Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[Ca:14]>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Ca+2:14].[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Ca+2:14].[Ca+2:14].[Ca:14].[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ca]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [Ca+2]

Procedure:
The amorphous water-soluble calcium citrate salts of this invention are prepared by reacting a calcium compound with citric acid in an aqueous medium to produce calcium citrate having a calcium to citrate mole ratio of less than 2.5:2. The resulting reaction mixture is then quickly dried (or quickly frozen for drying at a later time) in order to separate and isolate amorphous calcium citrate as a dry powder. It is important that the amorphous water-soluble calcium citrate reaction salt is recovered from the aqueous reaction mixture as a dry amorphous material before it can be transformed into insoluble crystalline tricalcium citrate (TCC) or other water-insoluble calcium citrate salts. As shown in the examples below, both the condition of providing a calcium:citrate mole ratio of less than 2.5:2, and the condition of drying the reaction mixture soon enough after the salt-producing reaction, as detailed herein, to avoid reaction product transformation into water-insoluble calcium citrate salts, are important to ensure that the solid calcium citrate reaction product is recovered in an amorphous state. Preferably rapid drying techniques are also used to minimize the opportunity for crystallization of the reaction product during the drying operation. Suitable rapid drying techniques include, for example, freeze drying and spray drying.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:16]O)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O1CCCC1>>[CH:10]1([CH2:9][C@H:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:16][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
A mixture of tert-butyl[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]carbamate (3.3 g, 13 mmol), phthalimide (2.10 g, 14.3 mmol), triphenylphosphine (3.75 g, 14.3 mmol), diisopropyl azodicarboxylate (3.58 mL, 18.2 mmol) in tetrahydrofuran (30 mL, 400 mmol) was stirred at room temperature overnight. Direct purification by combi-flash chromatography afforded 2.8 g (56% yield) of the desired product. LC-MS found: 287.1 (M−Boc)+.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: O=C1NCc2ccccc21
Reactant: Clc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol,), 1-bromomethyl-4-chloro-benzene (0.246 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.125 g, 97%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.76 (s, 2H), 7.22-7.54 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([O-:12])=[O:11].[Na]>CS(C)=O>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: [Na]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc([N+](=O)[O-])cc1
Yield: 30 %

Procedure:
1-bromooctane (1 g, 5.18 mmole) and 4-nitrophenol, sodium salt (0.92 g, 5.71 mmole) were refluxed in DMSO (30 ml) at 120° C. for 5 hours. The DMSO was distilled off to near dryness. The resulting brown residue was loaded onto a silica column and eluted with 10:1 mixture of petroleum ether and diethylether. The yield was 30%. 1H NMR (CDCl3, peaks at =8.18 (m, 2H), 6.93 (m, 2H), 4.04 (t, 2H), 1.81 (p, 2H), 1.33 (m, 10H), 0.89 (t, 3H)). Elemental analysis calculated for C14H21O3N: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.97; H, 8.34; N, 5.52.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18].[C:23]([C@@H:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:27]=1)#[N:24].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([O:19][C@H:25]([C:23]#[N:24])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:27]=1)=[O:18]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
Into 4.5 ml of methylene chloride containing 22.5 mg of 4-dimethylaminopyridine are added 439 mg (1.48 mmol) of (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid and 329 mg (1.46 mmol) of (S)-α-cyano-3-phenoxybenzyl alcohol. The solution is cooled in an ice bath and 380 mg (1.82 mmol) of dicyclohexylcarbodiimide is added. The mixture is stirred at 0° for 1 hour and is then worked up by partition between ether/hexane. The aqueous phase is extracted with ether, and the ether extract is washed with water (2×) and brine, dried over magnesium sulfate, filtered and evaporated. The product is purified by radial thin layer chromatography (2 mm silica gel rotor eluting with 12% ether/hexane). Higher diastereomeric purity is obtained by further radial tlc, yielding the final product (S)-α-cyano-3-phenoxybenzyl (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, specific rotation=+46.3° (in CHCl3), diastereomer purity=~98%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH2:22][CH2:23][NH2:24]>>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH2:22][CH2:23][NH:24][C:2]([O:4][CH2:5][CH:6]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:3])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCC[C@H](N)C(=O)O
Product: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 79 %

