Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21](=[O:25])[CH:22]=[CH:23][CH3:24])[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)C.O1CCCC1.[OH:34][CH:35]([C:40]1[CH:41]=[CH:42][C:43]([CH:46]=[O:47])=[N:44][CH:45]=1)[C:36]([OH:39])([CH3:38])[CH3:37]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:21](=[O:25])[CH2:22][CH:23]([CH3:24])[C:46]([C:43]3[CH:42]=[CH:41][C:40]([CH:35]([OH:34])[C:36]([OH:39])([CH3:37])[CH3:38])=[CH:45][N:44]=3)=[O:47])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccc(C(O)C(C)(C)O)cn1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)hex-4-en-3-one (200 mg) in a mixed solvent of ethanol (3 mL) and tetrahydrofuran (3 mL) were added 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (129 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (16.4 mg) and triethylamine (33.2 μL), and the mixture was stirred with heating under reflux under argon m atmosphere for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (235 mg, yield 76%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 558 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[CH:18]([OH:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:21][CH:18]([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1ccc(N)cc1Br
Temperature: 80 °C

Procedure:
3-Bromo-4-fluoronitrobenzene (1.0 eq) was added to a stirring solution of potassium carbonate (2.0 eq) in isopropanol. The solution was heated for 4 days at 80° C. The solution was cooled and filtered through Celite and the plug washed with EtOAc. The organic layer is then washed with brine and water, dried over MgSO4, filtered and concentrated to yield the desired product. Rt=8.72 min.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([P:25]([O:31]C(C)C)([O:27]C(C)C)=[O:26])=[O:24])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Br)(C)C.CO>C(Cl)(Cl)Cl.CC#N>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([P:25]([OH:31])([OH:27])=[O:26])=[O:24])(=[O:15])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)NCCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC#N
Product: O=C(NCCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)P(=O)(O)O
Temperature: 50 °C
Yield: 95.1 %

Procedure:
To 1-[4-phenoxybenzenesulfonamido]-4-[diisopropylphosphonoformamido] butane (0.14 g, 0.27 mmol) in 5 ml CHCl3 was added TMSBr (5 eq, 1.9 ml, 14 mmol) and reaction was stirred and heated at 50° C. for 3 h. The reaction mixture was followed by 31P NMR. To the mixture reaction was added 5 ml MeOH for 1 h and the solvent was evaporated to give yellow oil, which solidified in MeCN to give 0.11 g (96%) white solid, m.p.=143-145° C. m/z [M+H]+ calcd/found 429/429.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:17][CH2:16][C:15]2=[O:18])[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]3[NH:34][CH2:33][C:32]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:29]3=[N:30][CH:31]=2)[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:34]1[C:28]3[C:29](=[N:30][CH:31]=[C:26]([N:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH:27]=3)[C:32]3([CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:33]1)=[C:3]([CH3:19])[C:4]([N:14]1[CH2:17][CH2:16][C:15]1=[O:18])=[N:5]2
Reactant: Cc1c(N2CCC2=O)nc2cc(F)cc(F)c2c1Cl
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCC2=O)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)azetidin-2-one (130 mg, 0.44 mmol) and 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] in toluene (except using cesium carbonate as base) to give 1-(5,7-difluoro-3-methyl-4-(6′-(4-morpholinyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-2-quinolinyl)-2-azetidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.59 (1H, d, J=2.3 Hz), 7.45 (1H, ddd, J=9.5, 2.4, 1.2 Hz), 6.89 (1H, ddd, J=11.8, 9.0, 2.4 Hz), 5.72 (1H, d, J=2.3 Hz), 4.13 (2H, m, J=11.6, 4.2, 4.0, 4.0 Hz), 4.00-4.09 (2H, m), 3.98 (1H, d, J=9.4 Hz), 3.85 (1H, d, J=9.4 Hz), 3.69-3.80 (4H, m), 3.57 (2H, m, J=11.7, 11.7, 2.9, 2.7 Hz), 3.16 (2H, t, J=5.0 Hz), 2.96-3.07 (4H, m), 2.39 (3H, s), 2.31 (2H, dddd, J=15.8, 8.9, 8.6, 4.5 Hz), 1.80 (1H, d, J=14.5 Hz), 1.67-1.75 (1H, m). Mass Spectrum (ESI) m/e=522.4 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1.C([O-])(O)=O.[Na+].O.[C:32]1(C)[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(C)=O>[CH3:1][C@H:2]1[C:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]2[C:11]([CH2:24][O:25][C:32]([CH3:37])([CH3:33])[O:23]2)=[CH:10][CH:9]([C:15]3=[O:16])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]2(O)[C@H]1O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=CC23C(=O)C(C=C4COC(C)(C)O[C@H]4[C@]2(O)[C@H]1O)C1C(C[C@H]3C)C1(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 69 %

