Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:14][CH2:15][CH2:16][OH:17])[CH3:13])=[O:4].[BH4-].[Na+]>CN(C)C=O>[OH:17][CH2:16][CH2:15][N:14]1[CH:12]([CH3:13])[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:3]1=[O:4]
Reactant: CC(=NCCO)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1c2ccccc2NC(=O)N1CCO
Reaction time: 8 h

Procedure:
To 135 parts of N,N-dimethylformamide are added first 16.2 parts of 2,2,2-trichloro-N-[2-[1-[(2-hydroxyethyl)imino]ethyl]phenyl]acetamide and then portionwise 5.7 parts of sodium borohydride while stirring: exothermic reaction. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 8.5 parts of 3,4-dihydro-3-(2-hydroxyethyl)-4-methyl-2(1H)-quinazolinone as a solid residue.
Reaction SMILES: C([Mg]Cl)(C)C.[N:6]1[C:11]2[S:12][C:13]([C:15]([O:17]C)=O)=[CH:14][C:10]=2[CH:9]=[N:8][CH:7]=1.[CH3:19][O:20][N-:21][CH3:22]>C1COCC1>[CH3:19][O:20][N:21]([CH3:22])[C:15]([C:13]1[S:12][C:11]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:14]=1)=[O:17]
Reactant: C[N-]OC
Reactant: COC(=O)c1cc2cncnc2s1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc2cncnc2s1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
iPrMgCl (2M in THF, 1.1 mL) was added dropwise to a solution of methyl thieno[2,3-d]pyrimidine-6-carboxylate (intermediate 11) (138 mg) and N-methoxy-N-methylamide (104 mg) in THF at −20° C. maintaining the internal temperature below −5° C. The reaction was allowed to stir at −10° C. for 30 minutes and then quenched with NH4Cl (sat. aq). The solution was diluted with EtOAc and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×15 mL) and then the combined organics dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with hexane:EtOAc (1:1 to 1:4) afforded the title compound as a pale yellow solid (107 mg, 67%);
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1>ClC(Cl)C>[Cl:3][C:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[C:19]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH:8]=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Reactant: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=CC(=C(Cl)c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of phosphorus oxychloride (1.6 ml) and N,N-dimethylformamide (1.8 ml) in dichloroethane (6 ml) was stirred at ambient temperature for 1 hour. Dichloroethane (11 ml) and 4'-fluoro-2-(4-nitrophenyl)acetophenone (3 g) was added, and the mixture was refluxed overnight, washed with water twice, dried and evaporated. The oily residue (4 g) was purified by column chromatography on silica gel (80 g) eluting with toluene to give yellow crystals of 3-chloro-3-(4-fluorophenyl)-2-(4-nitrophenyl)propenal (2.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([O:39]CC)=[O:38])[CH:31]=3)=[CH:20][CH:19]=2)[CH:7]=1)[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>C1COCC1.C(O)C>[CH2:1]([O:3][C:4]([CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]2[CH:31]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)=[CH:20][CH:19]=1)=[O:42])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3cccc(CC(=O)OCC)c3)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)Cc1cccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3cccc(CC(=O)O)c3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (E)(E) [3-(5-{4-[5-(3-ethoxycarbonylmethyl-phenoxy)-pent-3-en-1-ynyl]-phenyl}-pent-2-en-4-ynyloxy)-phenyl]-acetic acid ethyl ester (example 21) (200 mg, 0.35 mmol) in THF (2 mL) and ethanol (6 mL) was added 1N sodium hydroxide (1 mL). After stirring at room temperature for 3 h, the reaction mixture was added 1N hydrochloride acid and ethyl acetate. The title compound was isolated by filtration of the mixture in 50 mg yield.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[Ce].[I:17]I>C(#N)C>[I:17][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: FC(F)(F)c1n[nH]cc1I
Yield: 160.9 %

Procedure:
An acetonitrile solution (30 ml) of 3-trifluoromethyl-1H-pyrazole (5.0 g), dicerium ammonium nitrate (10.0 g) and iodine (5.6 g) was refluxed for 1 hour. After cooling, the reaction solution was washed with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 4-iodo-3-trifluoromethyl-1H-pyrazole (9.3 g).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH2:7]1)(=O)=O.[C:42]([SH:45])(=[O:44])[CH3:43].[H-].[Na+].O>CN(C)C=O>[C:42]([S:45][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[CH2:7]1)(=[O:44])[CH3:43]
Reactant: CC(=O)S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.90 g) in dimethylformamide (2 ml) was added to a reaction mixture of thioacetic S-acid (0.16 ml) and sodium hydride (62.8% in oil suspension) (0.07 g) in dimethylformamide (9 ml) in a nitrogen stream and the mixture was heated at 70°-75° C. for 6 hours. The mixture was poured into water (100 ml), extracted with ethyl acetate (50 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with chloroform to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.60 g).
