Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.C(OCC)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:6]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[C:2]1[CH3:1])[CH3:32]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
(Scheme 1, (B)) To a solution of 2-methyl-4,5-diphenyl-1H-imidazole (0.20 g, 0.85 mmol) in DMF (6 mL) was added NaH (60% in mineral oil, 0.038 g, 0.94 mmol). The resulting mixture was stirred at rt for 10 min. The stirring continued for 2 hours after addition of ethyl 7-bromoheptanoate (0.21 g, 0.90 mmol). The reaction mixture was diluted with diethyl ether (30 mL), washed by water, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a colorless oil (0.24 g, 0.61 mmol, 72% yield): 1H NMR (DMSO-d6) δ1.08 (m, 4H), 1.15 (t, J=7.2 Hz, 3H), 1.33 (m, 4H), 2.16 (t, J=6.6 Hz, 2H), 2.40 (s, 3H), 3.68 (t, J=7.8 Hz, 2H), 4.03 (q, J=4.5 Hz, 2H), 7.05)m, 1H), 7.13 (m, 2H), 7.34 (m, 4H), 7.48 (m, 3H); 13C NMR (DMSO-d6) δ13.4, 14.4, 24.3, 25.7, 27.8, 29.6, 33.5, 43.3, 59.9, 125.8, 126.0, 128.1, 128.3, 128.8, 129.3, 131.1, 131.8, 135.2, 135.3, and 144.0. Anal. Calcd for C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found: C, 76.33; H, 7.67, N, 6.85.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([O:47]C)[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]>Cl.CO.O1CCOCC1>[OH:47][C:44]1[NH:43][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=4[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])[C:46]=2[N:45]=1
Reactant: COc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(O)nc12
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of 3-methoxy-4-(2-methoxy-1 H-benzimidazol-4-yl)carbonylamino-N-methyl-N-(4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (139 mg) in 10% hydrogen chloride in methanol (2 ml) was stirred at ambient temperature for 2 hours and 4 N hydrogen chloride in 1,4-dioxane (2 ml) was added to the mixture. After being allowed to stand at ambient temperature overnight, the reaction mixture was concentrated in vacuo and the residue was diluted with a mixture of chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-hydroxy-1 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (53 mg) as a powder.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6](O)=[O:7].[Cl:13]C1C=C(C=CC=1O)C(O)=O>S(Cl)(Cl)=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([Cl:13])=[O:7]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(Cl)c1ccc(O)c(Cl)c1

Procedure:
3-Chloro-4-hydroxybenzoic acid hemihydrate (14.5 g.) was heated under reflux for 1 hour with thionyl chloride (80 ml.). The mixture was then evaporated, the residue dissolved in ether and the subsequent solution evaporated. The residue obtained (3-chloro-4-hydroxybenzoyl chloride) was dissolved in ether (80 ml.). The stirred solution was then treated dropwise with a solution of 1,2,3,6-tetrahydropyridine (16.6 g.) in ether (50 ml.) with ice-cooling. The mixture was stirred for 17 hours and evaporated. Water (150 ml.) was then added and the mixture was stirred with ether (50 ml.). The insoluble material was separated by filtration, and combined with the solid obtained by basification of the aqueous phase. The combined solids were stirred with acetone (150 ml.), separated by filtration, washed with acetone (50 ml.) and air-dried to give 1-(3-chloro-4-hydroxybenzoyl)-1,2,3,6-tetrahydropyridine (13.6 g.), m.p. 186°-189° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24]CC4C=CC=CC=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2>[Pd]>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1O
Yield: 84.4 %

Procedure:
4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (600 mg) was mixed with HCONH4 (600 mg) and Pd/C (10%, 100 mg) followed by refluxing 30 min. The reaction was filtered while it was hot and the filtrate was evaporated and washed with water followed by filtration to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (400 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:18]=1)[C:15](O)=O.[OH-].[Na+]>O>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[C:15]1[C:14]1[CH:18]=[C:10]([NH2:9])[CH:11]=[N:12][CH:13]=1
Reactant: Nc1ncccc1O
Reactant: Nc1cncc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cncc(-c2nc3ncccc3o2)c1
Temperature: 200 °C
Reaction time: 6 h

