362.1609 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9]>>[C:8]([C:7](=[CH:1][CH3:2])[C:6]([O:5][CH3:4])=[O:10])#[N:9]
Reactant: CC=O
Reactant: COC(=O)CC#N
Product: CC=C(C#N)C(=O)OC

Procedure:
Similarly to Example 1a), acetaldehyde was reacted with methyl-cyanoacetate in a Knoevenagel reaction to give methyl 2-cyanobut-2-enoate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.C1COCC1>[O:1]([CH:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1)[Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CC(O)CCN1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCNC(=O)C1)(c1ccccc1)c1ccccc1
Yield: 26.5 %

Procedure:
(±) 4-hydroxypiperidin-2-one (0.80 g, 6.94 mmol) was dissolved in DMF. DMAP (0.085 g, 0.694 mmol) and imidazole (0.92 g, 13.88 mmol) were added. After the resulting mixture was stirred evenly, the solution of TBDPS-Cl (2.3 g, 8.33 mmol) in THF was added and stirred at room temperature overnight. After the reaction completed, the reaction mixture was dried by spinning. Column chromatography afforded colorless oily liquid 0.65 g, yield 60%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[NH2:25])=[CH:20][CH:19]=2)([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:27]1([CH2:33][NH:34][C:14]([C:11]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:26])[NH2:25])=[CH:22][CH:23]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(N)=O)cc2)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CC2(C(=O)NCC3CCCCC3)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of solution of 4-(4-carbamoylbenzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.38 mmol; 0.5 g) in DMF (5 mL) was added cyclohexylmethylamine (1.18 mmol; 0.154 mL), N,N-diisopropyl-N-ethylamine (2.81 mmol; 0.50 mL) and HBTU (1.38 mmol; 0.51 g), and the resulting mixture was stirred at room temperature overnight. The mixture was purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The residue was dissolved in tetrahydrofuran (2 mL) and a 4N HCl in 1,4-dioxane solution (3 mL), and the resulting mixture was stirred for 4 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 4-(4-carbamoylbenzyl)-piperidine-4-carboxylic acid cyclohexylmethyl amide as a hydrochloride salt. MS (ESI) m/z 358.40 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[N:13]=2)[N:8]=[CH:7][C:6]=1[C:16]#[N:17])([CH3:3])[CH3:2].[O:18]1CCOCC1>>[CH:15]([C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:16]#[N:17])=[C:5]2[O:4][CH:1]([CH3:3])[CH3:2])=[O:18]
Reactant: C1COCCO1
Reactant: Cc1ccc2ncc(C#N)c(OC(C)C)c2n1
Product: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Temperature: 25 °C

Procedure:
To a solution of 4-isopropoxy-6-methyl-[1,5]naphthyridine-3-carbonitrile (260.0 mg, 1.14 mmol) in 1,4-dioxane was added SeO2 (165.0 mg, 1.48 mmol) and the reaction mixture was refluxed for 3.5 hrs, when the TLC showed no starting material left, then cooled to room temperature and filtered through celite. The solid was washed with hot AcOEt and the filtrate was then concentrated to give 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile as a light yellow solid (270.3 mg, 98.3). HR-MS-EI (+) m/e calcd for C13H11N3O2 (M+) 241.0851. found 241.0854.