Procedure:
The reaction of 9-fluorenylmethyl chloroformate with L-ornithine according to the conditions described in example 2 provided the title product in 79% yield.
Reaction SMILES: C(S[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:22]([CH3:23])[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)C.Cl[C:25]1C=CC=C(C(OO)=O)[CH:26]=1.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:25]([S:35]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:22]([CH3:23])[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=1)(=[O:39])=[O:37])[CH3:26]
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.25 g) and chloroform (3 ml), 3-chloroperbenzoic acid (purity: not less than 65%, 0.43 g) was added under ice-cooling, and then heated to room temperature, and stirred for 1 hour. To the reaction mixture, chloroform was added under ice-cooling, and then saturated aqueous sodium thiosulfate solution was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crystal was washed with hexane, then methyl-tert-butyl ether to give 0.27 g of 2-(2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 6).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[CH2:16][CH2:15][NH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34](Br)=[O:35].[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:33][C:34]([NH:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OCc3ccccc3)c1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OCc3ccccc3)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(3-Benzyloxy-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[C:37]([C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[F:46])[NH2:42])#[CH:38]>ClCCCl>[C:37]([C:39]1[CH:40]=[C:41]([NH:42][C:9]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:43]=[CH:44][C:45]=1[F:46])#[CH:38]
Reactant: C#Cc1cc(N)ccc1F
Reactant: Cc1cc2c(=O)[nH]cnc2cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C#Cc1cc(Nc2ncnc3cnc(C)cc23)ccc1F
Temperature: 60 °C
Reaction time: 6 h
Yield: 13.3 %