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]2[O:10][C:11]3[C:16]([C:17]4([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.Br.[C:24](=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH3:24][N:20]1[CH2:19][CH2:18][C:17]2([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([OH:3])[C:9]=3[O:10][C:11]3[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]1
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Reactant: O=C([O-])O
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCC2(CC1)c1ccccc1Oc1c(O)cccc12

Procedure:
1'-Methyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride (1.0 g.) in a solution of 45% w/v hydrobromic acid in glacial acetic acid (10 ml.) is heated under reflux for 2 hours. The solution is basified with sodium bicarbonate, diluted with water and extracted with chloroform. The chloroform extract is washed with water, dried over MgSO4, and evaporated to dryness. The residue is recrystallised from toluene-petroleum ether (b.p. 60°-80° C.) to give 1'-methyl-4-hydroxyxanthene-9-spiro-4'-piperidine, m.p. 171°-173° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C:11]2[N:16]=[C:15]([N:17]([CH:27]3[CH2:29][CH2:28]3)CC3C=CC(OC)=CC=3)[C:14]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:13]3[N:12]=2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:3]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH:27]3[CH2:28][CH2:29]3)[C:14]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:13]3[N:12]=2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: COc1ccc(CN(c2nc(Nc3nc(C#N)ncc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: N#Cc1ncc(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was dissolved in DCE. Anisole (50 μL) was added followed by TFA (200 μL) and the reaction was stirred at 50° C. overnight. The reaction was concentrated and dried under vacuum. The crude product was purified by preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 0-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions concentrated and dried via centrifugal evaporation to afford 3.6 mg of 2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[C:24]1(C)[C:25]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[CH2:35](N(CC)CC)C>C1COCC1>[CH3:35][C:28]1[CH:29]=[CH:24][C:25]([S:30]([O:1][C:2]2[C:6]3[CH:7]=[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)(=[O:31])=[O:32])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3onc(O)c3c2)CC1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2noc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A cooled (0° C.) solution of tert-butyl 4-(3-hydroxy-1,2-benzisoxazol-5-yl)piperidine-1-carboxylate (286 mg, 0.898 mmol) in THF (5 mL) was treated with toluenesulfonyl chloride (188 mg, 0.988 mmol) followed by triethylamine (144 μL, 1.03 mmol). The reaction mixture was permitted to warm to rt and stir for 1.5 h. The reaction mixture was filtered, and the filtrate was concentrated. Purification by MPLC (silica, 50% ethyl acetate/hexanes) provided tert-butyl 4-(3-{[(4-methylphenyl)sulfonyl]oxy}-1,2-benzisoxazol-5-yl)piperidine-1-carboxylate. 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J=8.5 Hz, 2H), 7.47 (s, 3H), 7.41 (d, J=8.0 Hz, 2H), 4.31 (br m, 2H), 2.85 (br m, 2H), 2.80 (tt, J=12, 3.5 Hz), 2.50 (s, 3H), 1.87 (br d, J=13 Hz, 2H), 1.64 (dq, J=4.5, 13 Hz, 2H), 1.52 (s, 9H). ESI-MS calc. for C24H28N2O6S: 472; Found: 473 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+]>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:22]=1
Reactant: Brc1cccnc1
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(-c4cccnc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200g, 0.78 mmol), 3-bromopyridine (0.117 g, 0.74 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl2.CH2Cl2) (0.03 g, 0.37 mmol), and 2M aqueous sodium carbonate solution (2 mL) in 7 mL of tetrahydrofuran was heated at reflux, with stirring, overnight. The mixture was allowed to cool to room temperature, diluted with ethyl acetate and 2N aqueous sodium hydroxide solution, and the organic phase was separated, washed with brine solution, dried over sodium sulfate, concentrated in vacuo and purified by silica gel (flash) chromatography (solvent gradient: 100% dichloromethane—25:2 dichloromethane: methanol/aqueous ammonium hydroxide) to give 0.114 g (53%) of the title compound as an amorphous pink solid. FDMS m/e=291 (M+). EA calculated for C19H21N3: C, 78.32; H, 7.26; N, 14.42. Found: C, 78.39; H, 7.39; N, 14.36.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1.CN1CCOCC1>C(#N)C>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](OC2CCNCC2)CC[C@@H]1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H]1C[C@H](OC2CCN(C(C)=O)CC2)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (24 uL, 0.00033. mol) in 0.5 ml of ACN was added to a solution of 1-tert-butyl 2-methyl(1S,2S,4R)-4-(piperidin-4-yloxy)cyclohexane-1,2-dicarboxylate hydrochloride made above (50 mg, 0.0001 mol) and 4-methylmorpholine (44 uL, 0.00040 mol) in acetonitrile (1.5 mL, 0.029 mol) at 22 Celsius. It was stirred at rt for 30 min, then quenched with Water, extracted with EA, and concentrated to give 1-tert-butyl 2-methyl (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])[C:5]([C:18]#[N:19])=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>O1CCCC1.C(O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]([C:6]2[C:5]([C:18]#[N:19])=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)[CH:13]=1
