Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:8].[NH2:10][C@@H:11]([CH3:15])[C:12](O)=[O:13]>C(OCC)C>[ClH:8].[NH2:10][C@@H:11]([CH3:15])[C:12]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCO
Solvent: CCOCC
Product: CCCCOC(=O)[C@H](C)N
Product: Cl
Reaction time: 1 h

Procedure:
1-Butanol (1200 mL) was cooled to −20° C. and 50 mL of SOCl2 added with stirring followed by 50 g (33.67 mmol) of (S)-2-aminopropanoic acid. The solution was heated 24 hrs at reflux, most of the solvent stripped off, and the residue was dissolved in 800 mL of diethyl ether. The mixture was left for 1 hr at 0° C. to afford (S)-butyl 2-aminopropanoate hydrochloride (intermediate 11.47 g). Phenyl phosphorodichloridate (48.9 g, 232 mmol) and (S)-butyl 2-aminopropanoate hydrochloride (42 g, 232 mmol) were suspended in anhydrous CH2Cl2 (200 mL). N,N-diisopropylethylamine (59.9 g, 464 mmol) was added drop wise at −78° C., and after 4 hrs the reaction was concentrated. Diethylether (Et2O, 500 mL) was added and the resulting precipitate was filtered off and washed with dry Et2O (twice 100 mL). The filtrate was evaporated to dryness. (2S)-butyl 2-(chloro(phenoxy)phosphorylamino)propanoate (12) was stored as 0.5 M solution in THF at −18° C. until further reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:13])/[CH:10]=[CH:11]/[CH3:12].CS(O)(=O)=O>O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH:11]([CH3:12])[CH2:10][C:9]2=[O:13]
Reactant: C/C=C/C(=O)O
Reactant: Oc1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: O
Product: CC1CC(=O)c2cc(F)ccc2O1
Temperature: 92 °C

Procedure:
A mixture of 56.1 g (0.5 mol) 4-fluorophenol, 172 g (2 mol) crotonic acid and 1120 ml methane sulfonic acid was heated at 92° C. for 20 hours. The reaction was cooled to 0° C., poured onto 2 liters ice and 2 liters water and extracted with 3×800 ml diethyl ether. The combined organic layers were washed with 3×500 ml water, 4×500 ml 1N sodium hydroxide, 2×500 ml water and 500 ml brine, dried over magnesium sulfate and concentrated in vacuo to give 48.5 g crude solid. The latter was purified by flash chromatography on 1000 cc silica gel using diethyl ether:hexane (1:10) as eluant. The title compound was obtained as a yellow solid, 37 g (41%); m.p. 65°-68° C. The Chemical Abstracts Registry Nos. for this compound are 88754-96-5 and 82320-16-9.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([OH:4])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.17 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3-4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 68 mg of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid as a yellow solid, which was immediately used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[OH:20])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:9])([CH3:4])[CH3:3].[CH3:21][NH:22][CH3:23].C=O.[CH2:26](O)[CH3:27]>>[CH3:21][N:22]([CH2:26][CH2:27][C:18]1[CH:17]=[C:7]([CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:19]=1[OH:20])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9])[CH3:23]
Reactant: Cc1ccc(C(=O)c2ccc(O)c(C(C)(C)C)c2)cc1
Reactant: CNC
Reactant: CCO
Agent: C=O
Product: Cc1ccc(C(=O)c2cc(CCN(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
3-(1,1-Dimethylethyl)-4-hydroxy-4'-methylbenzophenone (2.68 g) was suspended in 45 ml of ethanol and heated with stirring to reflux for 8 hours with 1.80 g of a 50% aqueous solution of dimethylamine and 1.7 g of a 35% aqueous solution of formaldehyde. Insoluble material was filtered off, the filtrate evaporated to dryness in vacuo, and the residue crystallized from ethanol to give 2.36 g of white crystals, m.p. 123°-124.5° C.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([F:31])[C:6]=1[F:32])[CH3:3].[CH3:33]C(C)([O-])C.[K+].[CH2:39]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2(C=O)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[C:44]([F:56])[C:43]=1[F:57])[CH3:40].Cl>C1COCC1.C1(C)C=CC=CC=1.O>[F:56][C:44]1[C:43]([F:57])=[C:42]([O:41][CH2:39][CH3:40])[CH:47]=[CH:46][C:45]=1[C@H:48]1[CH2:49][CH2:50][C@H:51]([CH:33]=[CH:9][C:8]2[CH:29]=[CH:30][C:5]([O:4][CH2:2][CH3:3])=[C:6]([F:32])[C:7]=2[F:31])[CH2:52][CH2:53]1
