Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][C:6](F)(F)[C:7](=[O:13])CP(=O)([O-])[O-].C[O-:18].[Tl+]>ClCCl>[CH:16]12[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:6][C:7](=[O:13])[O:18]2
Reactant: CC(C)CCCC(F)(F)C(=O)CP(=O)([O-])[O-]
Reactant: C[O-]
Agent: [Tl+]
Solvent: ClCCl
Product: O=C1CC2CCCC2O1
Yield: 58 %

Procedure:
The compound (9-a) was reacted with dimethyl-3,3-difluoro-2-oxoheptylphosphonate (30.0 g) in dichloromethane in the presence of thallium methoxide (8.23 ml). The crude product obtained by the conventional treatment of the reaction mixture was purified on silica gel column to give the titled compound (10-a) [yield:24.4 g (58%)].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[N:7][CH:6]=[CH:5]2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: Cc1cc2cnccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccncc4cc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 6 h
Yield: 52.5 %

Procedure:
6-Hydroxy-7-methylisoquinoline (21 mg), 4-chloro-6,7-dimethoxyquinoline (81 mg), and 4-dimethylaminopyridine (44 mg) were suspended in o-dichlorobenzene (2.5 ml), and the suspension was stirred at 140° C. for 6 hr. The reaction solution was cooled to room temperature, water was then added to reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (24 mg, yield 58%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([CH3:10])[N:4]=1.[H-].[Na+].[H][H].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH3:15][N:16]([CH3:20])[C:17](=[O:18])[O:9][C:7]1[N:6]=[C:5]([CH3:10])[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=1
Reactant: Cc1nc(O)cc(CCl)n1
Reactant: [H][H]
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc(CCl)cc(OC(=O)N(C)C)n1

Procedure:
5 g (0.0315 mol) of 4-chloromethyl-6-hydroxy-2-methyl-pyrimidine are introduced portionwise under nitrogen into a suspension of 0.80 g (0.0331 mol) of sodium hydride (freed from a 50% dispersion in oil by two-fold extraction with n-pentane) in 50 ml of absolute tetrahydrofuran. After completion of the hydrogen evolution 2.9 ml (0.0315 mol) of dimethylcarbamoyl chloride are added dropwise and the mixture is heated at reflux for 16 hours. The cooled mixture is subsequently diluted with 150 ml of toluene, washed in succession with in each case 50 ml of 5% sodium bicarbonate solution, 0.1N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residual oil is filtered briefly on silica gel with 90% diethyl ether in n-hexane. There is obtained 4-chloromethyl-2-methyl-6-pyrimidinyl N,N-dimethylcarbamate as a colourless oil, nD22 1.5265.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:28]([NH:30][CH2:31][C:32]([NH:34][CH:35]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[O:29])[CH:25]=[CH:26][CH:27]=2)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:28]([NH:30][CH2:31][C:32]([NH:34][CH:35]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[O:29])[CH:25]=[CH:26][CH:27]=2)=[O:20])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cccc(C(=O)NCC(=O)NC(CC(=O)O)c3cccnc3)c2)cc1
Temperature: 25 °C
Yield: 563.7 %

