Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][NH:32][CH:29]2[CH2:31][CH2:30]2)[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CCc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(CCc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-ethyl-carbamic acid tert-butyl ester (80.1 mg, 0.257 mmol), Et3N (0.054 mL, 0.386 mmol) and cyclopropylamine (0.027 mL, 0.386 mmol) in MeOH (0.86 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (24.2 mg, 0.642 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) yielded the title compound (40 mg, 44%). LC-MS: tR=0.81 min; ES+: 353.22.
Reaction SMILES: O[CH:2]([CH2:16][OH:17])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[NH:6][C:5]1=[O:15].O=C1NC(=O)C2(CCN([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])CC2)N1>>[O:15]=[C:5]1[N:4]([CH2:3][CH:2]2[O:17][CH2:16]2)[C:8](=[O:9])[C:7]2([CH2:10][CH2:11][N:12]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:14]2)[NH:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Reactant: O=C1NC2(CCNCC2)C(=O)N1CC(O)CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)N(CC1CO1)C2=O

Procedure:
3-(2,3-Dihydroxypropyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione may also be prepared by reaction of tert-butyl 2,4-dioxo-1,3,8-triaza-8-spiro[4.5]decanecarboxylate with an epihalohydrin to give tert-butyl 2,4-dioxo-3-(2,3-epoxypropyl)-1,3,8-triaza-8-spiro[4.5]decanecarboxylate, followed by hydrolysis of the epoxy group and deprotection.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[O:7][CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][O:30][NH:31]C>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([NH:31][O:30][CH3:29])=[O:14])[O:7][CH2:6][CH2:5]2
Reactant: CNOC
Reactant: COc1c(Br)ccc2c1CCOC2C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CONC(=O)C1OCCc2c1ccc(Br)c2OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carboxylic acid (600 mg, 2.08 mmol) and CDI (475 mg, 2.93 mmol) in 20 mL of dry DCM was stirred at r.t. for 0.5 hours and then O,N-dimethyl-hydroxylamine (285 mg, 2.93 mmol) was added. The result mixture was stirred oversight. The solvents were removed under vacuum, and the residue was purified by preparative TLC to give 6-bromo-N,5-dimethoxy-3,4-dihydro-1H-isochromene-1-carboxamide.
Reaction SMILES: N1C=CC=CC=1.[S:7]1[CH2:11][CH2:10][S:9][CH:8]1[CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][OH:20].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([O:20][CH2:19][C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]1[CH2:12][CH:8]1[S:9][CH2:10][CH2:11][S:7]1)(=[O:23])[CH3:22]
Reactant: OC[C@@H]1CCCC[C@@H]1CC1SCCS1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1CCCC[C@@H]1CC1SCCS1
Reaction time: 0.25 h

Procedure:
At 0° C., 290 μL (3.5 mmol) of pyridine was added to 0.740 g (3.18 mmol) of rac-cis-2-(1,3-dithiolan-2-yl methyl)cyclohexanemethanol in 5 mL of dichloromethane, followed by dropwise addition of 235 μL (3.5 mmol) of acetyl chloride. After 15 min at 0° C. and 30 min at 20° C., the reaction mixture was partitioned between water and dichloromethane and the organic solution washed with 1.0N HCl and with 5% KHCO3 solutions, dried (MgSO4) and concentrated under vacuum to 865 mg (98%) of racemic cis-2-(1,3-dithiolan-2-yl methyl)cyclohexanemethanol acetate. TLC Rf 0.48 (SiO2, dichloromethane, I2 -brown).
