Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[N:57]=[C:56]([CH2:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[CH2:66][C:67]([O-:69])=O)[C:55]([C:70]([F:73])([F:72])[F:71])=[CH:54][N:53]=3)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:2][C:67](=[O:69])[CH2:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[CH2:59][CH2:58][C:56]1[C:55]([C:70]([F:73])([F:72])[F:71])=[CH:54][N:53]=[C:52]([NH:51][C:48]2[CH:49]=[CH:50][C:45]([CH:42]3[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[CH2:44][CH2:43]3)=[CH:46][CH:47]=2)[N:57]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Hydroxybenzotriazole (32.8 mg, 0.243 mmol), EDCl (46.6 mg, 0.243 mmol) and N,N-diisopropylethylamine (84.6 μL, 0.486 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I48) (0.130 g, 0.221 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (84.8 mg, 0.883 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (50 mL), transferred to a separating funnel and washed with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (2×50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow solid. The crude material was purified by column chromatography on silica gel (0-80% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I49) (90.8 mg, 70%) as a white foamy solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.53 (m, 3H), 7.31-7.23 (m, peaks obscured by CDCl3), 7.20 (d, J=8.5 Hz, 2H), 5.37 (s, 1H), 5.29 (s, 1H), 4.25 (b s, 2H), 3.72 (s, 2H), 3.15-3.03 (m, 4H), 2.80 (t, J=12.4 Hz, 2H), 2.69-2.59 (m, 1H), 1.83 (d, J=12.6 Hz, 2H), 1.68-1.55 (m, peaks obscured by water peak), 1.49 (s, 9H). LCMS Method C: rt 6.48 min; m/z 606 [M+Na]+, 584 [M+H]+, 528 [M-tButyl+2H]+, 484 [M-Boc+2H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CN(C=O)C>O>[CH2:31]([N:12]1[C:11](=[O:23])[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:13]1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: COc1ccc(-c2n[nH]c(=O)nc2-c2ccc(OC)cc2)cc1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nc1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
A mixture of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-one (2.14 g, 6.9 mmol), freshly ground potassium carbonate (1.45 g, 10.5 mmol), 1.43 g of iodopentane (7.2 mmol) and 11 mL of DMF were stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and stripped. Column chromatography gave 0.4 g of Compound 8.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1)#[N:2].Br[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34]>>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[N:20]([CH2:32][C:33]([OH:35])=[O:34])[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Product: N#Cc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CC(=O)O)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
[(5Z)-5-({1-[4-Cyano-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from [(5Z)-5-({1-[4-cyano-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 246) and tert-butyl bromoacetate following General Procedure I.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][NH:27][C:29](=[O:31])[CH3:30])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC(C)=O)cc1
Temperature: 0 °C
Yield: 85.3 %

Procedure:
2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (141 mg, 0.25 mmol, prepared as described in Example 1) and diisopropypethylamine (75 μl, 0.43 mmol) were dissolved in dichloromethane (10 ml) with stirring. The flask was then flush with nitrogen and sealed with a rubber septum before being cooled to 0° C. Acetyl chloride (20 μl, 0.28 mmol) was added dropwise to the solution, which was then warmed slowly to room temperature. After 2 hours of stirring, the reaction was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexane/ethyl acetate (3:1) as eluent, which afforded 95 mg (86%) of 7-(acetylamino-methyl)-2-amino-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][C:20](=[O:24])[NH:21]3)=[CH:17][CH:16]=2)=[O:14])[CH:8]=1)=[O:5].[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:19]1[C:18]2[C:22](=[CH:23][C:15]([C:13]([C:9]3[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[CH3:1])[CH:12]=[CH:11][CH:10]=3)=[O:14])=[CH:16][CH:17]=2)[NH:21][C:20]1=[O:24]
Reactant: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 83 %

