Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]1.[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:18]1[C:2]2([CH2:3][CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:7]2)[O:1][CH2:16][CH2:17]1
Reactant: OCCO
Reactant: COC(=O)C1CC(=O)CC(C(=O)OC)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(C(=O)OC)CC2(C1)OCCO2
Yield: 83 %

Procedure:
To a solution of dimethyl 5-oxocyclohexane-1,3-dicarboxylate (6.0 g, 28 mmol) in toluene (50 ml) was added ethylene glycol (3.73 g, 56.6 mmol) and p-toluenesulfonic acid (65 mg). The reaction was refluxed overnight, using a Dean-Stark trap to remove the excess water. The reaction was worked up by removing the toluene by rotary evaporation, adding brine (10 ml) and extracting with ethyl acetate (3×40 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give the desired product as a thick colorless liquid (6.0 g, 82%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:38])(=[O:37])[NH:26][CH2:27][CH2:28][O:29]CC4C=CC=CC=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:39]>CO.[Pd]>[ClH:39].[ClH:39].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([S:25](=[O:38])(=[O:37])[NH:26][CH2:27][CH2:28][OH:29])=[CH:23][CH:24]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)NCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)NCCO)cc3)cc3ccccc23)CC1
Reaction time: 48 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-benzyloxyethyl)sulfamoyl]phenyl}isoquinoline (0.34 g) was converted into a hydrochloride in a conventional manner. The resulting hydrochloride was dissolved in methanol (20 ml), followed by the addition of 10% palladium/carbon catalyst (0.08 g), and the catalytic reduction was conducted at atmospheric pressure for 2 days. The catalyst was filtered off, and the solvent was evaporated. Water was added to the resulting residue, to which was then added sodium carbonate to adjust the resulting solution to pH 8, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), give 0.19 g of the free compound of the title compound as a pale brown amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)cc4Cl)cc23)CC1
Yield: 69.4 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 6.4 μL (0.0458 mMol) 2,4-dichlorobenzoyl chloride, 12.2 mg (80%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][C:16]#[N:17]>C(O)(=O)C.CO.ClCCl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]3[C:16]#[N:17])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: N#CC=C(N)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)(F)F)NC(C(F)(F)F)=C3C#N)cc12

Procedure:
A mixture of 50 mg (0.31 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 106 mg (0.78 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] and a trace amount of powdered 4 Å molecular sieve in acetic acid (0.30 ml) was heated to reflux temperature for 2 h. After cooling, the reaction mixture was diluted with methanol/dichloromethane and filtered. The filtrate was evaporated, and the residue was purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 19 mg (15% of th.) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a solution of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate (3.77 g, 8.49 mmol) in a mixture of THF (200 ml) and H2O (100 ml) was added a solution of LiOH (1.20 g, 50 mmol) in H2O (50 ml). After stirring at room temperature for 3 h, the reaction was concentrated, acidified with 1 M HCl solution, and extracted with EtOAc (2×100 ml). The organic solution was dried over Na2SO4 and concentrated to give 3.09 g (95%) of 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylic acid as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1([CH3:12])[CH2:10][O:9]C(=O)[O:7][CH2:6]1)([O:3][CH3:4])=[O:2].OCC(CO)(C)C(O)=O>CO>[OH:7][CH2:6][C:5]([CH2:10][OH:9])([CH3:12])[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1(C)COC(=O)OC1
Agent: CC(CO)(CO)C(=O)O
Solvent: CO
Product: COC(=O)C(C)(CO)CO

