Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:18]([NH2:29])[C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:18][C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1)=[O:9]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc(Br)ccc1NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
A mixture of 1 g of the compound obtained in Step 1.1, 0.646 g of veratrylamine, 1.152 g of DIEA and 1.69 g of HBTU in 50 ml of DMF is stirred for 2 days at room temperature. The reaction medium is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 1.2 g of a solid, which is used without purification in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:33]=[CH:32][S:31][C:18]=3[N:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1.CC[N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:33]=[CH:32][S:31][C:18]=3[N:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:36])=[O:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(-c3ccc(C(N)=O)cc3)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
The mixture of (S)-4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid, EDCI (56 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol) and Et3N (39 mg, 0.39 mmol) in DCM (20 mL) was stirred at room temperature for 3 hrs, then ammonia was bubbled into this mixture for 3 h. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by column chromatography (DCM:MeOH=50:1) to afford (S)-4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (12 mg, 10%) as yellow solid. 1H NMR (300 MHz, DMSO): δ 9.99 (s, 1H), 9.40 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.49 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 5.88 (s, 1H), 3.93-3.90 (m, 1H), 3.79 (s, 3H), 3.43-3.40 (m, 1H), 3.18-3.15 (m, 1H), 2.06-1.98 (m, 3H), 1.69 (s, 1H), 1.15 (d, 3H, J=6.0 Hz). LC-MS: 461 [M+H]+, tR=1.6 min. HPLC: 95.06% at 214 nm, 95.01% at 254 nm, tR=5.55 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].C[O-].[Na+].[CH3:13][O:14][C:15](=[O:22])/[CH:16]=[C:17](/[O:20][CH3:21])\[CH2:18]Cl>CN(C=O)C>[CH3:13][O:14][C:15](=[O:22])/[CH:16]=[C:17](/[O:20][CH3:21])\[CH2:18][CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:2][CH3:1])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)/C=C(\CCl)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\CC(C(=O)OC)C(=O)OC)OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
66 g (0.5 mol) of malonic acid dimethyl ester was placed in 250 ml of N,N'-dimethylformamide. 27.8 g (0.5 mol) of sodium methylate was added at 20° C.; 10 minutes later 41.6 g (0.25 mol) of 4-chloro-3-methoxy-2E-butenoic acid methyl ester was added within 5 minutes. It was stirred for 2 hours at 20° C. Then 10.8 g (0.2 mol) of sodium methylate was added once more. After stirring for 15 hours at 20° C. it was distilled off. After working up according to Example (a) 53.8 g (81 percent) of the title compound, with a purity of 98 percent (GC), was obtained. Data for the title compound was:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccn1
Reactant: OB(O)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Product: C(=C1c2ccccc2CCc2ccccc21)c1ccccc1-c1ccccn1

Procedure:
Following procedures essentially as described in Example 225 and using 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylboronic acid (100 mg, 0.307 mmol) and 2-chloropyridine (52 mg, 0.460 mmol),provides the title compound. Purify further via silica gel chromatography to obtain 14.7 mg (13%) of material that is 84% pure by HPLC. MS (S) 360 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:33])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][C:12]=1SCC1C=CC(OC)=CC=1.O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:33][C:12]2[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: CCOC(=O)Cc1ccc(NC(=S)Nc2ccccc2C)c(SCc2ccc(OC)cc2)c1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc2nc(Nc3ccccc3C)sc2c1
Yield: 83.1 %

Procedure:
In ethanol (50 ml), ethyl 4-(N′-(2-methylphenyl)thioureido)-3-(4-methoxybenzylthio)phenylacetate (1.63 g, 3.40 mmol) and mercuric oxide (yellow) (1.10 g, 16.4 mmol) were stirred for one hour at 70° C. Water (50 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1) eluate fractions, ethyl 2-(2-methylphenylamino)-6-benzothiazolylacetate (922 mg, 83%) was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20](O)([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20]([CH2:24][CH2:25][CH3:26])=[CH:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCCC(O)(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC=C(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 110 °C