Procedure:
Ingenol (1.00 g, 2.30 mmol) was dissolved in a solution of p-toluenesulphonic acid monohydrate in acetone (0.47 mg/mL, 22.5 mL). The solution was stirred at room temperature for 25 min. To this solution was added a saturated aqueous solution of NaHCO3 (0.2 mL). The obtained mixture was concentrated in vacuo. The residue was taken up in brine and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 19:1→heptane/ethyl acetate 0:1), giving the title compound as a white solid (616 mg, 69%). (See also: Opferkuch, H. J. et. al., Z. Naturforsch., (1981), 86b, 878-887.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:18])[C:16]=1[NH2:17])C(OC1C=CC=CC=1)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:14]=[C:15]([Cl:18])[C:16]=1[NH2:17]
Reactant: Nc1c(Cl)cc(C(=O)Oc2ccccc2)cc1Cl
Solvent: O
Product: Nc1c(Cl)cccc1Cl
Temperature: 250 °C
Reaction time: 8 h
Yield: 127 %

Procedure:
49 g (0.174 mole) of phenyl 3,5-dichloro-4-amino-benzoate were initially introduced into an autoclave together with 200 ml of water. The mixture was heated to 250° C. and stirred at this temperature for eight hours. During the reaction, the reaction gas was let off continuously and a pressure of about 41 bar was established. The residue was steam-distilled, and 35.8 g of 2,6-dichloroaniline having a purity of 63% were obtained. This corresponds to a yield of 80%.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][C:14]3[N:18](CC4OC=CC=4)[N:17]=[CH:16][C:15]=3[C:10]=2[N:9]2[N:25]=[C:26]([CH3:28])[CH:27]=[C:8]2[N:7]=1)[CH2:2][CH2:3][CH3:4].COCCOCCOC.[Se](=O)=O>>[CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][C:14]3[NH:18][N:17]=[CH:16][C:15]=3[C:10]=2[N:9]2[N:25]=[C:26]([CH3:28])[CH:27]=[C:8]2[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc2cc(C)nn2c2c1cnc1c2cnn1Cc1ccco1
Agent: O=[Se]=O
Solvent: COCCOCCOC
Product: CCCCNc1nc2cc(C)nn2c2c1cnc1[nH]ncc12
Reaction time: 2 h

Procedure:
0.01 mol of N-butyl-8-furfuryl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5-amine is heated in 50 ml of diethyleneglycol dimethyl ether containing 0.01 mol of selenium dioxide at reflux temperature with stirring for two hours. The mixture is filtered hot and evaporated to dryness. N-butyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5-amine remains.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:13]=1[C:26]([NH2:28])=[O:27])=[O:10])(=[O:3])[CH3:2]>[Pd].O1CCCC1.CN(C)C=O.CCOCC>[C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:16][N:15]=[C:14]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[C:13]=1[C:26]([NH2:28])=[O:27])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Agent: [Pd]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)OCCCNC(=O)Nc1snc(-c2ccc(N)cc2)c1C(N)=O

