Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH3:2].C([Li])(C)(C)C.CN(C)[CH:31]=[O:32]>O1CCCC1>[CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]1[CH:9]=[CH:8][C:7]([CH:31]=[O:32])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCN(CCCCCCOC1CCCCO1)c1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCN(CCCCCCOC1CCCCO1)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
50.0 g (130 mmols) of N-ethyl-N-[6-(tetrahydropyran-2-yl)oxyhexyl]-4-bromoaniline was dissolved in 180 ml of anhydrous tetrahydrofuran in an atmosphere of argon, and the solution obtained was cooled to -78° C. To the reaction solution obtained, 174.4 ml (2.2-fold equivalent weight) of t-butyl lithium (1.64 M, n-pentane solution) was dropwise added, followed by stirring for 1 hour. To the mixture obtained, 12.3 g (1.3-fold equivalent weight) of N,N-dimethylformamide was dropwise added, which was then stirred at room temperature for 2 hours and 30 minutes. The resultant reaction solution was concentrated, and dissolved in 500 ml of ethyl acetate, followed by washing twice with 300 ml of water. The organic layer thus formed was dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing system: hexane/ethyl acetate=4/1) to obtain 34.7 g of N-ethyl-N-[6-(tetrahydropyran-2-yl)oxyhexyl]-4-formylaniline (yield: 80%; a pale-yellow oily liquid). 1H-NMR Spectrum [δ(ppm)]: 1.20(t, 3H, J=7.0 Hz), 1.35-1.95(m, 14H), 3.20-3.55(m, 6H), 3.73(m, 1H), 3.86(m, 1H), 4.57(t, 1H, J=3.6 Hz), 6.65(d, 2H, J=9.7 Hz), 7.71(d, 2H, J=9.7 Hz), 9.69(s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][NH2:23]>>[OH:20][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][NH:23][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: NCC(O)c1ccccc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCC(O)c3ccccc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (2-hydroxy-2-phenyl-ethyl)-amine to afford the title compound. MS: m/e=378 (M+H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][N:14]4[C:18](=[O:24])[CH2:19][NH:20][C:21](=O)[CH:22]=[C:13]4[C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ClCCCl.[CH:29]([C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)([CH3:31])[CH3:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][N:14]4[C:18](=[O:24])[CH2:19][N:20]=[C:21]([N:35]5[CH:36]=[C:32]([CH:29]([CH3:31])[CH3:30])[N:33]=[CH:34]5)[CH:22]=[C:13]4[C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c[nH]cn1
Reactant: O=C1C=C2c3nccc(-c4ccc(F)nc4)c3CCN2C(=O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)c1cn(C2=NCC(=O)N3CCc4c(-c5ccc(F)nc5)ccnc4C3=C2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
Example 94. To a stirred solution of 4-(6-fluoropyridin-3-yl)-5,6,9,10-tetrahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione (31 mg, 0.096 mmol) in 1,2-dichloroethane (2 mL) POCl3 (29.3 mg, 0.19 mmol) was added and the resulting suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and evaporated twice again and dried under high vacuo. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (5 mL), 4-isopropyl-1H-imidazole (53 mg, 0.48 mmol) was added and the mixture was stirred at 100° C. for 1 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by SFC (column: DEAP 5 μm, 250×30 mm, 60 A, Princeton; eluent: from 6% MeOH/CO2 to 11% MeOH/CO2 in 11 min; flow 100 mL/min; UV detection at 220 nm) and yielded the title compound as beige powder (11 mg). UPLC-MS: MS 417.2 (M+H+); UPLC rt 0.87 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17-1.34 (m, 6 H), 2.81-2.98 (m, 3 H), 4.05 (br. s., 2 H), 4.40 (s, 2 H), 7.09 (dd, J=8.3, 2.8 Hz, 1 H), 7.22-7.36 (m, 2 H), 7.77 (td, J=7.9, 2.1 Hz, 1 H), 7.96 (s, 1 H), 8.03 (s, 1 H), 8.23 (d, J=1.5 Hz, 1 H), 8.68 (d, J=4.8 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:29]#[N:30].[OH-].[K+].C([OH:37])(C)(C)C>O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:29]([NH2:30])=[O:37]
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1N1CCN(C)CC1
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask was charged with 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(4-methylpiperazin-1-yl)cinnoline-3-carbonitrile (Method 60) (360 mg, 0.89 mmol) and potassium hydroxide (4.9 g, 88.6 mmol). Anhydrous tert-butyl alcohol (30 ml) was added and the reaction was heated at vigorous reflux 1 h before being allowed to cool to rt. The reaction mixture was then poured into a separatory funnel containing water (˜100 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was washed with sat'd aqueous NaCl (˜100 mL), dried with MgSO4, filtered, and conc. in vacuo to give the crude product which was purified via silica gel chromatography (40 g) using EtOAc/MeOH (1:1) as eluent to give the title compound as a yellow solid. The solid was then recrystallized from 5 mL of MeOH which provided pure title compound (184 mg, 48.9%) as a pale yellow solid. 1HNMR: 11.60 (s, 1H), 8.55 (s, 1H), 7.85 (s, 1H), 7.16 (s, 1H), 7.37 (m, 2H), 7.10 (m, 1H), 6.21 (s, 1H), 4.05 (s, 3H), 2.46 (s, br, 4H), 2.70-2.60 (m, 7H), 2.35 (s, 3H); m/z 425.
Reaction SMILES: C([C:4]1[C:5](=[O:26])[N:6]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]([CH3:19])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:18])[CH3:17])(=O)C.OO.F[C:30](F)(F)[C:31]([O:33]C(=O)C(F)(F)F)=[O:32]>C(Cl)Cl.O>[C:31]([O:33][C:4]1[C:5](=[O:26])[N:6]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]([CH3:19])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:17])[CH3:18])(=[O:32])[CH3:30]
Reactant: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(C(C)=O)c1=O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(OC(C)=O)c1=O