Yield: 81.4 %

Procedure:
4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol (594 mg) and p-toluenesulfonic acid monohydrate (74 mg) were combined in 13 mL toluene and the stirred mixture was heated to 110° C. for 11 h. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was washed with additional ethyl acetate. The combined ethyl acetate was washed with brine, dried with magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 461 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, which was recrystallized from hexane, mp 86.7–88.2° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]#[CH:20])=[CH:11][CH:10]=1>C(N(CC)CC)C.[Cu](I)I.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>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]#[C:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: C#CCCC#Cc1ccc(F)cc1
Reactant: Ic1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccc(C#CCCC#Cc2ccccn2)cc1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (11 mg, 0.06 mmol) and triethylamine (3.4 mL), were added 2-iodopyridine (246 mg, 1.2 mmol) and Pd(PPh3)2Cl2 (42 mg, 0.06 mmol) under N2. A yellow suspension was obtained after 5 min of stirring at room temperature. A solution of 1-fluoro-4-(hexa-1,5-diynyl)benzene (210 mg, 1.2 mmol) in triethylamine (0.5 mL) was then added under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 48h. The reaction mixture was concentrated. The crude product was dissolved in DCM and the organic phase was washed with saturated NH4Cl, water and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by Flash chromatography (prepacked 25 g silicagel column, Cyclohexane/ethyl acetate from 90/10to 80/20 as eluent) to afford 87 mg of 2-(6-(4-fluorophenyl)hexa-1,5-diynyl)pyridine (Yield: 29%) as a brown powder (M.P.=68-69° C.).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9]([F:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[N:6][N:7]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9]([F:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[O:15])=[N:6][N:7]=1)[CH3:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1nnc(-c2cc(C(=O)O)c(C)cc2F)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2F)[nH]1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a round-bottom flask was added a solution of 5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid (compound 258.1, 125 mg, 0.500 mmol, 1.00 equiv) in DMF (10 mL). EDC.HCl (143 mg, 0.750 mmol, 1.50 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 122 mg, 0.550 mmol, 1.10 equiv), and 4-dimethylaminopyridine (183 mg, 1.50 mmol, 3.00 equiv) were added in portions. The resulting solution was stirred for 1 h at 40° C. in an oil bath, then quenched with 50 mL of NH4Cl (aq.sat.). The mixture was extracted with 40 mL of ethyl acetate and the combined organic layers were washed with 3×30 mL of NH4Cl (aq.sat.), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 180 mg (86%) of 4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile as a white solid.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:22](=[O:24])=[O:23].O>O1CCCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[C:15]=1[C:22]([OH:24])=[O:23])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1C(=O)O
Yield: 76.1 %

Procedure:
400 ml (600 mmol) of tert.butyllithium (1.5M in pentane) were added dropwise within 1 hour to a solution, cooled to -70°, of 57.2 g (250 mmol) of N-(tert.butoxycarbonyl)-3,4-difluoroaniline in 500 ml of tetrahydrofuran. Subsequently, 160 g of dry ice were added in small portions to the yellow suspension, the mixture was left to warm to 0° and 400 ml of water were added dropwise. The tetrahydrofuran and the pentane were distilled off and the aqueous phase was washed twice with ether and subsequently adjusted to pH=1 with conc. hydrochloric acid. The acidic aqueous phase was extracted three times with methylene chloride; the organic phase was dried over sodium sulfate, filtered and evaporated. The beige solid obtained was recrystallized from ethylene chloride and there were obtained 52 g (76%) of 2-(tert.-butoxycarbonyl)amino-5,6-difluorobenzoic acid as colourless needles of m.p. 159.5°-160.5°.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=[CH:16]2)[CH:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.4 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butylamide (example 278) (0.137 g, 0.24 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.100 g, 81%). MS (ISP) 519.2 [(M+H)+].
