Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:40])([F:39])[C:15]1[CH:16]=[C:17]([C:25]#[C:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[CH2:30][CH2:29]2)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>O1CCCC1>[F:22][C:21]([F:24])([F:23])[C:19]1[CH:18]=[C:17]([C:25]#[C:26][CH2:27][N:28]2[CH2:29][CH2:30][CH:31]([C:34]([CH3:37])([CH3:38])[CH2:35][O:36][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:32][CH2:33]2)[CH:16]=[C:15]([C:14]([F:39])([F:13])[F:40])[CH:20]=1
Reactant: CC(C)(CO)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(COS(C)(=O)=O)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 5 h
Yield: 67.1 %

Procedure:
Triethylamine (0.75 g), followed by methylsulphonyl chloride (0.85 g) were added to a solution of 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-hydroxyethyl)piperidino]-prop-1-yne (3.0 g) in tetrahydrofuran (50 ml). After stirring for 5 hours, the precipitate of triethylamine hydrochloride was filtered off, and the filtrate was evaporated in vacuo to give a brown gum. This gum was purified by medium pressure chromatography using a mixture of dichloromethane and ethyl acetate (85:15) as eluent to give 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-methylsulphonyloxyethyl)piperidino]prop-1-yne (2.4 g) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10](Cl)=[CH:9][C:8]=1Cl>O1CCOCC1>[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:9][C:8]=1[NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: COCCN
Solvent: C1COCCO1
Product: COCCNc1cc(NCCOC)c([N+](=O)[O-])cc1Cl
Reaction time: 4 h

Procedure:
0.9 mole (67.6 g) of 2-methoxyethylamine is heated to reflux in 30 ml of dioxane. 0.15 mole (34 g) of 1,2,4-trichloro-5-nitrobenzene is added portionwise. Heating under reflux is carried out for 4 hours. After cooling, dilution with iced water and neutralization with concentrated hydrochloric acid, the expected product is filtered off. Recrystallized from 96° ethanol, it melts at 106° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([OH:34])[CH:33]=1)[C:28](O)=[O:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:28](=[O:29])[C:27]2[CH:26]=[C:25]([OH:24])[CH:33]=[C:32]([OH:34])[CH:31]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Reactant: O=C(O)c1cc(O)cc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3cc(O)cc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 3,5-dihydroxybenzoic acid as brown solid (37%). MS 454 (MH+).
Reaction SMILES: [C@@H:1]1([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[CH:14][CH:15]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[I:17]I.[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C@@H:1]1([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: II
Reactant: O=c1[nH]cccc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1[nH]cc(I)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 110 °C
Yield: 29.3 %

Procedure:
3-(β-D-Ribofuranosyl)-pyridin-2(1H)-one (342 mg, 1.5 mmol) (Matulic-Adamic, J., Beigelman, L., Tetrahedron Lett., 1997, 38, p. 203-206; Ishikawa, M., Hirao, I., Yokoyama, S., Tetrahedron Lett., 2000, 41, p. 3931-3934), iodine (573 mg, 2.3 mmol) and potassium iodide (KI) (657 mg, 7.9 mmol) were added to 50 mM sodium carbonate (36 ml) and heated at 110° C. for 12 hours. After the reaction, dichloromethane was added to separate the aqueous layer, followed by washing with dichloromethane. The aqueous layer was concentrated under reduced pressure and then purified by C18 reversed-phase HPLC to give 3-(β-D-ribofuranosyl)-5-iodopyridin-2(1H)-one (155 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16]Br)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[I-:18].[Na+]>C(C(C)=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][I:18])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(N)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)/C(=N\OCCI)c1csc(N)n1
Yield: 90.5 %

Procedure:
80.55 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-bromoethoxy)imino]-acetate and 187.4 g of sodium iodide are boiled under reflux in 1.5 l of methyl ethyl ketone for 1.5 hours. After removal of the solvent by evaporation, the residue is partitioned between 0.6 l of water and 0.2 l of ethyl acetate, the aqueous phase is back-extracted twice with 0.2 l of ethyl acetate each time, the organic extracts are thereupon combined, washed with 0.2 l of aqueous 15% sodium chloride solution, dried and evaporated. The residue is recrystallized from 0.7 l of toluene. 83.5 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-iodoethoxy)imino]acetate are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62](Br)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH:50]2[CH2:68][CH:47]1[CH2:48][CH2:49]2)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([O:43][C:44]([N:46]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH:50]2[CH2:68][CH:47]1[CH2:48][CH2:49]2)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 37.1 %