Procedure:
The compound of Example 111 (500 mg, 0.095 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (350 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:14][C:15]1[C:22]([F:23])=[C:21]([C:24]([F:27])([F:26])[F:25])[C:20]([F:28])=[C:19]([F:29])[C:16]=1[CH2:17]Br>>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:17][C:16]2[C:19]([F:29])=[C:20]([F:28])[C:21]([C:24]([F:25])([F:27])[F:26])=[C:22]([F:23])[C:15]=2[F:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1[N+](=O)[O-]
Yield: 64.4 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-nitrobenzoic acid (1.03 g, 5.65 mmole) and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.01 g, 6.04 mmole) (ACROS, 33074-0010), 1.50 g (76.3% yield) of 2-nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1.C(Br)(Br)Br.C[OH:19].[OH-].[K+].CO.[O:24]1[CH2:29][CH2:28][O:27][CH2:26]C1>>[CH3:26][O:27][CH:28]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:12])[F:13])=[CH:11][CH:10]=1)[C:29]([OH:24])=[O:19]
Reactant: C1COCCO1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: BrC(Br)Br
Product: COC(C(=O)O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
4-Trifluoromethoxybenzaldehyde (25.0 g) was dissolved in a 1:1 mixed solution of methanol/1,4-dioxane (500 mL), and bromoform (30.3 g) was added thereto under ice cooling. Subsequently, a methanol solution (150 mL) of potassium hydroxide (3.3 g) was added dropwise thereto, and the mixture was stirred for 22 hours at room temperature. After distilling off the solvent under reduced pressure, the residue was diluted with water. The mixture was acidified with 3 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (50% to 100% ethyl acetate/hexane), and the title compound (29.4 g) was obtained as a crude product.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C[O:12]COC.C(=O)([O-])[O-].[NH4+].[NH4+].S(=O)(=O)(O)O>O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COCOC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
13.2 g of p-cyanobenzylamine, 30.0 g of formaldehyde dimethyl acetal, 38.4 g of ammonium carbonate and 80 ml of water were reacted after adjusting the pH of the solvent to 2.5 by sulfuric acid, at 90° C. for 4 hours while stirring. The reaction solution was cooled to room temperature and then cooled on ice. The crystals precipitated were collected by filtration, washed with water and dried to obtain 5.1 g (yield: 39%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[Al](C)C.C1(C)C=CC=CC=1.[I:16][C:17]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:20]([C:21](OC)=[O:22])=[CH:19][N:18]=1>ClCCl.O>[CH:1]1([NH:4][C:21](=[O:22])[C:20]2[C:25]([C:27]([F:29])([F:28])[F:30])=[CH:26][C:17]([I:16])=[N:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COC(=O)c1cnc(I)cc1C(F)(F)F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CC1)c1cnc(I)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylamine (862 mg, 15.1 mmol) was dissolved in 4 ml of dichloromethane and admixed dropwise under argon with a solution of trimethylaluminium in toluene (2 M, 7.55 ml, 15.1 mmol). The mixture was stirred for 30 min, and then methyl 6-iodo-4-(trifluoromethyl)nicotinate (500 mg, 1.51 mmol) (synthesis analogous to J. Med. Chem., 2008, 51, 3133-3144 by esterification of nicotinic acid) dissolved in 3 ml of dichloromethane was added dropwise. The mixture was heated under reflux overnight and, after cooling to room temperature, water was added cautiously. The mixture was extracted with ethyl acetate, the organic phase washed with potassium sodium tartrate solution, dried over magnesium sulphate and filtered, and the filtrate concentrated under reduced pressure. The purification was effected by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 30% EA).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[Br:11][CH2:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][C:19](CC(=[O:25])C)=[CH:18][CH:17]=1.Br[CH2:27][C:28]([O:30]C)=[O:29].Cl.[C:33]1([CH3:39])C=CC=C[CH:34]=1>C1COCC1>[Br:11][CH2:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:34][CH:33]([CH3:39])[C:27](=[O:25])[C:28]([OH:30])=[O:29]
