Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:19]([C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Product: CC(=O)c1sc(NS(=O)(=O)c2c(Cl)cccc2Cl)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and-2,6-dichlorobenzenesulfonyl chloride (66 mg) as described in the synthetic METHOD B to give a white solid (21.4 mg) with purity >90%: MS (pos) m/z 365.3, 367.3.
Reaction SMILES: [CH2:1]([C@H:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=O)[CH:2]([CH3:4])[CH3:3]>C(Cl)(=O)C>[CH2:1]([C@@H:5]1[CH2:9][C:10](=[O:11])[O:12][C:6]1=[O:8])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)O
Solvent: CC(=O)Cl
Product: CC(C)C[C@@H]1CC(=O)OC1=O

Procedure:
A solution of (2R)-2-isobutylsuccinic acid (35 mg, 0.2 mmol) in acetyl chloride (1.2 ml) was heated at reflux under nitrogen for 2.2 hours then volatile components removed by distillation in vacuo to leave (3R)-3-isobutyldihydrofuran-2,5-dione as an oily residue which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[O-]CC.[Na+].[CH:29]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH2:30]>C(O)C>[CH2:29]([S:31]([CH2:34][CH2:35][O:21][N:20]=[CH:19][C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: C=CS(=O)(=O)CC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCS(=O)(=O)CCON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O

Procedure:
In a manner similar to that employed in Example 12 an ethanol solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3 -carboxaldehyde oxime was reacted with sodium ethoxide and ethyl vinyl sulfone to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-[2-(ethylsulfonyl)ethyl]oxime, m.p. 144-148° C. Compound 27.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C@@H:7]1[CH2:13][C@H:12]2[N:14](C(OC(C)(C)C)=O)[C@@H:8]1[CH2:9][O:10][CH2:11]2)[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[CH:12]12[NH:14][CH:8]([CH:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH2:13]1)[CH2:9][O:10][CH2:11]2
Reactant: CCOC(=O)CO[C@@H]1C[C@@H]2COC[C@H]1N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)COC1CC2COCC1N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
To a solution of (1R,5R,6R)-tert-butyl 6-(2-ethoxy-2-oxoethoxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate 50a (racemic, 200 mg, 0.63 mmol) in DCM (10 mL) was added HCl/dioxane (2 mL, 7 M). The resulting mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo to give the compound 50b (150 mg, 94%). MS: calc'd (MH+) 216, measured (MH+) 216; 1H NMR (CDCl3, 400 MHz): 4.28 (m, 8H), 3.79 (m, 1H), 3.70 (s, 1H), 3.57 (d, J=12.4 Hz, 1H), 2.50 (m, 1H), 2.31 (m, 1H), 1.28 (m, 3H).
Reaction SMILES: [CH2:1]1[O:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>C(O)C>[CH2:17]([NH:18][CH2:1][CH:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:1][CH:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CCO
Product: CCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-nonene oxide (97.4 g.) and hexamethylenediamine (39.8 g.) and recrystallization of the resulting product (67 g.) from ethanol afforded N,N'-(1,6-hexylene)-bis[2-hydroxynonylamine] (I: R = CH3 (CH2)6, R' = H, X = (CH2)6, Z = H) (67 g., m.p. 122°-129.2° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.[Br-:18].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[Br:18][C:9]1[C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=[C:2]([F:1])[CH:10]=1
Reactant: [Br-]
Reactant: O=C(O)CC1CCc2c1[nH]c1ccc(F)cc21
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: O=C(O)CC1CCc2c1[nH]c1c(Br)cc(F)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at −40° C. The suspension was stirred for 10 min at 0° C. and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 0° C. The suspension was stirred for 15 min at 15° C. and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of 1N HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:11]1[CH:14]([S:15][CH3:16])[N:13]([CH:17](O)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.S(Cl)([Cl:43])=O>>[Si:1]([O:8][CH:9]([CH:11]1[CH:14]([S:15][CH3:16])[N:13]([CH:17]([Cl:43])[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure of Preparation 2, but using p-nitrobenzyl 2-[3-(1-t-butyldimethylsilyloxyethyl)-4-methylthio-2-azetidinon-1-yl]-2-hydroxyacetate (470 mg), 2,6-lutidine (168 μl) and thionyl chloride (85 μl) and purifying the product by silica gel column chromatography eluted with methylene chloride, there were obtained 450 mg of the desired compound as an oil.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:29][N:30](C)[C:31](C1CN(C)C(=O)C=1O)=O>>[F:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:29][N:30]([CH3:31])[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1cccc(F)c1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1cccc(F)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 60 %