Reactant: CCOc1ccc(C2(C=O)CCCCC2)c(F)c1F
Reactant: CC(C)(C)[O-]
Reactant: CCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(C=C[C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
4-Ethoxy-2,3-difluorobenzyltriphenylphosphonium chloride (11) (dried; 24.9 g) and THF (100 ml) were mixed under a nitrogen atmosphere and cooled to −10° C. Then, potassium t-butoxide (t-BuOK) (5.4 g) was added thereto in twice in the temperature range of −10° C. to −5° C. The stirring was continued at −10° C. for 60 minutes, and then the compound (18) (10.0 g) dissolved in THF (30 ml) was added thereto dropwise in the temperature range of −10° C. to −5° C. The stirring was continued at 0° C. for 30 minutes, and then the reaction mixture was poured into a mixture of water (100 ml) and toluene (50 ml), and mixed. The mixture was then allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure and the residue obtained was purified with a fractional operation by means of column chromatography (silica gel; toluene). The eluent obtained was concentrated under reduced pressure. Sodium benzenesulphinate dihydrate (2.6 g) was added, with stirring, to obtained light yellow crystals in Solmix A-11 (20 ml) and then 6N-hydrochloric acid (2.2 ml) was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was cooled to 30° C., and water (100 ml) and toluene (100 ml) were added to the mixture obtained, and mixed. The mixture was then allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The obtained organic phase were washed sequentially with water, aqueous 0.5 N-sodium hydroxide solution, a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure and the residue obtained was purified by means of column chromatography (silica gel; heptane: toluene=2:3 by volume), and the eluent was concentrated under reduced pressure. The residue obtained was purified by means of recrystallization (heptane: Solmix=3:2 by volume), giving 10.6 g of 2,3-difluoro-4-ethoxy-[trans-4-(2,3-difluoro-4-ethoxyphenylethenyl)cyclohexyl]benzene (No. 228). The yield based on the compound (18) was 67.5%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH2:41][CH2:42][CH:43]=O)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.[P:45]([O-])([O:54]CC1C=CC=CC=1)[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(#N)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[NH:14][C:43](=[P:45]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:54])[CH2:42][CH2:41][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1cccc2ccccc12
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)C[C@H](NC(CCc1cccc2ccccc12)=[P+]([O-])OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of L-leucyl-L-tryptophan benzyl ester (408 mg) and 3-(1-naphthyl)propionaldehyde (220 mg) in toluene (10 ml) was heated to reflux in a Dean-Stark apparatus for 2 hours. After cooling, dibenzyl phosphite (252 mg) and acetonitrile (10 ml) were added to the mixture and the resulting solution was stirred at 100° C. for 16 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (chloroform:ethyl acetate=5:1) to give two diastereomers of the title compound as colorless oil (a: 58 mg, b: 95 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]#[N:16])[CH:9]=1.Br[C:18]([CH3:22])([CH3:21])[CH:19]=[O:20]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[C:10]([C:15]#[N:16])[CH:9]=1
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: CC(C)(Br)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C=O)Oc1ccc(Cl)cc1C#N
