Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH2:17])[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH:17][C:19]4[N:27]=[CH:26][N:25]=[C:24]5[C:20]=4[N:21]=[CH:22][NH:23]5)[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1
Reactant: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 90 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of (S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethylamine (70 mg, 0.30 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (71.8 mg, 0.30 mmol), and DIPEA (0.153 mL, 0.90 mmol) in n-butanol (1.5 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (5 mL) and cooled in an ice bath. HCl in isopropanol (1.25 M, 3 mL) was added and the mixture stirred at 0° C. for 1.5 h and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) afforded 405 as a white solid (72.8 mg, 69%). LCMS (Method K): RT 2.68 min [M+H]+ 352.0. 1H NMR ((CD3)2SO, 400 MHz): 12.93 (1H, bs), 8.24 (1H, s), 8.15 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.43 (1H, dd, J=8.7, 4.8 Hz), 6.99 (1H, dd, J=10.8, 8.8 Hz), 5.83 (1H, bs), 4.31-4.29 (2H, m), 3.04-3.01 (2H, m), 2.08-1.94 (4H, m), 1.66 (3H, d, J=6.7 Hz)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1([CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[CH2:18][CH2:17]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(CC(=O)N3CCCC3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 2-(piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (0.108 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.55 mmol). The reaction mixture was heated at 45° C. for 22 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 70% ethyl acetate in dichloromethane and then 90% ethyl acetate in dichloromethane. The title compound was obtained as a yellow solid (0.162 g, 78%); 1H-NMR (500 MHz, DMSO-d6) 1.74 (m, 2H) and 1.85 (m, 2H) (pyrrolidine 3-CH2 and 4-CH2), 2.60 (br s, 4H, piperazine N(CH2)2), 3.04 (br s, 4H, piperazine N(CH2)2), 3.16 (s, 2H, NCH2CO), 3.27 (t, J=6.90 Hz, 2H) and 3.45 (t, J=6.70 Hz, 2H) (pyrrolidine 2-CH2 and 5-CH2), 7.02 (s, 2H, NH2), 8.16 (s, 1H, 6-H);
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:28][N:29]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and methyl-phenethyl-amine. The crude product was subjected to preparative HPLC (29%, oil). HPLC-MS: m/z=389.2 (M+1); Rt: 4.15 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[CH:35].C(#N)C>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[C:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CC#N
Product: COc1cnc2c(Oc3ccc(Nc4nnc(C#CC(C)(C)C)c5ccccc45)cc3)ccnc2c1
Temperature: 90 °C

Procedure:
A resealable pressure bottle, purged with argon, was charged with 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (120 mg, 0.28 mmol), bis(triphenylphosphine)palladium(ii) chloride (24 mg, 0.03 mmol), copper(I) iodide (6.4 mg, 0.03 mmol), 3,3-dimethyl-1-butyne (86 μl, 0.70 mmol), and ACN (2.8 mL, 0.1 M). To the mixture was added TEA (0.785 mL, 5.6 mmol). The reaction vessel was sealed and the mixture was heated to 90° C. for 16 h. The reaction mixture was cooled to RT, diluted with DCM and filtered over Celite. The filtrate was concentrated under reduced pressure to give a brown residue, which was purified by Gilson HPLC {5-65% (0.1% TFA in CH3CN) in H2O over 20 min}. The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with DCM. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(3,3-dimethylbut-1-ynyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine MS [M+H]=476.1 Calc'd for C29H25N5O2: 475.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[F:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([F:39])[C:36]=1[CH2:37]O)[O:30][CH2:31][C:32]#[N:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:37][C:36]3[C:35]([F:39])=[CH:34][C:29]([O:30][CH2:31][C:32]#[N:33])=[CH:28][C:27]=3[F:26])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Reactant: N#CCOc1cc(F)c(CO)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCC#N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Yield: 38.5 %

Procedure:
In a similar manner 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (227 mg, 0.60 mmol), 2-(3,5-difluoro-4-(hydroxymethyl)phenoxy)acetonitrile (156 mg, 0.78 mmol), PPh3 (173 mg, 0.66 mmol) and DIAD (137 μL, 0.66 mmol) in THF (0.8 mL) were reacted, processed and purified by flash chromatography (80% EtOAc/Hex) to provide 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)acetonitrile (129 mg, 39%). MS (EI) m/z 558.3 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3]>C(O)(=O)C.C(O)C.[Fe]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][CH:6]=[C:5]2[O:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCOc1ccnc2c([N+](=O)[O-])cccc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCOc1ccnc2c(N)cccc12
Yield: 90.9 %

Procedure:
A mixture of 4-allyloxy-8-nitroquinoline (110 mg) and iron (268 mg) in acetic acid (0.4 ml) and ethanol (1.6 ml) was refluxed for 1 hour. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, and the solution was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate-n-hexane) to give 8-amino-4-allyloxyquinoline (87 mg).