Procedure:
2-Methyl-N-[3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-benzamide (5.00 g, 13.499 mmol) and ethyl formate (3.24 mL, 40.3 mmol) were dissolved in anhydrous ethanol (135 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (25.2 mL, 67.47 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a light yellow precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-2-methyl-benzamide (4.464 g, 11.2 mmol, 81%).
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:21])[C:8]([NH:19][NH2:20])([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)(=[O:3])[CH3:2].BrC1[C:32]2[C:27](=[CH:28][CH:29]=C[CH:31]=2)C(=O)O1>>[O:3]=[C:1]1[C:2]2[C:29](=[CH:28][CH:27]=[CH:32][CH:31]=2)[CH:5]([O:6][C:7](=[O:21])[C:8]([NH:19][NH2:20])([CH3:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=2)[O:4]1
Reactant: CC(=O)OCOC(=O)C(C)(Cc1ccc(O)c(O)c1)NN
Reactant: O=C1OC(Br)c2ccccc21
Product: CC(Cc1ccc(O)c(O)c1)(NN)C(=O)OC1OC(=O)c2ccccc21

Procedure:
Following the procedure for preparation of compound 104, and substituting bromomethyl acetate with bromophthalide, provided the title compound 122 as a mixture of diastereomers. MS (ESI) m/z 359.03 (M+H+).
Reaction SMILES: [CH:1]([C:11]([O:13]C)=O)([C:7](OC)=[O:8])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl.[C:16]([NH2:19])(=[NH:18])[CH3:17].C[O-].[Na+]>CO>[OH:13][C:11]1[C:1]([CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:7]([OH:8])[N:19]=[C:16]([CH3:17])[N:18]=1
Reactant: CC(=N)N
Reactant: COC(=O)CC(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(O)nc(C)nc1O

Procedure:
Trimethyl ethane-1,1,2-tricarboxylate (204 g, 1 mol) and acetamidine hydrochloride (95 g, mol) are added to a solution of sodium methylate (108 g, 2 mol) in methanol (600 ml) with stirring. The mixture is stirred for 16 hours at room temperature. Acidification with concentrated hydrochloric acid, filtration, washing with cold water and drying gives the methyl 4,6-dihydroxy-2-methyl-pyrimidin-5-yl-acetate (or tautomeric forms thereof) as a colorless solid (210 g), m.p.>200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].Cl[CH2:27][O:28][C:29]([N:31]1[CH2:41][CH2:40][CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:27][O:28][C:29]([N:31]2[CH2:41][CH2:40][CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:32]2)=[O:30])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: CCOC(=O)C1CCN(C(=O)OCCl)CC1
Product: CCOC(=O)C1CCN(C(=O)OCOc2ccc(Cl)cc2C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Yield: 65.7 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt (compound of Example 43(1)) and ethyl 1-[(chloromethoxy)carbonyl]isonipecotate as the raw materials, the same operation as the Example 98 gave the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([Br:16])[C:18]=1[CH3:24])=[O:10]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: Cc1c(N)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
A mixture of thionyl chloride (3.15 g, 26.5 mmol) and 2-amino-3-methylbenzoic acid (2.00 g, 13.23 mmol) in THF (50 mL) was heated at reflux for 2 h. The cooled mixture was concentrated and the residue was combined with 3-bromo-2-methylaniline (4.92 g, 26.5 mmol) in THF (50 mL) and heated at reflux for 5 h. The mixture was cooled to room temperature, treated with 10% aqueous K2CO3 and stirred at room temperature for 30 min. The resulting mixture was extracted 3 times with DCM, and the combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-20%), to give 2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide as a yellow solid (1.71 g, 40% yield). Mass spectrum m/z 319, 321 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.70 (d, J=7.9 Hz, 1H), 7.64 (br. s., 1H), 7.50-7.40 (m, 2H), 7.24 (d, J=7.3 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.70 (t, J=7.6 Hz, 1H), 5.67 (br. s., 2H), 2.44 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[BH4-].[Li+]>O1CCCC1>[OH:13][CH2:12][C:10]1[N:11]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[S:8][CH:9]=1
Reactant: CCOC(=O)c1csc(NC(=O)C(C)C)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1nc(CO)cs1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
To a mixture of ethyl 2-(isobutyrylamino)-1,3-thiazole-4-carboxylate (1.4 g) and tetrahydrofuran (28 ml) was added lithium borohydride (252 mg) portionwise, and the mixture was refluxed for 6 hours. The reaction mixture was cooled to 0° C., quenched with methanol (5 ml) and concentrated in vacuo. The residue was suspended with 10% methanol/chloroform (100 ml), and the insoluble materials were filtered off. The filtrate was purified by flash column chromatography on silica-gel with 5% methanol/chloroform as an eluent. The crystalline residue was collected and washed with diisopropyl ether to give N-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-2-methylpropanamide (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[NH2:12][OH:13].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:12][OH:13]
Reactant: NO
Reactant: COc1cccc(C=O)c1C
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cccc(C=NO)c1C
Temperature: 0 °C

