Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([N:18]1[CH2:25][CH:24]2[CH:20]([C:21](=O)[C:22]3[C:28]([CH3:29])=[CH:27][S:26][C:23]=32)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(Cl)Cl>[CH2:11]([N:18]1[CH2:25][CH:24]2[CH:20]([C:21](=[CH2:1])[C:22]3[C:28]([CH3:29])=[CH:27][S:26][C:23]=32)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1csc2c1C(=O)C1CN(Cc3ccccc3)CC21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1c2c(C)csc2C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (9.6 g, 26.8 mmol) was dissolved in THF (67 ml), cooled to 0° C. and treated with potassium bis(trimethylsilyl)amide (KHMDS) (5.33 g, 26.8 mmol) producing a clear yellow solution. Next, a solution of the product from step f) (1.9 g mg, 6.70 mmol) in THF (33 ml) was added and the reaction was warmed to 22° C. After 1 hour, the reaction was diluted with CH2Cl2 (300 ml) and washed with brine (100 ml). The organic layer was dried (MgSO4) and the solvent evaporated in vacuo to give the crude subtitle product (3.1 g) that was used without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:18]2[C@@H:14]([O:15][C:16]([CH3:20])([CH3:19])[O:17]2)[C@@H:13]([CH2:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[O:12]1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>C(O)C.C(N(CC)CC)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:22][CH2:21][C@@H:13]1[C@H:14]2[C@@H:18]([O:17][C:16]([CH3:20])([CH3:19])[O:15]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:12]1
Reactant: NC1CCCC1
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21

Procedure:
To a solution of 1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-fluorobenzene, a compound of formula (3), (0.125 g, 2.86 mmoles) in 10 mL of ethanol and 1 mL of triethylamine was added cyclopentylamine in excess, and the mixture refluxed under nitrogen for 24 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC using 1:1 EtOAc:Hexanes to give (9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylamine, a compound of formula (4), as a yellow oil (80 mg, 56%)
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[C:4]([C:11]([OH:13])=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[N:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=1>C(#N)C>[Cl:34][C:31]1[N:30]=[N:29][C:28]([NH:27][C:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([F:1])[C:3]=2[OH:14])=[O:13])=[CH:33][CH:32]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: Cc1c(F)c(O)c(C(=O)O)c(=O)n1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1c(F)c(O)c(C(=O)Nc2ccc(Cl)nn2)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
300 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid and 266 mg of carbonyldiimidazole were added to 5 ml of acetonitrile. The mixture was stirred for 1 hour under heat refluxing condition. Thereafter, 212 mg of 3-amino-6-chloropyridazine was added to the mixture, and this was further stirred for 1 hour under heat refluxing condition. The reaction mixture was cooled to room temperature and crystals were produced. The crystals were collected by filtration to obtain 250 mg of N-(6-chloro-3-pyridazinyl)-5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (present compound 19):
Reaction SMILES: Br[CH2:2][C:3]1[CH:25]=[C:24]([Cl:26])[C:6]([C:7]([C:9]2[C:17]3[C:12](=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[C:5]([Cl:27])[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH2:35]>C(#N)C.O>[Cl:27][C:5]1[CH:4]=[C:3]([CH2:2][NH:35][CH3:34])[CH:25]=[C:24]([Cl:26])[C:6]=1[C:7]([C:9]1[C:17]2[C:12](=[C:13]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8]
Reactant: CN
Reactant: O=C(c1c(Cl)cc(CBr)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CNCc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Yield: 15.7 %