Reaction SMILES: BrC1SC(Cl)=C(Cl)C=1C(=O)CCl.[Br:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]([Br:21])[CH:15]=1.[Br:22][CH2:23][C:24](Br)=[O:25]>>[Br:22][CH2:23][C:24]([C:19]1[C:14]([Br:13])=[CH:15][C:16]([Br:21])=[CH:17][C:18]=1[Br:20])=[O:25]
Reactant: O=C(Br)CBr
Reactant: Brc1cc(Br)cc(Br)c1
Agent: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Product: O=C(CBr)c1c(Br)cc(Br)cc1Br
Yield: 45 %

Procedure:
General procedure described for compounds 1 and 2 starting from 1,3,5-tribromobenzene and bromoacetyl bromide. Purified by column chromatography column (hexane:ethyl acetate 6:1), yield 45% m.p.: 86-87° C., 1H-NMR (CDCl3): δ7.7 (s, 2H, Ar), 4.44 (s, 2H, CH2); 13C-NMR (CDCl3): δ193.4 (CO), 139.4 (C—CO), 134.5 (CH), 124.7 (C—Br), 119.4 (C—Br), 34.6 (CH2); M/z (EI): 440, 438, 436, 434, 432 (M+, 1, 3, 5, 3, 1%), 345, 343, 341, 339 (M-CH2Br, 35, 96, 100, 41%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 98%, r.t.=3.40 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4Cc3ccccc3)n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 100 mg (0.24 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 2.5 mL chloroform was treated with 0.25 mL (2.4 mmol) benzaldehyde and 160 mg (0.73 mmol) NaBH3(CN), followed by the addition of 2.5 mL methanol. The mixture was stirred at ambient temperature for 5 min when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 502 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[Cl:21][C:20]1[C:13]2[CH2:12][CH2:11][C@@:10]3([CH3:22])[C@H:15]([CH2:16][N:8]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[CH2:9]3)[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@]12CCc3c(Cl)cccc3[C@H]1CN(Cc1ccccc1)C2
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C[C@@H]2c3cccc(Cl)c3CC[C@]2(C)C1
Yield: 89.5 %

Procedure:
cis-2-Benzyl-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (18.60 mmol, 5.8 g) was dissolved in toluene and heated to reflux. Ethyl carbonochloridate (55.8 mmol, 5.33 ml, 6.06 g) was added dropwise and the reaction mixture left to stir at reflux for 2 hours. TLC and mass spec showed no starting material. Solvent removed in vacuo and crude material purified by silica column chromatography (eluting with 0-30% ethyl acetate:heptane) to give cis-ethyl 6-chloro-3a-methyl-3,3a,4,5-tetrahydro-1H-benzo[e]isoindole-2(9bH)-carboxylate (4.89 g), m/z=294.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4].[H-].[Na+].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>CS(C)=O.C(Cl)(Cl)Cl>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[C:3]([N:2]([CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4]
Reactant: CN(C(=O)c1nc2ccccc2[nH]1)c1ccccn1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CN(C)CCn1c(C(=O)N(C)c2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methyl-N-(2-pyridyl)benzimidazole-2-carboxamide (1.0 g) prepared in Example 5 was dissolved in dry DMSO (20 ml), 60% sodium hydride (0.17 g) was added and stirred at room temperature for 1 hr in an argon atmosphere. Excess β-dimethylaminoethyl chloride was added to the mixture and reacted at room temperature under agitation for 20 hrs. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous Na2SO4 and the solvent was distilled off. Purification of the residue by column chromatography on silica gel (using silica gel manufactured by Merck Co., Ltd.) gave the title compound (0.88 g) as an oily product.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].Br[C:10]([CH3:18])([CH3:17])[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].CS(C)=O>C(OCC)C>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([N+:1]#[C-:2])[C:10]([CH3:18])([CH3:17])[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH3:8]
Reactant: C=CCOC(=O)C(C)(C)Br