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]=12.[H-].[Na+].I[CH2:19][C:20]([NH2:22])=[O:21]>C(#N)C>[NH2:22][C:20](=[O:21])[CH2:19][N:2]1[CH:3]=[C:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2=[N:1]1
Reactant: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1Cc2cn(CC(N)=O)nc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2 L three neck flask fitted with a thermometer, a mechanical stirrer and an addition funnel was charged with a suspension of tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (18.01 g, 86.5 mmol) in anhydrous acetonitrile (1.0 L). Sodium hydride (60% dispersion in oil, 4.15 g, 104 mmol) was added to the suspension in one portion under nitrogen. The reaction was stirred at room temperature for 2 h. The resulting white suspension was then cooled in an ice bath and iodoacetamide (31.95 g, 173 mmol) was added. The ice bath was then removed and the mixture was stirred 18 h at room temperature. The mixture was quenched with water (50 mL) and the solvent was removed under reduced pressure. The residue was partitioned between diluted NaCl (50 mL brine and 100 mL water) and 1.0 L EtOAc. The aqueous layer was extracted with 2×1.0 L EtOAc. The organic layers were combined and dried over Na2SO4 and solvent was evaporated under reduced pressure. Crude material was purified on silica gel eluting with 20-50% EtOAc/CH2Cl2 to wash out excess iodoacetamide, and then with 2-10% MeOH/CH2Cl2 to afford a mixture of the two products which were separated on a chiral AD column by eluting with 30% MeOH/CO2 to afford the title compound (less mobile fraction). LC-MS=267.32 [M+1].
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])=[O:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCNS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.8 g (29.8 mmol) of N-(2-dimethylamino-ethyl)-phenylsulphonamide are dissolved in 100 ml of DMF and combined with 1.3 g (30 mmol) of sodium hydride (55% in oil). The mixture is stirred for one hour at ambient temperature. Then 4.2 g (29.8 mmol) of 4-fluoro-nitrobenzene are added, and stirring is continued for another 16 hours. After the addition of 300 ml of water the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated down. The residue is acidified with 1 N hydrochloric acid and washed with ethyl acetate. The aqueous phase is then made basic again with sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried and evaporated down.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[C:8]([C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12][CH:11]=1)=[CH:7][CH:6]=[N:5]2.[I:20]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[I:20][C:3]1[N:4]2[N:5]=[CH:6][CH:7]=[C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[N:12][CH:11]=3)[C:9]2=[N:1][CH:2]=1
Reactant: c1ccc2c(-c3ccnn4ccnc34)cncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Ic1cnc2c(-c3cncc4ccccc34)ccnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 4-(imidazo[1,2-b]pyridazin-8-yl)isoquinoline (220 mg, 0.893 mmol) in CHCl3 (10 mL) were added N-iodo succinimide (241 mg, 1.072 mmol) and TFA (0.275 mL, 3.57 mmol) In CHCl3 (1 mL). The reaction mixture was stirred at room temperature for 2 h and quenched with saturated NaHCO3. The layers were separated and the combined organic layer was washed with water and brine, dried over Na2SO4. The crude product was purified by BIOTAGE® (30-70% EtOAc/CH2Cl2, 0.8 L) to give the product (290 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 9.41 (1H, s), 8.72 (1H, s), 8.66 (1H, d, J=4.53 Hz), 8.07-8.17 (1H, m), 7.90 (1H, s), 7.71 (3H, d, J=3.02 Hz), 7.28 (3H, s), 7.26 (1H, d, J=4.53 Hz); LC/MS: Rt=1.53 min. LC/MS (Condition A): 373.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1.Cl>CCOCC>[ClH:1].[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:13][CH2:12]1
Reactant: NCCCN1CCOCC1
Reactant: Clc1ccc2nccn2n1
Agent: Cl
Solvent: CCOCC
Product: c1cn2nc(NCCCN3CCOCC3)ccc2n1
Yield: 32 %

Procedure:
Prepared from 6-chloroimidazo[1,2-b]pyridazine (4) and 3-morpholinopropylamine according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (125 mg, 32%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.73 (s, 1H), 7.63 (d, J=9.8 Hz, 1H), 7.45 (d, J=1.2 Hz, 1H), 6.74 (d, J=9.8 Hz, 1H), 3.89-3.88 (m, 4H), 3.45 (t, J=6.6 Hz, 2H), 3.20-3.13 (m, 6H), 2.14-2.08 (m, 2H); 13C NMR (125 MHz, CD3OD) δ 155.7, 137.0, 129.6, 125.2, 118.0, 115.8, 65.6, 56.9, 53.5, 39.7, 24.6; HPLC tR=6.5 min (Luna), >99%; ES-MS: (M+H)=262 m/z.