Procedure:
To a stirred solution of 3-acetyl-4-(2-isopropylphenyl)-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 3 above (0.65 g, 1.8 mmol) in CH2Cl2 (150 mL) at 0° C. was added 30% aqueous H2O2 (0.94 mL, 9 mmol) and trifluoroacetic anhydride (1.8 mL, 14 mmol). The resulting solution was refluxed for 1 h and then diluted with CH2Cl2 and water. The organic phase was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.325 g; NMR: OCOCH3 peak at 2.05 ppm; HPLC RT=22.81 min, method B).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.[N-:12]=[N+:13]=[N-:14].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(OCC)C>[N:12]1[N:13]=[N:14][N:7]2[CH:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][C:3]=12
Reactant: COC(=O)C1CCC(OC)=N1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C1CCc2nnnn21
Temperature: 60 °C
Reaction time: 48 h
Yield: 30.3 %

Procedure:
To a solution of starting methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (900 mg, 6.04 mmol) in 4 mL of acetic acid was added sodium azide (975 mg, 12.08 mmol) and the resulting suspension heat to 60° C. and stirred vigorously for 48 h. The solution was cooled to room temperature and diluted with 35 mL of ethyl ether. Solid potassium carbonate was added to the solution which was stirred at room temperature for 20 min. The solids were filtered off via fritted funnel, washed with cool ethyl ether and concentrated under vacuum. Solid precipitated during concentration and was filtered off after concentrating to one-fifth volume. The solids were washed once with cold ether (3 mL) and dried under high vacuum overnight to afford the title compound (308 mg, 31%). LC-MS: m/z (ES)=169 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]2)=O)=[CH:4][C:3]=1[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:65]=[N+:66]=[N-:67])(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:12]3)=[N:67][N:66]=[N:65]2)=[CH:4][C:3]=1[CH3:27]
Reactant: Cc1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-n2nnnc2C2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from step A (840 mg, 2.171 mmol) and triphenylphosphine (1139 mg, 4.34 mmol) in THF (8.0 ml) was treated with diisopropylazodicarboxylate (0.844 ml, 4.34 mmol) and trimethylsilyl azide (0.574 ml, 4.34 mmol) at rt. The mixture was stirred at rt for 24 h, then quenched with aqueous saturated NaHCO3, and extracted with MTBE. The combined organic layers were concentrated. Purification of the resulting crude product on SiO2 (0 to 100% EtOAc, hexanes) afforded the title compound as a clear colorless oil. HPLC/MS: 412.2/414.1 (M+1); Rt=1.22 min (LC2).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@@H:59]1[CH:64]2[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]2)[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@@H:59]5[CH:64]6[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]6)[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-(+)-3-aminoquinuclidine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.43 (m, 3 H) 1.57-1.92 (m, 12 H) 2.69 (d, J=6.57 Hz, 2 H) 2.71 (m, 3 H) 2.89 (m, 1 H) 3.13 (m, 1 H) 3.31 (s, 3 H) 3.95 (s, 3 H) 3.97-4.16 (m, 2 H) 4.45 (m, 1 H) 7.47 (d, J=8.0 Hz, 1 H) 7.49 (s, 1 H) 7.93 (s, 1 H) 8.14 (d, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.0 Hz, 1 H). [M+H] calculated for C29H37F2N7O3, 570; found 570.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([CH2:11][CH3:12])=[C:5]([CH3:13])[N:4]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:11]([C:6]1[C:5]([CH3:13])=[N:4][C:3]([O:2][CH3:1])=[C:8]([CH:7]=1)[CH:9]=[O:10])[CH3:12]
