Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][CH:30]([CH3:35])[C:31]([NH:33][NH2:34])=O>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:27][C:31]([CH:30]([CH3:35])[CH3:29])=[N:33][N:34]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)C(=O)NN
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)c1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)o1

Procedure:
100 mg the compound from Example 44A and 28 mg (0.273 mmol) of 2-methylpropanehydrazide were reacted according to the General Method 4. Yield: 45 mg (39% of theory).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[F:36])[C:30](Cl)=[O:31].O>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([NH:18][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:35]([F:36])=[C:27]([F:26])[CH:28]=3)[CH2:16][CH2:17]2)=[CH:3][CH:2]=1
Reactant: N[C@H]1CC[C@H](Oc2ccnc3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N[C@H]1CC[C@H](Oc2ccnc3ccccc23)CC1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-4-(4-Quinolyloxy)cyclohexylamine (400 mg, 1.65 mmol) was put in pyridine (12 mL) and catalytic amounts of triethylamine were added. At 0° C., 3,4-difluorobenzoyl chloride (291 mg, 1.65 mmol) was added. Then the reaction mixture was stirred at room temperature overnight. Water was added, and the precipitate was filtered off with suction. After drying, the desired product was obtained at 96% yield (610 mg).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:37]=[C:38]=O)(=O)=O.CN(C)C=O.Cl>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:38]#[N:37])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2)c1Cl)(c1ccccc1)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (1.20 g) in anhydrous dichloromethane (12 ml) was added a solution of chlorosulfonyl isocyanate (0.28 ml) in anhydrous dichloromethane (2.8 ml) dropwise in a dry ice-carbon tetrachloride bath. The mixture was stirred at the same temperature for 30 minutes and then at ambient temperature for additional 1 hour. Anhydrous dimethylformamide (0.4 ml) was added to this mixture dropwise in a dry ice-carbon tetrachloride bath. After stirring at the same temperature for 30 minutes and at ambient temperature for additional 1 hour, the reaction mixture was treated with 4N-hydrochloric acid under ice-water cooling for 30 minutes. The organic layer was isolated and the aqueous layer was extracted with chloroform twice. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluted with n-hexane—ethyl acetate to give 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]-2-cyanopyrrole (930 mg) as a pale yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([NH:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:26][CH2:25][CH2:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[I:12]
Reactant: NCCNc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1COCCO1
Product: Nc1nc(NCCNc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and N-phenylethylenediamine in dioxane. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: CCN(CC)CC.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]([C:30]2[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=2)[C:22](=[O:29])[NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:16][CH2:15]1>CN(C=O)C>[N:8]1([S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH:21]([CH2:20][CH:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[C:22]([NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[O:29])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reaction time: 0.17 h

Procedure:
NEt3 (120 μL, 868 μmol) and morpholine (76 μL, 868 μmol) were added to a stirred solution of 4-[2-(tetrahydropyran-4-yl)-1-(thiazol-2-ylcarbamoyl)ethyl]benzenesulfonyl chloride (Preparation 59, 300 mg, 723 μmol) in anhydrous DMF (4 mL). After 10 min, the solvents were removed in vacuo, then the residue was taken up in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with H2O (20 mL), 1M HCl (20 mL), H2O (20 mL), saturated aqueous Na2CO3 (20 mL), and brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and recrystallisation (CH2Cl2-IH) gave the title compound: RTA=3.15 min; m/z (ES+)=466.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([O:22][CH3:23])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:25]>O1CCOCC1>[NH2:25][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([O:22][CH3:23])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(NS(C)(=O)=O)c1
Reactant: N
Solvent: C1COCCO1
Product: COc1cc(NC(=O)c2c(N)ncnc2Cl)cc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 155.7 %

