Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]N=C(C)C(OCC)=O)=[C:8]([N+:21]([O-:23])=[O:22])[CH:7]=1.[OH2:24]>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]2[C:9](=[C:8]([N+:21]([O-:23])=[O:22])[CH:7]=1)[NH:12][C:7]([C:6]([O:5][CH2:4][CH3:3])=[O:24])=[CH:8]2
Reactant: CCOC(=O)C(C)=NNc1ccc(OCCOC)cc1[N+](=O)[O-]
Reactant: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCCOC)cc([N+](=O)[O-])c2[nH]1
Temperature: 110 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
A mixture of ethyl 2-{[4-(2-methoxyethoxy)-2-nitrophenyl]hydrazono}propanoate (250 mg) and polyphosphoric acid (2.0 g) was stirred at 110° C. for 1 hr. After cooling, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio) to give the title compound (40 mg, yield 17%) as yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give yellow prism crystals. melting point 90-91° C.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:17])=[CH:10][C:11]=3[C:12]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH2:18]([OH:22])[CH2:19][C:20]#[CH:21].O.Cl>C1COCC1.C(NC(C)C)(C)C.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>[OH:22][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:17])=[CH:10][C:11]=3[C:12]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)c2cc(O)ccc2-c2ccc(Br)cc21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)c2cc(O)ccc2-c2ccc(C#CCCO)cc21

Procedure:
14.7 g (0.048 mol) of 7-bromo-9,9-dimethyl-9H-fluoren-2-ol, 1.3 g (1.85 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.5 g (2.6 mmol) of copper(I) iodide are initially introduced in 200 ml of THF and 20 ml of diisopropylamine, and a solution of 9.5 ml (0.13 mmol) of but-3-yn-1-ol in 50 ml of THF is added over the course of 2 h under reflux. When the addition is complete, the batch is heated under reflux for a further 1 h, added to water, acidified using dil. hydrochloric acid and extracted three times with ethyl acetate. The combined org. phases are dried over sodium sulfate, and the solvent is removed in vacuo. Chromatography of the crude product on silica gel with toluene/ethyl acetate (4:1) gives 7-(4-hydroxybut-1-ynyl)-9,9-dimethyl-9H-fluoren-2-ol as colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[N+:25]([O-:48])[CH:26]=[C:27]([Cl:47])[C:28]=1[CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([O:21][C@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:40])[F:41])=[C:34]([O:42][CH2:43][CH:44]3[CH2:45][CH2:46]3)[CH:33]=1)[CH2:29][C:28]1[C:27]([Cl:47])=[CH:26][N+:25]([O-:48])=[CH:24][C:23]=1[Cl:22])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cn1ccc2cc(OCc3ccccc3)ccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.1 %

Procedure:
To a mixture of 2-(5-(benzyloxy)-1H-indol-1-yl)acetic acid (164 mg, 0.583 mmol) in DCM (20 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (245 mg, 0.583 mmol), EDC (335 mg, 1.749 mmol) and DMAP (35.6 mg, 0.291 mmol) were added, and the reaction was stirred at room temperature for 5 hours. The organic solution was washed with NaHCO3 sat. sol. and 1N HCl, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH from 99.5:0.5 to 98.5:1.5) affording (S)-4-(2-(2-(5-(benzyloxy)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (319 mg, 0.467 mmol, 80% yield). MS/ESI+ 683.0 [MH]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:29][CH2:28]1.N1CCCCC1>CN(C=O)C.CO>[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]([C:40]2[CH:46]=[CH:45][C:43]([NH:44]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:42][CH:41]=2)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:29][CH2:28]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(N)cc1
Solvent: C1CCNCC1
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Examples 1 and 187 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[N-(2-morpholinoethyl)-N-methylsulphonyl-amino]-aniline in DMF and subsequent treatment with piperidine in methanol.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:21]=[C:22]([NH:24]O)[CH3:23])[C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1>C([O-])(O)=O.[Na+]>[Br:1][C:2]1[N:3]2[N:24]=[C:22]([CH3:23])[N:21]=[C:4]2[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(=Nc1nc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1)NO
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2c(N3CCNCC3)ncc(Br)n2n1
Reaction time: 1.75 h
Yield: 61.2 %

