Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Temperature: 100 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (652 mg, 0.929 mmol), and copper (I) iodide (413 mg, 2.17 mmol) were combined in triethylamine (15 mL) under an atmosphere of nitrogen. Trimethylsilyl acetylene (4.2 mL, 29.7 mmol) was added and the mixture was heated to 100° C. The mixture solidified and was monitored by LC/MS. After completion, the mixture was diluted with methylene chloride and washed with 1 NHC1. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5-45%) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.09 (dd, J=6.10, 2.03 Hz, 1H) 7.77-7.97 (m, 1H) 7.54 (t, J=9.15 Hz, 1H) 0.15-0.32 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:16])=[CH:4][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1Oc1ccccc1

Procedure:
For example, 4-fluoro-3-phenoxy-toluene, when reacted with N-bromosuccinimide in the presence of a radical initiator, for example azodiisobutyronitrile, optionally using a diluent, for example carbon tetrachloride, optionally using a diluent, and 100° C., gives 4-fluoro-3-phenoxy-benzyl bromide. From this, 4-fluoro-3-phenoxy-benzaldehyde can be prepared in a Sommelet reaction, that is to say by reaction with hexamethylenetetramine in the presence of a diluent, for example methylene chloride, at temperatures between 0° and 50° C., followed by reaction with aqueous acetic acid and thereafter with hydrochloric acid, at temperatures between 80° and 120° C. The reaction of 4-fluoro-3-phenoxy-benzaldehyde with sodium cyanide in aqueous acetic acid at 20° C. gives α-cyano-4-fluoro-3-phenoxy-benzyl alcohol. The reaction sequence described above is outlined in the following equations: ##STR11##
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36]3[N:37]=[CH:38][O:39][CH:40]=3)=[CH:24][C:23]=2[CH2:41][CH3:42])[C:12]=1[CH2:43][CH2:44][CH3:45].B(F)(F)F.CCOCC.CCOCC>C(S)C>[CH2:41]([C:23]1[CH:24]=[C:25]([C:36]2[N:37]=[CH:38][O:39][CH:40]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:43][CH2:44][CH3:45])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:46])=[O:2])[CH3:42]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3cocn3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: FB(F)F
Solvent: CCS
Solvent: CCOCC
Product: CCCc1c(OCCCOc2cc(O)c(-c3cocn3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 46.9 %

Procedure:
To a solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (89 mg, 0.14 mmol) in ethanethiol (2 mL) was treated with boron trifluoride etherate (0.27 mL, 2.2 mmol) at room temperature for 4 h. The solution was poured into ether and washed once with water, once with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 34 mg (45%) of the title product as a light brown oil. 1H NMR (CDCl3) δ 7.99 (d, J=1 Hz, 1H), 7.90 (d, J=1 Hz, 1H), 7.88 (dd, J=8, 2 Hz, 1H), 7.38 (t, J=7 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.06 (d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J=9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 (t, J=8 Hz, 2H), 2.58 (q, J=8 Hz, 2H), 2.33 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=7 Hz, 2H), 1.17 (t, J=8 Hz, 3H), 0.91 (t, J=8 Hz, 3H); MS ES+m/e=532 (p+1).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:5][C:6]1[N:7]=[C:8]([N:3]([CH3:4])[CH3:2])[CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc(F)n1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)c1cccc(F)n1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
Dimethylamine hydrochloride (19.0 g, 91.2 mmol) was added to a suspension of 2,6-difluoropyridine (10.0 g, 86.9 mmol) and potassium carbonate (24.4 g, 177 mmol) in acetonitrile (100 mL). The suspension was stirred at reflux for 2 h before cooling to room temperature and filtering through a pad of celite, washing the filter cake with acetonitrile (500 mL). The filtrate was concentrated in vacuo to product desired product (11.3 g, 93% yield) as an orange oil. 1H NMR (CDCl3, 600 MHz) 5=7.33-7.66 (m, 1 H) 6.28 (dd, J=8.22, 2.35 Hz, 1 H) 6.09 (dd, J=7.63, 2.35 Hz, 1 H) 3.07 (s, 6 H); MS (FID)=140.0 (M)+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][NH:22][CH2:23]4)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:32](C)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O.CS(C)=O.CO>[CH3:3][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][N:22]([CH3:32])[CH2:23]4)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:1]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C)C4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(1,2,3,4-tetrahydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 3, 25.0 mg, 0.069 mmol) and formaldehyde (37% w/v in H2O, 8.0 μL, 0.10 mmol) in DCM (5 mL) was added NaBH(OAc)3 (29 mg, 0.14 mmol) and the resulting solution stirred at room temperature for 20 min. Brine (5 mL) was added, and the aqueous extracted with DCM (5 mL). The combined organics were concentrated in vacuo to give a white solid. This solid was redissolved in DMSO-MeOH, added to an SCX cartridge and washed with MeOH. The product was eluted with NH3 in MeOH; concentration in vacuo gave a white solid (20.1 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 8.41 (1H, d), 8.32 (1H, dd), 7.98 (1H, d), 7.29 (1H, t), 7.20 (1H, d), 7.12 (1H, d), 4.79 (1H, sept), 3.67 (2H, s), 3.30 (2H, t), 2.75 (2H, t), 2.49 (3H, s), 1.47 (6H, d).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1>N1C=CC=CC=1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:63]([CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:69])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)CCC(=O)O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reaction time: 0.33 h

