Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C(OC([NH:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[NH2:37])=O)(C)(C)C.Cl>CO>[NH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([NH:37][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(N)cc1OCCNC(=O)OC(C)(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Agent: Cl
Solvent: CO
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN
Reaction time: 20 h
Yield: 19 %

Procedure:
2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) was reacted with 3-(2-(t-butyloxycarbonylamino)ethoxy)-4-methoxyaniline (D11) following a procedure similar to that described in Example 1. The product was dissolved in methanol (10 ml), and treated with 3.3M ethereal HCl solution (3 ml) and left to stand at room temperature for 20 hours. After removal of the solvent in vacuo, the residue was dissolved in H2O solid potassium carbonate was added and the mixture extracted with EtOAC (3×). The combined organic extracts were dried and concentrated in vacuo. Flash column chromatography on silica gel eluting with 5% MeOH/CH2Cl2 gave the title compound as a white solid (0.06 g, 19%) mp 150°-153° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl.C(#N)C>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:18])[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCOCC1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), morpholine (313 uL, 3.59 mmol), potassium iodide (596 mg, 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into an argon purged vial fitted with a magnetic stirbar. Anhydrous acetonitrile (4 mL) was added, and the yellow suspension stirred in a heating block at a temperature of 65° C. for 18 hours. As starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a separatory funnel. The organic layer was collected, and the aqueous layer extracted twice more with dichloromethane (2×10 mL). The combined organics were washed with brine (15 mL) and dried over sodium sulphate. The solution was decanted and concentrated to afford a yellow oil. The product was purified using flash chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5-5:95-97.5) to afford a yellow oil. Yield: 88 mg yellow oil (77%). 1H-NMR (CDCl3) δ: 8.13 (dd, J=2.7, 9 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 4.04 (t, J=7.5 Hz, 2H), 3.72 (t, J=4.5 Hz, 4H), 3.01 (t, J=7.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.46-2.39 (m, 6H), 1.88-1.79 (m, 2H). MS (EI): 319 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH:14](OC)(OC)OC>>[CH3:13][N:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[N:1]=[CH:14]1
Reactant: COC(OC)OC
Reactant: CNc1ccc(C(=O)OC)cc1N
Product: COC(=O)c1ccc2c(c1)ncn2C

Procedure:
A solution of methyl 3-amino-4-methylaminobenzoate (prepared as in DE 1990390463 A1) (2.57 g, 14 mmol) in trimethyl orthoformate (50 mL) was refluxed for 16 hours. The solvent was then removed under reduced pressure to afford 2.31 g of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:14])(=[O:13])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][C:28](=[O:31])[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: COC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1

Procedure:
The title compound was prepared from (4-chlorosulfonyl-phenoxy)-acetic acid methyl ester (Chem. Pharm. Bull. 1995, 43, 1132) and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a grey solid; MS (ES) m/z: 418.9 (MH+); HRMS Calcd. for C20H23N2O6S(MH+): 419.1271. Found: 419.1271.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:23][C:22]=1[CH2:35]O.[Br:37]C(Br)(Br)Br.CCCCC>ClCCl>[Br:37][CH2:35][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=1[F:20])[CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1
Reactant: OCc1cc(COC2CCCCO2)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: Fc1ccc(COC2CCCCO2)cc1CBr
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
4.44 g (16.94 mmol) triphenylphosphine in 10 ml dichloromethane is added in drops to an ice-cold solution of 3 g (12.49 mmol) [2-fluoro-5-(tetrahydropyrane-2-yloxymethyl)-phenyl]methanol and (15.61 mmol) tetrabromomethane in 30 ml anhydrous dichloromethane and stirred for another 45 minutes at 0° C. The reaction solution is mixed with pentane, the precipitation is suctioned off and washed with dichloromethane. The filtrate is washed with 5% sodium hydrogen carbonate solution, water and sodium chloride solution and dried over magnesium sulfate. After removing the solvent, the residue is purified by way of column chromatography on silica gel using diethyl ether/petrol ether 1:10.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14]O.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][Cl:18]
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1CO
Reactant: O=S(Cl)Cl
Product: Cc1nn(-c2ccccc2)c(Cl)c1CCl