Procedure:
In a 50 mL round bottom flask, tert-butyl 4-(5-bromo-3-((1-(hydroxyamino)ethylidene)amino)pyrazin-2-yl)piperazine-1-carboxylate (2.3 g, 5.5 mmol) was treated with polyphosphoric acid (10 g) at 50° C. for 1 h then at 75° C. for 1.75 h. Work-up: the mixture was carefully neutralized with saturated aqueous NaHCO3 (300 mL) and extracted with CH2Cl2 (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5% EtOAc in CH2Cl2 (containing 2% Et3N), to afford 1.0 g (61%) of the product as a white solid. MS m/z: 297 (M+H+).
Reaction SMILES: C[C:2]([CH3:5])([O-:4])[CH3:3].[K+].[F:7][C:8]1([F:17])[O:12][C:11]2C=[CH:14][CH:15]=[CH:16][C:10]=2[O:9]1.C([Li])CCC.FC1(F)OC2C=CC=C([K])C=2O1.CN(OC)C(=O)C.Cl>O1CCCC1.CO>[C:2]([C:5]1[C:11]2[O:12][C:8]([F:17])([F:7])[O:9][C:10]=2[CH:16]=[CH:15][CH:14]=1)(=[O:4])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: FC1(F)Oc2ccccc2O1
Agent: CON(C)C(C)=O
Agent: Cl
Agent: FC1(F)Oc2cccc([K])c2O1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1OC(F)(F)O2
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
6.2 g (55 mmol) of potassium tert.-butoxide dissolved in 40 ml of tetrahydrofuran (THF) are added dropwise at -30° C. under argon, over a period of 20 minutes, to a solution of 8.0 g (50 mmol) of 2,2-difluoro-1,3-benzodioxole in 10 ml of THF in a 250 ml 3-necked flask. The mixture is then cooled to -90° C. (methanol/liquid nitrogen), and 35 ml (55 mmol) of n-butyllithium (1.58M in hexane) are added thereto over a period of 30 minutes. The deep red solution of 2,2-difluoro-1,3-benzodioxol-4-yl-potassium is maintained at -78° C. for 20 minutes. Then, 5.2 g (50 mmol) of N-methyl-N-methoxy-acetamide in 20 ml of THF are added thereto over a period of 15 minutes at -78° C. When the dropwise addition is complete, the beige reaction mixture is allowed to warm up to -10° C. and is then hydrolysed with 40 ml of 10% hydrochloric acid. The hydrolysed mixture is extracted three times with 70 ml of diethyl ether each time. The organic solutions are washed three times with 30 ml of 1N HCl each time, dried over Na2SO4 and concentrated in a vacuum rotary evaporator. Upon distillation of the residue, 7.1 g (79%) of the product distil over in the form of a colourless oil at boiling point (b.p.) 114°-116° C./30 mbar.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F-].[Cs+].[CH:9]1([NH:12][C:13](=[O:39])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[OH:37])[CH2:30][CH2:29]4)[C:22]3=[O:38])[CH:15]=2)[CH2:11][CH2:10]1.[N+](C1C=C(S(O[CH2:53][C@H:54]2[CH2:56][O:55]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C>[CH:9]1([NH:12][C:13](=[O:39])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH2:53][C@H:54]5[CH2:56][O:55]5)[CH2:30][CH2:29]4)[C:22]3=[O:38])[CH:15]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H]3CO3)CC2)c1=O
Reaction time: 72 h

