Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:34])[NH:20][C:21](=[O:33])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([OH:32])=O)[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].[NH2:35][C:36]1[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[NH:38][N:37]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:34])[NH:20][C:21](=[O:33])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([NH:35][C:36]5[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[NH:38][N:37]=5)=[O:32])[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: Nc1n[nH]c(C(F)(F)F)n1
Reactant: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)Nc3n[nH]c(C(F)(F)F)n3)co2)c(=O)[nH]c1=S

Procedure:
A solution of the product of example 2 step (iii) (0.34 g), 4-(dimethylamino)pyridine (0.34 g), 3-amino-5-trifluoromethyl-1,2,4-triazole (J. Gen. Chem. USSR (Engl. Transl.) 1983, vol53, part 7, p1514) (0.42 g) and N,N-diisopropylethylamine (1.46 ml) in N,N-dimethylformamide (6 ml) was treated with bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (1.3 g). After 2 hours the solution was quenched with aqueous tartaric acid. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in toluene. The product was triturated with ethyl acetate/isohexane and the solid collected.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[C:5]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:23])=O.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c2cccc(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
A mixture of intermediate (9) (1.32 g) and phosphorous oxychloride (5 ml) was refluxed for 2 hours, cooled, poured onto ice and neutralized by 1N NaOH. The aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried, concentrated, yielding 2-methyl-4-chloro-8-(2′,4′-dichlorophenyl)quinoline (intermediate 1) (1.31 mg. 300 MHz 1H NMR (CDCl3): δ 2.58 (s, 3H), 7.34 (s, 2H), 7.39 (s,1H), 7.53 (s, 1H), 7.63-7.65 (m, 2H), 8.26 (dd,1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[O:34][CH:35]=[CH:36][CH:37]=4)[O:30][C:31]=3[CH3:32])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[O:34][CH:35]=[CH:36][CH:37]=4)[O:30][C:31]=3[CH3:32])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1ccc(COc2nn(Cc3ccccc3)cc2C=O)cc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.4 %

Procedure:
A mixture of {1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzyl)oxy]-1H-pyrazol-4-yl}methanol (0.60 g), activated manganese dioxide (2.0 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.54 g, yield 90%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 142-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3F)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4F)nc3n2)cc1
Temperature: 4 °C
Yield: 32.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (6.1 g), N,N'-carbonyldiimidazole (6.5 g) and 2-amino-7-(2-fluorophenoxy)-1,8-naphthyridine (7.65 g). The product produced by precipitation in water (5.5 g; m.p. 200° C.) is dissolved in boiling ethanol (180 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-[7-(2-fluorophenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (3.8 g) is produced, m.p. 208° C.
Reaction SMILES: COC(=O)CSCC1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C3C=CC=CC=3OC)[CH:15]=2)[NH:10]C(C)(C)C=1.Br[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[CH:38]=2)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OC)(=O)CS>>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=[C:30]2[CH2:29][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]acetic acid methyl ester 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 52 μL of methyl thioglycolate reacted to give 4 mg of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:8]2[CH:9]=[C:4]([CH:5]=[C:6]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)[CH:7]=2)[C:3]([OH:44])=[O:2])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(OCCCOc2ccc(-c3ccccc3)cc2)cc(OCCCOc2ccc(-c3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cc(OCCCOc2ccc(-c3ccccc3)cc2)cc(OCCCOc2ccc(-c3ccccc3)cc2)c1
Yield: 88.7 %

Procedure:
A solution of 1.5 g (2.55 mmol) of 3,5-bis[3-(1,1'-biphenyl-4-yloxy)propoxy]benzoic acid methyl ester and 15 mL (15 mmol) of 1N NaOH in 45 mL of methanol and 40 mL of dioxane was stirred at reflux for 6 hours. The reaction mixture was concentrated at reduced pressure, the residue was acidified and the product was filtered and recrystallized from ethyl acetate to give 1.3 g (89% yield, mp 186°-187°) of 3,5-bis[3-(1,1'-biphenyl-4-yloxy)propoxy]benzoic acid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[C:4](=[O:3])[NH:5][CH2:6][CH2:7]2
Reactant: CCOC(=O)NCCc1cccc(C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2cc(C(F)(F)F)ccc21
Temperature: 105 °C
Reaction time: 2 h
Yield: 15.7 %

Procedure:
Using the same procedure and workup as described in Example 1, step 4, [2-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester (I-17b: 2.7 g, 10.34 mmol) in POCl3 (15 mL) was reacted with P2O5 (2.9 g, 20.68 mmol). The resulting mixture was stirred at 105° C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 350 mg of the product (15.74% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])O)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])O)[CH:7]=1>C(O)C.Cl.[C].[Pd]>[CH:8]([C:6]1[CH:7]=[C:2]([OH:1])[CH:3]=[C:4]([CH:12]([CH3:15])[CH3:14])[CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1cc(O)cc(C(C)(C)O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(O)cc(C(C)C)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 97.3 %