Procedure:
6.1 g of 5-chloro-4-hydroxymethyl-3-methyl-1-phenylpyrazole are added portionwise to 50 ml of thionylchloride. The mixture is refluxed for 2 hours, the excess thionylchloride distilled off, the oily product treated with water and then extracted with ether. The dried ethereal extract is evaporated in vacuo yielding 6.1 g of oily 5-chloro-4-chloromethyl-3-methyl-1-phenylpyrazole which, without further purification, is used in the next reaction step.
Reaction SMILES: [CH:1]([N:4]([CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[C:21]([C:23](OC)=[O:24])[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.O>[CH:1]([N:4]([CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)N(CCC(c1ccccc1)c1cc(CO)ccc1OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
(+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carbomethoxyphenyl)-3-phenylpropylamine (30 g, 0.065 mole) dissolved in diethyl ether (250 mL) was added dropwise under nitrogen to a suspension of lithium aluminiumhydride (1.9 g, 0.05 mole) in dry diethyl ether (150 mL). The mixture was stirred overnight at room temperature, and the excess hydride was decomposed by the addition of water (≈5 g). The mixture was stirred for 10 min, when sodium sulfate (s) was added. After stirring for 20 minutes, the mixture was filtered and then evaporated to give 28.4 g of the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:4]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[N:25].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:20]([C:4]1[CH:3]=[C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[C:7]([CH3:8])=[CH:6][C:5]=1[S:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:23])([CH3:22])[CH3:21]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(NS(=O)(=O)c3ccc(C#N)cc3)cc2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl) ester obtained from Example HHHH (0.20 g, 0.57 mmol), 4-cyanobenzenesulfonyl chloride (0.15 g, 0.74. mmol), pyridine (7 mL) and CH2Cl2 (1 mL) was stirred at room temperature under nitrogen overnight. 1N HCl was then added and the mixture was extracted with EtOAc. The organic phase was washed with 1N HCl and brine, dried (Na2SO4), filtered and concentrated. The resulting residue was flash chromatographed on silica gel, eluting with 19:1 CHCl3 :EtOAc to afford the title compound. 1H NMR (CDCl3) δ 1.16 (s, 9 H), 1.98 (s, 3 H), 2.43 (s, 3 H), 6.49 (s, 1 H), 7.23 (s, 1 H), 7.27 (d, partially obscured by CDCl3, 2 H), 7.48 (d, 2 H), 7.78 (d, 2 H), 7.87 (d, 2 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23](Cl)[N:24]=1)[C:19]([NH2:21])=[O:20].CN(C(C(C)C)C)C.O>CCOC(C)=O>[NH2:21][C:19]([C:18]1[CH:17]=[C:16]([Cl:15])[N:24]=[C:23]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[CH:22]=1)=[O:20]
Reactant: NC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(C)C(C)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1

Procedure:
tert-Butyl piperidin-4-ylcarbamate (500 mg, 2.62 mmol), was dissolved in anhydrous N,N′-dimethyl acetamide (4 ml). 2,6-Dichloroisonicotinamide (522 mg, 2.62 mmol) was added, followed by N,N-dimethyl isopropylethylamine (465 μl, 2.62 mmol). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 20 minutes. H2O (50 ml) and EtOAc (100 ml) were added, the EtOAc layer was washed (4×50 ml), dried over Na2SO4 and concentrated in vacuo to give the title product as a brown solid. (760 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:19]([O:26][CH2:27][CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:19]([O:26][CH2:27][CH2:28][NH:29][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCOCc1ccccc1
Reactant: Clc1ncnc2ccccc12
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(COCCNc2ncnc3ccccc23)cc1
Reaction time: 5 h
Yield: 66.2 %

Procedure:
To a solution of 3.3 g (0.02 mol) of 4-chloroquinazoline in 50 ml of benzene were added 2.0 g (0.02 mol) of triethylamine and 3.0 g (0.02 mol) of 2-benzyloxyethylamine, and the mixture was heated, with stirring, at 60°~70° C. for 5 hours. After completion of the reaction, the benzene was evaporated under reduced pressure, and the resulting crystals were washed with water, collected by filtration, dried and recrystallized from benzene/n-hexane, affording 3.7 g of 4-[2-(benzyloxy)ethyl]aminoquinazoline in the form of colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([OH:18])[C:15]([I:17])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].I[CH2:22][CH2:23][C:24]([OH:26])=[O:25]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([O:18][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:15]([I:17])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)CCI
Reactant: CCOC(=O)N1CCc2cc(O)c(I)cc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2cc(I)c(OCCC(=O)O)cc2CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.8 %

