Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[N:19]([CH3:30])[C:20](=[O:29])[N:21]([C:22]5[C:23]([CH3:28])=[N:24][N:25]([CH3:27])[CH:26]=5)[C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[CH3:27][N:25]1[CH:26]=[C:22]([N:21]2[C:12]3[C:11]4[CH:10]=[C:9]([C:5]5[CH:4]=[C:3]([CH2:2][NH:1][C:40](=[O:42])[CH3:41])[CH:8]=[N:7][CH:6]=5)[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:19]([CH3:30])[C:20]2=[O:29])[C:23]([CH3:28])=[N:24]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(CN)c4)cc3c21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1
Reaction time: 0.75 h

Procedure:
To a mixture of 8-(5-aminomethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 230, 0.053 mmol) and Hünig's base (0.014 ml) in dichloromethane (1 ml) was added acetyl chloride (Aldrich, Buchs, Switzerland, 0.058 mmol). The RM was stirred for 45 min at it then evaporated to dryness. The residue was taken in MeOH and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: tR 1.95 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.56-8.53 (m, 1H), 8.48-8.46 (m, 1H), 8.40 (t, 1H), 8.16-8.12 (m, 2H), 7.94-7.90 (m, 1H), 7.78-7.75 (m, 1H), 7.58-7.56 (m, 1H), 4.38-4.27 (m, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H), 1.89 (s, 3H))
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][C:24]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:20]=4[S:19][C:18]3=[N:31]C(=O)C(F)(F)F)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(=O)([O-])[O-].[K+].[K+].CO>[ClH:1].[ClH:1].[NH:31]=[C:18]1[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:25][C:20]=2[S:19]1
Reactant: O=C(N=c1sc2cc(OC(F)(F)F)ccc2n1CCCN1CCN(c2ccccc2)CC1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCCN1CCN(c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
3-[3-(4-Phenyl-1-piperazinyl)propyl]-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (3.6 g), dissolved in a mixture of 7% strength aqueous potassium carbonate solution (45 cc) and methanol (150 cc), is stirred for 4 hours at a temperature in the region of 20° C. After concentration to dryness, the reaction medium is taken up in distilled water (100 cc) and the organic phase extracted with ethyl acetate (2×100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa). After formation of the dihydrochloride by adding 4.2N ethereal hydrogen chloride (4 cc) in ethyl acetate, the precipitate is recrystallized in an absolute ethanol/ethyl ether mixture (50:50 by volume). 2-Imino-3-[3-(4-phenyl-1-piperazinyl)propyl]-6-trifluoromethoxybenzothiazoline dihydrochloride (1.6 g), m.p. 260° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Temperature: 10 °C
Reaction time: 24 h

Procedure:
(R)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (2.67 g, 10 mmol) (Salituro, G. M.; Townsend, C. A. J. Am. Chem. Soc. 1990, 112, 760-770) was dissolved in N,N-dimethylformamide (70 mL) in an ice bath. Sodium hydride (0.88 g, 60% in mineral oil, 22 mmol) was added in small portions. The mixture was warmed up to 10° C. for 1 hour. 2-(2-Bromo-ethoxy)-tetrahydropyran (1.7 mol, 11 mmol) in N,N-dimethylformamide (20 mL) was added drop wise. The reaction mixture was stirred for 24 hours and then diluted with ice/water. The mixture was extracted with ethyl acetate. The aqueous layer was cooled in an ice bath and acidified using 1.5 M aqueous potassium hydrogen sulfate to pH=2-3. The resulting mixture was extracted with ethyl acetate (5×), washed with water (5×), brine and dried over sodium sulfate. Filtration and evaporation of the solvents gave (R)-tert-butoxycarbonylamino-{4-[2-(tetrahydropyran-2-yloxy)-ethoxy]-phenyl}-acetic acid as a solid white foam (3.2 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reaction time: 17 h

