Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]1[C:21]([CH3:35])=[C:22]2[C:27](=[C:28]([CH3:31])[C:29]=1[CH3:30])[O:26][C:25]([CH2:33]I)([CH3:32])[CH2:24][CH2:23]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([O:19][C:20]1[C:21]([CH3:35])=[C:22]2[C:27](=[C:28]([CH3:31])[C:29]=1[CH3:30])[O:26][C:25]([CH2:32][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:33])[CH2:24][CH2:23]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CI)O2
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(COc1ccc(C=O)cc1)O2
Yield: 97.6 %

Procedure:
A mixture of 1.63 g of sodium hydride (as a 55% w/w dispersion in mineral oil) and 20 ml of dimethylformamide was cooled in an atmosphere of nitrogen; to the cooled solution were then added dropwise a mixture of 4.58 g of p-hydroxybenzaldehyde and 30 ml of dimethylformamide, whilst ice-cooling. 10.9 g of 6-benzyloxy-2-iodomethyl-2,5,7,8-tetramethylchroman (prepared as described in Preparation 2) and 50 ml of dimethylformamide were then added to the resulting solution, and the resulting mixture was heated under reflux for 5.5 hours. At the end of this time, the reaction mixture was extracted twice, each time with 100 ml of ethyl acetate. The combined extracts were washed with water, and the solvent was then removed from the extract by distillation under reduced pressure to afford 10.5 g of the title compound as an oil. Nuclear Magnetic Resonance Spectrum (CDCl3, 60 MHz), δ ppm: 1.43 (3H, singlet); 1.63-2.27 (2H, multiplet); 2.03 (3H, singlet); 2.13 (3H, singlet); 2.20 (3H, singlet); 2.43-2.90 (2H, multiplet); 4.00 (2H, singlet); 4.63 (2H, singlet); 6.97 (2H, doublet, J=9 Hz); 7.10-7.60 (5H, multiplet); 7.77 (2H, doublet, J=9 Hz); 9.77 (1H, singlet).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[CH2:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH:25]=[CH2:26])[CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: C=Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=Cc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 5.6 %

Procedure:
Pd(PPh3)2Cl2 (15 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.6 mL) and 3-vinylphenylboronic acid (29 mg, 0.19 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-vinylphenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (3 mg, 6%). 1H-NMR (MeOD): 1.40 (s, 9H), 2.44 (m, 1H), 2.61 (m, 1H), 3.25 (s, 3H), 5.85 (d, 1H), 6.14 (m, 1H), 6.23 (m, 1H), 7.05 (m, 1H), 7.16 (m, 1H), 7.32 (m, 2H), 7.49 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:10][C:4]=2[CH:3]=1.C([Li])CCC.Cl[CH2:23][C:24]1[CH:25]=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[O:6][C:5]3[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]2=3)=[CH:25][N:26]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Reactant: ClCc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)N(Cc1ccc(Br)nc1)Cc1ccccc1O2
Temperature: -23 °C
Reaction time: 0.42 h
Yield: 80.7 %

