Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:17])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)C.ClS[N:20]=[C:21]=[O:22]>ClCCl>[CH:14]1([N:13]2[C:6]3[C:5](=[CH:10][C:9]([F:11])=[C:8]([F:12])[CH:7]=3)[C:4](=[O:17])[NH:20][C:21]2=[O:22])[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cc(F)c(F)cc1NC1CC1
Reactant: O=C=NSCl
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Temperature: -20 °C
Yield: 38.2 %

Procedure:
To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid ethyl ester (Example 22) (5.0 g, 22.0 mmol) in dry dichloromethane (120 mL) under a N2 atmosphere is added chlorosulfanyl isocyanate (3.11 g, 22 mmol). The solution is reacted at room temperature for 4 hours, and the solvent is removed under reduced pressure. The residue is cooled to −20° C., and a cold brine solution (100 mL) buffered with NaHCO3 is added. The solution is warmed to room temperature for 1 hour. The volume is reduced by half with a stream of air, and the solid is collected by filtration. The dry solid is added to a solution of triethylamine (5 mL) in THF (250 mL) and refluxed overnight. The reaction is cooled, the solvent removed under reduced pressure, dissolved in water (100 mL), and acidified to pH 1–2 with 1.0 M hydrochloric acid. The resulting precipitate is collected via filtration to afford 2.0 g of the title compound. MS CI: m/z 239 (MH+).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=1>O>[C:12]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH:3]=[O:2])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(C(OC)OC)cc1C(C)(C)C
Solvent: O
Product: COc1ccc(C=O)cc1C(C)(C)C
Yield: 96.7 %

Procedure:
99.4 g of 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal are refluxed in 300 g of water for 3 hours. This is followed by cooling down, and the residue is filtered off and dried, leaving 77.5 g of 3-tert-butyl-4-methoxybenzaldehyde (mp. 52°-53 C.), which corresponds to a yield of 96.7%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.C(Cl)Cl.Cl>[OH-].[K+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCN1CCN(c2ccc(C(C)=O)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ccc(N2CCN(CCCCC(=O)O)CC2)cc1
Temperature: 100 °C
Yield: 47.9 %

Procedure:
4-(4-Acetylphenyl)-1-piperazinevaleric acid, methyl ester (15.3 mg) is suspended in 0.1 mL of potassium hydroxide solution (33.2 mg/mL). After heating at 100° C. for 150 min, the starting material is completely dissolved and absent by TLC (10% MeOH/CH2Cl2). After acidifying the reaction solution to pH 4 by adding 0.2N HCl, the aqueous solution is extracted with methylene chloride. After evaporation of the organic layer to dryness, the residue is dissolved in methylene chloride and filtered. Evaporation of the organic layer gives 7 mg of 4-(4-acetylphenyl)-1-piperazinevaleric acid as a white solid. 1H-NMR (CDCl3) spectrum is consistant with the assigned structure. MS (FAB) m/e 305 (M+ +H), 327 (M+ +Na), 348 (M+ +2Na--H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:25]([C:27]2[S:28][C:29]([CH3:32])=[CH:30][N:31]=2)=O)[CH:21]=[C:22]([Cl:24])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:25](/[C:20]1[CH:21]=[C:22]([Cl:24])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:27]1[S:28][C:29]([CH3:32])=[CH:30][N:31]=1)[CH3:16]
Reactant: Cc1cnc(C(=O)c2cc(Cl)cc(Br)c2)s1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/c1cc(Cl)cc(Br)c1)c1ncc(C)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
To a suspension of NaH (60%, 1.77 g, 44.2 mmol) in dry THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (10.12 g, 44.2 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of 14 g (44.2 mmol) (3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone in THF (10 mL) was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc mixtures to afford (Z)-3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-acrylic acid ethyl ester as an gel (18 g, yield=106%) The material is used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:15][CH:16]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1[Cl:26])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:46]1([CH2:52][CH2:53]O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:26][C:19]1[C:20]([F:25])=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH:16]([O:15][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:53][CH2:52][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:12][CH:13]=2)[CH:6]=[N:7][C:2]=1[NH2:1])[CH3:17]
Reactant: OCCN1CCOCC1
Reactant: CC(Oc1cc(-c2ccc(O)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(Oc1cc(-c2ccc(OCCN3CCOCC3)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a mixture of 6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ol (78 mg, 0.20 mmol), triphenyphosphine (63 mg, 0.24 mmol) and 2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) was added DEAD (0.034 mL, 0.22 mmol). After stirring overnight more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After several hours, more alcohol (0.026 mL, 0.22 mmol) was added. After several more hours, more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After stirring overnight, the mixture was partitioned between dichloromethane and half-saturated brine. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol to afford 5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-morpholin-4-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine (53 mg, 53%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5]1([N:11]2[C:15]([CH3:17])([CH3:16])[CH2:14][NH:13][C:12]2=[O:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N1C=CC=CC=1>C(Cl)Cl>[CH:5]1([N:11]2[C:15]([CH3:16])([CH3:17])[CH2:14][N:13]([C:1]([Cl:4])=[O:2])[C:12]2=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CNC(=O)N1C1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CN(C(=O)Cl)C(=O)N1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A 0° C. solution of phosgene (15% in toluene, 1.854 mL, 2.60 mmol) in DCM (10 mL) was treated drop-wise with a solution of 1-cyclohexyl-5,5-dimethylimidazolidin-2-one (0.34 g, 1.732 mmol) and pyridine (0.28 mL) in DCM (5 mL), stirred at 0° C. for 0.5 h, then concentrated to dryness to afford crude 3-cyclohexyl-4,4-dimethyl-2-oxoimidazolidine-1-carbonyl chloride (0.45 g, 100%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10](O)=[O:11]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[O:11])=[CH:5][CH:4]=1
Reactant: O=CO
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC=O)cc1
Temperature: 5 °C
Reaction time: 5 h

