Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](Cl)=[CH:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)CCCCCCC=CC=CC.[C:27]([O-:30])(=[O:29])[CH3:28].[K+].C(O)(=O)C>C(OCC)(=O)C.O>[C:27]([O:30][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12])(=[O:29])[CH3:28]
Reactant: CCCCCCCCC=CC=CCl
Reactant: CC(=O)[O-]
Agent: CC=CC=CCCCCCCCCl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC=CC=CCCCCCCCOC(C)=O
Reaction time: 1 h

Procedure:
The particulars of the conversion of the dodecadienyl chloride to the alcohol that is CM pheromone are set forth below. To a 100 mL glass round-bottomed flask equipped with a reflux condenser, a stir bar and a nitrogen atmosphere were added 1.0 g (5 mmol) of 8,10-dodecadien-1-yl chloride, 8.1 g (8.3 mmol) potassium acetate and 40 ml of glacial acetic acid. This mixture was placed in a 150° C. oil bath for 76 hours, after which time GC analysis indicated that the reaction was >98% complete. The reaction mixture was poured into 100 ml of water and ice and stirred for one hour. Ethyl acetate (100 ml) was added and the organic phase was separated from the aqueous phase. The organic phase was washed with 4×50 mL of sodium bicarbonate-saturated water until the pH of the water was neutral, dried with sodium sulfate, filtered and the organic solvent was removed under reduced pressure to yield 8,10-dodecadienyl acetate as a yellow liquid. This acetate was dissolved into 30 ml of methanol and 1 ml of 6 M sodium hydroxide and stirred at room temperature for two hours. Methanol was removed under reduced pressure, 10 mL of heptane and 1 mL of 1 M HCl were added and the aqueous phase removed. The organic phase was placed in a -20° C. freezer for 18 hours. White crystals were removed by filtration to yield 200 mg of E,E-8,10-dedecadienol. Gas chromatography, 1H NMR and 13C NMR analysis of the product were identical to a standard sample of E,E-8,10-dodecadienol.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18](O)[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.O.[CH:23]([OH:25])=[O:24]>>[CH:23]([O:25][CH2:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH:13]=[C:14]4[C@:15]3([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19]4)[C@@H:7]1[CH2:8][CH2:9][C:10]2=[O:11])=[O:24]
Reactant: O=CO
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O
Product: C[C@]12CCCCC1=CC[C@H]1[C@@H]3CCC(=O)[C@@]3(COC=O)CC[C@@H]12
Temperature: 60 °C

Procedure:
Following the procedure described by Ringold (H. J. Ringold, et al., J. Am. Chem. Soc. 78, 816, 1956), dehydroepiandrosterone (2.88 g, 10 mmol) dissolved in 85% formic acid (100 mL) is heated at 60° C for 1 h. After cooling, the mixture is poured into iced water and after 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:63][CH2:62]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccc(NC2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c(C)c1
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.097 g, 0.00040 mol) in DMF (1 mL) was added DIPEA (0.233 g, 0.00180 mol), HOBt (0.053 g, 0.00040 mol) and EDCI.HCl (0.138 g, 0.0007214 mol) at ambient temperature. After 2 minutes (2,4-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.12 g (77%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,4-dimethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 432.23 (M+1)+, 97.64%, 1H NMR (DMSO-d6): δ 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (t, 2H), 7.4 (d, 1H), 7.1 (s, 1H), 6.6 (d, 1H), 4.3 (m, 2H), 4.1 (t, 2H), 3.9 (d, 1H), 3.5 (bs, 1H), 3.2 (t, 1H), 2.8 (t, 1H), 2.2 (s, 3H), 2.1 (s, 3H), 1.9 (t, 2H), 1.5 (m, 1H), 1.3 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:13]2[N:14]=[CH:15][CH:16]=[N:12]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cn2nccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A 18-mL vial was charged with 1-(chloromethyl)-4-nitro-benzene (500 mg, 3 mmol, 1 eq.), triazole (310 mg, 4.5 mmol, 1.5 eq.), potassium carbonate (1.24 g, 9 mmol, 3 eq.) and DMF (5 ml). After the resulting mixture was stirred at rt overnight, water (20 ml) was added. The precipitate was collected by filtration and washed with small amount of water. After drying, 340 mg of the title compound was obtained as a mixture of two regioisomers (340 mg, 55% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:14]=[C:15]([NH2:24])[C:16]2[C:21]([CH2:22]Cl)=[CH:20][O:19][C:17]=2[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:12][C:13]1[N:14]=[C:15]([NH2:24])[C:16]2[C:21]([CH2:22][NH:1][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:20][O:19][C:17]=2[N:18]=1
Reactant: Nc1nc(N)c2c(CCl)coc2n1
Reactant: Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc(N)c2c(CNc3cccc4ccccc34)coc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a 50 ml three neck round bottom flask was added sequentially anhydrous DMSO (5 ml), 1-aminonaphthalene (0.66 g), Compound 117 (0.50 g) and anhydrous potassium carbonate (0.69 g). The reaction mixture was stirred at 50° C. for 8 h under nitrogen in the dark. The reaction was then quenched with distilled water (15 ml) and the resultant suspension stirred at room temperature for 4 h, cooled to 5° C. and filtered. The residue was washed with cold water (2×5 ml) and then dissolved in hot MeOH, and the solution mixed with silica gel (2 g). The mixture was evaporated under reduced pressure and then dried in vacuo. The residue was ground into a fine powder and poured on top of a dry column of silica gel (40 g). The column was washed with MeOH in CHCl3: 200 ml (0.5%), 100 ml (1%), 100 ml (2%). The column then eluted with 3% MeOH in CHCl3. Fractions corresponding to a single spot of the product (TLC) were pooled and evaporated. The residue was washed with ether and air dried to afford 0.25 g (33%) of compound 423 as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:11]([N:13]([CH2:16]C)CC)C.C(Cl)(Cl)=[O:19].C1(C)C=CC=CC=1>O1CCCC1>[CH3:11][NH:13][C:16](=[O:19])[NH:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccsc1C(=O)OC