Procedure:
To a stirred solution of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (2 g) in THF (25 mL) at -78° C. was added 1.6 M hexane solution of n-butyl lithium (5.4 mL). After 25 minutes, 3-chloromethyl-6-bromopyridine (1.79 g) in THF (5 mL) was added. After 30 minutes, the temperature was raised to -23° C. After 30 minutes, an excess saturated solution of NH4Cl was added and the mixture was extracted with ether. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel using 10% ethyl acetate in hexane as eluant. Appropriate fractions were pooled to give the title compound (2.8 g) as a thick gum.
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]=[C:8]([N:10]3[CH2:14][CH2:13][C@@H:12]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:11]3)[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.CCCCCCC.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:15]1([C@@H:12]2[CH2:13][CH2:14][N:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([OH:2])[CH:22]=[CH:21][C:6]=4[N:7]=3)[CH2:11]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of (R)-6-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 46) in N,N-dimethylformamide (˜0.05 M) is chilled to −78° C. under a dry nitrogen atmosphere. A 1 M solution of boron tribromide in heptane (4 equivalents) is added dropwise. When the addition is complete, the reaction mixture is allowed to warm to ambient temperature and stirring is continued for 18 hours. Ice water is carefully added to the reaction mixture and stirring is continued for 15 minutes. The pH of the reaction mixture is then adjusted to 7 by the addition of aqueous sodium bicarbonate. After rapid stirring for ten minutes, the organic layer is isolated. The aqueous layer is saturated with sodium chloride and extracted with CHCl3. The organic layers are combined, dried (MgSO4), and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel, eluting with 90:5:5 dichloromethane/acetonitrile/methanol. Fractions containing product are combined and concentrated under reduced pressure to give (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15]([N:17]1[CH2:21][CH2:20][CH:19]([CH2:22][O:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([C:34]4[C:38]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[N:37][N:36]5[CH2:45][CH2:46][CH2:47][C:35]=45)=[CH:29][CH:30]=[N:31]3)=[CH:26][CH:25]=2)[CH2:18]1)=O)C1C=CC=CC=1>O1CCCC1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>[CH3:15][N:17]1[CH2:21][CH2:20][CH:19]([CH2:22][O:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([C:34]4[C:38]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[N:37][N:36]5[CH2:45][CH2:46][CH2:47][C:35]=45)=[CH:29][CH:30]=[N:31]3)=[CH:26][CH:25]=2)[CH2:18]1
Reactant: O=C(OCc1ccccc1)N1CCC(COc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCC(COc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)C1
Temperature: 65 °C

Procedure:
To a 1 M solution of lithium aluminum hydride in tetrahydrofuran (0.60 mL, 0.59 mmol) is added a solution of 3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxymethyl]-pyrrolidine-1-carboxylic acid benzyl ester (215 mg, 0.39 mmol) in tetrahydrofuran (2 mL). The mixture is heated at 65° C. for 2 h, cooled to 0° C., and diluted with saturated aqueous sodium potassium tartrate solution. The mixture is extracted with chloroform and the organic portion chromatographed on SiO2 to yield the title compound, 112 mg (67%), as a yellow foam.
Reaction SMILES: [C:1]([C:23](OC)=[O:24])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:22])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH3:27][NH:28][CH2:29][CH2:30][OH:31]>C1COCC1>[C:1]([C:23]([N:28]([CH2:29][CH2:30][OH:31])[CH3:27])=[O:24])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:20])([F:22])[F:21])([F:18])[F:17])([F:15])[F:14])([F:11])[F:12])([F:8])[F:9])([F:6])[F:5])([F:2])[F:3]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CNCCO
Solvent: C1CCOC1
Product: CN(CCO)C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 76.4 %

Procedure:
C7F15C(O)N(CH3)C2H4OH was prepared by combining n-C7F15CO2CH3 (85 grams) and CH3NHCH2CH2OH (16.5 grams) in THF (50 grams) at 50° C. Progress of the reaction was monitered by GC and FTIR spectra. The isolated yield was 76.4% of C7F15C(O)N(CH3)C2H4OH. (b.p.: 110–125° C./1.5–3 mmHg).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:41][C:42]1([CH3:66])[CH2:51][CH2:50][C:49]([CH3:53])([CH3:52])[C:48]2[CH:47]=[C:46]([C:54]([C:56]3[CH:65]=[CH:64][C:59]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][CH:57]=3)=O)[CH:45]=[CH:44][C:43]1=2>C1C=CC=CC=1.ClCCl.CCCCCC>[CH3:66][C:42]1([CH3:41])[CH2:51][CH2:50][C:49]([CH3:52])([CH3:53])[C:48]2[CH:47]=[C:46]([C:54]([C:56]3[CH:65]=[CH:64][C:59]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][CH:57]=3)=[C:2]([CH3:4])[CH3:3])[CH:45]=[CH:44][C:43]1=2
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=C(C)C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
To a suspension of isopropyltriphenylphosphonium iodide (0.35 g, 0.807 mmol) in 3 mL of benzene under argon at room temperature was added a 0.5M solution of potassium hexamethyldisilazide in toluene (1.8 mL, 0.89 mmol), and the red solution was stirred for 5 min. A solution of keto-ester 3 (0.169 g, 0.481 mmol) in 3 mL of benzene was added, and the red solution was heated to 110° C., while approximately 4 mL of benzene was distilled out. After 1 h, the reaction mixture was diluted with 40% ethyl acetate/hexane and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4, filtered through a plug of silica gel, and concentrated to afford a solid. Flash chromatography (40% dichloromethane/hexane) yielded the desired product 19 as a white powder (0.128 g, 71%): Rf 0.44 (50% CH2Cl2 /hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[OH:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=2)=[CH:3]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccc2c(ccn2O)n1
Product: CN1CC=C(c2cn(O)c3ccc(N)nc23)CC1