Procedure:
Potassium carbonate (216 mg) and cesium fluoride (36.5 mg) were added to N-cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 167d, 500 mg) in DMF (9 mL) and stirred for 1 h. (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (311 mg) was added and the reaction stirred for 3 days. The reaction mixture was used without isolation/purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[SH:21])=[O:12].C(=O)([O-])[O-].[K+].[K+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:11](=[O:12])[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]=3[S:21][C:15]=2[CH:16]=1
Reactant: O=C(Nc1ccc(F)cc1S)c1c(Br)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1Nc2ccc(F)cc2Sc2sc3c(c21)CCCC3

Procedure:
In the same manner as in Example 74 and using 2-bromo-4,5,6,7-tetrahydro-N-(4-fluoro-2-mercaptophenyl)-benzo[b]thiophene-3-carboxamide, dimethyl sufoxide and potassium carbonate, 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one is obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:27]([C:26]4[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:31])[CH3:17])=[CH:30][CH:29]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(OCCCN(C)C)cc3)nc(=O)c1-2
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.03 g, 9.14 mmol), 4-[3-(dimethylamino)propoxy]benzaldehyde (2.76 ml), and xylenes was heated at 120° C. for 1 hour, then at 160° C. for 6 hours. p-Toluenesulfonic acid (300 mg) was added and the mixture was heated at 160° C. until the reaction was complete. The reaction mixture was cooled to room temperature, and a creamy white solid formed, which was collected by filtration, washed with methanol and recrystallized from ethyl acetate to afford 1-cyclopentyl-3-ethyl-6-[4-[3-(dimethylamino)propoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 175°-178° C.
Reaction SMILES: I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)([CH2:14]4)[CH2:12]3)[CH:7]=2)=[CH:31][CH:30]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1ccncc1
Yield: 31.6 %

Procedure:
5-Iodo-1-{3-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-propyl}-1H-pyrimidine-2,4-dione (Prep40, 46 mg, 0.09 mmol) was dissolved in degassed DME-water solution (5-1, 1 mL). Pyridine 4-boronic acid (22 mg, 0.18 mmol), Na2CO3 (20 mg, 0.18 mmol), 2-(dicyclohexylphosphino)biphenyl (7 mg, 0.02 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol) were added and the mixture was placed in a microwave oven and heated at 150° for 20 minutes. The mixture was diluted with ethyl acetate, and washed with water. The organic phase was dried (Na2SO4) and evaporated; the crude was dissolved in MeOH and loaded on SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5. The residue was purified by flash chromatography with DCM-MeOH—NH4OH (99-1-0.1) to give the title compound (13 mg, 32% yield) as free base.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=3[NH2:14])=[CH:10][N:9]([CH3:23])[C:8]=12.[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1.[Na].C(O)(=O)C>ClCCl>[CH:24]1([CH2:27][NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:12]=2[C:11]2[C:7]3[C:8](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=3)[N:9]([CH3:23])[CH:10]=2)[CH2:26][CH2:25]1
Reactant: O=CC1CC1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N)cn(C)c12
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CC3)cn(C)c12
Yield: 99.6 %

Procedure:
The product from Example 44A (0.1 g, 0.302 mmol), cyclopropanecarboxaldehyde (0.063 g, 0.905 mmol) and sodium triacetoxyhydroborate (0.192 g, 0.905 mmol) were combined in dichloromethane (1.0 mL) and acetic acid (1.0 mL) under nitrogen, stirred for 6 hours and partitioned into water/ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.116 g, 100%).
Reaction SMILES: [CH:1](=O)[CH3:2].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[S:13]([NH2:16])(=[O:15])=[O:14]>C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]2[NH:4][CH:1]([CH3:2])[NH:16][S:13](=[O:14])(=[O:15])[C:6]=2[CH:7]=1
Reactant: CC=O
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CCO
Product: COc1ccc2c(c1)S(=O)(=O)NC(C)N2