Procedure:
The intermediate, 4-methoxy formanilide is prepared by heating 369.6 parts by weight (3.0 mole) of para anisidine to 90° C. and adding to it 147 parts by weight (3.1 mole) of 97% formic acid over a period of 80 minutes at 95°-105° C. under reflux conditions. A water trap is then installed and heating continued at 91°-111° C. for about 5 hours while collecting water. Toluene is added to aid the removal of water. The reaction mixture is cooled, crystallization induced by scratching, and heptane added. The crystalline mass is cooled to 5° C. and filtered to obtain, after air drying 447.6 parts by weight of 4-methoxy formanilide as a purple solid.
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:11][C:10]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Reactant: OCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Temperature: 200 °C
Yield: 20.7 %

Procedure:
A mixture of 2-nitro-3-methylaniline (Newman, M. S.; Kannan R. J. Org. Chem., 1976, 41, 3356., 1.9 g, 12.4 mmol), 4-bromophenylethyl alcohol (2.5 g, 12.4 mmol), K2CO3 (1.7 g, 12.4 mmol) and Cul (230 mg, 1.24 mmol) was placed in a sealed tube and heated at 200° C. for 2 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 700 mg (21%) of the title compound as an orange oil: 1H-NMR (CDCl3) δ 7.77 (1H, br.s), 7.09-7.45 (6H, m), 6.69 (1H, d, J=6.3 Hz), 3.83 (2H, t, J=6.6 Hz), 2.82 (2H, t, J=6.6 Hz), 2.59 (3H, s).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])#[N:2].[C:15]([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>C(O)(C)C>[C:15]([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CCCCC(CC)COC(=O)CC#N
Solvent: CC(C)O
Product: CCCCC(CC)COC(=O)C(C#N)=Cc1ccc(NC(C)=O)cc1
Yield: 54 %

Procedure:
A mixture of 35 g (0.18 mol) of 2-ethylhexyl cyanoacetate and 30 g (0.18 mol) of 4-acetamidobenzaldehyde in 300 ml of isopropanol is refluxed for 3 hours. The reaction mixture is then allowed to cool and is crystallized. The crystals formed are separated out by filtration and are recrystallized from a minimum amount of isopropanol. After filtration and drying, 33.3 g (54% yield) of 2-ethylhexyl 3-(4-acetylaminophenyl)-2-cyanoacrylate are obtained in the form of a pale yellow powder.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH2:25]=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH3:25])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: C=O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: CN1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively alkylated with aqueous formaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-methyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 368.0 [M+H]+.
Reaction SMILES: C(O[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[N:12]=[C:11]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:33])[CH2:24][CH2:23]2)[N:10]=1)C1C=CC=CC=1.[O:34]1[CH2:37][C:36]([CH2:40][NH2:41])([CH2:38][NH2:39])[CH2:35]1>>[NH2:39][CH2:38][C:36]1([CH2:40][NH:41][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[N:12]=[C:11]([N:22]3[CH2:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[S:25](=[O:33])[CH2:24][CH2:23]3)[N:10]=2)[CH2:37][O:34][CH2:35]1
Reactant: NCC1(CN)COC1
Reactant: O=C(O)c1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(OCc3ccccc3)c2c1
Product: NCC1(CNc2nc(N3CCS(=O)c4ccccc4C3)nc3ccc(C(=O)O)cc23)COC1
Temperature: 170 °C