Reactant: Cc1ccccc1
Reactant: COC(=O)CBr
Reactant: CC(=O)Cc1ccc(SCCCBr)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: BrCCCSc1ccccc1
Product: CC(C)C(=O)C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of KHMDS (potassium hexamethyldisilazane) (4.96 moles) in toluene (8 L) and THF (8 L) at -78° C. under N2 was added dropwise the ketone of Step B (1.36 kg, 4.8 moles) in THF (1500 ml) over 21/2 hours. The reaction mixture was stirred 1 hour at -78° C. Methyl bromoacetate (520 ml, 5.6 moles) in THF (800 ml) was added dropwise over 1-1/2 hours. After stirring 1 hour at -78° C. the reaction mixture was poured with stirring into 16 L of HCl (lN). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (4 L). The combined organic layers were evaporated. The residue was dissolved in a mixture of THF (6 L) and EtOH (6 L), and NaOH (3 L, 2.6M) was added. After stirring 2 hours at room temperature the homogeneous reaction mixture was concentrated in vacuo to remove THF and EtOH. The aqueous residue was extracted with ethyl acetate (2×2 L). The aqueous layer was cooled in ice-water and acidified with concentrated HCl (approximately 800 ml). Extraction with ethyl acetate (1×4 L, 1×1 L), drying (Na2SO4) and evaporation afforded the title acid as a tan, oily solid, m.p. 9220 -96° C., which was used as is in Step D.
Reaction SMILES: [N:1]1([C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C@H:11]([OH:14])[CH2:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:22]([N:24](CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CN.C(O)C>ClCCl>[F:21][C:17]1[CH:16]=[C:15]([C@H:10]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C@H:11]([OH:14])[CH2:12][NH:24][CH3:22])[CH:20]=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)N1CCc2ccccc21
Agent: CN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCO
Solvent: ClCCl
Product: CNC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol (452 mg, 1.586 mmol) in dichloromethane (3 mL) under nitrogen was added triethylamine (1.1 mL, 7.93 mmol). The mixture was cooled to 0° C., and para-toluenesulfonyl chloride (423 mg, 2.22 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour and stored at 0° C. overnight. Methylamine in absolute ethanol (8 M, 5 mL, 40 mmol) was added and the reaction mixture was sealed, and stirred overnight while warming to room temperature. All volatiles were removed under reduced pressure. The oil residue was dissolved in dichloromethane (20 mL), washed with aqueous potassium carbonate (5 mL), dried (anhydrous sodium sulfate), and concentrated. Purification by Biotage chromatography (FlasH12i, silica, 0-15% MeOH/dichloromethane/0.5% triethylamine) gave (1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol, which was dissolved dichloromethane (5 mL) and treated with a 1 M ethereal solution of hydrochloric acid (1.9 mL, 1.9 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 209 mg (44%) of (1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol hydrochloride as a white powder. MS (ES) m/z 299.0 ([M+H]+); HRMS: calcd for C18H19FN2O+H+, 299.1554; found (ESI, [M+H]+), 299.1553.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.C(N=[C:18]=[O:19])CCC.C(Cl)(=O)[C:21](Cl)=[O:22]>ClC1C=CC=CC=1>[Cl:12][C:4]1[CH:3]=[C:2]([N:1]=[C:21]=[O:22])[CH:7]=[CH:6][C:5]=1[S:8]([N:11]=[C:18]=[O:19])(=[O:9])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCN=C=O
Reactant: Nc1ccc(S(N)(=O)=O)c(Cl)c1
Solvent: Clc1ccccc1
Product: O=C=Nc1ccc(S(=O)(=O)N=C=O)c(Cl)c1
Temperature: 100 °C