Procedure:
To a cooled solution of 3-bromo-4-hydroxybenzaldehyde (5 g) in acetic acid (50 ml) was added nitric acid (1.17 ml). The mixture was allowed to reach room temperature. After stirring for 17 h, the resulting precipitate was filtered off. The solid was washed with water and dried in vacuo.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=O)[CH2:2][CH2:3][CH3:4].[NH3:17]>>[NH2:17][C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: N
Reactant: CCCC(=O)CC(=O)OCc1ccccc1
Product: CCCC(N)=CC(=O)OCc1ccccc1

Procedure:
A mixture of benzyl butyrylacetate (22.0 g, 0.10 mol) and 10 g of 4 Å molecular sieves was treated with ammonia gas which was bubbled through the mixture for 38 hrs at 50° C. After filtration, benzyl 3-amino-2-hexenoate was obtained as a yellowish oil (21 g, 95%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][C:32]1[C:36](B(O)O)=[C:35]([CH3:40])[O:34][N:33]=1>>[CH3:31][C:32]1[C:36]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:3]=2[CH2:1][CH3:2])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2c(C)noc2C)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 3,5-dimethylisoxazol-4-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C20H21N2O4 (M+H): 353.1502. Found 353.1496
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]=1[CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=O.C[Si](C=[N+]=[N-])(C)C.[Cl:33][C:34]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:35]=1[NH2:36].C[Al](C)C.C([O-])(=O)C(C(C([O-])=O)O)O.[Na+].[K+]>FC(F)(F)C(O)=O.C(Cl)Cl.O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]=1[CH2:17][CH2:18][C:19]([NH:36][C:35]1[C:34]([Cl:33])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:41])=[O:21]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccc(F)cc1Cl
Agent: C[Al](C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1c(Br)cc(Br)nc1-c1ccc(F)cc1Cl)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-butyl 3-[-4,6-dibromo-2-(2-chloro-4-fluorophenyl)pyridin-3-yl]propanoate (3.42 g, 6.93 mmol) was dissolved in 12 mL of trifluoroacetic acid and stirred at rt for 0.75 h. 30 mL of toluene was added and the resulting mixture was concentrated under reduced pressure. The resulting solid was dissolved in 50 mL of benzene and 5 mL of methanol. A 2M solution of (trimethylsilyl)diazomethane in hexanes (4.16 mL, 8.32 mmol) was added dropwise and the reaction mixture was stirred for 30 min. 2 drops of trifluoroacetic acid were added and the solvent was removed under reduced pressure. The resulting methyl ester was dissolved in 12 mL of CH2Cl2. To 2,6-dichloroaniline (2.25 g, 13.9 mmol) in 36 mL of CH2Cl2 was added dropwise a 2M solution of trimethylaluminum in toluene (7.0 mL, 13.9 mmol) and the mixture was stirred for 15 min. Then the methyl ester solution in CH2Cl2 was added and the resulting mixture was stirred at rt overnight. 24 mL of water was added very carefully followed by 12 mL of an aqueous 1M solution of potassium sodium tartarate and 24 mL of CH2Cl2. The mixture was stirred vigorously for 1 h and then filtered. The filtered solids were dissolved with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give one pure crop. The filtrate was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with hot ethanol to give a second pure crop. The two crops were combined to give the 3-[4,6-dibromo-2-(2-chloro-4-fluorophenyl)pyridin-3-yl]-N-(2,6-dichlorophenyl)propanamide as a white solid.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:1]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]=[CH:5][C:4]=3[N:3]=[CH:2]2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: O=C(O)CCCCCn1cnc2cnc3ccccc3c21
Agent: O=C(Cl)C(=O)Cl
Product: O=C(CCCCCn1cnc2cnc3ccccc3c21)N1CCOCC1
Reaction time: 1 h
Yield: 100 %

Procedure:
6-(1H-Imidazo[4,5-c]quinolin-1-yl)hexanoic acid (2.5 g, 8.8 mmol) was treated with oxalyl chloride (1.39 mL, 15.9 mmol) and morpholine (2.31 mL, 26.5 mmol) according to a modification of the method described in Part F of Example 6. The reaction with oxalyl chloride was carried out at ambient temperature, and the reaction with morpholine was complete after one hour. Following the work-up procedure, 3.1 g of 1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[C:3]1=[O:15]>CO.Cl.CCOCC>[CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C)C1=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC1(C)CCCNC1=O