Procedure:
Taxol (0.5 g, 0.59 mmol) and succinic anhydride (0.90 g, 7.6 mmol) in 12 ml of pyridine were allowed to react for 3 hours at room temperature after which the mixture was evaporated to dryness in vacuo. The residue was treated with 20 ml of water, stirred for 20 min and then filtered. The precipitate was dissolved in acetone, water slowly added, and the fine crystals of 8 were collected; yield (75-85%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.CO>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=2)=[O:18])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)NCC(=O)N2CCC(Cc3ccccc3)CC2)ccn1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(NC(=O)NCCN2CCC(Cc3ccccc3)CC2)ccn1

Procedure:
The crude 1-[2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-3-(2-methyl-pyridin-4-yl)-urea (Example 39.1., 0.5 mmol) is dissolved in THF (5 mL) and added to a cooled (0° C.) suspension of LiAlH4 (100 mg, 2.5 mmol) in THF (20 mL). The mixture is warmed during 15 h to r.t. The reaction mixture is carefully added to EtOAc (100 mL) and MeOH (5 mL), and, subsequently, sat. aq. NaHCO3 (2 mL) are added. The mixture is filtered, the filtercake washed with MeOH (2×50 mL), and the filtrate is evaporated. The residue is taken up in a minimal amount of MeOH, diluted with CH2Cl2, dried (Na2SO4), filtered and evaporated. The residue is purified by HPLC to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][N:12]2[CH2:13][CH2:14]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]2[CH:16]([OH:17])[CH:15]3[CH2:18][CH2:19][N:12]2[CH2:13][CH2:14]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1C(=Cc2cccc([N+](=O)[O-])c2)N2CCC1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cccc(C=C2C(O)C3CCN2CC3)c1

Procedure:
The manner in which 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane is synthesized can vary. For example, in one method, 3-nitrobenzaldehyde can be condensed with 3-quinuclidinone in an aldol reaction using potassium hydroxide and ethanol to yield 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one. The latter compound can be converted to the corresponding dithioketal by treatment with 1,2-ethanedithiol and boron triflouride etherate. Reduction and desulfurization can be effected by hydrogenation using Raney nickel to yield 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane. Alternatively, in another method, the aldol product, 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one can be reduced by treatment with sodium borohydride in methanol to give the alcohol, 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-ol. The latter compound can be converted to the chloro intermediate, 3-chloro-2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octane dihydrochloride upon treatment with thionyl chloride. Dechlorination by hydrogenation with Raney nickel and carbon-carbon double bond reduction by hydrogenation over 10% palladium on carbon can then be effected to yield 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane. Replacement of 3-nitrobenzaldehyde with 2-nitrobenzaldehyde or 4-nitrobenzaldehyde in the above synthetic approach affords the isomeric compounds, 2-[(2-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane and 2-[(4-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)ccc1CCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a stirred solution of 4-bromo-1-chloromethyl-2-methoxybenzene (1.50 g, 6.36 mmol) in acetonitrile (64 mL) was added potassium carbonate (1.05 g, 6.36 mmol) and piperidine (0.63 mL, 6.36 mmol) then the reaction mixture was heated under reflux for 15 h. The reaction mixture was cooled to ambient temperature and then filtered, the filtrate was then concentrated under reduced pressure to afford a residue that was then loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia in methanol to afford the title compound (1.73 g, 96%). 1H NMR (CDCl3, 300 MHz): 7.23 (d, J=8.1 Hz, 1H), 7.05 (dd, J=8.1, 1.9 Hz, 1H), 6.97 (d, J=1.9 Hz, 1H), 3.80 (s, 3H), 3.45 (s, 2H), 2.39 (t, J=5.0 Hz, 4H), 1.62-1.51 (m, 4H), 1.47-1.39 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:20])=[N:17][C:18]=1[CH3:19]>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([S:8]([NH:20][C:16]2[CH:15]=[CH:14][C:13]([CH3:12])=[C:18]([CH3:19])[N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: Cc1ccc(N)nc1C
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2cccnc2Cl)nc1C
Yield: 85.7 %