Procedure:
To a solution of [2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (0.95 g, 1.82 mmol) and 3-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.96 g, 1.82 mmol, 1 equiv.) in DME (20 mL) was added K2CO3 (aqueous, 2 M, 3.6 mL, 7.2 mmol, 4 equiv.) and Pd(PPh3)4 (0.11 g, 0.09 mmol, 0.05 equiv.). The slurry was degassed with argon for 5 minutes and heated to 80° C. for 12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was back-extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes) to provide 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.53 g, 37%) as a yellow powder.
Reaction SMILES: I[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:34][CH:35]=2)O1>>[N:36]1([C:33]2[N:34]=[CH:35][C:30]([C:2]3[CH:21]=[N:20][C:5]4[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]5[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=5)[C:4]=4[CH:3]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(CN2CCNc3ncc(I)cc32)o1
Product: FC(F)(F)c1ccc(CN2CCNc3ncc(-c4ccc(N5CCOCC5)nc4)cc32)o1
Yield: 30 %

Procedure:
7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (60 mg) was reacted with 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholine as in General Procedure 4A to give the title compound as an orange foam (30% yield). M.p. (foam), LCMS: m/z=446.13 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.42-3.47 (m, 2H), 3.48-3.54 (m, 4H), 3.58-3.67 (m, 2H), 3.80-3.89 (m, 4H), 4.47 (s, 1H), 5.02 (bs, 1H), 6.30 (s, 1H), 6.67 (d, J=5.2 Hz, 1H), 6.72 (s, 1H), 6.85 (s, 1H), 7.55-7.62 (m, 2H), 8.31 (s, 1H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.S(=O)(O)[O-].[Na+].NCCCC(O)=O.C(CCCNC1C=CN([C@@H]2O[C@H](CO)[C@@H](O)C2)C(=O)N=1)(O)=O.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.NCCCCN.NCCCC.N[C:79]1[CH:80]=[C:81]([CH:85]=[CH:86][CH:87]=1)[C:82]([OH:84])=[O:83]>>[C:82]([C:81]1[CH:80]=[C:79]([NH:14][C:13]2[CH:15]=[CH:16][N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]3)[C:10](=[O:11])[N:12]=2)[CH:87]=[CH:86][CH:85]=1)([OH:84])=[O:83]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: NCCCC(=O)O
Agent: NCCCCN
Agent: O=C(O)CCCNc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: CCCCN
Product: O=C(O)c1cccc(Nc2ccn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)n2)c1

Procedure:
Efficient transamination of deoxycytidine is shown to have occurred when the reaction was carried out in the presence of 1M sodium bisulfite and 3M amine at pH 7.2 at a temperature of 48° C. While these conditions can be varied, it is noted that under the conditions used, the nucleoside was converted to 90% or greater of the transaminated product as determined by HPLC analysis. For example, transamination by 4-aminobutyric acid gave 93% of N4 -(3-carboxypropyl)deoxycytidine, 6% deoxyuridine and 1% deoxycytidine. Similar results were obtained when transamination was carried out with 1,4-diaminobutane or 1-aminobutane. Less efficient transamination was observed with 3-aminobenzoic acid, which gave N4 -(3-carboxyphenyl)deoxycytidine in approximately 30%. In this case, the lower extent of reaction appears to be due to the bulky nature of the amine and the lower solubility of the amine which only allowed a 1M solution to be prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1[C:48]([CH2:49]O)=[CH:47][CH:46]=[CH:45][N:44]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:49][C:48]2[C:43]([CH3:42])=[N:44][CH:45]=[CH:46][CH:47]=2)=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(O)ccc2Cl)cc1
Reactant: Cc1ncccc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccnc3C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 4-({[(2-chloro-5-hydroxyphenyl)carbonyl]amino}methyl)benzoate (100 mg, 0.31 mmol) in THF (5 ml) was treated with triphenylphosphine (1.2 eq, 98 mg, 0.37 mmol), (2-methyl-3-pyridinyl)methanol (38 mg, 0.31 mmol) and diisopropylazodicarboxylate (1.2 eq, 110 ul, 0.56 mmol) and stirred at room temperature for 4 hours. Mixture diluted with methanol and purified by SCX cartridge eluting with methanol first then 2M ammonia in methanol. Basic fractions combined and evaporated to give the title compound as an off-white solid. MS (ES+) m/z 425 [M+H]+ (C23H2135ClN2O4). 1H-NMR (400 MHz, d6-DMSO) δ 3.85 (3H, s), 4.51 (2H, d, J 6), 5.18 (2H, s), 7.10-7.96 (9H, m), 8.42 (1H, dd, J 1.6, J 4.8), 9.07 (1H, t, J 6).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1>>[S:12]1[C:13]([C:4]2[CH:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: Clc1ccnc2ccccc12
Reactant: c1ccc2sccc2c1
Product: Clc1cc(-c2cc3ccccc3s2)nc2ccccc12