Procedure:
To an ice-cooled and stirred suspension of 3-methoxy-2-methylbenzaldehyde (0.269 g, 1.8 mmol) in ethanol (15 ml) a solution of NaOAc.3H2O (1.3 eq) and NH2OH.HCl (1.3 eq) in water (5 ml) was added dropwise within 5 minutes. The resulting suspension was stirred at room temperature until the starting material was consumed (monitored by TLC). After evaporation of the ethanol in vacuo, water was added to the residue. Then the precipitated crystals were filtered off. The crude product was purified by column chromatography with a mixture of chloroform:ethyl acetate (95:5) as the eluent.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:28][CH:29]([CH3:33])[C:30]([O-:32])=[O:31])[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27].C(OCC)C>ClCCl.CCCCCCC>[CH2:8]([O:28][CH:29]([CH3:33])[C:30]([OH:32])=[O:31])[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(C)C(=O)[O-]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)propanoate (1.40 g, 3.36 mmol) in dichloromethane (10 mL) held under nitrogen and the reaction mixture was stirred at room temperature for three hours. Diethyl ether (50 mL) was added and the organic phase was washed with water (30 mL), dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using increasingly polar mixtures of heptane, ethyl acetate and formic acid (95:5:0.25→80:20:1) as eluent. Concentration of the appropriate fractions afforded 0.67 g of slightly impure product. This material was dissolved in heptane (15 mL), washed three times with water (5 mL), dried (Na2SO4), filtered and concentrated to afford 0.50 g (41% yield) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3): δ 0.99 (t, 3H), 1.40-1.48 (m, 5H), 1.67 (m, 2H), 2.09 (m, 4H), 2.80-2.60 (m, 8H), 3.53 (m, 2H), 4.01 (q, 1H), 5.31-5.47 (m, 10H); MS (electro spray): 359.2 [M−H]−.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:19])[C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@@H:23]([CH3:27])[N:22]3[C:12]2=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.[Pd].CO>[NH2:19][C:14]1[C:13]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH3:27])[N:22]3[C:12]=2[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]=1
Reactant: C[C@@H]1COCc2nc3c(N)nc4ccc(OCc5ccccc5)cc4c3n21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reaction time: 72 h
Yield: 42.1 %

Procedure:
(11R)-2-(Benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (840 mg, 2.33 mmol) was dissolved in ethanol (50 mL) and the solution was placed in a pressure bottle. Palladium on carbon (10%, 620 mg) was added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa) for 3 days. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/acetonitrile and the combined filtrates were concentrated under reduced pressure to give a pink solid. Chromatography (SiO2, 20-40% CMA/CHCl3) gave a white solid, which was dissolved in methanol and concentrated under reduced pressure (2×) to give (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (265 mg) as an off white solid, mp 262-264° C.
Reaction SMILES: C(O[C:4](=O)[N:5]([CH2:7][C:8]1[C:9]([CH:24]2[CH2:26][CH2:25]2)=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)C)C.[OH-].[K+].O.NN.CCOC(C)=O>C(O)CO>[CH:24]1([C:9]2[C:8]([CH2:7][NH:5][CH3:4])=[CH:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:10]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)N(C)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CNCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 210 °C
Yield: 87.3 %

