Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]#[N:21])=[CH:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:22]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:22])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]#[N:21])=[CH:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c(N)cccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c(N)c(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [4-amino-3-(cyanomethyl)-1H-indol-1-yl]acetate from Step A (150 mg, 0.526 mmol) in CH2Cl2 (5 mL) was added N-chlorosuccinimide (70 mg, 0.526 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then partitioned between saturated aqueous NaHCO3 (5 mL) and CHCl3 (15 mL). The aqueous phase was extracted further with CHCl3 (15 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=320 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)=[O:9])[CH:5]=[CH2:6].O>C1COCC1>[CH3:1][N:2]([CH3:3])[C:14]([C:13]1[CH:17]=[CH:18][C:10]([C:8]([O:7][CH2:4][CH:5]=[CH2:6])=[O:9])=[CH:11][CH:12]=1)=[O:15]
Reactant: C=CCOC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of dimethylamine (40% in water) were introduced into a round-bottomed flask and a solution of 2.5 g (11.6 mmol) of 4-(allyloxycarbonyl)benzoyl chloride in 50 ml of THF was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. 2.7 g (100%) of the expected amide were recovered in the form of a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)C.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([NH:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cccnc1N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ncccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2,3-diaminopyridine (45 g), ethanol (500 ml), triethylamine (42 g) and benzyl bromide (70.5 g) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue partitioned between chloroform (500 ml) and water (400 ml). The organic layer was eparated, filtered through a silica gel plug and evaporated in vacuo. The residue was triturated with hot chlorobutane to yield a brown powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:11][C:3]1[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[Cl:10]
Reactant: COc1ccc(Cl)c(CO)c1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1ccc(Cl)c(CBr)c1Cl
Reaction time: 0.17 h
Yield: 112.7 %

Procedure:
Dissolve (2,6-dichloro-3-methoxy-phenyl)-methanol (9.43 g, 45.5 mmol) in methylene chloride (180 ml) cool to 0° and add phosphorus tribromide (1.0M, 23 ml, 23 mmol) dropwise. Stir for 10 minutes at 0°, dilute with methylene chloride, quench with saturated aqueous sodium bicarbonate, separate layers, wash organic with water, brine dry over sodium sulfate, filter and concentrate to yield 7 g (57%) of the title compound: NMR (CDCl3) δ 7.28 (d, 1H), 6.85 (d, 1H), 4.77 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[C:10]([N+:18]([O-])=O)[C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=[O:4]>CO.[Pd]>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[C:10]([NH2:18])[C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=[O:4]
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c(O)cc12)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-5-nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-ethanone (575 mg, 1.82 mmol) was hydrogenated in methanol under a H2 atmosphere at (45 psi, or approximately 3 atmospheres) over 10% Pd/C (80 mg) for 1.5 hours then filtered through a Celite pad and concentrated to white solids (450 mg, 86%). (TLC 5% methanol/CH2Cl2 (NH3) Rf 0.6). 1H NMR (400 MHz, CD3OD) δ 6.67–6.59 (m, 2H), 4.12 (m, 1H), 3.73 (m, 1H), 3.73 (m, 1H), 3.51 (m, 1H), 3.07 (m, 2H), 2.24 (m, 1H), 1.94 (d, J=10.5 Hz, 1H). GCMS m/e 286 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:23])[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.Cl.N1CC([OH:41])C1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:23])[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:29]([N:31]4[CH2:32][CH:33]([OH:41])[CH2:35]4)=[O:30])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(c2cccc(F)c2)CCCN1c1ccn2ncc(N)c2n1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(c2cccc(F)c2)CCCN1c1ccn2ncc(NC(=O)N3CC(O)C3)c2n1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a DCM (0.7 mL) solution of 5-(2-(3-fluorophenyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (25 mg, 0.08 mmol) was added CDI (20 mg, 0.12 mmol) at ambient temperature in one portion. After stirring one hour, azetidin-3-ol hydrochloride (20 mg, 0.12 mmol) was added in one portion, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 30 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a yellowish oil (18 mg, 55% yield). MS (apci) m/z=411.2 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([C:15]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6].[CH3:26]I.O>CCCCCC.C1COCC1>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:26])[C:9]2[C:14]([C:15]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6]
Reactant: CI
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1c(Oc2ccccc2[N+](=O)[O-])c2ccccc2n1C
Reaction time: 3 h