Procedure:
To a solution of 5-hydroxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol (20.0 g, 95.1 mmol) in ethanol (600 mL), concentrated hydrochloric acid (12.0 mL) and a 10% palladium-carbon catalyst (11.0 g) were added, and the mixture was stirred under hydrogen atmosphere for 22 hours at room temperature. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure, to thereby yield a white solid. The thus-obtained solid was crystallized from hexane, to thereby yield 16.5 g of 3,5-diisopropylphenol as colorless needles (yield 97.3%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH:12]=O.[CH3:14][NH2:15].[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH2:12][NH:15][CH3:14]
Reactant: CN
Reactant: Cc1cccc2cc(C=O)n(C)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc2cccc(C)c2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To 1,7-dimethyl-1H-indole-2-carbaldehyde (1.57 g, 9.06 mmol) was added a solution of 2 M solution of methylamine in methanol (30 mL) and the resulting mixture stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue taken up in ethanol (30 mL). The solution was cooled to 0° C. and then NaBH4 (0.34 g, 9.1 mmol) was added in one portion. The mixture was stirred overnight. Additional NaBH4 (0.18 g, 4.5 mmol) was added and the mixture was again stirred overnight. The mixture was concentrated under reduced pressure and the residue combined with 1 M NaOH (200 mL). The mixture was extracted with diethyl ether (3×150 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a pale yellow oil (1.60 g, 94%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=7.8 Hz, 1H), 6.93-6.87 (m, 2H), 6.34 (s, 1H), 4.02 (s, 3H), 3.84 (s, 2H), 2.77 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2Cc1ccccc1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield from 5-fluoro-3-iodo-indazole and benzyl bromide according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 5.59 (2H, s), 7.11-7.21 (5H, m), 7.23-7.31 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:53]1[C:74](/[CH:75]=[CH:76]/[CH2:77][N:78]2[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]2)=[C:56]2[CH:57]=[C:58]([C:61]([N:63]([CH2:69][CH2:70][CH:71]([CH3:73])[CH3:72])[CH2:64][CH2:65][CH:66]([CH3:68])[CH3:67])=[O:62])[CH:59]=[CH:60][N:55]2[N:54]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:69]([N:63]([CH2:64][CH2:65][CH:66]([CH3:68])[CH3:67])[C:61]([C:58]1[CH:59]=[CH:60][N:55]2[N:54]=[C:53]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:74]([CH:75]=[CH:76][CH2:77][N:78]3[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83]3)=[C:56]2[CH:57]=1)=[O:62])[CH2:70][CH:71]([CH3:72])[CH3:73]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(Br)c(/C=C/CN3CCCCC3)c2c1
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2nn3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3c2C=CCN2CCCCC2)cc1
Temperature: 110 °C

Procedure:
In a sealed tube 4-methoxyaniline (18.34 mg, 0.149 mmol), tris(dibenzylideneacetone)dipalladium (4.55 mg, 4.97 μmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.75 mg, 9.93 μmol) were added to a suspension of (E)-2-bromo-N,N-diisopentyl-3-(3-(piperidin-1-yl)prop-1-en-1-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (50 mg, 0.099 mmol) and potassium phosphate, dibasic (57.1 mg, 0.328 mmol) in toluene (5 ml). The mixture was heated at 110° C. overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3×25 mL). The combined organics were washed with brine, dried over anh. sodium sulfate, filtered and concentrated. The residue was purified by SCX (silica-gel supported sulfonic acid) then by preparative HPLC (20% to 100% MeOH in water (0.05% TFA) in 7 minutes) to afford N,N-diisopentyl-2-((4-methoxyphenyl)amino)-3-(3-(piperidin-1-yl)prop-1-en-1-yl)pyrazolo[1,5-a]pyridine-5-carboxamide. LCMS m/z 546.4 (M+H)+ weak, 461.3 (strong); ret. time=2.19 min.
Reaction SMILES: [I:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([CH3:16])([CH3:15])[C:8]([O:10]C(C)(C)C)=[O:9])[N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([CH3:16])([CH3:15])[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)n1ccc(I)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C(=O)O)n1ccc(I)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-butyl 2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanoate 7.03 (530 mg, 1.58 mmol) was dissolved in DCM (7 mL) and TFA (7 mL). The reaction was stirred at r.t. for 18 h and was concentrated in vacuo to afford crude 2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanoic acid 7.04 that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H10IN2O2: 280.98; found: 280.91.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH:25]=[C:24](B(O)O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.O>[CH3:13][N:10]1[CH:11]=[N:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH:23]=3)=[N:3][CH:4]=2)=[N:9]1
Reactant: Cn1cnc(-c2ccc(Cl)nc2)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)n1