Procedure:
0.83 g (2.2 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-carbamic acid ethyl ester was dissolved in 15 ml of ethylene glycol. Then, 1.72 g (26.4 mmol) of potassium hydroxide (86%) and 0.44 ml=0.46 g (9.0 mmol) of hydrazine hydrate were added and the reaction mixture heated up to 190° C. (oil bath, 210° C.) for 90 minutes. After cooling down below 80° C., some pieces of ice were added to the reaction mixture followed by EtOAc. It was then extracted twice with EtOAc; the combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of MeCl2, MeOH) to give 0.59 g of the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31]1)[CH2:13][CH3:14]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 5,7-dichloro-3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-phenyl)-piperazine.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([CH3:12])=[N:7]1)C.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:12][C:8]1[NH:7][N:6]2[CH:5]=[CH:4][N:11]=[C:10]2[CH:9]=1
Reactant: CCOC(Cn1nc(C)cc1N)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2nccn2[nH]1
Yield: 41 %

Procedure:
The resultant (A) was heated in a mixture of 200 ml of ethanol and 80 ml of a 20% aqueous solution of sulfuric acid under reflux for 5 hours. After cooling, excess solid sodium carbonate was added thereto. The resulting mixture was filtered, and the solvent was removed from the filtrate. The thus obtained residue was recrystallized to provide 1.4 g of 6-methylimidazo[1,2-b]pyrazole. Yield was 41%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1.[OH-].[Na+:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:17])[C:14]([O-:16])=[O:15])=[CH:7][CH:8]=1.[Na+:19]
Reactant: COc1ccc(CCCCC(=O)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCCCC(=O)C(=O)[O-])cc1

Procedure:
4.5 g of 6-(4-methoxyphenyl)-2-oxo-caproic acid in 19.0 ml of 1 N sodium hydroxide solution are stirred for 15 minutes at room temperature. The mixture is filtered, washed once with diethyl ether and evaporated to dryness. The residue obtained after drying in vacuo at 30° consists of the pure sodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:18][C:12]1[O:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)co1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(Br)o1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.82 g (3.27 mmol) of the compound from Example 9A are provided in 21 ml of acetic acid, 0.17 ml (3.27 mmol) of bromine are added and the mixture is stirred at 60° C. overnight. A saturated aqueous sodium carbonate solution is added carefully, and the mixture is extracted with ethyl acetate. The organic phase is washed twice with water, dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 40:1). 1.05 g (91% of theory) of the title compound are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:13]=1[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1Br
Temperature: 100 °C
Yield: 80.7 %

Procedure:
To a solution of 1-fluoro-4-nitro-benzene (1.1 mL, 10.0 mmol, 1.0 eq.), 2-bromo-5-hydroxy-benzaldehyde (2.0 g, 10.0 mmol, 1.0 eq.) in DMF (30.0 mL) was added K2CO3 (1.7 g, 12.0 mmol, 1.2 eq.) under nitrogen atmosphere. The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was poured into EtOAc (30 mL) and sat. H2O (30 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×20 mL). Combined organic extracts was washed with brine (30 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 100:0) to give 2-bromo-5-(4-nitro-phenoxy)-benzaldehyde as a yellow fine powder. 1H NMR (CHLOROFORM-d) δ: 10.31-10.37 (m, 10H), 8.26 (dd, J=9.0, 0.3 Hz, 15H), 8.21-8.28 (m, 13H), 7.73 (d, J=8.6 Hz, 3H), 7.73 (dt, J=8.7, 0.5 Hz, 7H), 7.62 (dd, J=3.1, 0.3 Hz, 10H), 7.20-7.29 (m, 19H), 7.00-7.10 (m, 23H). Amount obtained, 2.6 g, 80.7% yield.