Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH:8]=1)[CH2:3][C:4]([OH:6])=O.[C:17](O)([C:19]([F:22])([F:21])[F:20])=[O:18].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CCOC(C)=O>O>[F:20][C:19]([F:22])([F:21])[C:17]([NH:1][CH:2]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH:8]=2)[C:4](=[O:6])[CH2:3]1)=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)Oc1cccc(C(N)CC(=O)O)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)Oc1ccc2c(c1)C(NC(=O)C(F)(F)F)CC2=O
Temperature: 95 °C
Yield: 23 %

Procedure:
Step AU (3). To a solution of 3-amino-3-(3-isopropoxyphenyl)propanoic acid (65 g, 291 mmol) and TFA (100 mL) was added TFAA (100 mL). The mixture was warmed up to 95° C. for 2 h. The solvent was evaporated under high vacuum to afford a sticky oil which was taken into EtOAc (500 mL) and water (300 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified using silica-gel chromatography (10-30% EtOAc/Hexane) to afford 20 g (23% yield) of 2,2,2-trifluoro-N-(6-isopropoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:11]>C(O)CCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:11])[C:7]=1[F:8]
Reactant: [NH4+]
Reactant: Fc1c(Cl)ncnc1Cl
Agent: [OH-]
Solvent: CCCCO
Product: Nc1ncnc(Cl)c1F
Temperature: 90 °C
Yield: 89 %

Procedure:
A mixture of 4,6-dichloro-5-fluoro-pyrimidine (1.67 g, 10.0 mmol), n-butanol (6 mL) and 28% ammonium hydroxide (12 mL) in a sealed tube was heated at 90° C. for 2 hours. The precipitated white crystals were collected by filtration to give the desired compound (1.31 g, 89% yield). LCMS (ESI) m/z: 147.9 [M+H+].
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:20](=O)[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[NH2:24][OH:25].CC([O-])=O.[Na+]>CO>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:20](=[N:24][OH:25])[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CC(=O)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone (1.32 g, 4.2 mmol) in MeOH (50 mL) at RT was added hydroxylamine hydrochloride (877 mg, 12.61 mmol) followed by NaOAc (3.45 g, 42.0 mmol). The reaction mixture was stirred at 80° C. for 1 h then concentrated tinder reduced pressure. Water (100 mL) was added to the reaction mixture, and the mixture extracted with EtOAc (50 mL×3). The combined organic layers were concentrated under reduced pressure to afford 1.35 g (97.6%) of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone oxime as yellow solid: MS (ESI) m/z: 320.1 [M+1]+.
Reaction SMILES: [C:1](=[O:3])=[O:2].CC(C)=O.[Si]([N:15]1[C@@H:18]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([CH2:39]O)[C:16]1=[O:41])(C(C)(C)C)(C)C.[Li]CCCC>O1CCCC1>[CH:1]([O:3][CH2:39][C@H:17]1[C@H:18]([S:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:15][C:16]1=[O:41])=[O:2]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CO)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=COC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.42 h
Yield: 60 %

Procedure:
To a cold (dry ice-acetone bath, -78° C.) solution of trans 1-(t-butyldimethylsilyl)-3-hydroxymethyl-4-tritylthio-2-azetidinone (4.89 g, 10 mmol) in tetrahydrofuran (15 ml) was added dropwise 1.6 M n-BuLi (8.2 mmol). The red solution was stirred in a cold bath for 25 min and then treated dropwise with a solution of paranitrobenzylchloroformate (2.6 g, 12 mmol). Stirring was continued for 2 h. The reaction mixture was partitioned between ammonium chloride and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2×10 ml). The organic layers were combined and washed with brine, dried (MgSO4), and evaporated in vacuo. The residual oil was chromatographed on a silica gel column (70 g). Elution with benzene gave the title compound 4.0 g (60%) as an amorphous solid. ir νmax (CDCl3) 1750, 1610 cm-1 1 Hmr (CDCl3) δ: 8.40 (2H, d, J=9), 7.45 (17H, m), 5.22 (2H, s, benzyl), 4.4 (1H, d, J=1.5, H-4), 4.05 (1H, dd, J=14, J=4.5, H-1'), 3.28 (1H, m, H-3), 3.18 (1H, dd, J=14, J=4, H=1'), 0.95 (9H, s, t-Bu) and 0.32 ppm (6H, s, CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([NH:36][S:37]([CH2:40][CH:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)(=[O:39])=[O:38])[CH:31]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([NH:36][S:37]([CH2:40][CH:41]5[CH2:42][CH2:43][O:44][CH2:45][CH2:46]5)(=[O:38])=[O:39])[CH:31]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(NS(=O)(=O)CC5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccnc(NS(=O)(=O)CC6CCOCC6)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 11.2 %