Procedure:
The title compound, m. p. 142-145° C., MS: m/e=295 (M+), was prepared from 4-chloro-quinoline and 1-benzothiophene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=O>CN(C1C=CN=CC=1)C.ClCCl>[C:21]([C:26]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17](=[O:19])[CH3:18])=[CH:3][C:2]=2[N:1]=1)([CH3:25])([CH3:22])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)Nc1ccc(NCC2CCCCC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCCCC1

Procedure:
Following the same procedure of Example 6, a mixture of N-{3-amino-4-[(cyclohexylmethyl)amino]phenyl}acetamide (1.57 g, 6.0 mmol) (for preparation see in Example 6, step D) and DMAP (0.15 g, 1.2 mmol) in dichloromethane (70 mL) was treated with trimethylacetyl choride (0.83 g, 6.6 mmol) at −10° C. After evaporation of the solvent, the residue was dissolved in 1,2-dichloroethane (40 mL) and then divided into eight Teflon-capped test tubes. The vessels were irradiated by microwave for 2 h at 170° C. After purification by MPLC (EtOAc as eluent on silica gel), the desired title compound was obtained as a white solid (1.42 g, 72%). 1H NMR (400 MHz, CD3OD): δ 1.24 (m, 5H), 1.64 (m, 2H), 1.67 (s, 9H), 1.70 (m, 1H), 1.77 (m, 2H), 2.12 (m, 1H), 2.18 (s, 3H), 4.45 (d, J=7.62 Hz, 2H), 7.50 (m, 1H), 7.84 (d, J=8.98 Hz, 1H), 8.43 (d, J=1.95 Hz, 1H). MS (ESI) (M+H)+: 328.3. Anal. Calcd for C20H29N3O+1.20 TFA+0.30H2O (469.71): C, 57.28; H, 6.61; N, 8.95. Found: C, 57.34; H. 6.67; N, 8.85.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)(=[O:7])=[O:6])[C:2]#[CH:3].[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([NH:4][S:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)(=[O:6])=[O:7])[C:2]#[CH:3]
Reactant: C#CCNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C#CCNS(=O)(=O)Cc1ccc(N)cc1

Procedure:
4-(Prop-2-ynylaminosulfonylmethyl)nitrobenzene (0.437 g, 1.72 mmol), iron (0.48 g, 8.6 mmol), and NH4Cl (0.24 g, 4.5 mmol) were vigorously stirred in ethanol:water (1:1, 40 mL) at 70° C. for 25 minutes. The reaction mixture was filtered hot through Celite and concentrated in vacuo. The residue was suspended in 10% 2N ammoniacal methanol in dichloromethane, sonicated, and filtered through Celite. Concentration gave 4-(Prop-2-ynylaminosulfonylmethyl)aniline as a brown oil which was purified by column chromatography (silica gel, dichloromethane ramped to methanol:dichloromethane (0.75:100)). 1H NMR (DMSO-d6): δ 7.45 (t, J=5.4 Hz, 1H), 6.99 (d, J=8.1 Hz, 2H), 6.50 (d, J=8.1 Hz, 2H), 5.15 (s, 2H), 4.12 (s, 2H), 3.68 (dd, J=2.1 and 5.7 Hz, 2H), 3.31 (t, J=2.1 Hz, 1H); LCMS: purity: 97%; MS (m/e): 225 (MH+).
Reaction SMILES: Cl.[C:2]1([C:8]2[NH:13][C:12]3[CH:14]=[N:15][CH:16]=[CH:17][C:11]=3[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[ClH:18].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:10]2[C:11]3[CH:17]=[CH:16][N:15]=[CH:14][C:12]=3[NH:13][C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(c1ccc(Cl)cc1)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 68 %

Procedure:
3.8 g (0.015 moles) of 3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with p-chlorobenzoyl chloride as described in Example 2 to obtain 1-(p-chlorobenzoyl)-3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 68%; m.p.: 215° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1.[OH-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:28][C:29]3[CH:38]=[C:37]4[C:32]([CH:33]=[CH:34][CH:35]=[N:36]4)=[CH:31][CH:30]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCc1ccccc1
Yield: 60.7 %