Reaction SMILES: Br[CH2:2][CH:3]=[O:4].[CH3:5][CH:6]([NH2:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O>[CH3:5][CH:6]([NH:12][CH2:2][CH:3]=[O:4])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=CCBr
Reactant: CC(C)CCC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC(C)NCC=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
The diethylacetal of 2-bromoacetaldehyde (40 grams) and 1,4-dimethylpentylamine (50 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture stirred for about 30 minutes. The reaction mixture was then extracted with ether. The ether extract was separated, dried over magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product the diethylacetal of 2-(1,4-dimethylpentylamino)acetaldehyde having a boiling point of 95° C. at 1 mm of Hg pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>CS(C)=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][N:16]([CH2:21][C@H:20]([OH:19])[CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.12 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.78 g, 4.12 mmol). The product was isolated as an orange granular solid. Yield 0.61 g (34%). mp 225°-230° C. FDMS m/e=432 (M+ of free base). α[D]589 =+1.98 (c=1.01 , dimethylsulfoxide).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:10]=4)=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 93.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (1.11 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.89 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.75 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]([C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28])=[CH:25][C:24]=1[Cl:37].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(Cl)Cl>[Cl:37][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1)[C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28]
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN(C)CCNC(=O)c1ccc(N)c(Cl)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC2(CC2)C(=O)N3C)c(Cl)c1
Temperature: 100 °C
Yield: 4.1 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.33 mmol) and 4-amino-3-chloro-N-(2-dimethylaminoethyl)benzamide (Intermediate 213; 89 mg, 0.37 mmol) were dissolved in 1,4 dioxane (4 mL) and caesium carbonate (234 mg, 0.72 mmol) was added. The reaction mixture was sparged with nitrogen for 15 minutes prior to addition of tris-dibenzylideneacetone dipalladium (II) (19 mg, 0.02 mmol) followed by XANTPHOS (19 mg, 0.03 mmol). The reaction mixture was heated at 100° C. overnight, cooled to room temperature and diluted with DCM (20 mL). The resultant mixture was filtered and the filtrate loaded onto an SCX-3 (5 g) cartridge. The cartridge was washed through with methanol (50 mL) and then eluted with 2M ammonia in methanol (50 mL). Evaporation of the ammoniacal fraction afforded an amber gum which was purified by acid modified reverse phase preparative HPLC. The resultant material was dissolved in MeOH/Water and poured onto an SCX-3 cartridge (2 g) and cartridge which was then washed with methanol and eluted with 2M ammonia in methanol, and the ammoniacal solution evaporated to yield the title compound as a solid (7 mg, 3%).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([N+]([O-])=O)[CH:11]=[CH:10][N:9]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[Cl:7][C:8]1[CH:13]=[C:12]([O:21][CH2:20][CH2:19][O:18][CH3:17])[CH:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCOc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Potassium 2-methylpropan-2-olate (4.214 g, 35.678 mmol) was slowly added under an atmosphere of dry N2 to a solution of 2-chloro-4-nitropyridine (5.142 g, 32.434 mmol) in 2-methoxyethanol (40.0 mL, 506.74 mmol). The reaction was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The resulting oil was diluted with water (200 mL) and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5.36 g (88%) of desired product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:35])[CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:30])=[O:31])=[O:25])=[CH:33][CH:34]=2)[CH2:9]/[C:10](=[N:37]\[OH:38])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:35])[CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCS(C)(=O)=O)cc2)c2ccc(Cl)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NCCS(C)(=O)=O)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-N-(2-methanesulfonyl-ethyl)-benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless foam containing 3% of the corresponding Z isomer, MS (ESI+): m/z=534.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH:15]=[CH:14]2.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH:15]=[CH:14]3)=[CH:6][CH:7]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCc3ccc(Cl)nc3)ccc2[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