Procedure:
The title compound of Step (B) (440 mg, 1.94 mmol) in 4 ml MeOH and 15 ml 1N HCl in Et2O was stirred at room temperature overnight. The solvent was evaporated and dried in vacuo to provide the title compound of this step as a light yellow solid which was relatively pure and was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]=[O:20])=[CH:11]1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]2[NH:10][C:18]3[C:13]([C:12]=2[CH:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Fc1ccc(CBr)cc1
Product: O=Cc1c(Cc2ccc(F)cc2)[nH]c2ccccc12
Yield: 91.1 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.74 g of 4-fluorobenzyl bromide and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.18 g of (4-fluorobenzyl) indole-3-carbaldehyde as colorless crystals. The yield thereof was found to be 91%.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[O:24]C)=[CH:5][CH:4]=1.[B].C(=O)=O.CC(C)=O.O>C(Cl)Cl>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[OH:24])=[CH:27][CH:28]=1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [B]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(O)c(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)S1
Reaction time: 72 h
Yield: 79.8 %

Procedure:
To a suspension of N-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide (800 mg) in anhydrous methylene chloride (30 ml), a 1.0N boron tribromidemethylene chloride solution (2.20 ml) was slowly added dropwise in an argon atmosphere under cooling with dry ice-acetone and stirring. After stirred for 6 hours at room temperature, the reaction liquor was allowed to stand for 3 days. After water was added and the mixture was stirred for 30 minutes, this was concentrated under reduced pressure. Ethyl acetate was added to the residue, which was washed with water and then dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (developing solvent; methylene chloride:methanol=40:1) to obtain 618 mg (80%) of aimed compound as crystals. These were recrystallized from ethanol-water to obtain purified aimed compound as a light brown powdery crystals. Melting point 146.0~148.0° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:3]=1.B(Br)(Br)Br.C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH3:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:3][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Reactant: C1CNCCN1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A stirring solution of 4-chloro-2-(2-methoxyphenyl)-7-methylquinazoline (91 g, 320 mmol) and CH2Cl2 (2.0 L) under an N2 atmosphere was cooled to −30° C. Boron tribromide (957 mL, 957 mmol, 1.0 M in CH2Cl2) was added dropwise over a period of 30 minutes at −30 to −40° C. The cooling bath was removed, and the mixture was allowed to warm to 25° C. The mixture was carefully poured into a stirring solution of saturated aqueous NaHCO3 (4.0 L). The organic portion was separated, dried over MgSO4, and evaporated to dryness. The resulting solid was suspended in CH2Cl2 (400 mL) under an N2 atmosphere, followed by the addition of triethylamine (64.8 g, 640 mmol). The solution was cooled to −10° C. A solution of piperazine (55.0 g, 640 mmol) in CH2Cl2 (400 mL) was added in a single portion, and the solution was stirred at ambient temperature for 1 hour. The solution temperature rose to 23° C. upon addition of the piperazine. The solution was partitioned between CH2Cl2 and H2O. The organic portion was dried over MgSO4 and evaporated to dryness. The residue was purified via silica gel chromatography using 5% MeOH in CH2Cl2 to obtain a tan solid. The resulting solid was triturated with 1:1 Et2O/hexanes to obtain a yellow solid which was vacuum dried to give 2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol as a light yellow solid (93.0 g, 290 mmol, 91%). LC/MS: m/z 321.1 (M+H)+ at 2.34 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[O:14])[CH3:13]>>[CH3:3][N:4]([CH3:6])/[CH:5]=[CH:13]/[C:12](=[O:14])[CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: COC(OC)C(C)=O
Reactant: COC(OC)N(C)C
Product: COC(OC)C(=O)/C=C/N(C)C
Temperature: 110 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110° C. for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[C:14]([O:20][CH2:21][C:22](N)=[S:23])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C(OCC)(=O)C>S1(CCCC1)(=O)=O>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14]([O:20][CH2:21][C:22]1[S:23][C:4]2[C:5]([N:11]=1)=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][N:3]=2)=[O:19]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCc1nc2cc([N+](=O)[O-])cnc2s1
Temperature: 105 °C
Yield: 16.7 %