Procedure:
To a solution of N-{3-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (50 mg, 0.11 mmol) in acetonitrile, cesium carbonate (70 mg, 0.21 mmol) was added and stirred at same temperature. Methyl amine (6.8 mg, 0.21 mmol) was added at 0° C. The reaction mixture was then stirred at room temperature for 3 h. On completion, the reaction mixture was diluted with water and extracted with ethyl acetate, organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-(3-{2,6-dichloro-4-[(methylamino)methyl]benzoyl}-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (7.2 mg, 16%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([O:17]C)=[O:16])[NH:6][N:5]=1>CO>[Cl:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([OH:17])=[O:16])[NH:6][N:5]=1
Reactant: COC(=O)c1cc(-c2[nH]nc(Cl)c2C)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c(-c2[nH]nc(Cl)c2C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
NaOH (2 M in water, 8 mL, 16 mmol) was added to a solution of methyl 5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 250.5, 1.10 g, 3.96 mmol) in MeOH (10 mL). The mixture was stirred at room temperature overnight and the solvents were removed under the reduced pressure. The residue was cooled to 0° C. and acidified to pH˜3-4 with 1M HCl in water. The resulting white solids were filtered, washed with water and dried to give the title compound as a white solid (1.07 g, 90%). m/z (ES+) 265 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([C:30]([F:33])([F:32])[F:31])[CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][C:23]=3[C:30]([F:31])([F:32])[F:33])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3C(F)(F)F)cccc2c1N
Yield: 81.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (116 mg, 0.375 mmol) and [4-methoxy-2-(trifluoromethyl)phenyl]boronic acid (164 mg, 0.75 mmol) were reacted to afford the title compound (124 mg, 82% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.02 (t, J=6.0 Hz, 1H), 8.45 (d, J=8.3 Hz, 1H), 7.67-7.78 (m, 2H), 7.26-7.38 (m, 3H), 3.91 (s, 3H), 3.29 (apparent q, J=7.0 Hz, 2H), 1.57 (apparent sextet, J=7.0 Hz, 2H), 0.90 (t, J=7.0 Hz, 3H). MS APCI, m/z=405 (M+H) HPLC 2.11 min.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C1C(=O)N([Br:19])C(=O)C1.C([O-])(O)=O.[Na+]>CC#N>[Br:19][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1nc(C)sc1Br
Reaction time: 0.08 h
Yield: 40.1 %

Procedure:
To a solution of ethyl 2-methyl-1,3-thiazole-4-carboxylate (14.53 g) in MeCN (150 mL) was added NBS (22.66 g), followed by heating under reflux for 3 hours. To the reaction mixture was added NBS (7.55 g), followed by heating under reflux for 2 hours. Under ice-cooling, to the reaction mixture was added a saturated aqueous NaHCO3 solution, followed by stirring for 5 minutes, and then extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:EtOAc=from 100:0 to 60:40) to obtain ethyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate (8.52 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:4].[CH3:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[N:10]([C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([CH3:23])[CH2:25][CH2:26]1)=[O:31])[CH:11]1[CH2:12][CH2:13][S:14][CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CCSCC1
Reactant: CC1CCC(C(=O)Cl)CC1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCSCC1

Procedure:
Amidation of 5-phenyl-3-(tetrahydro-thiopyran-4-ylamino)-thiophene-2-carboxylic acid methyl ester (0.2 g, 0.6 mmol) and 4-Methyl-cyclohexanecarbonyl chloride was carried out as described for example 19, step 2 gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-(tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.208 g, 75.7%). NMR 1H (CDCl3, 400 MHz): 7.68-7.62 (m, 2H), 7.5-7.4 (m, 3H), 7.04 (s, 1H), 4.68-4.58 (m, 1H), 3.86 (s, 3H), 2.9-1.2 (m, 16H), 0.78 (d, 3H), 0.76-0.56 (m, 2H). s
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[Cl:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.O>C1COCC1>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([O:11][C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[CH:13][CH:14]=2)[C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: Cn1c(Oc2ccc(N)cc2)nc2ccccc21
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(Oc2ccc(Nc3ncnc(Cl)c3[N+](=O)[O-])cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (0.30 g) and TEA (0.26 ml) in THF (15 mL) was added 4,6-dichloro-5-nitropyrimidine (0.24 g) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5%-50% AcOEt in hexane) to give 6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine (0.24 g) as a yellow solid.
Reaction SMILES: C[N:2](C)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CN.C(N(CC)CC)C.FC(F)(F)C1C=C(C=CC=1)C(Cl)=[O:26]>C1COCC1>[C:3]([NH2:2])(=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C(CN)c1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
As shown in reaction scheme 83, N,N-dimethyl-1-phenylethane-1,2-diamine represented by Formula 101 (439.1 mg, 2.67 mmol, purchased from Alfa Aesar Co.) and triethylamine (0.75 mL, 5.35 mmol) in THF (10 mL) solution were cooled to 0° C. under a nitrogen atmosphere, then, 3-(trifluoromethyl)benzoic acid chloride represented by Formula 153 (613.17 mg, 2.94 mmol, purchased from TCI Co.) in THF (15 mL) solution was slowly added thereto. After agitating the mixture at the same time for 30 minutes, the mixture was left at room temperature for 18 hours. A precipitate generated during the reaction was removed through filtration. The remaining solution was diluted with chloroform and this diluted solution was washed with a potassium carbonate (K2CO3) solution, followed by separation and drying the same with sodium sulfate (Na2SO4). The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 83 as a desired product (VVZ-078; 632.5 mg, 70% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cu]([C:12]#[N:13])C#N>CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1