Procedure:
condensing 1-hydroxy-5-aminopyrrolo[3,2-b]pyridine (G) with 1-methyl-4-piperidinone in the presence of a base to provide 1-hydroxy-5-amino-3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)pyrrolo[3,2-b]pyridine (H); and
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:10][N:11]3[C:16](O)=[C:15]([CH3:18])[C:14]([CH3:19])=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:38].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:38][C:16]1[N:11]2[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[C:14]([CH3:19])[C:15]=1[CH3:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(O)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(Cl)c1C
Temperature: 100 °C

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5,6-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ol (I-4A-1a; 0.277 g, 0.721 mmol) and diisopropylethylamine (0.188 ml, 1.08 mmol) in toluene (7.2 ml) at room temperature was added POCl3 (0.336 ml, 3.60 mmol), dropwise. The mixture was heated at 100° C. for 7 hours, cooled to room temperature, and then slowly added to a stirred mixture of ice, saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product. Purification on a Biotage™ Flash 40S column using 0–8% ethyl acetate in hexanes as eluant afforded I-4A-1b (146 mg, 50%) as a yellow solid: +ESI MS (M+1) 402.0; 1H NMR (400 MHz, CD2Cl2) δ 7.55–7.35 (m, 6H), 7.25 (d, J=8.7 Hz, 2H), 2.66 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11](I)[N:10]=[N:9]1.[N:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[S:17][CH:16]=1.C([O-])(=O)C.[Na+]>CN(C=O)C.O>[N:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[S:17][C:16]=1[C:11]1[N:10]=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[CH3:13]
Reactant: c1cnc2scnc2c1
Reactant: Cc1c(I)nnn1-c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2nc3cccnc3s2)nnn1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
Under nitrogen atmosphere, 344 mg of 1-(2-chlorophenyl)-4-iodo-5-methyl-[1,2,3]-triazole and 276 mg of thiazolo(5,4-b)pyridine (B. Stanovnik, Synthesis, 1974, 120) were dissolved in 3 ml of DMF. Then, 100 mg of sodium acetate and 103 mg of Herrman catalyst were added, and the mixture was stirred at 140° C. for 8 hours. After diluting the reaction solution with water, the resultant was extracted with chloroform. Organic layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents were separated and purified by thin-layer silicagel column chromatography (ethyl acete/hexane=1/1) to obtain 30 mg of the above compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.Cl[P:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCCCC>[C:28]1([P:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:14]=[C:7]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: N=C(Nc1nccs1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCC
Product: c1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2nccs2)cc1
Yield: 26.8 %