Reactant: CCc1cc(CO)c(OC)nc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: CCc1cc(C=O)c(OC)nc1C
Yield: 90.1 %

Procedure:
Activated manganese dioxide (2.0 g) was added to a solution of 2-methoxy-3-hydroxymethyl-5-ethyl-6-methylpyridine (1.18 g, 6.5 mmol) in dry benzene (20 mL) and refluxed 5-10 hours. The warm suspension was filtered through a pad of anhydrous Na2SO4 and evaporated to yield 1.05 g (90%) of a viscous oil which solidified.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>C1COCC1.CCOC(C)=O>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([O:15][CH3:28])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (1 eq) in 30 mL of THF was added sodium hydride (1.5 eq) and followed by methyl iodide (5 eq) at 0° C. The reaction mixture was allowed to stir at room temperature for 3 hours. The crude mixture was diluted with 120 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:5) to yield (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-methoxypiperidine-1-carboxylate (93%). LC/MS (m/z): 380.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:7][CH2:6]1)=[O:4].[CH3:14][Mg]Br.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[F:13][C:2]([F:1])([F:12])[C:3]([C:5]1([S:8]([NH2:11])(=[O:9])=[O:10])[CH2:7][CH2:6]1)([OH:4])[CH3:14]
Reactant: NS(=O)(=O)C1(C(=O)C(F)(F)F)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(C(F)(F)F)C1(S(N)(=O)=O)CC1
Reaction time: 4 h

Procedure:
Under inert gas, 250 mg 1-(2,2,2-trifluoroacetyl)cyclopropanesulfonamide were initially charged in 6 ml of THF and then, at a temperature of −78° C., 1.15 ml of a 3.0 N methylmagnesium bromide solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 4 hours. The reaction solution was admixed with 5 ml of a saturated aqueous ammonium chloride solution and allowed to come to room temperature while stirring. After adjustment to pH 5 with 2 N aqueous hydrochloric acid, the mixture was extracted with 10 ml of ethyl acetate, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (208 mg) with a molecular weight of 233.2 g/mol (C6H10F3NO3S); MS (ESI): m/e=234 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[N:19]=[N:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[CH:33][CH:32]=4)[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=3)=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1.O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH:26]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[CH:35][CH:36]=1)[C:23]1[CH:22]=[CH:21][C:20]([C:17]2[N:18]=[N:19][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2nnc(-c3ccc(C(c4ccc(OCc5ccccn5)cc4)C(C)(C)C)cc3)n2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(c1ccc(OCc2ccccn2)cc1)c1ccc(-c2nnn(CC3CCNCC3)n2)cc1