Reactant: N#Cc1ccc(F)cc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(F)cc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5,2′-Difluoro-5′-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was treated with tin(II) chloride dihydrate (9.86 g, 43.8 mmol) and the mixture left to stir at ambient temperature for 18 h. The solvent was evaporated and the residue stirred with 2 N sodium hydroxide solution (40 ml) for 2 h. The resulting suspension was diluted with water (100 ml) and extracted with dichloromethane (3×200 ml). The combined organics were washed with water (200 ml), brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound as a brown solid: 1H NMR (360 MHz, CDCl3) δ 3.68 (2H, s), 6.67-6.76 (2H, m), 7.02 (1H, dd, J 9, 9 Hz), 7.12-7.27 (2H, m), 7.78 (1H, dd, J 9, 6 Hz).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[C:32]1(B(O)O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:14])=[O:13])(=[O:22])=[O:23]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc4ccccc34)c2c1
Yield: 58 %

Procedure:
2-Methylsulfonyl-N-(3-naphthalen-1-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 298 mg of 1-naphthaleneboronic acid, 20 ml of dimethylformamide, 1.9 ml of a saturated aqueous sodium hydrogencarbonate solution and 24.5 mg of tetrakis(triphenylphosphine)palladium[0]. 240 mg of 2-methylsulfonyl-N-(3-naphthalen-1-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 186° C. (analysis C24H19N3O4S2 % calculated C, 60.36; H, 4.01; N, 8.80; O, 13.40; S, 13.43. % found C, 59.78; H, 4.05; N, 8.76; S, 13.34).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[OH:51][CH2:52][C@@H]1NC[C@@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[C@@H:27]([CH2:52][OH:51])[CH2:26][C@H:24]([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC[C@H]1C[C@H](O)CN1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2C[C@@H](O)C[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (3S,5R)-5-(hydroxymethyl)pyrrolidin-3-ol hydrochloride and isolated as white solid. MS (m/e): 417.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCc1cc(C(=O)OCC)n(CC(=O)N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94–7.0 (m, 2H), 6.82–6.90 (dd, 2H), 6.7 (s, 1H), 5.5 (s, 2H), 4.26–4.32 (q, 2H), 3.62–3.82 (m, 4H), 3.04–3.18 (m, 4H), 2.58–2.64 (t, 2H), 1.64–1.74 (m, 2H), 1.34–1.38 (t, 3H), 0.96–1.0 (t, 3H). 13C NMR (400 MHz, CDCl3): 165, 160, 156.2, 152.4, 146.8, 132.8, 118.2, 118.1, 115.8, 115.4, 110.2, 61, 53, 50.6, 50.2, 45, 42, 30, 22.8, 14.2, 14.
Reaction SMILES: ClC1C=C(Cl)C2N(C(C(O)=O)=CN=2)N=1.[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([OH:28])=O)=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1.C(Cl)(=O)C(Cl)=O.[F:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][C:41]=1[NH2:42].C(N(CC)C(C)C)(C)C.ClC1C=C(Cl)C2N(C(C(NC3C=CN=CC=3F)=O)=CN=2)N=1>ClCCCl.CN(C)C=O>[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([NH:42][C:41]3[CH:40]=[CH:39][N:38]=[CH:37][C:36]=3[F:35])=[O:28])=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C(O)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1ccncc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Nc1ccncc1F)c1cnc2c(Cl)cc(Cl)nn12
Agent: O=C(O)c1cnc2c(Cl)cc(Cl)nn12
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Temperature: 65 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A ˜1:1 mixture 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid 1D (4.7 g, 18.6 mmol) was suspended in DCE (140 mL), and treated with neat oxalyl chloride (2.65 mL 30.4 mmol) followed by N,N-dimethylformamide (0.08 mL, 1.034 mmol). The reaction mixture was heated at 65° C. for 5 hours, concentrated and dried under high vacuum for 1 hr and taken into the next step without further purification. The crude mixture of acid chloride was suspended in DCE (100 mL) and treated with 3-fluoropyridin-4-amine (2.73 g, 24.31 mmol) and N,N-diisopropylethylamine (5.31 mL, 30.4 mmol) and stirred at room temperature for 2 hours. The reaction mixture was filtered through Buchner funnel, washed with DCE (2×25 mL) to isolate a 1:1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (5.2 g, 15.0 mmol, 80% yield) as light brown solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.1 (M+H=326.07 and M+H=372.01).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=S)=[CH:7][CH:6]=1)=[O:4].[C:14]([O:18][C:19](=[O:45])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[C:29]([C:31]([N:33]([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH:28]=[CH:27][C:26]=1[NH2:44])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[CH3:42][CH:41]([CH3:43])[CH2:40][CH2:39][N:33]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([C:29]1[CH:28]=[CH:27][C:26]2[N:44]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[N:24]([CH2:23][CH2:22][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:45])[C:25]=2[CH:30]=1)=[O:32]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1ccc(N=C=S)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
4-methoxycarbonylphenyl isothiocyanate (327 mg, 1.5 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are added successively to a solution of tert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate (500 mg, 1 eq) in tetrahydrofuran (30 ml). The mixture is heated under reflux for 17 hours then cooled down to ambient temperature and aminomethylpolystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent:heptane/ethyl acetate 1:1) produces the expected compound in the form of a white solid (409 mg; 60% yield).