Procedure:
The title compound (5.0 g, 16.8 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (5.0 g, 23.7 mmol) and 5,6-dimethylpyridin-2-amine (2.4 g, 19.6 mmol) in pyridine (25 mL) at rt using the methods of (IntC1), step 1.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:3])[CH3:2].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].O.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>CS(C)=O>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1occc1S(=O)(=O)c1ccc(OCCCBr)cc1
Reactant: CC(C)(C)N
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1occc1S(=O)(=O)c1ccc(OCCCNC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
A mixture of 0.00282 mol of 2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan and 0.013 mol of tert-butylamine in 7 ml of dimethylsulphoxide was stirred at room-temperature for 24 hours. After that, the mixture was poured into water, distilled in the presence of ethyl acetate, dried on sodium sulphate, filtered and concentrated. The residue so obtained was purified on a silica column using a methanol/ethyl acetate 2/8 mixture as eluent. The oily base so provided was then treated with an ethereal solution of oxalic acid and the precipitate was recrystallized from ethanol.
Reaction SMILES: [S:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1N)([OH:4])(=[O:3])=[O:2].C1C(C(O)=O)=CC2C=CC([OH:27])=CC=2C=1.S(=O)(=O)(O)O.S(=O)(=O)=O.S(=O)(=O)=O>>[S:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:27])([OH:4])(=[O:3])=[O:2]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1S(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1ccc2c(S(=O)(=O)O)c(O)ccc2c1

Procedure:
The 1-sulfo-6-carboxy-2-aminonaphthalene starting compound has not been disclosed before. It can be prepared according to the present invention by first sulfonating 2-naphthol-6-carboxylic acid in a sulfuric acid/sulfur trioxide mixture (oleum) having a sulfur trioxide content of 0 to 65% by weight at a temperature between 0° C. and 40° C., preferably at 0° to 10° C., to 1-sulfo-6-carboxy-2-naphthol, isolating this compound and then reacting it at a temperature between 100° and 160° C. in an autoclave in aqueous medium with ammonium hydrogen-sulfite. The 1-sulfo-6-carboxy-2-naphthol is isolated from the reaction mixture in a conventional manner by carefully pouring the reaction batch onto ice. The precipitated product is filtered off with suction and suspended in ice-water, and any sulfuric acid still present is neutralized with sodium carbonate by adjusting the suspension to a pH between 4 and 4.5. The compound can then be isolated by filtering off with suction and drying.
Reaction SMILES: NC1C=C(C2CCCCC2)C=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:24][C:25]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:28]=[CH:27][C:26]=1[S:37]([NH:40][C:41]([NH:43][CH:44]([CH3:46])[CH3:45])=S)(=[O:39])=[O:38].C(Cl)(Cl)=O>>[CH:31]1([C:29]2[CH:28]=[CH:27][C:26]3[S:37](=[O:39])(=[O:38])[N:40]=[C:41]([NH:43][CH:44]([CH3:46])[CH3:45])[NH:24][C:25]=3[CH:30]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)NC(=S)NS(=O)(=O)c1ccc(C2CCCCC2)cc1N
Agent: CC(C)N=C=S
Agent: Nc1cc(C2CCCCC2)ccc1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: CC(C)NC1=NS(=O)(=O)c2ccc(C3CCCCC3)cc2N1