Procedure:
Crude 2h (0.102 mmol) was dissolved in a pre-mixed solution of 4N HCl in dioxane (5.00 mL) and deionized water (250 μL) at 10° C. The resultant solution was warmed to room temperature and aged for approximately 1.3 h. After concentrating in vacuo, the residue was purified by flash chromatography on silica gel [100% EtOAc (120 mL) followed by 0%-100% EtOAc/(DCM:MeOH:ammonium hydroxide (95:5:1)] to afford compound Ie-2bx, Ie-2bx: m/z (ES) 497 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.59 (d, 1H, J=4.3 Hz), 8.05 (d, 2H, J=8.2 Hz), 7.70 (dt, 1H, J=7.6, 1.4 Hz), 7.53 (m, 3H), 7.36 (d, 2H, J=8.7 Hz), 7.21 (dd, 1H, J=6.9, 5.1 Hz), 6.92 (d, 2H, J=8.4 Hz), 5.19 (s, 2H), 4.51 (d, 2H, J=7.1 Hz), 3.75 (s, 1H), 3.10 (bd, 2H, J=12.4 Hz), 2.60 (dt, 2H, J=12.1, 2.0 Hz), 2.21 (m, 1H), 1.86 (bs, 1H), 1.60 (bd, 2H, J=12.3 Hz), 1.28 (m, 2H), 1.04 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]2[CH:7]=[CH:8][N:9]3[CH:20]=[CH:19][CH:18]=[C:10]3[C:11](=[CH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]=2[CH:4]=1)#N.C[OH:24]>>[CH:1]([C:3]1[CH:22]=[CH:21][C:6]2[CH:7]=[CH:8][N:9]3[CH:20]=[CH:19][CH:18]=[C:10]3[C:11](=[CH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]=2[CH:4]=1)=[O:24]
Reactant: CO
Reactant: CN(C)CCC=C1c2cc(C#N)ccc2C=Cn2cccc21
Product: CN(C)CCC=C1c2cc(C=O)ccc2C=Cn2cccc21

Procedure:
Similarly, by substituting 9-cyano-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine or its intermediate carbinol as starting material, there is produced 9-formyl-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])(O)=O.[Na+].[Cl:17][CH2:18][C:19](Cl)=[O:20]>C1COCC1.O>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)CCl
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a stirred solution of methyl 2-aminobenzoate (906 mg, 6.0 mmol) and NaHCO3 (554.4 mg, 6.6 mmol) in THF (12 mL) and water (12 mL) at 0° C. was added 2-chloroacetyl chloride (806 mg, 7.2 mmol) dropwise. After 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was purified by flash chromatography to give methyl 2-(2-chloroacetamido)benzoate (1.31 g, 96%). LC-MS (ES-API); rt 8.65 min; m/z calculated for C10H10ClNO3 [M+Na]+ 250.0, found 250.0.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+]>CN(C)C=O>[CH2:13]([N:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=[N:3]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCn1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
Sodium hydride (60% in oil, 4.00 g, 100 mmol) was added in small portions within 1 hours to a solution of benzotriazole (14.3 g, 120 mmol) and 1-iodooctane (25 g, 104 mmol) in anhydrous dimethylformamide (100 mL) stirred under argon at room temperature. After the addition, stirring was continued for 3 days. The reaction mixture was poured into ice/water (100 mL), treated with 2 N NaOH (100 mL) and extracted with hexane/ethyl ether (1:1, 3×200 mL). The extract was washed with water (200 mL), dried over anhydrous sodium carbonate, and the solvent was removed under reduced pressure. The residue was chromatographed using silica gel (500 g) and hexane/dichloromethane (1:1) as an eluent. The first fraction gave 2-octyl-2H-benzo[d][1,2,3]triazole (8.16 g, 35% yield) as an oily product. 1H NMR (400 MHz, CDCl3): δ 7.85 (m, 2H, benzotriazole), 7.37 (m, 2H, benzotriazole), 4.71 (t, J=7.3 Hz, 2H, octyl), 2.10 (m, 2H, octyl), 1.32 (m, 4H, octyl), 1.23 (m, 6H, octyl), 0.85 (t, J=7.3 Hz, 3H, octyl).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[NH3:13]>CC(O)C>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:13])[C:4]=2[CH:3]=1
Reactant: N
Reactant: Clc1ncnc2ncc(Br)cc12
Solvent: CC(C)O
Product: Nc1ncnc2ncc(Br)cc12