Procedure:
4,6-Dichloro-N-(3-methoxy-5-(methylsulfonamido)phenyl)pyrimidine-5-carboxamide (617 mg, 73% purity, 1.14 mmol) was dissolved in dioxane (5 ml) and cooled in an ice bath. Ammonia (819 μl, 7N in MeOH, 5.7 mmol) was added dropwise and the mixture stirred at 0° C. for 6 h and at room temperature overnight. The solvent was removed and ethyl acetate added. The solid precipitate was filtered off and the filtrate was concentrated to give 660 mg (100% yield) of the title compound as an oil that was used in the next step without further purification. Purity 65%
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC([CH2:14][N:15](C)[C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:28]4[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:29]=4[Cl:35])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][N:17]=2)=CC=1>C(Cl)Cl>[NH2:34][C:32]1[CH:31]=[CH:30][C:29]([Cl:35])=[C:28]([C:21]2[C:22](=[O:27])[N:23]([CH3:26])[C:24]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:15][CH3:14])[CH:25]=3)[CH:33]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)ccc2Cl)c(=O)n3C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1cc(N)ccc1Cl)c(=O)n2C
Yield: 58.7 %

Procedure:
TFA (10 mL, 134 mmol) was added to a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (4 g, 9.2 mmol) in DCM (50 mL) and heated to reflux for 3 h. The reaction mixture was concentrated under reduced pressure, dissolved in HCl, washed with EtOAc (3×), neutralized with satd. Na2CO3 and extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by chromatography to give 3-(5-amino-2-chlorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1.7 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.63 (s, 1H), 7.06-7.00 (m, 2H), 6.54-6.50 (m, 2H), 6.14 (s, 1H), 5.21 (s, 2H), 3.48 (s, 3H), 2.84 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 314.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:7][C:5]3[S:6][C:2]([CH3:1])=[N:3][N:4]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Cc1nnc(S)s1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnc(C)s3)C(=O)O)cc2)cc1

Procedure:
Example 31 is prepared from 5-methyl-1,3,4-thiadiazole-2-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@@H:22]([NH2:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:30][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(Cl)cc3)ncnc12

Procedure:
Compound 36 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-chloro-phenyl)-ethylamine dihydrochloride to give the title compound as an off-white solid. LC/MS [383 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.27-8.84 (m, 2H), 8.53 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 5.37-4.98 (m, 2H), 3.16-2.94 (m, 3H), 2.78 (dd, J=11.9, 5.3 Hz, 1H), 2.07-1.65 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH2:6][CH2:5]1.[C:28](O)(=[O:30])[CH3:29]>>[CH3:1][CH:2]([C:21]1[CH:22]=[C:23]([NH:24][C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1)[CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH2:8][CH2:9]1
Reactant: Cc1ccc2c(N3CCN(CC(C)c4cccc(N)c4)CC3)cccc2n1
Reactant: CC(=O)O
Product: CC(=O)Nc1cccc(C(C)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield according to the general procedure for the preparation of amides (Method C) starting from 3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D21) and acetic acid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:10]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:11][CH2:12][CH3:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:4]([O:6][CH2:16][C:15](=[O:18])[NH:14][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: CCCCNC(=O)CCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCCNC(=O)COC(=O)/C=C/C(=O)OC
Yield: 20.3 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-butyl chloroacetamide (0.69 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.19 g (21% yield) of the title compound (4) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.98-6.92 (m, 2H), 6.09 (br s, 1H), 4.68 (s, 2H), 3.82 (s, 3H), 3.34-3.29 (q, 2H, J=6.4 Hz), 1.54-1.48 (m, 2H), 1.38-1.32 (m, 2H), 0.956-0.920 (t, J=7.6 Hz, 3H). MS (ESI): m/z 244.04 (M+H)+.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([S:14]C(=O)N(C)C)=[CH:6][C:5]=1C.[CH3:22]C(C[AlH]CC(C)C)C.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:10]([C:8]1([CH3:22])[CH:9]=[C:4]([CH2:3][OH:21])[CH:5]=[CH:6][CH:7]1[SH:14])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: COC(=O)c1cc(C(C)(C)C)c(SC(=O)N(C)C)cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)C1(C)C=C(CO)C=CC1S
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 12.2 g (39.4 mmol) of 5-tert-butyl-4-dimethylcarbamoylsulfanyl-2-methyl-benzoic acid methyl ester (prepared in Example DDD) in toluene (140 mL) cooled to -78° C. under nitrogen was added 1.0 M DIBAL/CH2Cl2 (236.6 mL), dropwise over a 2.5 hour period. The reaction mixture was stirred an additional 30 minutes at -78° C. following addition, then at 0° C. for 1 hour. Saturated aqueous citric acid solution (approximately 600 mL) was added very slowly and carefully. The mixture was then extracted twice with EtOAc; the organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.47 (s, 9 H), 2.27 (s, 3 H), 3.57 (s, 1 H), 4.63 (s, 2 H), 7.06 (s, 1 H), 7.32 (s, 1 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:7](O)=[O:8]>>[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:7]([Cl:3])=[O:8]
Reactant: CCCCCCC(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCC(C)C(=O)Cl
Yield: 100 %