Procedure:
Starting from 2-amino-4-cyclohexylbenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-4-cyclohexylbenzenesulfonyl)-N′-isopropylthiourea was prepared; m.p. 131-133° C. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; m.p. 264-266° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[O:12][CH3:13].BrC1C=CN2C(=O)NN=C2C=1O.CCN(C(C)C)C(C)C.Cl[CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[N:9]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:10]=[C:4]2[C:3]=1[O:12][CH3:13]
Reactant: COc1c(Br)ccn2c(=O)[nH]nc12
Reactant: C[Si](C)(C)CCOCCl
Agent: O=c1[nH]nc2c(O)c(Br)ccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(Br)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 20 %

Procedure:
To a stirred suspension of the mixture of 7-bromo-8-methoxy-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one and 7-bromo-8-hydroxy-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (from step 4) in DCM (120 mL) at 0° C. was added DIPEA (35 mL, 0.2 mol). After 5 min, (2-chloromethoxy-ethyl)-trimethylsilane (11.9 mL, 67.2 mmol) was added. The mixture was stirred at 0° C. for 1 hour and at RT for a further 2 hours. The resulting mixture was diluted with DCM (200 mL) and washed successively with 0.5 M HCl (aq) (400 mL) and water, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 30% ethyl acetate in cyclohexane) to afford the title compound (1.30 g, 20%) as a yellow solid. Fractions containing 7-bromo-8-(2-trimethylsilanyl-ethoxymethoxy)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one were evaporated and the resultant residue was dissolved in MeOH (120 mL). The solution was stirred for 8 days at RT before evaporating to dryness. The resultant residue was dissolved in DMF (25 mL), cooled to 0° C., and cesium carbonate (13 g, 40 mmol) and iodomethane (3.11 mL, 50 mmol) were added. The reaction mixture was stirred at RT for 16 hours. EtOAc and water were added, the aqueous phase was isolated and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 30% EtOAc in cyclohexane) to afford a further quantity of the title compound (3.26 g, 51%) as a yellow solid. LCMS (Method A): RT=4.70 min, [M+H]+=396/398.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][CH2:35][OH:36])=[N:31][CH:32]=2)=[CH:23][CH:22]=1.[N:37]1([CH2:42][C:43]2[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][CH2:35][O:36][C:46]3[CH:45]=[CH:44][C:43]([CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:48][CH:47]=3)=[N:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(CN2CCCC2)cc1
Reactant: OCC#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(C#CCOc3ccc(CN4CCCC4)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
131 mg (0.5 mmol) triphenylphosphane are added to a solution of 100 mg (0.41 mmol) 3-[5-(4-chloro-phenyl)-pyridin-2-yl]-prop-2-yn-1-ol and 88 mg (0.5 mmol) 4-pyrrolidin-1-ylmethyl-phenol in 4 mL THF. Then 0.1 mL (0.5 mmol) diisopropyl azo-dicarboxylate is slowly added dropwise and the reaction mixture is stirred for 3 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 1 mL DMF and purified by HPLC. The product obtained, which still contains triphenylphosphane oxide, is again purified by chromatography (silica gel, EtOAc after EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH:21]1([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[C:30]([F:43])[CH:29]=2)=[O:26])[CH2:23][CH2:22]1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>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].CCO.O.COCCOC>[CH:21]1([NH:24][C:25](=[O:26])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=4[N:7]=3)=[C:30]([F:43])[CH:29]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Yield: 18.9 %

Procedure:
A solution of methyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 25) (10 mg, 0.335 mol), 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) (122 mg, 0.382 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (14 mg, 0.0168 mmol) and sodium carbonate (107 mg, 1.01 mmol) in 2 ml of a 7:3:1 mixture of DME:H2O:EtOH respectively was heated in the microwave at 115° C. for 45 minutes. The reaction was concentrated in vacuo and the residue redissolved in a mix of MeOH/DCM. It was loaded onto an SCX cartridge and washed with two column volumes of MeOH/DCM before being eluted with 2M NH3 in MeOH and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH to yield the title compound (33 mg, 22%).