Procedure:
As set out hereinabove, the binder component of the dispersion of the invention is an organic polycarbonate polymer. The resulting polymer of the polymerization of 5-carbomethoxy-5-methyl-1,3-dioxan-2-one may be used as a component of the polymer binder. The polycarbonate polymer of 5-carbomethoxy-5-methyl-1,3-dioxan-2-one may be prepared as disclosed in Weilandt, K. D., Keul, H. and Hocker, H., Macromol. Chem. Phys. 197, 3851-3868 (1996). 5-Carbomethoxy-5-methyl-1,3-dioxan-2-one may be prepared via the reaction of 2,2-bis(hydroxymethyl)propionic acid with methanol to give methyl 2,2-bis(hydroxymethyl)propionate, which was then reacted with triphosgene in the presence of triethylamine to afford the desired product, 5-carbomethoxy-5-methyl-1,3-dioxan-2-one, as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C:14](=[O:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[NH:21][CH:22]=[C:23]([C:24]3[C:25]([NH:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=3)[C:3]=12.B1C2CCCC1CCC2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([OH:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[NH:21][CH:22]=[C:23]([C:24]3[C:25]([NH:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=3)[C:3]=12
Reactant: CNc1ncccc1-c1c[nH]c2ncc(-c3cncc(C(=O)C(=O)N(C)C)c3)c(Cl)c12
Agent: B1C2CCCC1CCC2
Solvent: Cc1ccccc1
Product: CNc1ncccc1-c1c[nH]c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(Cl)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
A mixture of 2-{5-[4-chloro-3-(2-methylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-2-oxo-acetamide (35 mg, 0.08 mmol), 9-BBN-dimer (98 mg, 0.4 mmol) in toluene (5 ml) was stirred at 60° C. overnight. The solvent was removed under vacuum and the crude was dissolved in DMSO, filtered and purified by reverse phase HPLC, lyophilized afforded 2-{5-[4-chloro-3-(2-methylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]-pyridin-5-yl}-pyridin-3-yl]-2-hydroxy-N,N-dimethyl-acetamide (18 mg, 50% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.74 (d, 3H), 2.85 (s, 3H), 2.96 (s, 3H), 5.68 (m, 1H), 5.82 (s, 1H), 6.53 (d, 1H), 7.28 (d, 1H), 7.62 (s, 1H), 7.84 (m, 1H), 8.02 (d, 1H), 8.24 (s, 1H), 8.58 (m, 2H), 12.26 (s, 1H). MS: m/z 437.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=O.C1C[O:22][CH2:21]C1>>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH2:6][CH2:21][OH:22]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC
Reactant: C1CCOC1
Product: COc1cc(CCO)c([N+](=O)[O-])c(OC)c1OC

Procedure:
To a stirred solution of the 3,4,5-Trimethoxy-2-nitrobenzoic acid (5 g, 19.40 mmol) in THF (30 ml) was added by BH3 (1.0 M in THF, 29.1 ml) under nitrogen. The mixture was stirred and refluxed for 2 hours. After cooling, the reaction mixture was extracted with water and CH2Cl2. The combined organic layers were dried over MgSO4, and then evaporated to afford 3,4,5-Trimethoxy-2-nitrobenzyl methanol. The crude 3,4,5-trimethoxy-2-nitrobenzyl methanol was dissolved in anhydrous CH2Cl2 (20 mL) and was subjected to PBr3 (2.40 ml, 25.22 mmol) in an ice bath. After 2 h, the mixture was extracted with water and CH2Cl2. The organic layers were combined and evaporated. The residue was purified by flash chromatography (EtOAc:n-hexane=1:2) to afford B1 as a pale yellow oil, yield 68%. 1H NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 3.92 (s, 3H), 3.98 (s, 3H), 4.44 (s, 2H), 6.72 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:22])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.O[Li].O>C1COCC1.O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:22])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)cn(C)c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cccc(C(F)(F)F)c2)c2ccc(C(=O)O)cc21
Yield: 84.9 %

Procedure:
A solution of compound 15f (264 mg, 0.93 mmol), and LiOH.H2O (156.4 mg, 3.73 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The aqueous layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give compound 15g (252 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 270.1.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: BrCc1ccccc1
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O

Procedure:
From 8-Chlorotheophylline (50 g, 233 mmol) and benzyl bromide.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Agent: CN(C)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using (2-chloroethyl)-dimethylamine hydrochloride. The title compound: ES-MS: 413.9 [M+H]+; single peak at tR=3.17 min (System 2); Rf=0.22 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]#[N:16])[CH:9]=[CH:8]2>CC(O)=O>[Br:1][C:6]1[C:5]([O:4][CH3:3])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([C:15]#[N:16])=[CH:11]2
Reactant: COc1ccc2cc(C#N)ccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc2cc(C#N)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Bromine (7.0 mL, 0.137 mol) in 100 mL of glacial HOAc was added under nitrogen dropwise over 4 h to a solution of 6-methoxy-naphthalene-2-carbonitrile (25.02 g, 0.137 mol) in 700 mL of glacial HOAc at room temperature. After the addition the reaction was stirred at room temperature overnight. The solid that formed was collected by filtration, rinsed with glacial HOAc and dried under reduced pressure to give 5-bromo-6-methoxy-naphthalene-2-carbonitrile (31.35 g, 88%) as a white solid, mp 177-178° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16](Cl)(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(OCc3ccccc3)cc2)c(OC)c1
Reaction time: 0.5 h