Procedure:
5,7-Dichloro-4-[4-(methylcarbamoyl)-2-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester ##STR39## Dissolve 4-amino-2-chlorobenzenesulfonamide (0.96g, 5mmol) in chlorobenzene (10% solution) and distill the mixture to remove any traces of water. Cool to 100° C. and add n-butyl isocyanate (99mg, 1mmol). Heat to reflux and add, by dropwise addition, oxalyl chloride (1.5mL). Purge with nitrogen at 130°-132° C. for 30 minutes and distill to give 2-chloro-4-isocyanatobenzenesulfonyl isocyanate.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-:15].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:15][C:7]1[CH:8]=[CH:9][CH:2]=[CH:3][C:4]=1[CH:5]=[O:6])[CH2:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CCCBr
Reactant: O=Cc1cccc(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccccc1C=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.6 %

Procedure:
To 3-hydroxybenzaldehyde (12.2 g) dissolved in DMF (100 ml) were added 1-bromopropane (14.7 g) and potassium carbonate (20.7 g), and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate and washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 2-propoxybenzaldehyde (16.18 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:3]=1.O.[NH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:5]=[C:6]([NH2:22])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)nc(-c2ccc(Cl)c(OC)c2F)nc1Cl
Reactant: N
Solvent: O
Product: COc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1Cl
Temperature: 125 °C
Yield: 88 %

Procedure:
4,6-Dichloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxy-pyrimidine (500 mg, 1.5 mmol) was suspended in ammonia saturated ethanol (10 mL) and heated in a CEM microwave at 125° C. for 30 min. The mixture was poured into 15 mL water and extracted with ethyl acetate thrice. The combined organic phases were washed once with brine, dried and evaporated to give the title compound (420 mg, 88% yield: 1H NMR (DMSO-d6) δ 7.59 (dd, 1H), 7.45 (br s, 2H), 7.39 (dd, 1H), 3.91 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:31]([N:33]1[CH2:38][CH2:37][C:36]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([OH:39])[CH2:35][CH2:34]1)=[O:32])[CH2:10][S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:47](OC(=O)C)(=[O:49])[CH3:48]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:31]([OH:49])=[O:32])[CH2:10][S:11][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2].[C:47]([O:39][C:36]1([CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:35][CH2:34][NH:33][CH2:38][CH2:37]1)(=[O:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC(O)(Cc2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC1(Cc2ccccc2)CCNCC1
Product: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of N-t-butoxycarbonyl-S-trityl-L-Cysteinyl4-benzyl-4-piperidinol (100 mg, 0.16 mmol) in dry pyridine (2 ml), was added 4-dimethylaminopyridine (25 mg, 0.20 mmol) and acetic anhydride (0.030 ml, 0.32 mmol). The solution was heated to 50° C. (oil bath temp.) for 2 days and then allowed to cool to room temp. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and brine. The EtOAc layer was dried (MgSO4) and concentrated in vacuo to a brown oil. This material was purified by column chromatography on silica with 18-20% EtOAc/hexane as eluent. The appropriate fractions were combined and concentrated in vacuo to afford the product as a glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]=O)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH:14]=[C:11]([C:12]#[N:13])[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:21]
Reactant: CCOC(N)=O
Reactant: COc1ccc(C(C#N)C=O)cc1OC
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC=C(C#N)c1ccc(OC)c(OC)c1

Procedure:
To the mixture of 2-(3,4-Dimethoxy-phenyl)-3-oxo-propionitrile (20.5 g, 0.1 mol), urethane (8.9 g, 0.1 mol) in toluene (400 mL) was added concentrated sulfuric acid (0.5 mL, 10 mmol). The mixture was refluxed and was concentrated by slow distillation to a volume to about 50 mL. The cooled mixture was filtered and the precipitate was washed with benzene and dried. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% methylenechloride) afforded [2-Cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-carbamic acid ethyl ester as a solid: LC-MS m/e calcd for C14H16N2O4 (MH+) 277, found 277. 1H NMR (300 MHz) compatible.
Reaction SMILES: Cl.[C:2]1([N:12]2[CH:17](C)[CH2:16][CH2:15][C:14]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:13]2=[O:24])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.[CH2:36](N(CC)CC)C>CCO>[C:11]1([CH2:2][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:19][CH2:20][N:21]([C:26]4[CH:35]=[N:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH2:22][CH2:23]3)[C:13]2=[O:24])[C:6]2[C:7](=[CH:8][CH:3]=[CH:4][CH:5]=2)[CH:36]=[CH:9][CH:10]=1
Reactant: CC1CCC2(CCNCC2)C(=O)N1c1cccc2ccccc12
Reactant: CCN(CC)CC
Reactant: Clc1cnc2ccccc2n1
Agent: Cl
Solvent: CCO
Product: O=C1N(Cc2cccc3ccccc23)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 160 °C
Yield: 68.7 %