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCOCC
Solvent: CS(C)=O
Product: [C-]#[N+]C(C(=O)OCC)C(C)(C)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl isocyanoacetate (2.19 g, 19.4 mmol) and allyl 2-bromo-2-methylpropionate (4.40 g, 21.3 mmol) are dissolved in diethyl ether (50 mL) and methyl sulfoxide (50 mL) with stirring. In a separate flask sodium hydride (775 mg of 60% dispersion in mineral oil) is rinsed with hexane and suspended in diethyl ether (10 mL). The suspension is added dropwise to the stirring solution and an additional methyl sulfoxide (50 mL) is added to the mixture. The reaction is stirred for 2 hours at room temperature. The mixture is diluted with diethyl ether (250 mL) and washed several times with water. The organic phase is dried over sodium sulfate and evaporated to give 3-isocyano-2,2-dimethyl-succinic acid 1-allyl ester 4-ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[C:8]2=[O:17]
Reactant: CC(=O)[O-]
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Intermediate 73 (24 g, 0.096 moles) was taken in a RB flask and to this acetic anhydride (230 ml) and sodium acetate (55.2 g, 0.673 moles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as brown solid (26 g, quant. yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.87 (dd, J=8.2, 3.0 Hz, 1H), 7.48-7.36 (m, 3H), 7.10-6.99 (m, 3H), 2.33 (s, 3H).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cccc(Cl)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cccc(Cl)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Lithium hydroxide (0.142 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.28 g) and diethyl [(3S,8aR)-3-(3-chlorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (0.52 g) in tetrahydrofuran (1 mL)-ethanol (4 mL), and the reaction solution was stirred under shading at room temperature for three hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.438 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]#[N:17])=[CH:12][NH:13][C:14](=O)[C:5]=3[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:20].CC(OC)(C)C>O1CCOCC1>[Cl:20][C:14]1[C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:11]([C:16]#[N:17])=[CH:12][N:13]=1.[ClH:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c(=O)c2c1[nH]c1ccc(F)cc12
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: Cl
Product: N#Cc1cnc(Cl)c2c1[nH]c1ccc(F)cc12
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To 8-fluoro-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-4-carbonitrile (23.5 g, 103 mmol) in dioxane (235 mL) was added POCl3 (95 g, 621 mmol) at 85° C. The reaction mixture was left to stir at 85° C. for 3 h, cooled to 0° C., and treated with MTBE. The reaction mixture was filtered, and washed with MTBE. The solid was treated with isopropanol, warm to 45° C. for 2 h, cooled to room temperature, filtered, washed with MTBE, and dried to afford the title compound as an HCl salt. 1H NMR (600 MHz, CD3COCD3) δ 8.68 (s, 1H); 8.15 (dd, 1H); 7.78 (dd, 1H); 7.48 (dt, 1H). LRMS (APCI) calc'd for (C12H5ClFN3) [M+H]+, 246.0. found 246.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>ClCCl.CN(C)C1C=CN=CC=1>[Br:7][C:4]1[S:3][C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:25][CH3:26])=[N:6][CH:5]=1
Reactant: Nc1ncc(Br)s1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)Nc1ncc(Br)s1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 2-amino-5-bromothiazole (1220 mg, 6.81 mmol) in dichloromethane (10 ml) was added triethylamine (1.235 ml, 8.86 mmol) and 4-dimethylamino pyridine (83 mg, 0.681 mmol), followed by addition of 5-chloro-2-methoxybenzoyl chloride (1397 mg, 6.81 mmol) and stirred overnight. The reaction was concentrated and water was added to the residue. The mixture was sonicated and filtered to obtain the title compound as off-white solid (1.56 g, 66%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.88 (m, 3H) 7.23 (d, J=8.81 Hz, 1H) 7.58-7.67 (m, 3H) 12.32 (s, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1>>[S:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccsc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccsc4)cc23)CC1