Temperature: 4 °C
Yield: 94.7 %

Procedure:
Anhydrous potassium carbonate (2.76 g) was added to a stirred solution of 4-chloro-2-cyanophenol (1.53 g) and 2-bromo-2-methyl propanal (2.26 g) in THF (50 ml) and the mixture heated at reflux for 5 hours. The mixture was then cooled to 4° C., the suspended solid removed by filtration and the filtrate evaporated to give a yellow oil which crystallised on standing. The solid was triturated with hexane and collected by filtration to give 2-(4-chloro-2-cyanophenoxy)-2-methylpropanal (2.11 g), m.p. 85°-88° C.; NMR: 1.52(6H,s), 6.79(1H,d,J=8 Hz), 7.42(1H,dd,J=8,2.5 Hz), 7.57(1H,d,J=2.5 Hz), 9.80(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:15][C@@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1)=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)=[O:18])=[CH:27][CH:28]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)C1)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 34 mg, 0.17 mmol) in DMF (5 mL) was added 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-1-one hydrochloride (Preparation 103, 50 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIPEA (94 μL, 0.54 mmol). After 5 min, EDCI (43 mg, 0.23 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (25 mL) and ethyl acetate (3×20 mL). The combined organic layer was washed with 2N sodium hydroxide solution (2×10 mL), brine (10 mL), dried (MgSO4) and concentrated in vacuo. Purification via chromatography on silica gel eluting with methanol:dichloromethane (7:93) gave the title compound. m/z (ES+)=431 [M +H]+; RT=3.49 min.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[S:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1)[CH3:14].COC1C=NS(=O)(=O)N=1.[CH3:35][C:36]1[C:37]([CH2:41][S:42][CH2:43][CH2:44][NH2:45])=[N:38][O:39][N:40]=1>>[CH3:14][N:13]([CH2:15][C:16]1[S:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:3]2[C:7]([NH:45][CH2:44][CH2:43][S:42][CH2:41][C:37]3[C:36]([CH3:35])=[N:40][O:39][N:38]=3)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=2)=[CH:18][CH:17]=1)[CH3:12]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: Cc1nonc1CSCCN
Reactant: CN(C)Cc1ccc(CSCCN)s1
Agent: COC1=NS(=O)(=O)N=C1
Product: Cc1nonc1CSCCNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)s1

Procedure:
When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine and the resultant 3-55 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with 2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamine [prepared in Example 58, Step B], the title compound is thereby produced.
Reaction SMILES: [K].[C:2]1(=[O:18])[N:6]([CH:7]([S:9]([OH:12])(=[O:11])=[O:10])[CH3:8])[C:5](=[O:13])[C:4]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:3]12.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>P(Cl)(Cl)(Cl)=O>[S:9]([Cl:20])([OH:12])(=[O:11])=[O:10].[C:5]1(=[O:13])[N:6]([CH2:7][CH3:8])[C:2](=[O:18])[C:3]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:4]12
Reactant: CC(N1C(=O)c2ccccc2C1=O)S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K]
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1C(=O)c2ccccc2C1=O
Product: O=S(=O)(O)Cl

Procedure:
Using the process of Synthesis 739 (1976), 2.9 g of the potassium salt of phthalimido ethane sulfonic acid, 10 ml of phosphorus oxychloride and 2 g of phosphorus pentachloride were reacted to obtain 1.9 g of phthalimido ethane sulfochloride melting at 162° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=[C:22]([Cl:25])[C:23]=1Cl>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=[C:22]([Cl:25])[C:23]=1[CH:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)C(c2c(Cl)cc([N+](=O)[O-])cc2Cl)C(=O)C1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of 30.98 g (0.221 mol) of 5,5-dimethyl-1,3-cyclohexanedione