Reaction SMILES: CO[C:3](=[O:39])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:7]=[C:6]([F:37])[C:5]=1[OH:38].[CH3:40][NH:41][CH3:42]>C1COCC1>[F:37][C:6]1[C:5]([OH:38])=[C:4]([CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:7]=1)[C:3]([N:41]([CH3:42])[CH3:40])=[O:39]
Reactant: COC(=O)c1cc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)cc(F)c1O
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(O)c(C(=O)N(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
22 mg (40 μmol) of 3-fluoro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester was dissolved in 2 ml of a 2 M solution of dimethylamine in THF. The solution was heated to 100° C. in a closed vial for 24 h and then concentrated. The residue was dissolved in 2 ml of methanol and 350 μl of 50% w/v aqueous potassium hydroxide added. The mixture was left at ambient temperature for 1 h and then neutralized by addition of glacial acetic acid. The crude was directly purified by mass triggered reverse phase HPLC purification to afford 6.0 mg (14 μmol; 37% yield) of 3-fluoro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as an ivory solid. 1H-NMR (d6-DMSO): δ 11.91 (s, 1H), 8.51 (d, 1H), 8.14 (d, 1H), 7.73 (d, 1H). 7.64 (d, 1H) 7.62 (dd, 1H), 7.32-7.25 (m, 2H), 7.14 (d, 1H), 7.05 (m, 1H), 3.82 (s, 3H), 2.99 (s, 3H), 2.87 (s, 3H). MS: m/z 406 [MH+].
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl>[Br:20][C:13]1[CH:12]=[C:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:18])[CH3:19])[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-phenylamine (as prepared in the previous step, 1.41 g, 5.04 mmol) in 25 mL of DCM at 0° C. was slowly added N-bromosuccinimide (NBS) (898 mg, 5.04 mmol) in three portions over five minutes. After stirring at RT for 2 h, the mixture was treated with 50 mL of EtOAc and washed with H2O (2×30 mL) and brine H2O (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM) to give 1.59 g (88%) of the title compound as a light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C16H28BrNOSi, 358.1 (M+H). found 358.4.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:24](=[O:27])[CH2:25][CH3:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:13]([CH3:28])[CH2:12]1)=O)C1C=CC=CC=1.CO>[Pd].C(O)(=O)C>[CH3:28][C@H:13]1[C@H:14]([N:17]([C:24](=[O:27])[CH2:25][CH3:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][NH:11][CH2:12]1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(=O)N(c1ccccc1)[C@@H]1CCNC[C@H]1C
Reaction time: 24 h

Procedure:
A mixture of trans-N-benzyloxycarbonyl-3-methyl-4-[(1-oxopropyl)phenylamino]-piperidine (1.5 g, 3.94 mmol), 10% Pd-C (200 mg), methanol (20 ml), and acetic acid (20 ml) is hydrogenated at 50 psi for 24 hours. The resultant suspension is filtered through a bed of Celite and the filtrate concentrated. The residue is diluted with ethyl acetate (50 ml), basified to pH 11 with 2N NaOH and shaken. The organic layer is separated, dried over magnesium sulfate, and concentrated to trans-3-methyl-4-[(1-oxopropyl)-phenylamino]-piperidine: 720 mg; 96%.