Procedure:
A mixture of 4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinazoline-6-carboxylic acid (170 mg, 0.37 mmol) and oxetane-3,3-diyldimethanamine (128 mg, 1.11 mmol) was heated at 170° C. for 30 minutes. Then the reaction mixture was cooled to room temperature and purified by preparative HPLC to afford 4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid, MS obsd. (ESI+) [(M+H)+] 468, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91-8.61 (m, 2 H), 8.09-8.00 (m, 1 H), 7.77-7.74 (m, 1 H), 7.68-7.65 (m, 1 H), 7.51-7.42 (m, 2 H), 7.27-7.13 (m, 1 H), 5.26-5.17 (m, 2 H), 4.89-4.68 (m, 4 H), 452-4.45 (m, 2 H), 4.40-4.31 (m, 2 H), 4.10-3.84 (m, 2 H), 3.20-3.01 (m, 2 H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([NH2:10])([CH3:9])[CH3:8].[C:11]([Si:15]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]I)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].O>C1COCC1>[Si:15]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:10][CH:7]([CH3:9])[CH3:8])([C:11]([CH3:12])([CH3:13])[CH3:14])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)N
Reactant: CC(C)(C)[Si](OCCCCCI)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
K2CO3 (1.50 g, 11.05 mmol), isopropylamine (0.65 mL, 11.05 mmol) and iodide 3 (2.50 g, 5.83 mmol) in dry THF (15 mL) were heated at 66° C. in a sealed tube under an argon atmosphere. After 12 h, water (5 mL) was added to the reaction mixture which was then extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to afford 4 as a colorless liquid (1.90 g, 92%) sufficiently pure it was used without further purification. TLC:MeOH/CH2Cl2 (1:4), Rf˜0.30; 1H NMR (400 MHz) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 3.65 (t, J=6.4 Hz, 2H), 2.70-2.82 (m, 1H), 2.55 (t, J=7.3 Hz, 2H), 1.50-1.64 (m, 2H), 1.32-1.50 (m, 4H), 1.05 (d, J=5.8 Hz, 3H), 1.04 (s, 9H); 13C NMR (100 MHz) δ 135.68, 134.21, 129.63, 127.70, 63.95, 48.81, 47.64, 32.60, 30.27, 27.0, 23.76, 23.15, 19.34.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12>C1COCC1>[CH2:35]([O:34][C:32]([N:42]1[CH2:47][CH2:46][CH:45]([N:52]2[C:51](=[O:53])[C:50]3=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]3[C:48]2=[O:58])[CH2:44][CH2:43]1)=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 50 %

Procedure:
A solution of DEAD (1.61 mL, 10.2 mmol) in 20 mL of THF was added to a solution of triphenylphosphine (2.69 g, 10.3 mmol), the N-Cbz-piperidine prepared in Example 16A (2.36 g, 100 mmol) and phthalimide (1.50 g, 10.2 mmol) in 80 mL of THF. After stirring 10.5 h at R.T. the mixture was quenched with water, extracted with EtOAc (3×) and the combined extracts washed with brine solution, dried over Na2SO4 and concentrated to give the crude product. Purification of this material by chromatography (hexanes/EtOAc; 2:1) gave 1.81 g, (50%) of 1-benzyloxycarbonyl-4-phthalimidylpiperidine. [1H]-NMR(CDCl3) consistent with structure.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:40]([O:39][C:37]([CH:36]([O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH3:42])=[O:38])[CH3:41]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)OC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 0.5 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.15 ml of ethyl 2-bromopropionate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.93/6.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[C@@H:4]([NH:23][C:24](=[O:45])[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([O:32][CH2:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)=[CH:27][C:26]=1[Cl:44])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3](=[O:46])[C@@H:4]([NH:23][C:24](=[O:45])[C:25]1[C:26]([Cl:44])=[CH:27][C:28]([O:32][CH2:33][CH2:34][CH2:35][NH2:36])=[CH:29][C:30]=1[Cl:31])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(OCCCNC(=O)OC(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(OCCCN)cc1Cl
Reaction time: 15 h
Yield: 118.5 %