Procedure:
Under inert gas, 4.89 g of (4-benzyloxyphenyl)methanesulfonyl chloride were initially charged in 120 ml of THF, then, at a temperature of −20° C., 6.10 ml of 2,4-dimethoxybenzylamine were added dropwise and the reaction solution was allowed to come to 0° C. within 30 minutes. The reaction solution was diluted with 150 ml of ethyl acetate and washed with water, dilute aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined, concentrated by rotary evaporation and dried under high vacuum. This gave the product (3.23 g) with a molecular weight of 427.5 g/mol (C23H25NO5S).
Reaction SMILES: [OH:1][C@@:2]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]([NH:45][CH3:46])=[O:44])[CH:39]=2)[CH:34]=1)([C:9]1[N:10]=[CH:11][N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[CH2:3][C:4](OCC)=[O:5].[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].Cl>C(OCC)(=O)C.O.C(O)C.C1COCC1>[OH:1][C@@:2]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[C:38]([C:43]([NH:45][CH3:46])=[O:44])[CH:37]=[CH:36]2)([C:9]1[N:10]=[CH:11][N:12]([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[CH2:3][CH2:4][OH:5]
Reactant: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
13 mL of THF was added to 1.3 g (2.13 mmol) of ethyl (3S)3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate, and 0.645 g (17.1 mmol, 8 eq) of sodium borohydride was added. 0.95 g (8.53 mmol, 4 eq) of calcium chloride was added at 2° C. 13 mL of ethanol was added dropwise at 2° C. over 15 minutes. The mixture was stirred at 3˜4° C. for 30 minutes, and at 40˜43° C. for 4 hours. 56 mL of water was added dropwise. 17.1 mL of 1N hydrochloric acid was added dropwise, followed by dilution with 40 mL of ethyl acetate. Then, the layers were separated. The aqueous layer was re-extracted with 20 mL of ethyl acetate. The organic layers were combined, and washed with 20 mL of an aqueous saturated sodium chloride solution two times. After concentration under reduced pressure, IPE was added to the concentration residue, crystals were loosened, filtered and washed with IPE. Vacuum drying (50° C.) to a constant weight afforded 1.08 g of 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (yield 89%, enantiomer excess 92.0% ee).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13].N([O-])=[O:15].[Na+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O.O>[OH:15][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13]
Reactant: O=N[O-]
Reactant: COc1cccc2cc(N)cnc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COc1cccc2cc(O)cnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 53 ml of 33%(v/v) sulfuric acid was dissolved 6.2 g of 3-amino-8-methoxy quinoline [compound (IV)]. The solution was cooled to 0° C., and to the solution was slowly dropped 2.6 g of sodium nitrite which is dissolved in 12 ml of water. The solution was agitated at 0° to 5° C. for 30 minutes. The resulting solution was dropped in 47 ml of 50%(v/v) which was kept 160° C., agitated for 1 hour, and cooled. To the solution was added 300 ml of water and neutralized with aqueous potassium carbonate. By filtering and drying the solid portion, 3.8 g of 3-hydroxy-8-methoxy quinoline [compound (V)], which is yellow-red, was obtained in a solid state.
Reaction SMILES: CSC.B.[Cl:5][CH2:6][CH2:7][N:8]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](O)=[O:21])=[CH:14][CH:13]=1)[CH2:9][CH2:10][Cl:11].CS(C)=O.C(Cl)(=O)C(Cl)=O.CCN(CC)CC>C1COCC1>[Cl:5][CH2:6][CH2:7][N:8]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH:20]=[O:21])=[CH:16][CH:17]=1)[CH2:9][CH2:10][Cl:11]
Reactant: O=C(O)CCc1ccc(N(CCCl)CCCl)cc1
Agent: B