Procedure:
A mixture of 2-chloro-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (3BX) (400 mg, 2.06 mmol); N-Tert-Butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (1.4 g, 4.53 mmol); Cesium carbonate (2.3 g, 7.07 mmol) and PdCl2dppf (100 mg) in dioxane/H2O (v/v 10:1, 20 ml) was stirred at 100° C. for 2 hours. The reaction was cooled, diluted with CH2Cl2 (300 ml) and H2O (100 ml), organic layer separated, dried over Na2SO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with EtOAc yielding title product 4BX as a solid (400 mg, 57%) MS (MH, 342).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[NH:4][N:3]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>O1CCOCC1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:8]1[C:9]([CH2:11][OH:12])=[CH:10][C:5]2[NH:4][N:3]=[C:2]([N:1]3[C:24](=[O:25])[C:23]4[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]3=[O:26])[C:6]=2[C:7]1=[O:20]
Reactant: Nc1n[nH]c2cc(CO)n(-c3ccccc3Cl)c(=O)c12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2cc(CO)n(-c3ccccc3Cl)c(=O)c12
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of 3-amino-5-(2-chlorophenyl)-6-(hydroxymethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step H (450 mg), phthalic anhydride (321 mg) and 1,4-dioxane (5.20 mL) was refluxed overnight, and cooled to room temperature. The resulting solid was collected by filtration, and washed with ethyl acetate to give the title compound (320 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:22][CH:21]=[CH2:20])[C:6]=2[CH:13]=1
Reactant: C=CCI
Reactant: O=c1n[n+]([O-])c2ccc(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Yield: 56 %

Procedure:
6-Chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (700 mg, 3.544 mmol) was suspended in dry DMF (20 ml) under argon at rt, and the stirred suspension was treated with K2CO3 (1.614 mg, 11.695 mmol) and allyl iodide (0.43 ml, 4.607 mmol). It was then stirred at rt for 2 h before addition of further allyl iodide (0.86 ml, 9.214 mmol) and then the reaction was heated at 60° C. for 1 h before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow solid which was purified by column chromatography on silica with a 0-5% MeOH in DCM gradient to give the desired product as a light brown solid (472 mg, 56%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Br[CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH:13]([N:21]([CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1S(=O)(=O)NC(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CN(C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of compound 2c (500 mg, 1.1 mmol) in DMF (10 mL) at 10° C., NaH (60 wt %, 44 mg, 1.1 mmol) was added in portions. The mixture was stirred for an additional 30 min and then the solution of methyl 2-(bromomethyl)-benzoate (253 mg, 1.1 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at 10° C. for 30 min and warmed to rt overnight. The reaction was quenched with water and diluted with EA (40 mL), washed with brine (3×20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purification by silica gel flash chromatography (PE:EA=2:1) to give compound 2d as a white solid (520 mg, 79% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCc2ccccn2)c1
Solvent: CO
Product: Nc1cccc(S(=O)(=O)NCc2ccccn2)c1

Procedure:
Hydrogenation of a stirred solution of 3-nitro-N-pyridin-2-ylmethyl-benzenesulfonamide [CAS-No. 309726-30-5; commercially available] (1.37 g, 4.67 mmol) in methanol (140 ml) on palladium/carbon (10%, 0.14 g) for 2 h at room temperature yielded after removal of the catalyst by filtration, evaporation and crystallization from ethyl acetate/hexane the title compound (1.16 g, 94%) as an off-white solid. MS (ISP) 262.0 [(M−H)−]; mp 124° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][NH2:41]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 97.7 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added N,N-dimethyl-1,3-propanediamine (0.023 mL, 0.18 mmol). The resultant solution was stirred at room temperature over night. The result mixture was then concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (21 mg, 97%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.58 (m, 2H), 2.19 (s, 6H), 2.20 (m, 2H), 2.30 (s, 3H), 3.15 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:17]([CH:22]=2)[C:18]([O:20]C)=[O:19])(=[O:12])=[O:11])[CH2:6][CH2:5]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:17]([CH:22]=2)[C:18]([OH:20])=[O:19])(=[O:12])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(S(=O)(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Temperature: 50 °C

Procedure:
LiOH (15.39 mg, 0.64 mmol) was added to a stirred solution of methyl 5-[(4-methyl-1-piperazinyl) sulfonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 71; 260 mg, 0.64 mmol) in a mixture of tetrahydrofuran and water (3:1, 40 ml). The mixture was heated at 50° C. for 6 h and then diluted with ethyl acetate (50 nil). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a white solid. 120 mg.