Procedure:
3-[({[4-(aminocarbonyl)-3-(4-nitrophenyl)isothiazol-5-yl]amino}carbonyl)amino]propyl acetate (12.0 g,) and 10% palladium on carbon (3 g) in tetrahydrofuran (400 mL) and dimethylformamide (100 mL) was hydrogenated at 80 psi over 24 hr. in metal bomb. Filter the catalyst on celite and washed with tetrahydrofuran. The filtrate was concentrated in vacuo to give off white solid, which was stirred in ether (100 mL) and filtered gave the title compound as an off white solid (8.5 g, 77%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[N:41]=[CH:40][N:39]=[C:38]2[O:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([O:47][C:38]3[C:37]4[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=4)[N:41]=[CH:40][N:39]=3)[CH:49]=2)=[O:19])[N:7]([CH2:20][CH:21]([CH3:22])[CH3:23])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4CC(C)C)c3)c2cc1OC
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.47 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane: methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (60 mg, 38%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.94 (m, 1H), 6.01 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.71 (d, J=7.6 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.4 Hz, 6H); LC-MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: [Mg].C(Br)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9](I)=[C:8]([Cl:13])[CH:7]=1.C[Mg]Cl.[CH2:17]([OH:22])[C:18]#[C:19][CH2:20][OH:21].[NH4+].[Cl-]>C(OCC)C.C1COCC1>[Cl:13][C:8]1[CH:7]=[C:6]([Cl:5])[CH:11]=[CH:10][C:9]=1[CH:17]([OH:22])[CH:18]=[CH:19][CH2:20][OH:21]
Reactant: OCC#CCO
Reactant: Clc1ccc(I)c(Cl)c1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: CCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC=CC(O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
A suspension under nitrogen of magnesium (0.8 g; 32.7 mmoles) in ethyl ether (17 ml) kept at 20° C. under stirring, was added with ethyl bromide (25 mg). After 15 minutes a solution of 1,3-dichloro4-iodobenzene (5.95 g; 21.8 mmoles) and ethyl bromide (25 mg) in dry ether (13 ml) was dropwise added (about 1 hour) keeping the temperature at 15-20° C. At the end of the dropping the suspension was kept at 15-20° C. for 2 hours more. The magnesium in excess was removed and the obtained solution was dropped, keeping the temperature at 0-5° C., in a second flask containing a suspension formerly prepared. Such suspension was obtained by adding, at 0-5° C., a THF solution of 3M methyl magnesium chloride (9.6 ml; 29 mmoles) to a solution of 2-butin-1,4-diol (1.25 g; 14.5 mmoles) in THF (30 ml). At the end of the addition the suspension was refluxed and stirred at mild reflux for 24 hours. After cooling to 0° C., an aqueous solution of saturated NH4Cl was added, the phases were divided and the aqueous one extracted in ether (30 ml). The joined organic phases were washed with water (30 ml), anhydrified over dry Na2SO4, dried. The product was purified by flash chromatography (SiO2; petrolatum/ethyl acetate 60/40) to give 0.24 g of (E) (2,4dichlorophenyl)-2-buten-1,4-diol (yield 7,3%). The 1H-NMR effected on the product is practically the same of the one reported in example 4.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:35]=[CH:34][C:9]([C:10]([NH:12][C:13]3[CH:14]=[C:15]([CH:28]=[CH:29][C:30]=3[N+:31]([O-])=O)[O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1>[C].[Pd].C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:35]=[CH:34][C:9]([C:10]3[NH:12][C:13]4[CH:14]=[C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH:28]=[CH:29][C:30]=4[N:31]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc([N+](=O)[O-])c(NC(=O)c2ccc(OCC3CC3)cc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)cc3)[nH]c2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of tert-butyl ((2S)-1-(3-((4-(cyclopropylmethoxy)benzoyl)amino)-4-nitrophenoxy)propan-2-yl)carbamate (1.00 g), 10% palladium-carbon (containing water (50%), 1.00 g) and THF (10 mL) was stirred at room temperature for 30 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. A solution of the obtained solid in acetic acid (20 mL) was stirred at 80° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (901 mg).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:11]Br>C(O)(=O)C.O>[Br:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: Cc1cccc(C=O)c1O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
The solution of 2-Hydroxy-3-methylbenzaldehyde (1.0 g, 7.35 mmole) in acetic acid (6 mL) was cooled to 0° C. (ice bath). Bromine (1.36 g, 8.52 mmole) was added dropwise and allowed to stir for 2 hours. The reaction was warmed to room temperature and diluted with water (100 mL) yielding a light orange precipitate. The solid was filtered and washed with water (10 mL). Dried on high vacuum to give a light brown solid (1.4 g, 88.6%). 1H NMR (CDCl3/400 MHz) 11.16 (s, 1H), 9.79 (s, 1H), 7.48 (s, 1H), 7.46 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][CH:21]=2)=[N:14][CH:15]=1.Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][CH:21]=2)=[N:12][CH:11]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCCCCCOc1ccc(-c2ncc(-c3ccc(O)c(F)c3F)cn2)cn1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(-c2ncc(-c3ccc(OCCCCCCCC)c(F)c3F)cn2)cn1
Yield: 51 %