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of borane dimethyl sulphide (23 mmol of a 10M solution in THF) was added slowly to a stirred solution of 3-[4-(N,N-bis(2-chloroethyl)amino)phenyl]propanoic acid (VIII, n=2) [Everett, J. L., Roberts, J. J., Ross W. C. J., "Aryl-2-halogenoalkylamines. Part XII. Some carboxylic acid derivatives of N,N-di-2-chloroethylaniline", J. Chem. Soc., 1953 2386-2392] (5.5 g, 19 mmol) in TEF (190 mL) maintained at 0° C. under a N2 atmosphere. After the initial effervescence the solution was stirred for a further 4 h before being quenched with MeOH and concentrated under reduced pressure. The product was partitioned between aqueous NaHCO3 and EtOAc, and the residue from the organic phase was percolated through a pad of SiO2 (EtOAc elution) to give the crude alcohol, which was used without further purification. DMSO (1.15 mol equiv.) was added to a stirred solution of oxalyl chloride (1.1 mol equiv.) in THF (5 mL per mmol of alcohol) maintained at -78° C. under a N2 atmosphere. Stirring was continued for 10 min after which a solution of the above alcohol (1 mol equiv.) in THF (5 mL per mmol of alcohol) was added. Stirring was continued at -78° C. for a further 15 min before Et3N (5.0 mol equiv.) was added and the mixture brought slowly to room temperature. The reaction mixture was partitioned between H2O/EtOAc and the residue from the organic layer was chromatographed on SiO2 and eluted with petroleum ether/EtOAc (3:1) to give pure 3-[4-(N,N-bis(2-chloroethyl)amino]phenyl)propanal (IX, n=2) as an unstable oil (3.4 g, 68% overall yield). 1H NMR (CDCl3) δ 9.80 (t, J1,2 =1.6 Hz, 1 H, CHO), 7.08 (d, J2',3' =8.8 Hz, 2 H, H-2',H-6'), 6.62 (d, J2',3' =8.8 Hz, 2 H, H-3',H-5'), 3.69 (complex t, J=6.5 Hz, 4 H, NCH2CH2Cl), 3.68 (complex t, J=6.5 Hz, 4 H, NCH2CH2Cl), 2.87 (t, J2,3 =7.4 Hz, 2 H, H-3), 2.72 (br dt, J2,3 =7.4 Hz, and J1,2 =1.6 Hz, 2 H, H2), 2.12 (complex m, 4 H, H-2). 13C NMR δ 201.88, 144.56, 129.53, 129.36, 112.28, 53.54, 45.50, 40.48, 27.04. HRMS (EI, 70 eV) : calcd. for C13H17NO3Cl2 273.068720. Found: 273.06881.
Reaction SMILES: C[Si]([C:5]#[C:6][Si](C)(C)C)(C)C.[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12].Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:18]([C:17]1[CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:23]([OH:24])=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1)(=[O:19])[C:5]#[CH:6]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: C#CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A solution of 3.40 g (20.0 mmol) of bis(trimethylsilyl)acetylene and 4.03 g (15.0 mmol) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride [which is prepared from 3,5-di-t-butyl-4-hydroxybenzoic acid by treatment with oxalyl chloride (benzene, 60°, 2h)] in 80 mL of methylene chloride is treated at -78° with 1.78 mL (16.5 mmol) of titanium tetrachloride. The resulting dark mixture is stirred at -78° for 30 minutes and then is allowed to warm to 0° and stirred for an additional 30 minutes. The reaction solution is poured into 3N HCl and the layers are separated. The aqueous portion is extracted with pentane and the combined organic phase is washed with sat. NaCl and dried (MgSO4). The crude silylacetylene intermediate is concentrated, dissolved in 100 mL of methanol and then is treated at room temperature with 20 mL of 0.01M borax. After stirring the mixture at 25° overnight, it is poured into 3N HCl and the aqueous layer is extracted with pentane. The combined organic phase is washed with sat. NaCl and dried (MgSO4). Recyrstallization from hexane affords 2.40 g (62%) of the title compound: mp 100°-101°; IR (CCl4) 3620(s), 3300(m), 2950(s), 2090(m), 1640(s), 1580(s), 1290(s), 1215(vs) cm-1 ; 1H-NMR (CDCl3)δ(ppm) 1.45(s, 18H), 3.30(s, 1H), 5.80(s, 1H), 8.00(s, 2H); 13C-NMR (CDCl3)δ30.09, 34.41, 79.84, 80.80, 127.76, 128.51, 136.34, 160.02, 176.67 ppm.