Procedure:
In a typical run, 790 mg of 2-amino-3-hydroxypyridine (7.24 mmol) and 1.00 g of 5-aminonicotinic acid (7.24 mmol) were mixed with 10 mL of PPA and stirred at 200° C. for 6 hours. The reaction mixture was cooled to about 100° C. and carefully poured into 100 mL of water. The pH was brought to 6 with solid NaOH and the solids were collected by filtration. After drying under high vacuum, a total of 180 mg of 5-oxazolo[4,5-b]pyridin-2-yl-pyridin-3-ylamine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[N:12][CH:13]=1.[CH3:26][C:27]1[CH:28]=[C:29]([NH:42][C:43]2[N:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][N:44]=2)[CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Si:17]([O:16][CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:31]2[CH:30]=[C:29]([NH:42][C:43]3[N:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][N:44]=3)[CH:28]=[C:27]([CH3:26])[CH:32]=2)=[CH:13][N:12]=1)([OH:25])[CH3:24])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cn1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(C)(O)CO[Si](C)(C)C(C)(C)C)nc2)c1
Temperature: 85 °C

Procedure:
2-Methyl-THF (1.48 mL), sodium carbonate (2M, 223 μL, 0.446 mmol) and 2-(5-bromopyridin-2-yl)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (170 mg, 0.490 mmol) were added to N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (169 mg, 0.446 mmol) and purged and flushed with Ar(g) (3×). PdCl2(dppf)-dichloromethane adduct (18.2 mg, 0.022 mmol) was added to the reaction mixture, purged and flushed with Ar(g) (3×) and heated to 85° C. for 2 hours. The reaction was cooled to room temperature and was diluted with water (5.00 mL), extracted with DCM (5.00 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (acetone/hexanes) to yield 1-{[tert-butyl(dimethyl)silyl]oxy}-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propan-2-ol. The isolated intermediate was dissolved in neat TFA (1.00 mL) and stirring for 20 minutes at room temperature. The excess TFA was removed under reduced pressure and the resultant residue was partitioned with dichloromethane (5.00 mL) and 1M NaOH (aq) (5.00 mL). The organic layer was washed with brine (5.00 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (acetone/hexanes) to yield 2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propane-1,2-diol. MS APCI calc'd for C20H20F3N4O2 [M+H]+ 405. found 405. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.83 (d, J=5.5 Hz, 1H), 8.72 (s, 1H), 7.96 (d, J=16.2 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H), 7.55 (s, 1H), 7.27 (d, J=5.5 Hz, 1H), 7.18 (s, 1H), 5.13 (s, 1H), 4.64 (s, 1H), 3.57 (d, J=7.6 Hz, 2H), 2.36 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].Cl>ClCCCl.CCCCCC>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=1[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[O:16][CH3:15])=[O:20]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCCl
Product: COc1ccccc1C(=O)c1ccc(OC)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 3.9 g of AlCl3 and 4.67 g of 2,3-dichloroanisole in 70 ml of 1,2-dichloroethane at -10° C., 5 g of o-methoxybenzoyl chloride is added dropwise. The mixture is stirred for 2.5 hours and is gradually warmed to 5° C. The reaction mixture is poured into concentrated HCl and ice. The mixture is stirred one half hour to decompose the complex. The aqueous layer is extracted with additional organic solvent. The combined organic layers are washed until neutral, dried over Na2SO4 and evaporated to give an oil which solidifies on trituration with hexane. The crude product is recrystallized from 95% ethanol giving 2,3-dichloro-2',4-dimethoxybenzophenone, mp 94°-96° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])[CH2:5][CH3:6])[CH3:2].[OH-].[K+:16].CO>>[CH2:1]([O:3][CH:4]([O:7][CH:8]([CH3:14])[C:9]([O-:11])=[O:10])[CH2:5][CH3:6])[CH3:2].[K+:16]
Reactant: CCOC(=O)C(C)OC(CC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(CC)OC(C)C(=O)[O-]
Reaction time: 2 h