Procedure:
Then, 2.38 g (19.0 mmol) of thionyl chloride was charged into a flask and maintained at a temperature of 36°~38° C., to which was added dropwise 2.15 g (15.9 mmol) of the above (+)-2-methyloctanoic acid in 7 minutes with stirring. The resulting mixture was stirred at room temperature for 40 minutes and at a temperature of 80° C. for 30 minutes. Then, the reaction product was distilled to obtain 2.81 g (15.9 mmol, yield 100%) of a colorless and transparent (+)-2-methyloctanoic acid chloride.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([NH:15][C:16]2[N:21]=[C:20]([N:22]([CH:32]3[CH2:34][CH2:33]3)CC3C=CC(OC)=CC=3)[C:19]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]3[N:17]=2)=[CH:13][C:12]([C:40]#[N:41])=[CH:11][C:10]=1[N:42]1[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][C:43]1=[O:55].C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:10]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][C:43]2=[O:55])=[CH:11][C:12]([C:40]#[N:41])=[CH:13][C:14]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][CH:32]2[CH2:34][CH2:33]2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C(=O)OC(C)(C)C)CC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCNCC2=O)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazine-1-carboxylate (10 mg, 0.015 mmol) and anisole (6.53 μl, 0.060 mmol) in DCE (1 mL) and the reaction mixture was heated at 60° C. for 30 min. LC-MS indicated completion, then it was cooled and concentrated. The crude was dissolved in methanol and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated, purification via preparative HPLC gave the title compound as a yellow solid (3.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[C:18]([O:23]C(=O)C)[CH:19]=[C:20]([CH3:22])[CH:21]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[C:18]([OH:23])[CH:19]=[C:20]([CH3:22])[CH:21]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Oc1cc(C)cc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)cc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of acetic acid 3-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-5-methylphenyl ester (1.97 g; 4.88 mmol), 2N-aqueous sodium hydroxide (10 ml) and methanol (20 ml) was stirred at 40° C. for 1 hour. The solvent was evaporated under reduced pressure. To the residue were added water and 2N-aqueous hydrochloric acid to be neutral. Ethyl acetate was added thereto and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (ethyl acetate) to give 3-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-5-methylphenol as colorless amorphous solid (1.83 g; 100%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33]O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cccc(C=O)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Diisopropylazodicarboxylate (2.0 mL, 10 mmol) was added to a solution of 3-hydroxybenzaldehyde (1.23 g, 10 mmol), 2-(t-butyloxycarbonylamino) ethanol (1.6 g, 10 mmol), and triphenylphosphine 2.7 g, 10 mmol) with stirring in dry THF (50 mL) in an ice bath. After allowing the reaction mixture to warm to room temperature overnight, the solvent was evaporated under vacuum. The mixture was diluted with EtOAc (300 mL) and extracted with 1M NaOH (20 mL), water (2×20 mL), and brine (10 mL). After drying (MgSO4), and evaporation, the product was purified by chromatography on silica gel, eluting with 0% to 50% EtOAc in hexane. Evaporation of solvent yielded a pale yellow viscous oil (1.6 g), which was only about 80% pure. 1H NMR(300 MHz, CDCl3): major component 9.97 (s, 1H), 7.48-7.13 (m, 4H), 4.97 (br, 1H), 4.09-4.05 (m, 2H), 3.58-3.53 (m, 2H), 1.45 (s, 9H). IR(neat): cm-1 3353 (s, br), 1694 (s). MS(NH3): 283 (base, M+NH4).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:36][CH2:35][N:34]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:33][CH2:32]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: COc1ccccc1C1CCNCC1
Product: COc1ccccc1C1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4-(2-methoxyphenyl)piperidine (1.2 equiv) to give 186 (17.9 mg, M+1 487.1)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([CH2:7][C@@H:8]2[C@H:11]([NH:12]C(=O)OCC3C=CC=CC=3)[C:10](=[O:23])[NH:9]2)[N:3]=1>CO.[Pd]>[NH2:12][C@H:11]1[C@@H:8]([CH2:7][N:4]2[CH:5]=[N:6][C:2]([CH3:1])=[N:3]2)[NH:9][C:10]1=[O:23]
Reactant: Cc1ncn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ncn(C[C@H]2NC(=O)[C@H]2N)n1
Reaction time: 2 h