Procedure:
To a stirred solution of methyl-3-amino-thiophene-2-carboxylate (5 g, 31,8 mmole) and triethylamine (4,43 ml, 31,8 mmole) in dry tetrahydrofuran (100 ml) was added dropwise a 20% phosgene solution in toluene (31,8 mmole). After the addition had been completed the mixture was heated to reflux for 30 min, followed by filtration at room temperature. The filtrate was evaporated in vacuo, whereafter the crystalline residue was suspended in water (200 ml). Filtration of the suspension left the title compound as white crystals. M.p. 141°-142° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[CH:3]=[CH:4][N:5]=[CH:6][C:7]=2[C:8](=[O:10])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1ccncc1C(=O)O
Product: O=c1[nH]cnc2ccncc12
Yield: 47 %

Procedure:
Crude 4-amino nicotinic acid (2.72 g, 11.4 mmol) in formamide (20 mL) is heated to 170° C. for 12 h. The volatiles are distilled out under reduced pressure (0.8 mmHg). The residual solid is then purified on a medium pressure silica gel column, eluting with 10% MeOH in CHCl3 to give 3H-pyrido[4,3-d]pyrimidin-4-one (780 mg, 47%) as a whitish yellow solid. 1H NMR (DMSO) δ 12.64 (1H, brs), 9.28 (1H, s), 8.83 (1H, d, J=5.5 Hz), 8.30 (1H, s), 7.58 (1H, d, J=5.8 Hz).
Reaction SMILES: [C:1]([Cl:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([O:32][C:33](=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][OH:49])[CH3:31])=[O:28]>C(Cl)(Cl)Cl>[Cl:10][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([O:32][C:33](=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:49][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([Cl:10])=[O:9])[CH3:31])=[O:28])=[O:7])=[O:9]
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(OC(=O)CCCCCCCCCCCCCCCOC(=O)CCCCC(=O)Cl)OC(=O)CCCCCCCCCCCCCCCOC(=O)CCCCC(=O)Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
In a three-necked round bottomed flask equipped with a reflux condenser, a glass gas inlet tube and a pressure equalizing dropping funnel was placed freshly distilled adipoyl chloride (2.60 ml, 17.50 mmol) dissolved in absolute chloroform (15 ml). The temperature was raised to ca. 50° C. and under a gentle stream of nitrogen through the solution, a solution of ethylidene bis(16-hydroxy-hexadecanoate) (1.0 g, 1.75 mmol) in absolute chloroform (30 ml) was added dropwise and left at this temperature a further 3 hours after addition. The mixture was then cooled to room temperature and quickly transferred into a 50 ml round bottomed flask equipped for distillation under reduced pressure. Chloroform was first distilled off at normal pressure, then oil-pump vacuum was established and excess adipoyl chloride distilled off at ca. 75° C., 5 mbar pressure, leaving the residual title compound (1.56 g).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[CH:16]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([NH:13][C:15]2[CH:16]=[C:17]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(Cl)ncn1
Reactant: CC(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 90 °C
Yield: 13.5 %