Procedure:
3-[(3-Fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 49-C) was reacted with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (60% yield); mp 119° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.74 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.87 (2H, s, NCH2), 6.99–7.35 (4H, m, aromatics). Anal. calcd for C14H15FN2O4: C, 57.14; H, 5.14; N, 9.52. Found: C, 57.04; H, 5.02; N, 9.42.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[C:12]2=[CH2:28])=[CH:7][CH:6]=1)=[O:4].[H][H]>CN(C)C=O.[Pd]>[CH3:27][O:26][C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15](=[O:16])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:12]2[CH3:28])=[CH:19][CH:20]=1)=[O:25]
Reactant: [H][H]
Reactant: C=C1N(c2ccc(C(=O)OC)cc2)C(=O)C(=O)N1c1ccc(C(=O)OC)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2C(=O)C(=O)N(c3ccc(C(=O)OC)cc3)C2C)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A solution of 40.8 g (0.1 mole) of 1,3-bis-(4'-methoxycarbonylphenyl)-2-methylene-imidazolidine-4,5-dione in 500 ml of dimethylformamide is hydrogenated in a laboratory hydrogenating apparatus, after addition of 2 g of a 5% palladium on charcoal catalyst, at room temperature and with vigorous stirring under slight hydrogen overpressure, until the uptake of hydrogen has ceased. The catalyst is filtered off and the solution is poured into 3 liters of ice water with vigorous stirring. The precipitated product is recrystallised from xylene, to yield 32 g of colourless crystals with a melting point of 250° C. The IR and NMR spectra confirm the presumed structure.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][C:11]([CH3:13])([CH3:10])[O:5][CH2:4]1
Reactant: CC(C)=O
Reactant: OCC(CO)(CBr)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)OCC(CBr)(CBr)CO1

Procedure:
A solution of 2,2-bis(bromomethyl)-1,3-propanediol (5.0 g, 19.1 mmol), anhydrous acetone (20 mL) and p-TsOH (100 mg) in benzene (75 mL) was refluxed for 12 h, with azeotropic removal of water. The reaction mixture was concentrated under reduced pressure, EtOAc (100 mL) was added and the organic layer was washed successively with H2O (3×30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The white solid obtained was triturated with n-pentane (20 mL) to afford 5,5-bis(bromomethyl)-2,2-dimethyl-[1,3]dioxane (521) as colourless crystals.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]([CH2:14][C:15](Cl)=[O:16])#[N:13].N1C=CC=CC=1>ClCCCl>[C:12]([CH2:14][C:15]([NH:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:16])#[N:13]
Reactant: CCOC(=O)c1nccn1N
Reactant: N#CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)c1nccn1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
In a 100 ml RB flask was added ethyl 1-amino-1H-imidazole-2-carboxylate (0.4 g, 2.58 mmol) from (1a), DCE (12.0 mL), 2-cyanoacetyl chloride (0.320 g, 3.09 mmol) and pyridine (0.417 mL, 5.16 mmol). The resulting mixture was stirred overnight under nitrogen at room temperature. The reaction was concentrated and diluted with ethyl acetate and washed with water (2×), then the aqueous was back-extracted with ethyl acetate. The organics were collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide ethyl 1-(2-cyanoacetamido)-1H-imidazole-2-carboxylate (0.38 g, 66.3% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr

Procedure:
To a 2-L round-bottom flask equipped with an mechanical overhead stirrer, a reflux condenser and a N2inlet was added ethyl 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (85g, 0.27moles, 1.0eq) and dry carbon tetrachloride (750ml, 0.38M). Freshly recrystallized N-bromo succinimide (52.72g, 1.1eq) was added as a solid, Benzoyl peroxide (6.5g, 10mol %) was added at room temperature all at once as a solid, and the reaction mixture was refluxed for 5hrs. The reaction was monitored by 1H NMR and was determined to be composed of a 9:1mixture of mono-bromination product (i.e. desired product) and di-bromination product with a 90% conversion. After cooling to 0° C. (to precipitate out the succinimide) the reaction was filtered through Celite and the solvent was removed under reduced pressure to yield a brown oil. The oil was crystallized using hexanes to yield 100g (94%) of an off-white product of 90% purity.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)(=O)=O)=CC=1.[NH:40]1[CH:44]=[N:43][N:42]=[N:41]1.C(N(CC)CC)C>CN(C=O)C>[N:40]1[N:41]([CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)[N:42]=[N:43][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Reactant: c1nnn[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O[C@@H]1[C@@H](O)[C@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)O[C@H](Cn2ncnn2)[C@H]1O
Yield: 23.8 %

Procedure:
The solution of toluenesulfonate 90 (612 mg, 1.03 mmol), tetrazole (0.45 M in acetonitrile) (11.5 mL 5.17 mmol) and triethyl amine (0.72 mL 5.17 mmol) in DMF (2.0 mL) was stirred at 80° C. for 3 d. Reaction mixture was evaporated under reduced pressure. The residue was purified by prep HPLC (C18) to afford the titled compound 98 (120 mg, 24%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:25][NH:26][CH2:27][CH2:28][CH3:29].[N:30]#[C:31]Br>C(O)C>[NH2:30][C:31]1[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][C:3]2[C:2](=[CH:24][CH:23]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:13][S:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[CH:4]=2)[N:1]=1
Reactant: CCCNCc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CCCN1Cc2cc(Oc3cccc(NS(=O)(=O)c4ccccc4)c3)ccc2N=C1N
Temperature: 25 °C

Procedure:
A mixture of N-[3-(4-amino-3-propylaminomethyl-phenoxy)-phenyl]-benzenesulfonamide (0.0044 mol) in ethanol (50 mL) was stirred at room temperature and cyanogen bromide (0.0064 mol) was added, then the reaction mixture was stirred and refluxed for 4 hours. After cooling, the precipitate was filtered off and was stirred in boiling CH3CN with CH3OH. The resulting solids were filtered off, washed with diisopropyl ether and dried to yield the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(O)C>CCOCC>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][CH2:8][C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)CNc2ccc(Br)cc2)cc1
Reaction time: 16 h

Procedure:
p-Cyanophenacyl bromide (29.8 g, 0.138 mole) and p-bromoaniline (47.13 g, 0.266 mole) were combined with 53.2 g of absolute ethanol and stirred 16 hours. The solution was then diluted with ether and the resulting slurry filtered. The filter cake was repulped in 500 ml ether, filtered, repulped in 400 ml acetone and again filtered to yield title product: 17.14 g (40.9%); m.p. 154°-157°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.Br[C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O>[CH2:35]([O:34][C:32]([C:31]1[CH:30]=[CH:29][C:39]([O:40][CH2:41][O:42][CH3:43])=[C:38]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)[CH:37]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)c1ccc(OCOC)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(OCOC)c(-c2cccn2C(=O)OC(C)(C)C)c1