Procedure:
829 μl of acetaldehyde are added to a suspension of 20 g of 2-amino-5-methoxy-benzenesulphonamide in 20 ml of anhydrous ethanol. The reaction mixture becomes homogeneous and is heated at reflux for 30 min. The ethanol is evaporated off in vacuo. The solid is taken up in ether and filtered off. The solid is taken up in 40 ml of ethanol, refluxed for 15 min. and allowed to return to ambient temperature. The expected product is obtained after filtration.
Reaction SMILES: Br[CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1)=[N+:26]=[N-:27]
Reactant: CCCC(C)COc1ccc([C@H](CBr)NC(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C)COc1ccc([C@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of t-butyl (1R)-2-bromo-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (17.8 g, 44.5 mmol) in dimethylformamide was added sodium azide (11.56 g, 178 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by addition of water (25 mL) and the mixture was transferred to a separatory funnel and the aqueous layer was extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30→40% ethyl acetate in hexanes) to afford t-butyl (1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (14.2 g, 88% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.01 (d, J=7.8 Hz, 1H), 4.78 (br. s., 1H), 3.78 (dd, J=9.1, 5.8 Hz, 1H), 3.68 (dd, J=8.8, 6.5 Hz, 1H), 3.57 (d, J=4.8 Hz, 2H), 1.86-1.97 (m, 1H), 1.42 (s, 9H), 1.26-1.51 (m, 3H), 1.14-1.24 (m, 1H), 0.99 (d, J=6.5 Hz, 3H), 0.90 (t, J=7.2 Hz, 3 H); LRMS (ESI) m/e 363.3 [(M+H)+, calcd for C19H31N4O3Br 363.2].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8](=[O:13])[CH:9]([CH3:12])[CH2:10]2
Reactant: CC(CO)C(=O)c1ccc(F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1Cc2cc(F)ccc2C1=O

Procedure:
A mixture of 18.2 g. (0.10 mole) of 4'-fluoro-3-hydroxy-2-methylpropiophenone and 12 g. of phosphorous pentoxide in 100 ml. of xylene is refluxed for one hour. The reaction is cooled, water is added and the xylene layer is washed with aqueous sodium hydroxide and water. The organic layer is then concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M17) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (62 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[F-].[Cs+].Cl[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([NH:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])=[N:19][N:20]2[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][CH:15]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([NH:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])=[N:19][N:20]3[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C)cc3)ccc12
Temperature: 104 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
555 mg of 4-methylphenylboronic acid, 1.24 g of caesium fluoride, 13.5 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 25, in 30 cm3 of dioxane, the mixture is then heated at about 104° C. for 5 hours 30 minutes and the temperature is then allowed to return to room temperature over 16 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and filtered through a sinter funnel packed with Celite, and the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41. 1.1 g of N-[6-(4-methylphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16](Cl)[CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl.C(=O)([O-])O.[Na+]>O1CCCC1.O>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Yield: 93.2 %

Procedure:
Into a 50 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 1.30 g (0.005 mol) of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine and 10 ml of anhydrous tetrahydrofuran were charged and dissolved, and then the mixture was cooled to -10° under stirring in a nitrogen gas atmosphere. Then, 1.28 g (0.0114 mol) of potassium tert-butoxide was dissolved in 10 ml of anhydrous tetrahydrofuran and dropwise added thereto at a temperature of from -8° to -12° C., and the mixture was stirred at -15° C. for one hour. Then, 5 ml of 1N hydrochloric acid was dropwise added thereto, and 50 ml of water and a small amount of sodium hydrogen carbonate were added to bring the pH of the aqueous layer to 7. Then, the mixture was extracted with 70 ml of toluene, and the extract was dried over anhydrous sodium sulfate. The toluene layer was concentrated and subjected to silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 1.04 g of 2-anilino-4-methyl-6-(1-propynyl)pyrimidine having a melting point of from 125° to 126° C. The yield was 93.2%.