and 76.36 g (0.553 mol) of anhydrous potassium carbonate in 300 ml of dimethylformamide was heated to 75° C. with stirring under N2 for one hour. The 3,4,5-trichloronitrobenzene (50.0 g, 0.221 mol) was dissolved in 100 ml of dimethylformamide and added to the reaction mixture, while stirring and maintaining the temperature at 75° C. A deep red-colored solution was formed, and when the addition was complete the temperature was raised to 100° C. and the mixture stirred over night at this temperature. Most of the dimethylformamide was removed by vacuum distillation, and 21 of water was added to the residue. The aqueous solution was extracted three times with 500 ml portions of benzene, then N2 was passed through the aqueous solution while warming to remove dissolved benzene. The solution was cooled in an ice bath and acidified with 6N HCl to give 63.8 g (87%) of 2-(2',6'-dichloro-4'-nitrophenyl)-5,5-dimethyl-1,3-cyclohexanedione as a tan powder, m.p. 288°-290° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:41]3=[N:42][CH:43]=[CH:44][C:45](I)=[C:40]3[CH:39]=[N:38]2)=[CH:33][CH:32]=1.C(N(CC)CC)C.[CH3:54][C:55]1([CH3:62])[C:59]([CH3:61])([CH3:60])[O:58][BH:57][O:56]1>CC#N.CC#N.Cl[Pd]Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:41]3=[N:42][CH:43]=[CH:44][C:45]([B:57]4[O:58][C:59]([CH3:61])([CH3:60])[C:55]([CH3:62])([CH3:54])[O:56]4)=[C:40]3[CH:39]=[N:38]2)=[CH:33][CH:32]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OB(c2ccnc3c2cnn3-c2ccc(F)cc2)OC1(C)C
Temperature: 110 °C
Reaction time: 14 h

Procedure:
A vial was charged with bis(acetonitrile)palladium(II) chloride (1.038 mg, 4.00 μmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.28 mg, 8.00 μmol), and Intermediate 2A (0.068 g, 0.200 mmol). The vial was capped with a rubber septum and then evacuated and backfilled with N2 (this sequence was carried out a total of 2 times). Dioxane (0.120 mL) was added via syringe, through the septum, followed by the addition of triethylamine (0.084 mL, 0.600 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.044 mL, 0.300 mmol) dropwise. The septum was then replaced with a Teflon screw valve, and the vial sealed. The reaction mixture was heated at 110° C. After 14 h, the reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with CH2Cl2. The filtrate was concentrated to afford the title compound as a yellow solid. Intermediate 105B: MS (ESI): m/z=340.2 [M+H]+ HPLC Peak ret. T=2.00 minutes was product. (HPLC conditions: Column:Luna C18 4.6×30 mm 3 u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:27][CH2:28][S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)/[C:9](/[F:26])=[C:10](\[F:25])/[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>C(Cl)Cl>[C:30]1([S:29]([CH2:28][CH2:27][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)/[C:9](/[F:26])=[C:10](\[F:25])/[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[O:44])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: F/C(Cc1cccc(Oc2ccccc2)c1)=C(/F)C(CCSc1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(CCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of 1-[(2E)-4-(4-chlorophenyl)-2,3-difluoro-6-(phenylsulfanyl)-2-hexenyl]-3-phenoxybenzene (0.311 g, 0.61 mmol) in methylene chloride (13 ml) under nitrogen was added dropwise a solution of m-chloroperbenzoic acid (m-CPBA; 0.13 g, 0.65 mmol) in methylene chloride (2 ml) over one minute. The reaction mixture was stirred at room temperature for two hours, diluted with methylene chloride (50 ml) and washed successively with saturated aqueous sodium bicarbonate and water. The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a colorless syrup (0.318 g), which was characterized by IR, 1HNMR, 19FNMR and mass spectral analysis, and used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[NH3:5].[CH:12]1[C:13]2[C:8](=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: O=C(CCl)Nc1ccc2cnccc2c1