Procedure:
A mixture of 18b (1.1 g, 5.9 mmol), 6a (1.5 g, 4.84 mmol) and diisopropylethylamine (3 mL, 18.1 mmol) in 15 mL of DMF was heated at 80° C. for 17 h and at 90° C. for 24 h. The mixture was diluted with 100 mL of DCM, washed with brine (3×50 mL) and the extracts were dried, filtered and concentrated under vacuum. The residue was purified by flash chromatography (elution with 50-100% ethyl acetate and 0.1% TEA in hexanes) and finally purified on preparative HPLC to afford 0.3 g (14%) of 18-1. tR=5.21 (Method 5). EC50: 611 nM.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:13][CH:14]=2)=[CH:4][CH:3]=1.[N:26]#[C:27][NH2:28].Cl>C(OCC)(=O)C.C(O)C>[NH2:28][C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:25])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[NH:26]
Reactant: N#CN
Reactant: Nc1ccc(CCc2csc(NC(=O)OCc3ccccc3)n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ccc(CCc2csc(NC(=O)OCc3ccccc3)n2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 53.6 %

Procedure:
A mixture of benzyl 4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-ylcarbamate (25 mg), cyanamide (6.0 mg), 4N hydrogen chloride in ethyl acetate (0.018 ml) and ethanol (1 ml) was stirred at 100° C. for 72 hours. The reaction mixture was concentrated in vacuo. To the residue was added ethyl acetate (5 ml) and saturated aqueous sodium hydrogen bicarbonate (5 ml). The precipitated solid was filtered and washed with ethylacetate and water to give benzyl 4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-carbamate (15 mg).
Reaction SMILES: C([S:4][CH2:5][S:6][C:7]1[N:8]=[N:9][NH:10][CH:11]=1)(=O)C.C[O-].[Na+].[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:59])[C@@H:38]([NH:39][C:40](=[O:58])/[C:41](/[C:45]4[N:46]=[C:47]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[S:48][CH:49]=4)=[CH:42]\[CH2:43][CH3:44])[C@H:35]3[S:34][CH2:33][C:32]=2OS(C)(=O)=O)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.CO.Cl.O>[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:59])[C@@H:38]([NH:39][C:40](=[O:58])/[C:41](/[C:45]4[N:46]=[C:47]([NH:50][C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])[S:48][CH:49]=4)=[CH:42]\[CH2:43][CH3:44])[C@H:35]3[S:34][CH2:33][C:32]=2[S:4][CH2:5][S:6][C:7]2[N:8]=[N:9][NH:10][CH:11]=2)=[O:30])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CC(=O)SCSc1c[nH]nn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
To a solution of 4-acetylthiomethylthio-1,2,3-triazole (230 mg: 1.22 mMol.) in dimethylformamide (6 ml) is dropwise added a 1.26N-sodium methoxide in methanol (1.9 ml) at -60° C., and the mixture is stirred for 20 minutes, mixed with a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (740 mg: 1 mMol.) in dimethylformamide (3 ml), and stirred at the same temperature for 40 minutes. The reaction mixture is diluted with 10% hydrochloric acid (2 ml) and water (30 ml) and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and purified by silica gel chromatography (toluene: ethyl acetate=2:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (553 mg) as colorless foam. Yield: 70%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]2[CH2:16][CH2:17]2)=[O:14])=[C:5]3[NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][N:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)cc1
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3cc(F)c(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 24.1 %

Procedure:
Following general procedure D, ((6-bromo-4-(4-((dimethylamino)methyl)phenylamino)-7-fluoroquinolin-3-yl)(cyclopropyl)methanone (40 mg, 0.090 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (31 mg, 0.113 mmol) to afford the desired product (11 mg, 24%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.06 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.75 (d, J=12 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.21 (d, J=6.5 Hz, 2H), 7.09 (d, J=8.5, 2H), 3.40 (s, 2H), 2.77 (quint, J=15 Hz, 1H), 2.13 (s, 6H), 0.86 (m, 4H); ESI MS m/z 508, [C28H24ClF2N3O2+H]+; HPLC 98.7% (AUC), tR=10.83 min.
Reaction SMILES: [CH3:1][NH2:2].S(C1C=CC(C)=CC=1)(O[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=O)=O>O1CCCC1>[CH3:1][NH:2][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCc1ccc(C)cc1
Yield: 180.8 %