Yield: 92.3 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.5 mg (0.09 mMol) 3-thienoic acid, 9.4 mg (92%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:29])[C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:19][CH:18]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:12]1([NH:11][C:4]2[C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:29])[C:24]([CH:26]4[CH2:27][CH2:28]4)=[O:25])=[CH:21][CH:22]=3)[N:3]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Clc1nc(NC2CCC2)c2cc[nH]c2n1
Reactant: CN(C(=O)C1CC1)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN(C(=O)C1CC1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Temperature: 115 °C
Yield: 6.2 %

Procedure:
To a suspension of 2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (67 mg, 0.3 mmol) in nBuOH (0.8 mL) was added N-(4-aminophenyl)-N-methylcyclopropanecarboxamide (85 mg, 0.45 mmol) and TMSCl (0.02 mL, 0.15 mmol). After heating at 115° C. for 2 h, the mixture was cooled and purified by preparative HPLC to give N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylcyclopropanecarboxamide (7 mg). MS found for C21H24N6O as (M+H)+ 377.2. λ=208.7, 272.4, 304.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH2:14])=[CH:12][N:11]([CH3:15])[N:10]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]2[N:30]=[CH:31][C:32]([C:33](Cl)=[O:34])=[C:26]2[N:25]=1>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]2[N:30]=[CH:31][C:32]([C:33]([NH:14][C:13]3[C:9]([C:3]4[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10][N:11]([CH3:15])[CH:12]=3)=[O:34])=[C:26]2[N:25]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cn1cc(N)c(-c2cc(Cl)ccc2Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cc(Cl)ccc2Cl)n1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To an ice-cooled solution of 3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-amine (121 mg, 0.50 mmol) and triethylamine (101 mg, 1.00 mmol) in dichloromethane (15 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (162 mg, 1.5 mmol). The reaction mixture was warmed to room temperature for 3 hours. The mixture was then washed with saturated aqueous sodium chloride solution. The collected organics were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded 5-chloro-N-(3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a solid (110 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): 9.34 (d, J=7.6 Hz, 1H), 9.21 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.54 (s, 1H), 7.36 (d, J=6.8 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH:1](=[N:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[N+](=C[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-].O1CCC[CH2:19]1>>[CH2:1]([N:5]1[CH:7]([CH2:8][CH2:9][CH3:19])[CH:6]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=NCCCC
Reactant: C1CCOC1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCCCN1C(CCC)C1C(=O)OCC
Temperature: -5 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of 0.5 mmol of N-butylidenebutylamine, 1 mmol of ethyl diazoacetate, 0.025 mmol of di-p-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir2Cl2(cod)2], and 0.5 ml of tetrahydrofuran was stirred at −5° C. in an argon atmosphere for 3 hours. As a result, 1-butyl-2-ethoxycarbonyl-3-propylaziridine was obtained in a yield of 66%. Separately, small amounts of diethyl fumarate and diethyl maleate were formed as by-products in total yield of 19%.