Procedure:
A 1-bromo-4-methyl-benzene of general formula F-1, where B, R1, R2, R3 and R4 are as defined above is reacted with copper cyanide in a polar solvent as dimethylformamide at elevated temperature as for example 150-200° C. to obtain the 4-methyl-benzonitrile of general formula F-2. The 4-methyl-benzonitrile of general formula F-2 is brominated by the treatment with N-bromosuccinimide in refluxing tetrachloromethane in the presence of a radical initiator like AIBN to obtain the 4-Bromomethyl-benzonitrile of general formula F-3.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16](I)[N:11]3[N:10]=2)[CH:8]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:16]2[N:11]3[C:12]([S:13][C:9]([C:7]4[CH:8]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:4]([NH2:18])=[N:5][CH:6]=4)=[N:10]3)=[N:14][CH:15]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(-c2nn3c(I)cnc3s2)cc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc3sc(-c4cnc(N)c(C(F)(F)F)c4)nn23)cc1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
3-(trifluoromethyl)-5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyridin-2-amine (0.100 g, 0.243 mmol, 1 eq) was dissolved in dioxane (1.5 mL), then 4-(methylsulfonyl)phenylboronic acid (0.078 g, 0.389 mmol, 1.6 eq) was added followed by 2M aq. Na2CO3 (0.5 mL, 4 eq). The suspension was degassed (N2, 15 min) and equipped with an argon balloon. Pd(Ph3P)2Cl2 (0.043 g, 0.061 mmol, 0.25 eq) was quickly added, and the reaction flask was placed in a pre-heated bath (115° C.). After stirring at reflux temperature for 3 h the mixture was cooled to RT and concentrated. The residue was taken up in water, and the solid obtained was filtered off, washed with Et2O and dried. The crude product was suspended in CH3CN at 50° C., filtered off and dried in vacuo to afford the desired product (0.061 g, 57%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.04 min, [M+H]+ m/z 440.0; 1H-NMR (DMSO-d6+TFA): δ=8.88 (1H, s), 8.36 (2H, d, J=8.4 Hz), 8.28 (1H, s), 8.17 (1H, s), 8.06 (2H, d, J=8.4 Hz), 3.24 (3H, s) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[CH2:11][N:12]([CH2:20][CH3:21])[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[CH2:20]([N:12]([CH2:11][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[N:7]=2)[CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:21]
Reactant: NCCc1ccc(O)cc1
Reactant: CCN(Cc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCN(Cc1cccnc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 23 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 440. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.63 (s, 1H) 8.49 (m, 1H) 8.26 (m, 1H) 8.15 (s, 1H) 8.05 (s, 1H) 7.45 (m, 2H) 7.25 (m, 1H) 7.05 (m, 3H) 6.99 (d, 1H) 6.75 (m, 4H) 3.4-3.8 (m, 4H) 2.88 (t, 2H) 2.75 (t, 2H) 2.55 (m, 2H) 1.05 (t, 3H).
Reaction SMILES: [I:1][C:2]1[C:3]([O:25][CH3:26])=[C:4]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14](I)[C:13]=2[O:23][CH3:24])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:27]([Li])CCC.CI>C1COCC1.[Cl-].[NH4+]>[CH3:26][O:25][C:3]1[C:2]([I:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([CH3:27])[C:13]=1[O:23][CH3:24]
Reactant: [Li]CCCC
Reactant: COc1c(I)cc2ccccc2c1-c1c(OC)c(I)cc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1c(C)cc2ccccc2c1-c1c(OC)c(I)cc2ccccc12
Temperature: 25 °C