Procedure:
9.2 g of methylamine are condensed at −20° C. into a solution of 5.8 g of 2-p-tolylethyl tosylate in 15 ml of abs. tetrahydrofuran and the mixture is stirred overnight at room temperature in a pressure vessel. After the pressure vessel has been opened at −20° C., it is allowed to come to room temperature in order to allow excess methylamine to evaporate. The reaction solution is taken up in ether, washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness in vacuo. 5.39 g of methyl-(2-p-tolylethyl)amine are obtained, which is reacted further as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[NH2:40].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:47][O:46][C:42]1[CH:41]=[C:39]([NH:40][C:24]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:26])[CH:38]=[C:37]([O:36][CH3:35])[C:43]=1[O:44][CH3:45]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(OC)c(OC)c(OC)c4)cc3)c2cc1OC
Yield: 85.7 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (66 mg) was added, and the admixture was refluxed with heat for 2 minutes. 3,4,5-Trimethoxyaniline (76 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 19 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 76 mg of the title compound (yield: 87%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:17])[CH2:11][N:12]1[N:16]=[CH:15][CH:14]=[N:13]1)[CH3:8].Br[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30].Cl>C1COCC1.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:17])[CH:11]([N:12]1[N:13]=[CH:14][CH:15]=[N:16]1)[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:28][C:29]=1[CH3:30])[CH3:8]
Reactant: Cc1oc(-c2ccccc2)nc1CCCC#CCBr
Reactant: CCOC(=O)Cn1nccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#CCCCc1nc(-c2ccccc2)oc1C)n1nccn1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Potassium t-butoxide (2.6 mL, 2.6 mmol) was added to a to a solution of [1,2,3]triazol-2-yl-acetic acid ethyl ester (355 mg, 2.3 mmol) in THF (30 mL) at −78° C. under N2 atmosphere and stirred for 1 hour. A solution of bromide 1-9 (1.5 g, 4.5 mmol) in THF (30 mL) was then added and the solution allowed to equilibrate to 0° C. for 1 hour. Reaction was then poured into dilute aqueous HCl and diluted with EtOAc. The organic layer was washed with water, brine, and dried over MgSO4. Chromatography with 20% EtOAc/Hex gave 550 mg of a mixture of mono-1-4 and bis-alkylated products. The mixture was not separated, and was taken on to hydrolysis step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([N:16]3[C:20]4=[C:21]5[CH:27]=[CH:26][NH:25][C:22]5=[N:23][CH:24]=[C:19]4[NH:18][C:17]3=[O:28])[CH2:11]2)=[N:8][CH:9]=1)([O-])=O.O.C([O-])=O.[NH4+]>C(O)C.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([N:16]3[C:20]4=[C:21]5[CH:27]=[CH:26][NH:25][C:22]5=[N:23][CH:24]=[C:19]4[NH:18][C:17]3=[O:28])[CH2:11]2)=[N:8][CH:9]=1
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1[C@@H]1CCCN(c2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCC[C@@H](n3c(=O)[nH]c4cnc5[nH]ccc5c43)C2)nc1
Temperature: 75 °C
Reaction time: 0.83 h
Yield: 47.8 %

Procedure:
To a solution of 1-[(3R)-1-(5-nitro-2-pyridinyl)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (19.3 mg) in ethanol (3 mL), tetrahydrofuran (1 mL), and water (0.15 mL) was added 10% Pd—C (50% wet, 10 mg) and ammonium formate (32 mg). After stirring for 50 minutes at 75° C., catalyst was removed by filtration, and solvent was also removed under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous sodium hydrogencarbonate, and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1 to 8:1) to give 1-[(3R)-1-(5-amino-2-pyridinyl)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (8.5 mg) as a pale brown crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[C:12]([CH2:14][N:15]1[C:20]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=2[O:18][CH2:17][C:16]1=[O:26])#[N:13].[H-].[Na+]>S(=O)(=O)(O)O.O>[C:12]([CH2:14][N:15]1[C:20]2[CH:21]=[C:22]([N+:1]([O-:4])=[O:2])[C:23]([F:25])=[CH:24][C:19]=2[O:18][CH2:17][C:16]1=[O:26])#[N:13]
Reactant: O=[N+]([O-])O
Reactant: N#CCN1C(=O)COc2cc(F)ccc21
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 95.2 %

Procedure:
98% nitric acid (0.71 g) was added dropwise to acetic anhydride (11.3 ml) at a temperature of 0° C. Subsequently a few drops of concentrated sulfuric acid were added thereto as catalyst, and the mixture was stirred for a while at 0° C. 4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.06 g) was added little by little thereto and stirred continuously at 0° C. for 30 minutes. A solution consisting of sodium hydride (10 g) and water (88 ml), cooled previously to 0° C., was added dropwise at 0° C. to neutralize the reaction liquor. The liquor was extracted with methylisobutyl ketone, and the extraction liquor was washed with water and a table salt solution, then dried with anhydrous sodium sulfate. The solvent was distilled off to give the desired 4-cyanomethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.39 g). mp. 204°-206° C.