Procedure:
6.73 g (0.16 mole) of 57% sodium hydride in mineral oil was washed with hexane and suspended in 500 ml of THF. To this was added 43.4 g (0.139 mole) of methyl-3-[o-nitrophenoxy]-indole-2-carboxylate. The mixture was stirred at reflux for 1 hour, then 42.6 g (0.3 mole) of methyl iodide was added and reflux continued for 3 hours. Water (5 ml) was added, the THF removed by distillation and the gummy residue recrystallized from isopropanol to give analytical material as yellow needles, mp. 119°-21°.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CCO>O=[Pt]=O.CC(O)=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2ccncc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2CCNCC21
Yield: 113.6 %

Procedure:
A mixture of tert-butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.85 g) and a catalytic amount of PtO2 in the mixture solvent of EtOH (10 mL) and AcOH (10 mL) was heated overnight under H2 (2.0 MPa). The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/MeOH) to afford the product as viscous liquid (2.18 g, 100.00%).
Reaction SMILES: C1(C)C=CC=CC=1.S(Cl)(Cl)=O.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[N:28]=[C:27]([C:33](O)=[O:34])[CH:26]=1.[OH-].[NH4+:37]>ClCCl>[O:22]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:12])[N:14]1[CH2:23][CH2:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[N:28]=[C:27]([C:33]([NH2:37])=[O:34])[CH:26]=1
Reactant: CCCn1nc(C(=O)O)cc1CCN1C(=O)c2ccccc2C1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCn1nc(C(N)=O)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Toluene (70 mL) and thionyl chloride (70 mL) were added to 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylic acid (28.8 g, 87.8 mmol) and the mixture was heated at reflux for 1 hour, cooled to ambient temperature, and concentrated under reduced pressure to yield a yellow solid. The solid was dissolved in dichloromethane (200 mL). The solution was cooled to 0° C., then concentrated ammonium hydroxide (125 mL) was added in one portion. The resulting mixture was stirred for 1 hour at 0° C. The dichloromethane was removed under reduced pressure. A solid was isolated by filtration, washed with water, and dried to afford 28.70 g of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxamide.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:14]=O)=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[F:1][C:2]1[C:3]([CH:14]=[N:16][OH:17])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)OB(O)c2cc(F)c(C=O)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2cc(F)c(C=NO)cc21
Reaction time: 2 h

Procedure:
To a solution of 6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (200 mg, 0.96 mmol) and NH2OH.HCl (79.5 mg, 1.15 mmol) in THF (4 mL) and H2O (1 mL) at rt was added NaOAc (110 mg, 1.34 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted with DCM (60 mL×3) and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude compound 6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[O:23][N:22]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][C:19]3[CH:33]=[CH:34][C:16]([OH:15])=[CH:17][CH:18]=3)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
To a trifluoroacetic acid (5 mL) solution of 5-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (270 mg, 0.755 mmol) described in Example 28 was added thioanisole (355 μL, 3.02 mmol) at 0° C., which was stirred for 1 hour and 20 minutes at room temperature. Sodium hydrogencarbonate and water were added to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (150 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([CH:14]=O)=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:11]=[C:10]([S:24][CH3:25])[N:9]=1.[CH3:26][C:27](OC(C)=O)=[O:28]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH:14]=[CH:26][C:27](=[O:28])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:12]=2[N:11]=[C:10]([S:24][CH3:25])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1nc(Nc2ccccc2F)c(C=O)c(-c2ccccc2F)n1
Solvent: c1ccncc1
Product: CSc1nc(-c2ccccc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Yield: 76 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde, as described in Example 22, (400 mg, 1.1 mmol) in pyridine (2 mL) was added Ac2O (2 mL) and the reaction mixture was heated under reflux for 48 h, solvent was evaporated and the residue was dissolved in EtOAc (40 mL), washed with 1 M aq Na2CO3, and H2O and satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was purified by Flash chromatography to afford pure 4,8-bis-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (320 mg, 76% yield). 1H-NMR (CDCl3) δ 2.21 (s, 3H), 6.76 (d, 1H, J=9.6 Hz), 7.22-7.42 (m, 4H), 7.45-7.67 (m, 5H). LC MS (m/e)=382 (MH+).
Reaction SMILES: C([N:8]([C@H:10]([C:21]#[CH:22])[C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[CH3:9])(OC(C)(C)C)=O.[F:23][C:24]1[C:25](I)=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:34]\[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:23][C:24]1[C:25]([C:22]#[C:21][C@@H:10]([NH:8][CH3:9])[C@H:11]([OH:13])[CH3:12])=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:34]\[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN[C@H](C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)[C@@H](C)O
Reaction time: 2 h