Procedure:
To a suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.82 g, 6.1 mmol), (prepared as described for the starting material in Example 1), in DMF (50 ml) was added potassium carbonate (2.50 g, 18.1 mmol) and 7-hydroxyquinoline (1.06 g, 7.3 mmol), and the reaction heated under reflux at 90C for 4 hours. The reaction was poured into 1N aqueous sodium hydroxide and the resulting precipitate filtered, washed with water, and dried under suction. Further drying in a vacuum oven gave 7-benzyloxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (1.50 g, 3.7 mmol, 60%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: COC(=O)C1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)CCC(=O)CC1
Yield: 95.4 %

Procedure:
Methyl 1-methyl-4-oxo-2-cyclohexenecarboxylate [J. Am. Chem. Soc., 101, 6996 (1979)] (100 g) was dissolved in ethyl acetate (600 ml), 10% Pd-C (5 g) was added, and catalytic reduction was carried out at room temperature and 1 atomosphere. About 14 liters of hydrogen was absorged in about 2 hours. The catalyst was filtered off, and the filtrate was concentrated and distilled under reduced pressure to give methyl 1-methyl-4-oxocyclohexanecarboxylate (96.5 g, 95.4%, b.p. 82°-84° C./0.5 mmHg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:23]([O-])=O)[N:3]=1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:23][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.720 g, 2.097 mmol) and NH4Cl (3.37 g, 62.9 mmol) in MeOH (10 mL) and THF (10 mL) was treated with zinc dust (1.371 g, 20.97 mmol) and stirred at RT overnight. The mixture was diluted with EtOAc, the solids removed via filtration and the filtrate concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (658 mg, 100%). MS (ESI) m/z: 314.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[N:22]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:32][CH2:31]4)=[O:34])=[CH:36][CH:37]=3)=[CH:15][C:6]1=2
Reactant: O=C1CNc2ncc(I)cc2N1Cc1c(Cl)cccc1Cl
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)C(=O)CN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 35 %

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (60 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a brown solid (35% yield). M.p.=199° C., LCMS: m/z=564.03 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.89 (6H, m), 2.25 (1H, m), 2.59 (5H, s), 2.99 (3H, m), 3.80 (1H, bs), 4.26 (2H, d, J=1.3 Hz), 4.60 (1H, bs), 4.84 (1H, bs), 5.56 (2H, s), 7.17 (1H, m), 7.33 (5H, m), 7.41 (2H, d, J=8.1 Hz), 7.94 (1H, d, J=1.8 Hz),
Reaction SMILES: [CH3:1][OH:2].[F:3][C:4]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6](Cl)=[O:7]>C(OCC)(=O)C>[F:3][C:4]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([O:2][CH3:1])=[O:7]
Reactant: CO
Reactant: Cc1cc(F)c(C(=O)Cl)cc1F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(C)cc1F
Yield: 62 %

Procedure:
Methanol (10 mL) was added to 2,5-difluoro-4-methyl-benzoyl chloride (500 mg, 2.6 mmol) and the solution evaporated to give an oil. The oil was dissolved in ethyl acetate and extracted with saturated aqueous sodium carbonate solution (20 mL) and brine (2×20 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound as clear colourless solid (300 mg, 62%).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:17]=[C:16]([NH:18][C@H:19]([C:29](O)=[O:30])[CH2:20]C3C=CC(OC)=CC=3)[O:15][C:14](=[O:32])[C:13]=2[C:33]=1[CH3:34])=[O:6])[CH3:3].[N:36]1(C(N)=O)[CH2:41]COC[CH2:37]1>>[CH3:37][N:36]([CH3:41])[C:29](=[O:30])[C@H:19]([CH3:20])[NH:18][C:16]1[O:15][C:14](=[O:32])[C:13]2[C:33]([CH3:34])=[C:9]([CH2:8][NH:7][C:5]([O:4][C:2]([CH3:3])([CH3:1])[CH3:35])=[O:6])[CH:10]=[CH:11][C:12]=2[N:17]=1
Reactant: NC(=O)N1CCOCC1
Reactant: COc1ccc(C[C@H](Nc2nc3ccc(CNC(=O)OC(C)(C)C)c(C)c3c(=O)o2)C(=O)O)cc1
Product: Cc1c(CNC(=O)OC(C)(C)C)ccc2nc(N[C@@H](C)C(=O)N(C)C)oc(=O)c12

Procedure:
N-[6-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl]-O-methyl-L-tyrosine, morpholineamide;
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:25][CH:24]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Product: O=c1ccc(-c2ccc(CCNCC(O)COc3ccc(CCOCC4CCC4)cc3)cc2)n[nH]1

Procedure:
Prepared analoqously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethyl)phenyl]-3(2H)-pyridazinone.