Procedure:
Crude 2-naphthalen-1-yl-methyl-2,9-diaza-spiro[5.5]undecan-1-one hydrochloride (100 mg, 0.29 mmol), 2-chloro-quinoxaline (81 mg, 0.49 mmol) and triethylamine (0.12 ml, 0.87 mmol) were dissolved in EtOH (1 ml) in a microwave tube. The tube was sealed and the suspension was heated at 160° C. over 20 min under microwave conditions. The solvent was removed under reduced pressure and the resulting crude product was purified by preparative reverse phase chromatography (Sun Fire C18 column, 16 min linear gradient: elution 20-60% (CH3CN in H2O (0.1% TFA)); flow rate 50 ml/min) to yield 87 mg (53%) of the title compound. [1H NMR (DMSO, 600 MHz) δ 8.86 (s, 1H), 8.07-8.00 (m, 1H), 7.98-7.91 (m, 1H), 7.86 (d, 1H, J=8.28 Hz), 7.82 (d, 1H, J=8.02 Hz), 7.64-7.56 (m, 2H), 7.56-7.50 (m, 2H), 7.48 (t, 1H), 7.38 (t, 1H), 7.34 (d, 1H, J=7.06 Hz), 4.98 (s, 2H), 4.37-4.26 (m, 2H), 3.46 (t, 2H), 3.23-3.10 (m, 2H), 2.20-2.08 (m, 2H), 1.93-1.82 (m, 2H), 1.80-1.70 (m, 2H), 1.67-1.53 (m, 2H), LCMS RtD=3.10 min, [M+H]+=437.2].
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>N1C=CC=CC=1>[CH2:1]([O:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 70 %

Procedure:
1-hexadecyl glycerol (105g, 0.33mol) and 93 g (0.33mol) tritylchloride were dissolved in 300 ml of pyridine. The mixture was heated at 100° C. for 16 hours. After cooling to room temperature 1500 ml of ethyl ether was added and the slurry washed 3 times with cold 0.5N H2SO4, 5% sodium bicarbonate and 2 times with water. The organic phase was dried over MgSO4, the ether removed on a rotary evaporator and the residue recrystallized from ethanol, yielding the intermediate 1-hexadecyl-3-trityl glycerol (129 g, 70%). The 2 position of this intermediate was alkylated with tetradecyl bromide in the same manner (powdered KOH in toluene) as described earlier for the dialkylation of benzyl glycerol in the preparation of 1,2-dihexadecyl glycerol. The resulting 1-hexadecyl-2-tetradecyl-3-trityl glycerol (128 g) was dissolved in 300 ml of petroleum ether. At room temperature 30 g of anhydrous hydrogen chloride was added. A precipitate formed within a short time. The slurry was stirred at room temperature for 4 hours and then filtered. The solids were recrystallized from acetone (10° C.) to give 45.6g of product, m.p. 42°-3° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20](O)=[O:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:6][CH:5]=2.Cl.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]([NH:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([OH:25])=[O:35])=[CH:28][CH:29]=2)=[O:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)O
Agent: Cl
Product: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)NCc1ccc(C(=O)O)cc1

Procedure:
Same procedure as Example 82 except (2-Methyl-5-trifluoromethanesulfonylamino-indol-1-yl)-acetic acid and methyl-4-(aminomethyl)benzoate hydrochloride was used. 1H-NMR (400 MHz, DMSO-d6) δ 12. 84 (s, 1H, COOH), 11.45 (s, 1H, SNH), 8.75 (t, J=6.4 Hz, 1H, NHCO), 7.89 (d, J=8.6 Hz, 2H, ArH), 7.3 (m, 4H, ArH, H-7, & H-4), 6.93 9dd, J=2, 8.5 Hz, 1H, H-6), 6.27 (s, 1H, H-3), 4.86 (s, 2H, CH2N-2), 4.37 (d, J=6.6 Hz, 2H, NCH2Ar), 2.35 (s, 3H, CH3), MS m/z 468 (M−H).