2-chloro-5-(chloromethyl)pyridine (0.995 g, 6.14 mmol) was added slowly to a well-stirred mixture of 6-hydroxyquinolin-2(1H)-one (0.9 g, 5.58 mmol), K2CO3 (1.158 g, 8.38 mmol) and potassium iodide (0.927 g, 5.58 mmol) in DMF (18 mL) at 40° C. The reaction mixture was stirred at 40° C. for 18 h and poured into ice/water. The suspension was filtered and the filter cake taken up in methanol/DCM and purified by flash chromatography on silica gel using 1-5% (10% ammonium hydroxide in methanol)/DCM. The desired fractions were concentrated to give 6-((6-chloropyridin-3-yl)methoxy)quinolin-2(1H)-one as a beige solid (1.0 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (1H, s), 8.55 (1H, d, J=2.01 Hz), 7.98 (1H, dd, J=8.03, 2.51 Hz), 7.85 (1H, d, J=9.54 Hz), 7.58 (1H, d, J=8.03 Hz), 7.18-7.32 (2H, m), 6.51 (1H, d, J=9.54 Hz), 5.19 (2H, s). LCMS: R.T.=3.07; [M+H]+=287.01.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6]([OH:9])(=O)=[O:7])[CH:3]=[N:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:11]>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[C:4]([S:6]([Cl:11])(=[O:9])=[O:7])[CH:3]=[N:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cn[nH]c1
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1cn[nH]c1
Temperature: 180 °C

Procedure:
A mixture of 1H-pyrazole-4-sulfonic acid (J. Am. Chem. Soc.; 1955, 77, 6532) (1.0 g, 4.0 mmol) and phosphorous pentachloride (1.6 g, 7.7 mmol) were heated up to 180° C. over the period of an hour. The mixture began to reflux but not fully molten. The reaction mixture was cooled to 130° C. and toluene (5 ml) was added and allowed to cool to room temperature with stirring. The white solid was filtered off. The filtrate solvent was removed under reduced pressure and azeotroped with toluene and DCM to afford the title compound as a colourless oil and impure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]1[NH:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10]1.[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:13]1[CH:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10][CH:9]1[C:3]1[CH:4]=[C:5]([O:8][C:2](=[O:1])[CH3:3])[CH:6]=[CH:7][C:2]=1[O:1][C:5](=[O:8])[CH3:4])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1CSC(c2cc(O)ccc2O)N1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(OC(C)=O)c(C2SCC(C(=O)O)N2C(C)=O)c1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
To a solution of 0.241 g (0.85 mmol) of 2-(2,5-dihydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (1:1 mixture of isomers at C2) was added 3 mL of pyridine, and the solution was cooled to −30° C. with a dry ice acetone bath. To the heterogeneous mixture was added 0.34 mL of acetyl chloride under constant stirring. The cooling bath was removed and the reaction mixture was allowed to warm up gradually to room temperature. After overnight stirring at room temperature, the solvent was removed under high vacuum. To the remaining oily residue were added 19 mL of water and 1 mL concentrated HCl. The precipitate was filtered and washed with 2×5 mL of water. After drying at high vacuum, 0.13 g of acetylated product (5) was obtained (34%), as a mixture of diastereoisomers and rotamers. 1H NMR (DMSO-d6) 67 ; 1.76 s, 1.79 s, 1.99 s, 2.03 s, 2.06 s, 2.26 s, 2.33 s, 2.34 s, 9H; 3.2-3.4 m, 3H; 5.11 d, J=8 Hz and 5.36 d, J=8 Hz, 1H; 6.10 s, 6.20 s, 6.33 s and 6.36 s 1H; 6.99-7.22 m, 2H; 12.95 bs, 1H.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH2:8]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[OH-].