Procedure:
6Methyl-pyrido[3,4-d]pyrimid-4-one (44 mg, 0.27 mmol), polymer -supported triphenylphosphine (0.462 g of about 3.0 mmol P/g resin, 1.55 mmol) and anhydrous carbon tetrachloride (0.261 mL, 2.71 mmol) were combined in 1,2-dichloroethane (1.25 mL). The reaction mixture was heated to 60° C. under an atmosphere of dry nitrogen for 2 hours. 3-Ethynyl-4-fluoro-aniline (55 mg, 0.407 mmol) was added and heating was continued at 60° C. for 6 hours. The polymer was filtered off and washed several times with 50% methanol/chloroform. The filtrate and washings were concentrated in vacuo and flash chromatographed on silica with gradient from 0 to 10% methanol/methylene chloride to afford the title product (10 mg; M.P. 225° C.; LC-MS: 279 (MH+); anal. RP-HPLC: 3.94 min.).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[CH3:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1C(=O)O
Agent: Cl
Product: Cc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Part A. A 2-L, three-necked, round-bottomed flask equipped with an addition funnel, reflux condenser, and a nitrogen sweep to an HCl gas scrubber was charged with 2-methylbenzoic acid (503 g, 3.69 mol). The apparatus was cooled in an ice bath, and thionyl chloride (750 mL, 10.3 mol) was added over a period of 15 minutes. After complete addition, the ice bath was removed and the reaction mixture was warmed to about 45° in order to completely dissolve the 2-methylbenzoic acid. The reaction mixture was then allowed to gradually cool with stirring to room temperature overnight. The excess thionyl chloride and the HCl and SO2 reaction side-products were removed by vacuum distillation to afford 2-methylbenzoyl chloride as an oil, which was used without further purification. This material was transferred immediately into an addition funnel and added with mechanical stirring in 30-50 mL portions over a period of one hour to a commercial 40% dimethylamine solution (1500 mL, 13.35 mmol) which was maintained below 25° by periodic cooling with a dry ice-acetone bath. After complete addition the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with ether, and the combined organic extracts were washed with water, dried, and concentrated. The resulting oil was distilled under vacuum to afford N,N,2-trimethylbenzamide (409 g, 2.49 mol, 68% yield) as an oil: bp 88° (0.4 torr); IR(neat) 1650 cm-1 ; 1H NMR(CDCl3) δ 7.07-7.30 (m,4H), 3.11(s,3H), 2.81(s,3H), 2.27(s,3H). Anal. Calcd for C10H13NO: C,73.59; H,8.03; N,8.58. Found: C,73.66; H,8.18; N,8.42.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:19]([CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:22](Cl)=[O:23])[CH3:20]>ClCCl.O>[CH3:20][CH2:19][CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:23]
Reactant: CC(N)C(=O)O
Reactant: CCCCCCC(CC)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(CC)C(=O)NC(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.6 g (0.211 mol) of D,L-alanine and 46.6 g (0.41 mol) of triethylamine are initially charged in 300 ml of dichloromethane. At 0° C., 50.09 g (0.461 mol) of trimethylsilyl chloride are added dropwise, and the mixture is stirred at room temperature for 1 h and then at 40° C. for 1 h. The solution is cooled to −10° C., and 40 g (0.21 mol) of 2-ethyloctanoyl chloride in 50 ml of dichloromethane are added dropwise. The mixture is stirred at room temperature overnight, 100 ml of water are then added dropwise with ice-cooling and the mixture is stirred for 10 minutes. The phases are separated, the aqueous phase is reextracted twice with in each case 100 ml of dichloromethane and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is crystallized from toluene by adding n-hexane and is dried at 60° C.
Reaction SMILES: [Mg].II.[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7]Br)[CH3:5].Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH3:5]
Reactant: CCCCC(CC)CBr
Reactant: Brc1ccsc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a mixture of magnesium turnings (3.0 g, 0.12 mol), anhydrous THF (20 mL) and a small amount of iodine in a 300 mL flask, a solution of 2-ethylhexylbromide (23.5 g, 0.12 mol) in anhydrous THF (35 mL) was added slowly at 0° C. under N2. After refluxing for 1 h, the solution was added dropwise to a mixture of 3-bromothiophene (15 g, 0.09 mol, (9-3)), Ni(dppp)Cl2 (0.51 g, 0.001 mmol) and anhydrous THF (35 mL) placed in a 500 mL flask at 0° C. After the mixture was stirred overnight at room temperature, the reaction was quenched by pouring cold HCl aq. (2 N) into the mixture. The product was extracted with CHCl3 and dried over anhydrous Mg2SO4. The crude product was further purified by column chromatography using hexane as the eluent to give (9-4) as a clear liquid (11 g, 61%). 1H NMR (CDCl3, 300 MHz, ppm): 7.20-7.22 (m, 1H), 6.88-6.90 (m, 2H), 2.56 (d, 2H, J=6.9 Hz), 1.49-1.57 (m, 1H), 1.24-1.33 (m, 8H), 0.86-0.89 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[CH3:15][S-:16].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([S:16][CH3:15])[N:7]=1
Reactant: C[S-]
Reactant: CON(C)C(=O)c1ncc(Cl)nc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ncc(SC)nc1Cl
Reaction time: 5 h

Procedure:
To a solution of 55B (2 g, 8.47 mmol) in DMF (10 mL), 1 eq. of sodium methanethiolate was added to the solution. After 5 hours, 0.5 eq. of sodium methanethiolate was added to the suspension. The reaction was stirred overnight then diluted with EtOAc and washed with NaHCO3 (aq) and brine. The organic layer was concentrated and purified by flash chromatography to provide the title compound. MS (m/z) 248 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([CH:24]([OH:34])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].ClC1C=C(C(=O)CCC2C=CC=CC=2)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=O>>[Cl:1][C:2]1[CH:23]=[C:22]([C:24](=[O:34])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: O=C(NC[C@H](NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl)C(=O)O)c1cccs1
Agent: O=C(CCc1ccccc1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Product: O=C(CCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1