Procedure:
A slurry of benzyl ((2R,3S)-2-((3-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (250 mg, 0.79 mmol) and Pd on C (10%, 100 mg) in MeOH (20 mL) was evacuated and backfilled with H2 (3×), bringing the final pressure to 35 psi. After 2 h of stirring the mixture was filtered over celite, washing with MeOH and the filtrate was concentrated in vacuo. The crude residue was used as such in the following step.
Reaction SMILES: C(NC(OC1C=C(C(=O)C[Br:21])C=C(OC(=O)NCC)C=1)=O)C.[CH2:23]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[BrH:21].[CH2:23]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNC(=O)Oc1cc(OC(=O)NCC)cc(C(=O)CBr)c1
Agent: CC(C)(C)NCc1ccccc1
Solvent: CC(C)=O
Product: Br

Procedure:
To a solution of 8.0 g of 3',5'-bis-(N-ethylcarbamoyloxy)-2-bromo acetophenone in 100 ml of acetone was added 7.0 g of N-benzyl-t-butylamine. The mixture was refluxed for 18 hours. The 4.1 g of N-benzyl-t-butylamine hydrobromide formed and precipitated during the reaction was filtered off and the filtrate was acidified with conc HCl. The filtrate was now evaporated to dryness and the title compound was isolated by column chromatography on Silica gel 60 using 1) CHCl3 /ethanol (2:1), 2) ethanol as eluants. The title compound was eluted in the ethanol fraction and recrystallized from ethanol/diethylether. The identity of the product was confirmed with NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:14][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: BrP(Br)Br
Reactant: Cc1ccc([N+](=O)[O-])cc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1CBr
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a slight suspension of (2-methyl-5-nitrophenyl)methanol (2.0 g, 12 mmol) in DCM (20 ml) in an ice-water bath under nitrogen was a added a solution of phosphorus tribromide (1.13 mL, 12 mmol, Aldrich) in DCM (20 ml). The resulting solution was allowed to warm to ambient temperature and stirred for 45 min. The solution was poured onto a mixture of ice-water (50 ml) and saturated sodium hydrogen carbonate (50 ml). The biphasic mixture was diluted with dichloromethane (50 ml) and the phases separated. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give 2-(bromomethyl)-1-methyl-4-nitrobenzene as a pale yellow solid (1.81 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[C:3]=1[C:12]1[C:21]2[N:20]=[CH:19][CH:18]=[N:17][C:16]=2[C:15]([C:22]([OH:24])=O)=[CH:14][CH:13]=1.Cl.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:22]([C:15]3[C:16]4[N:17]=[CH:18][CH:19]=[N:20][C:21]=4[C:12]([C:3]4[C:4]([CH3:11])=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([CH3:8])[C:2]=4[Cl:1])=[CH:13][CH:14]=3)=[O:24])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: COc1cc(C)c(Cl)c(-c2ccc(C(=O)O)c3nccnc23)c1C
Agent: Cl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(C)c(OC)cc(C)c4Cl)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2-chloro-5-methoxy-3,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Step 98.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Step 26.1) and stirring the reaction mixture for 20 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 545.0 [M+H]+; tR=3.91 min (System 1); TLC: R=0.23 (DCM/MeOH/NH3aq, 94:5:1).