Procedure:
(S)—N-(4-(4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide (55 mg, 0.07 mmol) was treated with trifluoroacetic acid (2 ml, 26 mmol) and a solution of ammonia (7N in methanol, 2 ml, 91 mmol) according to the method described in Example 27 to give 5 mg (11% yield) of the title compound. Purity 99%.
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@H:6]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[NH:7][C@H:8]2[CH3:13].[CH3:23][C:24]([OH:28])([CH:26]=[CH2:27])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CN(C)C=O>[Si:16]([O:15][CH2:14][C@H:6]1[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2/[CH:27]=[CH:26]/[C:24]([CH3:25])([OH:28])[CH3:23])[C@H:8]([CH3:13])[NH:7]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: C=CC(C)(C)O
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(Br)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(/C=C/C(C)(C)O)cccc21
Temperature: 125 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
Add (1S,3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (310 g, 723.83 mmol) and 2-methylbut-3-en-2-ol (508.95 g, 5.79 mol) to N,N-dimethylformamide (1.08 L) in an appropriate vessel and degas by bubbling nitrogen through the solution for 10 minutes. Add potassium carbonate (315.12 g, 2.28 mol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15.32 g, 36.19 mmol) and palladium (II) acetate (8.29 g, 36.19 mmol) and degas by bubbling nitrogen through the mixture for 15 minutes then heat to 125° C. After 16 hours, cool the mixture to 20° C. and dilute with ethyl acetate (1.5 L) and water (2.5 L). Wash the ethyl acetate layer with brine (2.5 L), then dry over sodium sulfate and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography, eluting with 0-50% ethyl acetate in isohexanes to give the title compound (193 g, 459.1 mmol). MS (m/z): 376(M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24](=[O:36])[CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>O1CCCC1.C(OCC)(=O)C>[CH:43]1([C:46]([NH:1][C:2]2[S:3][C:4]3[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24](=[O:36])[CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=5)[CH:17]=4)[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:47])[CH2:45][CH2:44]1
Reactant: COC(=O)c1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(N)sc12
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a solution of methyl 2-amino-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazole-7-carboxylate (2.50 mg, 4.81 mmol) in tetrahydrofuran (20 mL) were added pyridine (770 μL, 9.62 mmol) and cyclopropanecarbonyl chloride (790 μL, 8.66 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (80 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (50 ml) and saturated brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→80/20), and a fraction containing the object product was concentrated under reduced pressure. The obtained pale-yellow residue was recrystallized from ethyl acetate/n-hexane (3/2) to give the title compound (2.25 g, 80%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O(Br)[Br:24].[P+5].[OH-].[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.O>[Br:24][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1O
Reactant: BrOBr
Agent: [Na+]
Agent: [OH-]
Agent: [P+5]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1Br
Yield: 76.5 %