Reactant: C1COCCN1
Solvent: CO
Product: N
Product: O=C(CN1CCOCC1)Nc1ccc2cnccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 2 %

Procedure:
To 2-chloro-N-(isoquinolin-6-yl)acetamide (E1) in MeOH is added KI and the solution is heated to 60° C. for 40 minutes. The mixture is cooled to 45° C. and morpholine is added and stirred at 45° C. After 2-4 hours, the solvents are evaporated and the residue is taken up in EtOAc and extracted with NaHCO3(sat). The organics are dried (Na2SO4), filtered and evaporated. Flash chromatography (2% NH3(2M)/MeOH/3% MeOH/CH2Cl2) gives N-(isoquinolin-6-yl)-2-morpholino acetamide (E105).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C@H:14]([OH:26])[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20](CCN)=[CH:19][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[C:8]1([C@H:14]([OH:26])[CH2:15][NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O[C@H](CNc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-(2-phenyl-2-(S)-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate 31 (0.144 g, 0.3 mmole) in methanol (10 mL) was added aq. NaOH solution (1.0 M, 0.625 mL). The solution was concentrated to dryness and the residue was dissolved in anhydrous THF (5 mL). α,α-Dihydroxy-4-hydroxy-3-methoxycarbonylacetophenone 12 (0.067 g, 0.3 mmole) was added and the reaction mixture was stirred for 12 h at rt. BH3-Me2S (0.2 mL, 2 M) was added at 0° C. and the reaction mixture was heated at 75° C. for 6 h. After cooling the reaction mixture in ice bath, MeOH (5 mL) was slowly added to it to quench the reaction, and the reaction mixture was stirred for 30 min., at rt. The organics were removed and the residue was dissolved in TFA/MeOH (1/9; 20 mL), and concentrated. The crude product was dissolved in 20% MeCN/H2O, and purified by preparative HPLC: 5 to 20% MeCN/H2O; 20 mL/min; 254 nm.) to give 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)-amino]benzene 33.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.Cl.[C:20]([CH2:23][O:24][NH2:25])([OH:22])=[O:21].[C:26](CON)(O)=O.N1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[C:20]([CH2:23][O:24][N:25]=[CH:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:26][C:13]=1[C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[NH:10][C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Cl:1])([OH:22])=[O:21]
Reactant: NOCC(=O)O
Reactant: c1ccncc1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2ccccc2C=NOCC(=O)O)c1Cl
Yield: 54 %

Procedure:
A mixture in ethanol (20 mL) of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde (1.10 g, 3.9 mmol), prepared as in step 1 above, O-carboxymethyl hydroxylamine hemihydrochloride (0.945 g, 4.3 mmol), and pyridine (8 mL) was stirred at reflux for 18 hours. After cooling the reaction was concentrated and the residue was acidified to pH 2 with 10% aqueous citric acid. The mixture was then extracted with ethyl acetate (4×100 mL), the combined organic layers were washed with water and brine, dried over MgSO4, filtered, evaporated in vacuo. Purification by chromatography on silica gel (9:1 hexane/ethyl acetate, followed by 9:1 CH2Cl2 /CH3OH) and crystallization from ethyl acetate-ether-hexane gave 2-[(2,6-dichloro-3-methylphenyl)aminophenyl]benzaldehyde-O-carboxymethyl oxime (751 mg, 54%). mp 129°-130° C.; 1H NMR (300 MHz, DMSO-d6)δ2.37 (s, 3H), 4.70 (s, 2H), 6.21 (d, J=9 Hz, 1H), 6.83 (t, J=7.5 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 7.33 (d, J=9 Hz, 1H), 7.45 (d, J=9 Hz, 1H), 7.50 (d, J=9 Hz, 1H), 8.58 (s, 1H), 8.73 (s, 1H), 12.81 (broad s, 1H); MS (DCI-NH3) m/z 353 (M+H)+, 370 (M+NH4)+. Anal. Calcd for C16H14Cl2N2 O3 : C, 54.41, H, 4.00, N, 7.93. Found: C, 54.13, H, 3.92; N, 7.69.