Procedure:
Procedure as described for NP Amidine XVII using the following amounts: 3.06 g of N1-(thiazol-2-yl)benzamidine (Amidine XVI, 15.0 mmol), 7.50 mL of 2.0 M butyllithium (15.0 mmol), 0.93 mL of chlorodiphenylphosphine (15.0 mmol). Following removal of lithium chloride, the solvent was removed from the filtrate to give a sticky residue. The sticky residue was suspended in 100 mL of pentane. Vigorous stirring and scraping eventually yielded an off-white solid after 2 hours. The solid was collected and dried (2.59 g). The lithium chloride solid separated from reaction solution was extracted with 100 mL of diethylether, filtered, taken to dryness, and treated with 100 mL of pentane. Stirring and scraping produced white solid that was collected and dried yielding an additional 1.56 g of solid. Combined yield 4.15 g (71%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:9]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:20][C:21]([OH:23])=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: O=C(O)CC(=O)O
Reactant: COCCOc1ccc(C=O)cc1OCCOC
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COCCOc1ccc(C=CC(=O)O)cc1OCCOC
Temperature: 110 °C
Yield: 93.2 %

Procedure:
To a solution of 3,4-Bis-(2-methoxy-ethoxy)-benzaldehyde (19 g, 72.4 mmol) in pyridine (60 ml), malonic acid (11.3 g, 108.6 mmol) was added, followed by piperidine (2 ml), the resulting mixture was heated at 110° C. for 6 hs under N2. After removal of most of pyridine, the residue was poured into water (200 ml) and acidified to PH=3 by aq.HCl. The precipitate was collected and dried to give product (20 g, 93.3%). LC-MS: m/e 295 (M−1)
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]1S(C1C=CC=CC=1)(=O)=O)#[N:4].C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:3]([C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: COc1cccc2c1C=CN(S(=O)(=O)c1ccccc1)C2C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COc1cccc2c(C#N)nccc12
Temperature: 25 °C

Procedure:
Sodium hydride (1.2 g of 60% in mineral oil) is added to a stirred suspension of 1-cyano-2-benzenesulfonyl-1,2-dihydro-5-methoxyisoquinoline (10 g) in xylene (100 ml). The reaction mixture is refluxed under nitrogen for 3 hrs, cooled to RT, stirred for an additional hour, and filtered. The filtered solid is washed with xylenes. The filtrate is evaporated in vacuo. The filtered solid is stirred with methylene chloride and aqueous 5% sodium hydroxide solution. The methylene chloride phase is combined with the residue from the evaporated filtrate and the combined extracts are washed with 5% sodium hydroxide solution, H2O and dried over sodium sulfate. The dried extract is filtered and the filtrate evaporated in vacuo, affording a moist solid which is triturated in hexanes. The triturated solid is filtered, washed with hexanes, and dried, affording a fluffy orange solid, M.P. 166°-175° C. The crude product is dissolved in ethyl acetate, treated with charcoal, filtered and recrystallized from ethyl acetate, affording the desired cyanoisoquinoline as a crystalline solid, M.P. 180°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)[C@@H:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C[CH2:37][N:38](C(C)C)[CH:39](C)C>C(Cl)Cl.CNC.C1COCC1>[CH3:37][N:38]([CH3:39])[CH2:30][CH2:29][CH2:28][N:12]([S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[C@@H:13]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc(S(=O)(=O)N(CCCOS(C)(=O)=O)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)N(CCCN(C)C)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.7 %