Procedure:
6-Bromo-4-chloropyrido[2,3-d]pyrimidine (1.0 g) and 4% NH3 in i-PrOH (25 mL) were stirred in a sealed tube at room temperature overnight. The pale brown heterogeneous slurry was concentrated, diluted with water and filtered. The brown solid thus collected was suction dried to obtain 6-bromopyrido[2,3-d]pyrimidin-4-amine (1.3 g, purity: 97%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (d, J=2.5 Hz, 1H), 9.01 (d, J=2.5 Hz, 1H), 8.52 (s, 1H), 8.31 (br s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[N:6]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:10]([C:8]1[CH:7]=[N:6][N:5]([CH2:4][C:3]([N:2]([CH3:17])[CH3:1])=[O:16])[CH:9]=1)#[CH:11]
Reactant: CN(C)C(=O)Cn1cc(C#C[Si](C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnn(CC(=O)N(C)C)c1
Yield: 77 %

Procedure:
N,N-Dimethyl-2-(4-((trimethylsilyl)ethynyl)-1H-pyrazol-1-yl)acetamide (Preparation 100, 0.55 g, 2.2 mmol) was dissolved in dry THF (10 ml). To the stirred solution was then added a solution of TBAF in THF (2.4 ml of a 1M solution in THF, 2.4 mmol). After 20 minutes the reaction was concentrated in vacuo and the residue taken up in ethyl acetate. The organic solution was washed with water, brine and dried over sodium sulphate. The organic solution was then concentrated in vacuum and the crude product purified by silica gel column chromatography eluting with neat ethyl acetate to afford the title compound as a pale brown powder (0.3 g, 77%). 1H-NMR (500 MHz, CDCl3): δ 2.98 (s, 3H), 3.01 (s, 1H), 3.07 (s, 3H), 4.95 (s, 2H), 7.62 (s, 1H), 7.69 (s, 1H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH:6]([NH:9][CH2:10][CH2:11]O)([CH3:8])[CH3:7].C1(C)C=CC=CC=1>O>[S:1]([O:3][CH2:11][CH2:10][NH:9][CH:6]([CH3:8])[CH3:7])([OH:2])(=[O:5])=[O:4]
Reactant: CC(C)NCCO
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)NCCOS(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50-ml three-necked flask, 1.01 g (10 mmol) of sulfuric acid (97%) was diluted with 1 g of water, and the resulting dilution was ice-cooled. A mixture of 1.03 g (10 mmol) of 2-isopropylaminoethanol and 1 g of water was slowly dropped into the cooled dilution. After completion of the dropping, the resulting mixture was warmed to room temperature and 10 ml of toluene was added thereto. The mixture thus obtained was dehydrated by heating with vigorous stirring after attaching a Dean-Stark trap to the flask. The mixture was heated and stirred for 4 hours until a theoretical amount of water was removed. Then, the reaction was continued for another 1 hour. After a large portion of the toluene was removed by decantation, the residual toluene was distilled off under reduced pressure to obtain a crude product of 2-isopropylaminoethyl hydrogensulfate, the desired compound, quantitatively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][N:13]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:7][CH:6]=2>CO.O.NN>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2ncc(Br)cc2c1
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1ccc2ncc(Br)cc2c1

Procedure:
A solution of 2-(3-Bromo-quinolin-6-ylmethyl)-isoindole-1,3-dione (635 g, 1.73 mmol) in 15 mL of methanol and 1 mL of hydrazine monohydrate was heated at 80° C. for 2 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. LCMS (method A): [MH]+=237/239, tR=2.795 min.