[Na+]>C(Cl)Cl>[CH3:11][CH2:10][CH2:9][CH2:8][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:8]2[C:7]3[CH2:16][C:15]4[CH:14]=[CH:13][CH:21]=[CH:20][C:5]=4[CH2:4][NH:3][C:6]=3[CH:11]=[CH:10][CH:9]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)c2cccc3c2Cc2ccccc2CN3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6,11-dihydro-5H-dihydro-5H-dibenz[b,e]azepine (0.12 g, 0.6 mmol) in methylene chloride (2 ml) is added triethylamine (0.12 g, 1.2 mmol), followed by 4-butoxybenzoyl chloride ((0.15 g, 0.72 mmol). The resulting mixture is stirred at room temperature for 2 hours, and then treated with 4 ml of 1N NaOH. The mixture is extracted with ethyl acetate (10 ml), and the extract is washed with 1N sodium hydroxide and brine (5 ml), dried over anhydrous sodium sulfate, and filtered through hydrous magnesium silicate. The filtrate is evaporated, and the crude material is triturated with isoctane to give 0.24 g of white solid; Mass spectrum (CI), 372(MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[CH2:22]([CH2:24][NH2:25])[OH:23].C(N(CC)CC)C.Cl>ClCCl>[OH:23][CH2:22][CH2:24][NH:25][C:13]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: NCCO
Reactant: COc1ccc2ccccc2c1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ccccc2c1C(=O)NCCO
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-methoxy-naphthalene-1-carboxylic acid (0.50 g, 2.5 mmol) in anhydrous dichloromethane at 0° C. was treated dropwise with a 2.0 M solution of oxalyl chloride in dichloromethane (1.9 mL, 3.8 mmol). The resulting solution was stirred under a N2 atmosphere at 0° C. for 20 min, then allowed to warm to r.t. and stirred 1 hr. The solution was cooled to 0° C., and ethanolamine (0.3 mL, 5.0 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added. The resulting mixture was stirred at 0° C. for 15 min, then allowed to warm to r.t. and stirred 90 min. The mixture was poured into 1N HCl (20 mL) and extracted with dichloromethane (2×20 mL), and the combined organic layers were washed with saturated NaHCO3 (20 mL) and dried over Na2SO4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as colorless syrup.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[C:9]([O:22][CH3:23])[CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:32])=[C:29](I)[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:32])=[C:27]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:2])[CH3:3])(=[O:5])=[O:6])=[CH:8][C:9]=2[O:22][CH3:23])[CH:26]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: COc1cc(S(=O)(=O)C(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(S(=O)(=O)C(C)C)ccc1-c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
To a solution of 2-(4-(isopropylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 36, 374 mg, 1.10 mmol) and 5-bromo-2-fluoroiodobenzene (300 mg, 1.00 mmol) in dioxane (6 mL) and water (2.5 mL) was added sodium carbonate (317 mg, 3.00 mmol). The mixture was degassed with nitrogen for 20 minutes, tetrakis(triphenylphosphine)palladium(0) (58.0 mg, 0.05 mmol) was added and the reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc/cyclohexane 25/75 to afford the title compound as a yellow oil in 69% yield, 0.27 g.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[SH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>C(#N)C>[Br:1][C:2]1[C:3]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: OCCCCS
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCCCSc1nc(Cl)ncc1Br

Procedure:
A solution of 2.27 g (10.0 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 30 ml of acetonitrile is mixed while being stirred at −20° C. with 1.39 ml (10 mmol) of triethylamine. Then, a solution of 1.06 g (10 mmol) of 4-mercapto-1-butanol in 1 ml of acetonitrile is added in drops. The reaction mixture is heated overnight to room temperature while being stirred. The batch is filtered, and the filtrate is evaporated to the dry state. The residue that is obtained is purified by chromatography (Flashmaster II, hexane/ethyl acetate 1:1). 2.89 g (9.7 mmol, 97% of theory) of the product 4-(5-bromo-2-chloro-pyrimidin-4-ylsulfanyl)-butan-1-ol is obtained.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:60]([O:61][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:69]([CH3:71])[CH3:70])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:60]([OH:61])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:69]([CH3:70])[CH3:71])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Yield: 58.7 %

Procedure:
43.3 mg of compound (51) was stirred together with 435 μl of dry tetrahydrofuran and 65.3 μl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution at room temperature for 1 hour. The reaction solution was concentrated in vacuo to give the crude product. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×20 cm) and eluted with n-hexane-ethyl acetate (8:1) to give 22.5 mg of compound (52) as a colorless oily substance.