Procedure:
Using Method C above, (2R,3R)-3-(N-Boc-N-methylamino)-2-(tert-butyldimethylsilyloxy)-pent-4-yne (370 mg, 1.13 mmol) (Example 117C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.39 mmol) (Starting Material 6) using (Ph3P)4Pd (45 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-40% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(3R,4R)-4-hydroxy-3-methylamino-1-pentynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess pentane. (Yield 53 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[S:42]([Cl:45])(=[O:44])=[O:43]>>[ClH:45].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:42]([C:33]3[CH:34]=[CH:35][C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=3)(=[O:44])=[O:43])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: Cl
Product: O=S(=O)(Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1)c1ccc2ccccc2c1

Procedure:
N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-naphthalenesulfonamide hydrochloride was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.084 g, 0.19 mmol) and, 2-naphtylsulfonyl chloride (0.055 mL, 0.24 mmol) to give 67.8 mg of a light purple solid; Anal. (C24H27ClN4O3S) C, H, N, S; M+ 529.2 Calcd 529.12.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O)(=O)C.O>[CH2:3]1[C:2]2[NH:17][C:11]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[CH2:6][CH2:5][CH:4]1[C:8]([OH:10])=[O:9]
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CCc2c([nH]c3ccccc23)C1
Yield: 75.4 %

Procedure:
A mixture of 3-ketocyclohexanecarboxlic acid (4.78 g, 33.9 mmol) and phenyihydrazine (3.66 g, 40 mmol) in 35 mL of acetic acid was heated under reflux for one hour, then cooled, diluted with water and acidified with HCl. The resultant solid was collected by filtration, washed with water and dried to give 5.5 g of the title compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+].O.Cl>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1

Procedure:
To a solution of ethyl 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionate (6.00 g, 13.1 mmol) in THF (60 mL) and ethanol (30 mL) were added 5 M aqueous sodium hydroxide (3.14 mL, 15.7 mmol) and water (30 mL) and the resulting solution was refluxed for 1 hour. The reaction solution was cooled with ice. To the reaction solution were added 5 M hydrochloric acid (4.0 mL, 20.0 mmol) and water (100 mL). The obtained solid was collected by filtration, and recrystallized from water-containing acetone, to thereby yield 5.60 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][C:43](=[O:45])[O:42][N:41]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][C:43](=[O:45])[O:42][N:41]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
6-Butyl-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.4 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.42 g) were dissolved in dichloromethane (4 mL) and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.37 g, 93%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.CN(C)C(=N)N(C)C.Cl.[N+:35]([CH3:38])([O-:37])=[O:36]>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH2:38][N+:35]([O-:37])=[O:36])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1
Reactant: COC(=O)C=Cc1ccc2c(C)cn(CCCc3ccccc3)c2c1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Temperature: 65 °C

Procedure:
A stirred solution of methyl 3-(3-methyl-1-{3-(phenyl)propyl}-1 H-indol-6-yl)-propenoate (0.263 g, Reference Example 39) in nitromethane (5 ml) was treated with tetramethylguanidine (0.091 g). The mixture was heated to 65° C. for 2 hours then treated with a further aliquot of tetramethylguanidine (0.091 g). After heating at 65° C. for a further hour the reaction mixture was cooled to room temperature then poured into hydrochloric acid (20 ml, 1N) then extracted three times with ethyl acetate (25 ml). The combined extracts were dried over magnesium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (1:2, v/v) as eluent to yield the title compound (0.296 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[Cl:8].[N+](C1C=CC(CCl)=CC=1)([O-])=O.NC1C=CC(CN2C(=O)C(Cl)=C(Cl)C=N2)=CC=1.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(O)(=O)C.N1C=CC=CC=1.[Fe]>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:49]([CH3:48])(=[O:51])=[O:50])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Agent: [Fe]
Agent: Nc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Agent: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
4.5 g (15 mmoles) of 4,5-dichloro-2-(4-nitrobenzyl)-3(2H)-pyridazinone (prepared according to method III but using 4-nitrobenzyl chloride instead of 3-phenyl-2-propenyl chloride (M.P. 128-130 celsius)) are dissolved in 150 ml of 99.5% acetic acid solution. Then 7.5 g of iron dust are added to the solution at such a rate that the temperature should not exceed 20° C., and the suspension is stirred at room temperature for 8 hours. By working up the reaction mixture in the usual manner 3.15 g (77%) of 2-(4-aminobenzyl)-4,5-dichloro-3(2H)-pyridazinone melting at 187°-189° C. are obtained, which is dissolved in 34 ml of anhydrous pyridine. To the solution 1.24 ml (16 moles) of methanesulfonyl chloride are dropped under stirring and cooling at such a rate that the inner temperature should remain between 0° C. and 5° C. The mixture is then stirred at room temperature for 4 hours and poured onto water. The separated crystals are filtered and washed with water. Thus 2.34 g (57%) of the desired compound are obtained. M.p.: 152°-154° C.