Procedure:
To a solution of (S)-2-[4-(3-tert-butoxycarbonylaminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (7.5 g, 7.98 mmol) in dichloromethane (100 mL) was added an excess of TFA (9.12 g, 5.9 mL, 80 mmol) at room temperature. The resulting solution was stirred for 15 h. Then, the solvent was removed under vacuum and the residue was azeotrophed one time with toluene. After drying under high vacuum, 5.8 g (99%) of (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester was obtained as a white solid. ES(+)-HRMS m/e calcd. for C27H25Cl4N3O5 (M+H)+ 612.0621, obsd. 612.0619.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:22]=[O:23])C1C=CC=CC=1.S(=O)(=O)(O)O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: Fc1ccc(F)cc1
Reactant: CN(C=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1F
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 77.6 %

Procedure:
To a stirred solution of 194.5 g (1.70 mol) of 1,4-difluorobenzene in 2 of dry tetrahydrofuran at -60° C. was added dropwise over 45 mins 1.70 mol (2.2 M in hexane) of n-butyllithium at a rate such that the temperature remained below -55° C. The reaction mixture was stirred for 45 mins at below -50° C. and 1.5 hr at -50° to -45° C. The solution was then cooled to -60° C. and a solution to 230 g of N-methylformanilide in 300 ml of tetrahydrofuran was added dropwise over 30 mins. The mixture was stirred for 1 hr at -50° C. and allowed to warm to -30° C. over 15 mins. The mixture was then poured into ice water, neutralized (pH 6-7) with 10% sulfuric acid and extracted three times with hexane. The extracts were washed once with 1N sulfuric acid, once with saturated sodium chloride solution and concentrated to an oil. Distillation at 64°-65° C. (20 mm) provided 187.5 g (77.5%) of product.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH2:6][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](OCC)=O.P(Cl)(Cl)(Cl)=O.Cl([O-])(=O)(=O)=[O:24].[Na+].[CH3:29][NH:30][C:31](=O)[CH3:32]>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:32][CH:31]1[N:30]([CH3:29])[CH:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N+:6]1=[O:24]
Reactant: CCOC(=O)c1cccc[n+]1N
Reactant: CNC(C)=O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1N(C)C=C2C=CC=CN2[N+]1=O
Yield: 83 %

Procedure:
To a solution of 12 g (45 millimoles) of 1-amino-2-carbethoxy-pyridinium perchlorate in 25 ml of N-methyl-acetamide 20 ml of phosphorus oxychloride are added at 90° C. The reaction mixture is allowed to stand for an hour, thereafter poured onto ice, the aqueous solution is saturated with sodium perchlorate and the separated product is filtered off. 10.3 g (83%) of 2,3-dimethyl-1-oxo-pyrido[2,1-f]-as-triazinium perchlorate are obtained.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CCC(O)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 12 h

Procedure:
To a solution of 1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propan-1-ol (2.20 g, 7.85 mmol) in CH2Cl2 was added the Dess-Martin periodinane (4.24 g, 10.00 mmol). After 12 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and filtered through diatomaceous earth and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% EtOAc in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford 1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CO>[CH2:23]([S:12][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC(SCc1ccccc1)=N2
Reaction time: 0.5 h

Procedure:
To a solution of 1.43 parts of 7-chloro-5phenyl-3-H-1,4-benzodiazepine-2-thione in 12.5 parts by volume of 0.4 N sodium methoxide in methanol is added dropwise with stirring 0.6 part by volume of benzyl bromide and the stirring is continued for an additional 30 minutes. Water is added to the reaction mixture and the resulting oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over sodium sulfate. Evaporation of the solvent yields 2-benzylmercapto-7-chloro-5-phenyl-3H-1,4-benzodiazepine as an oil.