Procedure:
A mixture of 7-chloro-3-(4-chloro-benzenesulfonyl)-quinolin-4-ol (0.5 g, 1.41 mmol) and phosphorus(V) oxybromide (1.2 g, 4.2 mmol) in chloroform (30 ml) and triethylamine (1 ml) was refluxed for 6 hours. The reaction mixture was diluted with water (30 ml) and the pH was adjusted to 10 with aqueous sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The obtained crude product was purified by crystallization from diethyl ether to obtain 0.45 g of the title compound in 77% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[I-].[Na+].[H-].[Na+].Cl.Cl[CH2:17][CH2:18][N:19]([CH2:27][CH2:28]Cl)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:19]1[CH2:27][CH2:28][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)([C:9]#[N:10])[CH2:17][CH2:18]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: Cc1ccc(CC#N)cc1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc(C2(C#N)CCN(Cc3ccccc3)CC2)cc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
4-Methylphenyl-acetonitrile (1.66 g, 12.6 mmol), sodium iodide (0.25 g), and sodium hydride (50.4 mmol) were combined in dimethylformamide (50 mL) and stirred until gas evolution ceases. A solution of N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (2.8 g, 12.6 mmol) in dimethylformamide (50 mL) was added dropwise. After 24 hours, the reaction mixture was heated to 70° C. and stirred for 2 days. The solvent was removed by evaporation in vacuo to give a residue and the residue was partitioned between water and dichloromethane. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo to give a residue which was chromatographed on silica gel eluting with 2/1 hexane/ethyl acetate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:21])=[N:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[CH:42]=1)#[N:25]
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCNC(=NCCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.50 g (1.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[4-[3-(piperidinomethyl)phenoxy]butyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=629 ([M+H]+, 18), 229 (98), 109 (100); IR (KBr): 2164 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 102°-105° C. (isopropanol/ether).
Reaction SMILES: Cl.[CH:2]1[C:12]2[C:11]3[CH2:13][CH2:14][CH:15]=[CH:16][C:10]=3[CH:9]=[CH:8][N:7]([CH2:17][CH:18]([OH:35])[CH2:19]N3CCN(C4N=CC=CC=4C(O)=O)CC3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH2:46]([O:48][C:49]([C@@H:51]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52]1)=[O:50])[CH3:47].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH2:46]([O:48][C:49]([C@@H:51]1[CH2:56][CH2:55][CH2:54][N:53]([CH2:19][CH:18]([OH:35])[CH2:17][N:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:12]=3[CH2:11][CH2:13][C:14]3[CH:15]=[CH:16][CH:10]=[CH:9][C:8]2=3)[CH2:52]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: O=C(O)c1cccnc1N1CCN(CC(O)CN2C=CC3=C(CCC=C3)c3ccccc32)CC1
Agent: Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCN(CC(O)CN2c3ccccc3CCc3ccccc32)C1
Temperature: 60 °C
Yield: 53 %