Procedure:
21 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 4.2 g of tetrakistriphenylphosphine palladium and 153 ml of aqueous sodium carbonate solution (2 M) were added in order to a dimethoxyethane (350 ml) solution of 21 g of ethyl 3-bromo-4-methoxymethoxybenzoate, and the reaction liquid was heated overnight under reflux in a nitrogen atmosphere. After cooled, the reaction liquid was diluted with water, extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=12/1 to 10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:38])[CH2:36][CH3:37]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35](=[O:38])[CH2:36][CH3:37])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (0.3 g) obtained in Example 2 was suspended in dimethyl sulfoxide (20 ml), and to the suspension was added potassium carbonate (0.2 g), and the mixture was stirred at room temperature for 30 minutes. 1-bromo-2-butanone (0.1 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water, and the precipitated crystals were recovered by filtration. The resulting crude crystals were washed with methanol and ethanol in succession to obtain the title compound (192 mg, 55%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]#[CH:12].Cl[CH2:14][C:15]([N:17]1[CH2:36][CH2:35][C:20]2[N:21]=[C:22]([NH:25][CH:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[N:23]=[CH:24][C:19]=2[CH2:18]1)=[O:16]>O1CCCC1>[CH2:9]([NH:8][CH2:14][C:15]([N:17]1[CH2:36][CH2:35][C:20]2[N:21]=[C:22]([NH:25][CH:26]3[CH2:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:34]3)[N:23]=[CH:24][C:19]=2[CH2:18]1)=[O:16])[CH2:10][C:11]#[CH:12]
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: C#CCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCNCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 55 °C

Procedure:
Add triethylamine (0.85 mL; 2.0 equiv; 6.13 mmoles) followed by 1-amino-3-butyne (0.38 mL; 1.5 equiv; 4.59 mmoles) to a solution of 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (1.05 g; 1.0 equiv; 3.06 mmoles) in tetrahydrofuran (10.2 mL), and heat to 55° C. for 16 hours, then concentrate and use the 2-(but-3-ynylamino)-1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]ethanone directly in the next step: MS (m/z): 376(M+1).
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34](C(OCCCC)=O)[NH2:35].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:31][CH2:32]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:34]([CH3:33])[N:35]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Reactant: CCCCOC(=O)N(C)N
Solvent: CC(=O)O
Solvent: O=CO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)n(C)n3)nc21
Temperature: 35 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A mixture of (Z)-N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 72B, 70 mg, 0.155 mmol) and tent-butyl 1-methylhydrazinecarboxylate (0.046 mL, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (0.5 mL) was added and stirred at 60° C. for 6 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The impure product was further purified by preparative HPLC to give N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (45 mg, 63.9% yield) as an off-white solid.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[F:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([NH:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])=[O:12])=[CH:9][CH:8]=1.[Na]>C(O)C>[NH2:4][C:3]1[N:5]=[C:15]([OH:16])[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][C:7]([F:6])=[CH:8][CH:9]=2)=[C:20]([OH:21])[N:2]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(O)c(NC(=O)c2ccc(F)cc2)c(O)n1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
Guanidine hydrochloride (1.35 g, 14.1 mmol) and diethyl 2-(4-fluorobenzamido)malonate (example 1, 3.0 g, 10.1 mmol) were added to a solution of sodium (0.46 g, 20.2 mmol) in ethanol (50 ml). The reaction mixture was refluxed for 3 hours. The reaction was cooled down to room temperature. The solid product was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCl. The precipitate was collected, washed with water and dried to give the title compound as a white solid (1.41 g, 53%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]([F:16])([F:15])[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>>[F:6][C:7]([F:15])([F:16])[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][CH2:3][CH2:2][C:1]([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: Nc1ccccc1C(F)(F)F
Product: O=C(O)CCNc1ccccc1C(F)(F)F
Temperature: 75 °C
Reaction time: 32 h
Yield: 88 %

Procedure:
672 g of acrylic acid were added to 500 g of o-trifluoromethylaniline at 20°-25° C. with stirring while bubbling nitrogen therethrough and then 0.5 g of hydroquinone were added thereto in the dark. The mixture was heated to 75° C. over one hour and was then held at 75° C. for 32 hours. The mixture was cooled to 65°-70° C. and 500 ml of technical cyclohexane and 500 ml ofdemineralized water were rapidly added thereto. The mixture was refluxed for 10 minutes and was then slowly cooled to 2° to 4° C. andheld there for one hour. The mixture was vacuum filtered and the recovered crystals were washed and dried to obtain 636.7 g of β-(o-trifluoromethylanilino)-propanoic acid.