Procedure:
To a 250 mL flask containing 52.3 g (0.27 mole) ethyl 2-[(1'-ethoxy)propoxy]propanoate at 25° C. is added a mixture of 18.5 g (0.33 mole) potassium hydroxide and 56 g (1.75 moles) methanol. After two hours at 25° C., the reaction mixture is evacuated and a very viscous liquid, 70.8 g, potassium 2-[(1'-ethoxy)propoxy]propanoate is recovered.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:28]([NH:30][CH2:31][CH2:32][OH:33])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.C(Cl)(Cl)=O>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:27])[C:23]([CH3:26])([CH3:24])[CH3:25])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:28]1[O:33][CH2:32][CH2:31][N:30]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C(=O)NCCO)N(C(=O)OC(C)(C)C)C2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C3=NCCO3)N(C(=O)OC(C)(C)C)C2)CC1
Reaction time: 48 h
Yield: 61.4 %

Procedure:
The product of Step A, (2S,4S)-1-Boc-2-{[(2-hydroxyethyl)amino]carbonyl}-4-[dimethylpropanoyl(4,4-dimethylcyclohexyl)amino]pyrrolidine (410 mg, 0.58 mmol) together with DMAP (70.7 mg, 0.58 mmol) and DIPEA (0.39 ml, 2.32 mmol) were dissolved in toluene (3 ml), and phosgene (20% in toluene, 0.31 ml, 0.87 mmol) was added dropwise. After the reaction solution was stirred at 30˜40° C. for 48 h, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated NaHCO3 aqueous solution, water and 1N HCl. The organic solution was dried over MgSO4, concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc) to give the title compound (160 mg, 62%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:28])[C@@H:22]([NH:23][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:24][CH:25]([CH3:26])[CH3:27])[CH3:19]
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and L-leucine ethyl ester hydrochloride according to the procedure of Example 154 as a white flake; 1H NMR (300 MHz, CDCl3) δ 0.99(t, J=6.2 Hz, 6 H), 1.30(t, J=7.1 Hz, 3 H), 1.60–1.80(m, 3 H), 2.56(t, J=6.0 Hz, 4 H), 3.72(t, J=6.0 Hz, 4 H), 4.22(q, J=7.1 Hz, 2 H), 4.80–4.90(m, 1 H), 6.42(d, J=8.2 Hz, 1 H), 6.94(d, J=7.0 Hz, 2 H), 7.77 (d, J=7.0 Hz, 1 H); MS (ES) m/z: 361.3 (MH+); HRMS Calcd. for C20H28N2O4(M+): 360.2049. Found: 360.2081.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[CH:20]=[N:19][NH:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[CH:20]=[N:19][NH:18][C:13]3=2)[N:8]=1
Reactant: Oc1nc2ccc3cn[nH]c3c2nc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2[nH]ncc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
Finely powdered potassium nitrate (0.11 g, 1 mmol) was added to a stirred solution of 7,8-dihydroxy-1H-pyrazolo[3,4-f]quinoxaline (0.2 g, 1 mmol) in 2 ml of conc. sulfuric acid at room temperature. The solution was stirred for 1 h at this temperature and then poured into 50 ml of ice/water. After 30 min the precipitated solid was isolated by filtration and washed with water. Recrystallization from N,N-dimethylformamide/water afforded 0.13 g (53%) of the nitro compound; m.p.>300° C.; IR (KBr): 3300-2500, 1705 cm-1 ; 1H-NMR (DMSO-d6): 7.83 (s, 1H, ArH), 8.37 (s, 1H, ArH), 12.2 (broad s, 2H, 20H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:10][CH2:11][CH2:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)O>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:11][Cl:10])=[CH:3][C:2]=1[Cl:1]
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: ClCC[C@H](Oc1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
Prepared by Procedure A using 3,4-dichlorophenol and (1R)-3-chloro-1-phenyl-1-propanol.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[C:8]([CH3:25])[CH:7]=1)=[O:5])[CH3:2].[ClH:26]>O1CCOCC1.C(OCC)C>[ClH:26].[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[C:8]([CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Tert-butyl 4-(4-(ethylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (0.9323 g, 2.68 mmol) was diluted with 4.0M HCl in dioxane (8 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen, washed with ether (5 mL) and dried in vacuum to afford N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (0.7528 g, 2.65 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3H) 2.29 (s, 3H) 3.00-3.14 (m, 4H) 3.16-3.32 (m, 6H) 7.07 (d, J=8.34 Hz, 1H) 7.62-7.71 (m, 2H) 8.34 (t, J=5.43 Hz, 1H) 9.17 (br. s., 2H). ESI-MS: m/z 248.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH:3]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42](Cl)(Cl)([Cl:44])[Cl:43]>ClCCl.[Zn]>[CH3:1][C:2]([CH3:22])([CH:3]=[C:42]([Cl:44])[Cl:43])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C=O)COCc1ccc(F)c(Cc2ccccc2)c1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C=C(Cl)Cl)COCc1ccc(F)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 2,2-dimethyl-3-(3-benzyl-4-fluoro-benzyloxy)propan-1-al (0.4 g), triphenylphosphine (0.77 g), zinc dust (0.10 g) and carbon tetrachloride (3 cm3) in dichloromethane (3 ml) was heated at the reflux temperature for five hours. After cooling to the ambient temperature (ca 25° C.), the mixture was allowed to stand for 14 hours where upon it was triturated with diethylether. The solvent was evaporated under reduced pressure and the residue was passed through a short plug of silica gel using petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% by volume) as eluent to give 2,2-dimethyl-1-(3-benzyl-4-fluorobenzyloxy)-4,4-dichlorobut-3-ene (0.44 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6]([CH:9]([CH2:13][CH2:14][CH3:15])[C:10](Cl)=[O:11])[CH2:7][CH3:8].[OH-].[Na+]>O>[CH2:6]([CH:9]([CH2:13][CH2:14][CH3:15])[C:10]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:11])[CH2:7][CH3:8]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(CCC)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
In 63 ml of water was dissolved 6.93 g of glycine, and under ice-cooling, 15 g of 2-n-propyl-n-pentanoyl chloride and 13 ml of a 36% sodium hydroxide solution were alternately added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours to conduct the reaction, adjusted a pH thereof to about 2 with a 1 N hydrochloric acid, and precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. Crystals obtained by condensing the solvent under reduced pressure were recrystallized from hexane-ethyl acetate to give 10.9 g (Yield: 59%) of the title compound as colorless needle crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([N:23](C(C5CC5)=O)[C:24]([CH:26]5[CH2:28][CH2:27]5)=[O:25])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1.[Cl-].[NH4+].CN(C)C=O>C(OCC)(=O)C.O.C(O)C>[CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]5[CH2:28][CH2:27]5)=[O:25])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(C1CC1)N(C(=O)C1CC1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)C1CC1
Yield: 41 %