Procedure:
A mixture of 6 g (29.48 mmol) of 2-chloro-3,5-dinitropyridine and 7.74 g (44.22 mmol) of 2-amino-2-thioxoethyl pivalate in 50 mL of sulfolane is heated for 2 hours at 105° C. After this time, 150 mL of ethyl acetate are added to the mixture, and the organic phase is washed three times with 200 mL of water and then once with 100 mL of saturated sodium chloride solution. The organic phase is then separated out, dried over sodium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate. 1.45 g of a yellow solid are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:50])[C@H:17]([N:25]([C:27](=[O:49])[C@H:28]([N:40](C(OC(C)(C)C)=O)[CH3:41])[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:50])[C@H:17]([N:25]([C:27](=[O:49])[C@H:28]([NH:40][CH3:41])[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH3:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
At 0° C., trifluoroacetic acid (3 mL) was added to a solution of 3-((2R)-2-(N-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate (885 mg, 1.50 mmol) in dichloromethane (3 mL). The reaction mixture was stirred for 5 min. The solvents were removed in vacuo at 20° C. The residue was dissolved in dichloromethane (40 mL). The procedure was repeated twice. The crude product was purified by flash chromatography on silica (45 g) with dichloromethane/methanol/25% solution of ammonia in water (100:10:1) to give 497 mg of 3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:15]O)[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:15])[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1
Reactant: CCCC(=NO)c1ccc(OCOC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(N)c1ccc(OCOC)cc1
Yield: 91.2 %

Procedure:
A solution of 1-(4-(methoxymethoxy)phenyl)butan-1-one oxime (3.4 g, 15.2 mmol) in tetrahydrofuran (50 mL) was added drop-wise to a stirred suspension of lithium aluminum hydride (1.83 g, 45.7 mmol) in tetrahydrofuran (100 mL) at room temp under nitrogen. After the initial foaming subsided the mixture was gradually heated to reflux. After 7 hours under reflux the mixture was allowed to cool, and an additional 1.0 g of lithium aluminum hydride was added to the mixture, which was reheated at reflux for 4 hours and then again allowed to cool. An additional 0.2 g of lithium aluminum hydride was added and the mixture was reheated at reflux for 1 hour and then allowed to cool. 3 mL of water was added drop-wise, followed by 3 mL of 15% aq sodium hydroxide, and then 9 mL of water. After stirring until the precipitate was well-granulated, the mixture was filtered and the residue washed twice with tetrahydrofuran. The filtrate/washings were concentrated in vacuo and the residue dissolved in dichloromethane and dried over magnesium sulfate. The solvent was removed in vacuo, leaving 2.9 g of purplish syrupy residue, which was flash chromatographed on a column (50×90 mm) of silica gel, eluting with Hxa/EtOAc/acetone 8:1:1 to afford 0.4 g of pure product as a clear golden oil, plus 1.4 g (57% total) of material of slightly lesser purity.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:8]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCCCC1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CNC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of cyclohexylamine (9.34 g) in methanol (300 ml) was added benzaldehyde (10.0 g) followed by activated 3 Å molecular sieves. After 1 h, sodium cyanoborohydride (7.13 g) was added followed by the dropwise addition of acetic acid (9.2 ml), and the reaction was stirred overnight. The reaction mixture was filtered through hiflo, the solvent removed in vacuo and the resulting white solid was heated under reflux in 5M potassium hydroxide solution for 30 mins. The product was extracted into dichloromethane (3×100 ml) and the combined organic layers were washed with brine (100 ml), dried over sodium sulphate and the solvent was removed in vacuo to give a clear oil. The product was purified by column chromatography (eluting with ethyl acetate) then distillation; bpt=137° C. at 1.0 mbarr. 1H NMR (360 MHz, D6 -DMSO) δ0.94-1.24 (5H, m), 1.48-1.88 (5H, m), 2.32 (1H, m), 2.32 (1H, m), 3.10 (2H, s(b)), 3.72 (2H, s), 7.14-7.40 (5H, m).