Procedure:
The etherification of 1.3 mmol of 5-(2,3-difluoro-4-hydroxyphenyl)-2-(6-dodecyloxypyridin-3-yl)pyrimidine using 1.7 mmol of 1-bromooctane in 80 ml of DMF is carried out analogously to the procedure indicated for Example 3. Chromatographic purification on silica gel 60 using dichloromethane as eluent and recrystallization from methanol gives 380 mg (51%) of colorless crystals, X 67 X1 76 SC 118-123 SA 147 I.
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(Cl)(Cl)Cl.CC(C)=O>O>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:24](=[O:26])[CH3:25])[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (100 mg) was dissolved in water (3 ml). To this solution was added acetic anhydride (30 μl), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and acetone (1:1, v/v) to afford 11-acetyl-4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (80.5 mg).
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.FC1C=C(C=CC=1CCCN1CCCCC1)C(O)=O.[CH2:44]([N:46]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([CH2:74][CH2:75][CH2:76][N:77]2[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]2)=[C:70]([F:83])[CH:69]=1)[C:47]1[CH:52]=[C:51]([O:53]C)[CH:50]=[CH:49][C:48]=1[CH:55]1[CH2:64][CH2:63][C:62]2[C:57](=[CH:58][CH:59]=[C:60]([O:65]C)[CH:61]=2)[CH2:56]1)[CH3:45]>>[CH2:44]([N:46]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([CH2:74][CH2:75][CH2:76][N:77]2[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]2)=[C:70]([F:83])[CH:69]=1)[C:47]1[CH:52]=[C:51]([OH:53])[CH:50]=[CH:49][C:48]=1[CH:55]1[CH2:64][CH2:63][C:62]2[CH:61]=[C:60]([OH:65])[CH:59]=[CH:58][C:57]=2[CH2:56]1)[CH3:45]
Reactant: CCN(Cc1ccc(CCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(O)c1ccc(CCCN2CCCCC2)c(F)c1
Product: CCN(Cc1ccc(CCCN2CCCCC2)c(F)c1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 89.5 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 3-fluoro-4-(3-piperidin-1-ylpropyl)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, ethyl[3-fluoro-4-(3-piperidin-1-ylpropyl)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (377 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (320 mg).
Reaction SMILES: Cl[NH:2][C:3]1[N:8]=[C:7]([NH:9]Cl)[N:6]=[C:5]([NH:11]Cl)[N:4]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:2][C:3]1[N:8]=[C:7]([NH:9][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Cl:13])[N:6]=[C:5]([NH:11][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Cl:13])[N:4]=1)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: ClNc1nc(NCl)nc(NCl)n1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCl)Nc1nc(NC(=O)CCCCl)nc(NC(=O)CCCCl)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 2.3 g trichloromelamine, 20 ml carbon tetrachloride, 8.46 g 4-chlorobutyryl chloride and 30 mg N,N-dimethylaminopyridine was placed in a 100 ml flask fitted with a magnetic stirring bar, a reflux condenser and argon inlet. The reaction mixture was slowly heated in an oil bath to 60° C. and was stirred at 60° C. for 5 hours. It was then allowed to cool down to room temperature and diluted with 50 ml hexanes. The contents were stirred at room temperature for 30 minutes and then filtered. The residue was washed with hexane and dried under reduced pressure. It was characterized to be N,N',N"-tris(4-chlorobutyryl) melamine on the basis of NMR and mass spectroscopy (4.2 g; 95% yield);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1>CN(C1C=CN=CC=1)C>[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:14](=[O:15])[CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:11]=23)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:37]([F:42])[CH:36]=1
Reactant: COC(=O)c1ccc(N)c(F)c1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 9.6, [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (example 9.3) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-fluoro-benzoic acid methyl ester (CAS Reg. No. 185629-32-7) in the presence of DMAP to give the title compound as off-white solid. MS: m/e=538.3 [M+H+].
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
To a stirred solution of the crude azaindoline 7 (0.64 mmol) in CH2Cl2 (10 mL) was added DDQ (145 mg, 0.64 mmol) in one portion. After 20 min the resulting black mixture was diluted with saturated aqueous NaHCO3 solution and stirred vigorously for 15 min. The aqueous layer was extracted with CHCl3 (2×) and the combined organic solutions were dried (MgSO4), filtered and concentrated to afford azaindole 8 as a brown oil, which was used directly in the next step without purification.