Procedure:
To a −80° C. solution of (+/−)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl (2.016 g, 3.6 mmol) in THF (dry, distilled, 80 mL, 0.044 M) was added n-butyl lithium (2.8 mL, 3.9 mmol) dropwise. The reaction mixture turned yellow and was stirred for 1 h before the addition of methyl iodide (dry, distilled, 0.35 mL, 5.6 mmol). The reaction mixture was allowed to gradually warm to room temperature. After stirring for a further 3 h saturated aqueous ammonium chloride solution (4 drops) was added. The reaction mixture was evaporated to dryness, the residue taken up in diethyl ether and washed with water. The organic layer was dried (MgSO4), filtered and the filtrate evaporated to dryness to give a pale yellow solid. Purification of the crude material by flash column chromatography (4% ethyl acetate/hexane) yielded (+/−)-2,2′-dimethoxy-3-iodo-3′-methyl-1,1′-binaphthyl.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].C(Cl)(=O)C.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:2]([C:1]([OH:7])=[O:6])[C:3]([OH:5])=[O:4])=[CH:15][CH:14]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(=O)Cl
Product: O=C(O)C(=Cc1ccc(Cl)cc1)C(=O)O
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
Under nitrogen, malonic acid (powdered, 20 g., 0.192 mole) was mixed with acetyl chloride (15 g., 0.192 mole) and heated to 65° C. in an oil bath. p-Chlorobenzaldehyde (21.6 g., 0.153 mole) was added and the mixture further heated to 80° C. A yellow, slowly refluxing solution resulted, followed by copious precipitation of solids. The mixture was cooled and product recovered by filtration, resuspended in water, stirred for 5 minutes and refiltered to yield title product [21.1 g.; 61% of theory; m.p. 215° C. (dec.)].
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH:16]([CH3:20])[C:17]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: CC(Cl)C(=O)Cl
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
Benzyl alcohol (242 mL, 253 g, 2.34 mol) and pyridine (204 mL, 204 g, 2.57 mol) were dissolved in methylene chloride (2.5 L) and cooled to 0° C. 2-Chloropropanoyl chloride (250 mL, 327 g, 2.57 mol) was added dropwise keeping the temperature between 0° C. and 5° C. After addition the mixture was allowed to warm to RT overnight. The mixture was washed with 20% aqueous citric acid (2.5 L), saturated aqueous NaHCO3 (2.5 L), brine (2.5 L), dried (MgSO4), filtered and concentrated in vacuo. The resulting brown liquid (450 g) was dissolved in a small amount of methylene chloride and filtered through a short path of silica gel. After concentration, the crude was purified via bulb-to-bulb distillation (2*10-2 mbar, 90-95° C.) affording the title compound as a pale yellow liquid (420 g, 90%). 1H-NMR: (CDCl3, 300 MHz): δ ppm 1.75 (d, 3H, CH3), 4.45 (q, 1H, CHCl), 5.25 (s, 2H, CH2Ar), 7.40 (m, 5H, ArH).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:31][C:16]([F:15])([F:30])[C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:22][CH2:21]1
Reactant: O=CCCc1cc(-c2cccs2)no1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN1CCN(CCCc2cc(-c3cccs3)no2)CC1
Yield: 60.2 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (10.0, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 17 hr and followed the same processes as in Example 1 to obtain 13.1 mg (62.7%) of the target compound.
Reaction SMILES: [Na].N.[OH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH:11]([CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])O)=[CH:6][C:5]=1[CH3:18]>C(O)C.C(OCC)C>[CH3:18][C:5]1[CH:6]=[C:7]([CH2:11][CH2:13][Si:14]([CH3:15])([CH3:17])[CH3:16])[CH:8]=[C:9]([CH3:10])[C:4]=1[OH:3]
Reactant: Cc1cc(C(O)C[Si](C)(C)C)cc(C)c1O
Agent: N
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(CC[Si](C)(C)C)cc(C)c1O

Procedure:
Mix sodium metal (520 mg, 22.6 mmol) and liquid ammonia (13 mL). To this solution add, by dropwise addition, a solution of 4-hydroxy-3,5-dimethyl-α-[(trimethylsilyl)-methyl]benzenemethanol (2.22 g, 10 mmol) in ethyl alcohol (0.5 g) and ethyl ether (5 ml). After the blue color disappears, cautiously add water (13 mL), extract with ethyl ether, dry (MgSO4), and evaporate the solvent. Purify the residue by silica gel chromatography to yield the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[CH2:15][CH:16]([OH:27])[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[CH2:15][CH:16]([OH:27])[CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCNCC(O)CN(CCS(=O)(=O)O)CC(O)CNCCCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCCCCCN(CC(O)CN(CCS(=O)(=O)O)CC(O)CN(CCCCCCCC)C(=O)CCC(=O)O)C(=O)CCC(=O)O
Yield: 80.5 %

Procedure:
A reactor was charged with 27 g (0.05 mole) of 11,15-dihydroxy-13-sulfoethyl-9,13,17-triazapentacosane and 100 g of xylene, to which 12 g (0.12 mole) of succinic anhydride were then added with stirring to conduct a reaction at 50° C. for 6 hours. After xylene was distilled off under reduced pressure, 300 ml of water were added, and 10% sodium hydroxide was further added to keep the pH of the reaction mixture at 7. Thereafter, the reaction mixture was subjected to electrodialysis and lyophilized, thereby obtaining 28 g (isolation yield: 76%) of 6,10-dihydroxy-4,12-dioctyl-3,13-dioxo-8-sulfoethyl-4,8,12-triaza-1,15-pentadecanedicarboxylic acid as white crystals.