Procedure:
N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyp henyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine; N-[2-chloro-4-(1-oxo-3-phenylpropyl)benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Si:10](Cl)([CH3:13])([CH3:12])[CH3:11].[Li]CCCC.O>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
4-Bromoanisole (9.35 g, 50.0 mmol, 1.0 eq) was dissolved in anhydrous THF (200 mL). Me3SiCl (12.7 mL, 100.0 mmol, 2.0 eq) was added at 0° C. followed by n-BuLi (2.5 M in hexanes, 40 mL, 100.0 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 1 h. Water (150 mL) was then added, the organic layer was separated and the aqueous layer was extracted with Et2O (150 mL×2). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (4-methoxyphenyl)trimethylsilane as a light yellow oil (8.1 g, 90% yield). 1H NMR (300 MHz, CDCl3) δ: 7.48 (d, J=11.2 Hz, 2H), 6.95 (d, J=11.2 Hz, 2H), 3.84 (s, 3H), 0.27 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)=[O:6].Cl[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[CH2:26][CH2:25]2)=[CH:19][N:18]=1>>[F:34][C:31]([CH3:33])([CH3:32])[CH2:30][N:27]1[CH2:26][CH2:25][CH:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([N:12]3[C:13]4[C:9](=[CH:8][C:7]([C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:6])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)=[N:18][CH:19]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(F)CN1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: O=C(NCCO)c1ccc2[nH]ccc2c1
Product: CC(C)(F)CN1CCC(Oc2ccc(-n3ccc4cc(C(=O)NCCO)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using N-(2-hydroxyethyl)-1H-indole-5-carboxamide (intermediate-19) and 2-Chloro-5-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridine (intermediate-54).
Reaction SMILES: O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(OC([NH:20][C@@H:21]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:22][N:23]([CH2:33][CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])=O)(C)(C)C>CCO.CCOCC>[NH2:20][C@@H:21]([CH2:37][CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)[CH2:22][N:23]([CH2:33][CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])=[O:25]
Reactant: CCCCN(C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCCCN(C[C@@H](N)CC1CCCCC1)C(=O)OCC[Si](C)(C)C
Yield: 151.6 %

Procedure:
A solution of toluenesulfonic acid monohydrate (199.4 mg, 1.0 mmol) in absolute EtOH (1.0 mL) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane (468.5 mg, 1.03 mmol) in Et2O (10 mL). This solution was placed in a flask on a rotary evaporator and the Et2O was removed at rt. The flask was then lowered into the water bath (temperature: 60° C.) and the selective removal of the Boc group proceeded concurrently with removal of the remainder of solvent to afford (2S)-2-amino-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane (556.7 mg, 98%) as a white solid.
Reaction SMILES: C(OC(=O)[C:5](=[O:27])[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][C:8]=1[N+:24]([O-:26])=[O:25])C.[OH-:29].[Li+]>CO>[CH2:17]([O:16][CH2:15][CH2:14][O:13][C:11]1[CH:10]=[CH:9][C:8]([N+:24]([O-:26])=[O:25])=[C:7]([CH2:6][C:5]([OH:27])=[O:29])[CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(=O)Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Li+]
Solvent: CO
Product: O=C(O)Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 3-[5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-2-oxo-propionic acid ethyl ester(37.77 g, 97.50 mmol) in methanol (370 ml) was added 1 N lithium hydroxide solution (230 ml, 0.23 mol). The deep red reaction mixture was stirred at 55° C. for 30 min and worked up to give [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-acetic acid (22.42 g, 69%) as an off-white solid. Analysis calculated for C17H17NO6 : C, 61.63; H, 5.17; N, 4.23. Found: C, 61.66; H, 5.08; N, 4.18.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[NH:6][C:5](=[O:7])[N:4](CN2CCOCC2)[C:3]1=[O:15].N([CH2:20][CH2:21][CH2:22][CH2:23]CC)=C=O>>[CH3:1][C:2]1([CH3:16])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:15].[CH2:2]([C:3]([NH2:4])=[O:15])[CH2:16][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCN=C=O
Reactant: CC1(C)NC(=O)N(CN2CCOCC2)C1=O
Product: CC1(C)NC(=O)NC1=O
Product: CCCCCCC(N)=O

Procedure:
5,5-Dimethyl-3-morpholin-4-ylmethylimidazolidine-2,4-dione (100 mg, 0.44 mmol) and 1-isocyanatohexane (56 mg, 0.44 mmol) were reacted in analogy to example 1. Yield: 8 mg (7%), M+H+: 256.21.