Procedure:
A mixture of crude (10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2,3-epoxypropane (6.0 g, 20.8 mmol, prepared as described in Example 19), (R)-3-piperidinecarboxylic acid ethyl ester (L)-tartrate (6.24 g, 20.8 mmol), potassium carbonate (11.5 g, 83.2 mmol) and sodium iodide (3.12 g, 20.8 mmol) in dry N,N-dimethylformamide (25 ml) was stirred and heated at 60° C. for 48 h. The reaction mixture was concentrated in vacuo and the residue dissolved in toluene (100 ml) and ethyl acetate (100 ml). The solution was washed with water (2×50 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of toluene, ethyl acetate and triethylamine (35:6:1) as eluent to give 4.5 g (53%) of (R)-1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxy-propyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:24]([O:26]CC)=[O:25])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+:33].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:24]([O-:26])=[O:25])=[CH:14][N:13]=1.[Na+:33]
Reactant: CCOC(=O)c1cnc(Nc2cc([N+](=O)[O-])ccc2C)nc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(C(=O)[O-])c(-c2cccnc2)n1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
1.0 g ethyl 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylate and 0.8 g sodium carbonate in 20 mL ethanol and 4 mL water is suspended. The mixture is refluxed for 4 hours by distillating the ethanol and compensating with water the volume loss. The mixture is cooled at room temperature, and the precipitate is filtrated, yielding 0.84 g of product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.CSC.B>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1ccc(CC2OCCO2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a cooled (0° C.) solution of 4-((1,3-dioxolan-2-yl)methyl)benzoic acid (1.02 g, 4.92 mmol) in anhydrous THF (63.5 mL), a solution of borane dimethylsulfide complex (2.0 M in THF, 12.29 mL, 24.59 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 5 minutes and then the coolant removed. The reaction mixture was stirred at RT for 16 hours. The reaction mixture was cooled to 0° C. and methanol (1 mL) was added. The reaction mixture was diluted with water and saturated aqueous sodium hydrogen carbonate and then extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried (magnesium sulphate) filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-50% ethyl acetate in iso-hexane to afford the title compound (0.936 g, 98%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13]>C1(C)C=CC=CC=1>[Cl:13][C:12]1[N:11]=[C:18]([Cl:19])[N:17]=[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc(Cl)nc(Oc2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
An aqueous solution of 52 parts of phenol and 50 parts by volume of a 33% aqueous solution of sodium hydroxide in 250 parts of water is treated, at a temperature of between 30° and 35° C., with a solution of 92.5 parts of cyanuric chloride in 700 parts by volume of toluene, with thorough stirring. The reaction mixture is heated to 50° C. and stirred for a further 1 hour at this temperature. The organic phase is separated off and dried with magnesium sulfate and the bulk of the toluene is distilled off. The distillation residue is filtered off with strong suction and washed with twice 20 parts by volume of toluene. After drying under reduced pressure at 30° C., 80 parts of the compound 2,4-dichloro-6-phenoxy-1,3,5-triazine melting at 111 to 116° C. are obtained.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]1([C:13](=[O:24])[CH2:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1(C)C=CC=CC=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:7]1([C:13](=[O:24])[CH:14]([CH3:1])[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)CCCCC(=O)CC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CI
Product: CC(C)CCCCC(=O)C(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A mixture of 55.2 g anhydrous potassium carbonate, 1.6 g tetrabutylammonium fluoride, 24.8 g 1-phenyl-3-isoheptyl-1,3-propanedione and 150 ml. toluene were stirred and heated to reflux for 2 hours with a Dean-Stark trap under a nitrogen atmosphere. The mixture was cooled to room temperature, 7.0 ml methyl iodide was added and the mixture was heated with stirring to 50 degrees Centigrade overnight. The product was diluted with toluene and water, and the organic phase washed with water, and stripped under reduced pressure. The residue was distilled in a Kugelrohr apparatus at 100-110 degrees Centigrade at 0.3 mm Hg to give 25.6 g distillate. The distillate was purified on a silica gel column and redistilled in a Kugelrohr apparatus to give 16.4 g of 1-phenyl-2-methyl-3-isoheptyl-1,3-propanedione. Employing the same procedure using benzyl iodide will provide the corresponding 1-phenyl-2-benzyl-3-isoheptyl-1,3-propanedione.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][CH3:14])=[O:12])[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>CN(C)C=O>[NH2:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][CH3:14])=[O:12])[N:10]=2)[N:7]=1
Reactant: Nc1cccc(O)c1
Reactant: CNC(=O)c1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 35.7 %

Procedure:
Using 6-iodo-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (0.30 g, 0.99 mmol), N,N-dimethylformamide (3.0 mL), potassium carbonate (275 mg, 1.99 mmol) and 3-aminophenol (163 mg, 1.49 mmol) as starting materials and in the same manner as in Example 91, the title compound (0.10 g, 36%) was obtained as a dark brown powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=O)=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[CH2:19]/[C:20](=[N:39]\[OH:40])/[C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(C(=O)O)c(F)c2)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(C(=O)O)c(F)c2)cc1F

Procedure:
In analogy to example 151, step 3, 2-fluoro-4-{3-fluoro-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=519.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C@H:9]([OH:11])[CH3:10]
Reactant: CC(=O)Cc1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-bromophenyl) propane-2-one (30 g, 140 mmol) in MeOH (100 ml) was added NaBH4 (6.09 g, 210 mmol) at 0° C. and stirred at room temperature for 2 h. The reaction mixture was quenched with water and concentrated under reduced pressure to afford crude compound. The title compound was purified by separation methods A, E and M (Yield 28.0 g). The enantiomer-1 showed up at tr=7.86 min with Chiralcel OD-H (4.6×250 mm) 5μ, hexane:2-PrOH:TFA (90:5:0.1), 1 ml/min.