Procedure:
To a solution of benzyl N-[(3-methoxyphenyl)sulfonyl]-3-methyl-N-{3-[(methylsulfonyl)oxy]propyl}-D-valinate (2.00 g, 3.79 mmol) in DCM (15 mL), dimethylamine in THF (2M, 9.5 mmol, 19.0 mmol) and DIPEA (1.99 mL, 11.4 mmol) are added, and the reaction mixture is allowed to stir at rt for 18 h. Additional 3.0 mL of dimethylamine in THF (2M) is added to the reaction mixture and is allowed to stir for additional 3 d. The reaction was approximately 50% complete. The reaction mixture is concentrated in vacuo and is purified by silica gel chromatography eluting with a gradient of 5-100% EtOAc/heptane to obtain the desired intermediate (500 mg, 28% yield). Mass spectrum (477.5; M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH2:13])=[S:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:15][C:16](=O)[CH3:17]>CN(C=O)C>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]2[S:12][CH:15]=[C:16]([CH3:17])[N:13]=2)=[CH:3][C:2]=1[OH:1]
Reactant: COc1ccc(NC(N)=S)cc1O
Reactant: CC(=O)CBr
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(C)cs2)cc1O
Yield: 26 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 1-(3-hydroxy-4-methoxyphenyl)thiourea (100 mg, 0.50 mmol) and bromoacetone (83 mg, 0.60 mmol) in dry DMF (2.0 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 26% yield (30 mg).
Reaction SMILES: [Sn](O)(C)(C)C.C[O:7][C:8]([C:10]1[N:11]=[C:12]([CH:15]([OH:40])[CH2:16][CH:17]([N:21]([CH3:39])[C:22](=[O:38])[CH:23]([NH:28][C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[CH3:37])=[O:30])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH:18]([CH3:20])[CH3:19])[S:13][CH:14]=1)=[O:9]>ClC(Cl)C>[OH:40][CH:15]([C:12]1[S:13][CH:14]=[C:10]([C:8]([OH:9])=[O:7])[N:11]=1)[CH2:16][CH:17]([N:21]([CH3:39])[C:22](=[O:38])[CH:23]([NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[CH3:37])=[O:30])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH:18]([CH3:20])[CH3:19]
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)OC)cs1)C(C)C
Agent: C[Sn](C)(C)O
Solvent: CC(Cl)Cl
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)O)cs1)C(C)C
Temperature: 60 °C
Yield: 88.1 %

Procedure:
Me3SnOH (496 mg, 2.74 mmol) was added to a 0.020 M solution of methyl ester 23 (175 mg, 0.343 mmol) in dichloroethane (17.0 mL). The reaction mixture was heated to 60° C. for 20 h and then concentrated. Column chromatography (100% CH2Cl2 to elute tin containing materials followed by 80:20:1 CH2Cl2:MeOH:NH4OH to elute the product) afforded 150 mg (88%) of 24 as an amorphous solid. The 1H NMR corresponds to a 6:1 mixture of rotamers, with the major isomer reported. [α]D23=−17.4 (c=1.0, MeOH). IR: 1276, 1368, 1471, 1616, 2874, 2961 cm−1. 1H NMR (500 MHz, d6-DMSO): δ 0.70 (m, 3H), 0.75-0.82 (m, 3H), 0.83-0.90 (m, 6H), 1.04-1.16 (m 1H), 1.17-1.28 (m, 2H), 1.37-1.55 (m, 3H), 1.56-1.72 (m, 3H), 1.73-1.91 (m, 3H), 2.00-2.24 (m, 2H), 2.22 (s, 3H), 2.84 (br s, 1H), 2.94-3.00 (m, 1H), 3.04 (s, 3H), 4.16-4.60 (br s, 1H), 4.49 (d, 1H, J=10.5), 4.56 (app t, 1H, J=9.0), 5.93-6.40 (br s, 1H), 8.05 (s, 1H), 8.25 (s, 1H). 13C NMR (125 MHz, d6-DMSO): δ 10.0, 14.7, 19.1, 19.5, 19.6, 21.8, 23.58, 23.62, 28.75, 28.8, 35.2, 36.7, 42.6, 52.3, 54.1, 67.1, 67.5, 126.7, 147.8, 162.2, 170.7, 172.0, 177.6. HRMS (FAB) calcd for C24H41N4O5S (M+H): 497.2798. Found: 497.2793.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C(=O)C(C[O:46][S:47]([CH3:50])(=O)=O)=CC(C2C=CC(S(C)=O)=CC=2)=N1)C(C)C.CN1CCNCC1>>[CH2:29]([N:16]1[C:15](=[O:33])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[C:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:47]([CH3:50])=[O:46])=[CH:23][CH:22]=2)=[N:17]1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)Cn1nc(-c2ccc(S(C)=O)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: Cc1c(-c2ccc(S(C)=O)cc2)nn(CC(C)C)c(=O)c1N1CCN(C)CC1
Yield: 61.8 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 61.8%).