Procedure:
N1-Cyclopropyl-5-({2-[di(cyclopropylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide (190 mg), ammoniumchloride (660 mg), dimethylformamide (5 ml), water (5 ml) and ethanol (5 ml) were stirred at 100° C. for 1 hour. Water and ethyl acetate were added for extraction, and the extract was washed 6 times with water. After drying over magnesium sulfate, the drying agent was filtered off and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the precipitated solid was filtered out to obtain 66 mg of a white powder.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1.[NH3:16]>>[NH2:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: Cc1ccc2nc(Cl)c([N+](=O)[O-])cc2c1
Product: Cc1ccc2nc(N)c([N+](=O)[O-])cc2c1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
2.0 g of 2-chloro-6-methyl-3-nitroquinoline (compound C2) is dissolved in 100 ml of ethanolic ammonia solution and stirred at 130° C. for 6 h in an autoclave. After cooling to from temperature, the reaction mixture is concentrated in vacuo and the residue redissolved in 50 ml of ethyl acetate and extracted two times each with 50 ml of halfsaturated aqueous potassium carbonate solution. The organic phase is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is filtered over silica gel (dichloromethane). 1.5 g of the title compound are obtained as violet solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1)=[O:3]
Reactant: COC(=O)c1cccc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)c1cccc(NC=O)n1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A mixture of formic acid (559.3 g.) and acetic anhydride (1033.4 g.) was stirred for 30 minutes at 40° to 50° C. and thereto was added methyl 6-amino-2-pyridinecarboxylate (616 g.) at 40° C., and then the mixture was stirred for 1 hour at 80° C. After the removal of the solvent from the reaction mixture, the residue was dissolved in a mixture of benzene and n-hexane and then filtered. Thus obtained precipitates were recrystallized from benzene (2 l.) to give methyl 6-formamido-2-pyridinecarboxylate (647.8 g.), mp. 134° to 136° C.