Procedure:
Into a 100 ml flask, the product of step (d) (1.28 g, 3.54 mmol) dissolved in DMF (15 ml) was added. The solution was cooled to 0° C. and NaH (354 mg, 8.86 mmol) was added, followed by 3-iodopropionic acid (1.06 g 5.31 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours, after which time it was heated to 70° C. for an additional 1 hour. The reaction mixture was cooled to room temperature and quenched by the addition of water (100 ml) and 2M NaOH (15 ml). The aqueous mixture was washed with EtOAc (2×), acidified with 2M HCl to pH 2, and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give crude product. Purification by silica-gel chromatography (gradient elution: 0 to 60% EtOAc in hexanes) gave the sub-title compound as an off-white solid (580 mg) and recovered starting material (515 mg). MS: ESI (positive): 434 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[CH:10]=[CH:11][C:12]([O:14]C)=[CH:13][C:8]=3[S:7](=[O:17])(=[O:16])[NH:6][CH2:5]2)[CH2:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:9]3[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=3[S:7](=[O:16])(=[O:17])[NH:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S1(=O)NCN(C2CC2)c2ccc(O)cc21
Reaction time: 20 h

Procedure:
A solution of the compound of Example 84 (50 mg) in chloroform (3 mL) is cooled on an ice bath and then boron tribromide (0.15 mL) is added. After stirring for 20 hours, water (5 mL) is added to the mixture, which is then concentrated under reduced pressure and subsequently extracted with ethyl acetate (3×20 mL). The organic phases are collected and dried over anhydrous MgSO4. After filtration, the filtrate is evaporated to dryness and the residue is dissolved in ethyl acetate (1 mL); hexane (5 mL) is then added. The precipitate obtained is collected by filtration, washed with hexane and dried to yield the expected product in the form of a white solid.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[C:10]([NH:16][CH:17]=[O:18])=[C:9]([F:19])[C:8]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[F:28]>CCOCC.C1COCC1>[CH3:4][O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([C:13]([OH:15])([CH3:1])[CH3:14])[C:10]([NH:16][CH:17]=[O:18])=[C:9]([F:19])[C:8]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[F:28]
Reactant: COC(=O)c1cc(C(C)=O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)(C)O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of MeMgBr (3.20 equiv., 3.0 M solution in diethyl ether) in ether is added a solution of 5-acetyl-2-(4-bromo-2-fluorophenylamino)-3-fluoro-4-formylamino-benzoic acid methyl ester (1.00 equiv.) in THF at 0° C. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction is quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is used directly without further purification.
Reaction SMILES: [C:1]([C:3]([NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:4])#[N:2].[CH2:21](O)[CH3:22]>[OH-].[NH4+].[Ni]>[CH3:4][C:3]1([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:1][NH:2][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:21][CH3:22])=[N:9]1
Reactant: CCO
Reactant: CCCCCCCCCC(=O)NC(C)(C#N)C(C)(C)C
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Product: CCCCCCCCCCCC1=NC(C)(C(C)(C)C)CN1
Yield: 52 %

Procedure:
15 g of 2-cyano-2-decanoylamino-3,3-dimethylbutane (prepared from acylation of aminonitrile obtained from treatment of pinacolone with sodium cyanide and ammonium chloride) in 250 ml of 95% ethanol and 70 ml of ammonium hydroxide was hydrogenated with T-1 Raney Nickel. The catalyst was filtered off. The filtrate was concentrated and the residue was distilled at reduced pressure to give 7.5 g (52%) of the product.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na].S([O-])([O-])(=O)=O.[Zn+2:15]>O>[N+:1]1([O-:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Zn:15]
Reactant: [Zn+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Agent: [O-][n+]1ccccc1S
Solvent: O
Product: [Zn]
Reaction time: 0.5 h

Procedure:
To a 419.9 gm aliquot of the above solution of sodium pyridine-2-thiol-N-oxide (29.9 gm dry basis; 0.200 mole) was added a solution of zinc sulfate (20.0 gm, 52.5% concentration as hydrate; 0.111 mole) and water (80 gm) at room temperature. After 0.5 hour agitation, zinc pyridine-2-thiol-N-oxide was filtered and washed with water. The wet cake (60.2 gm) was dried to constant weight (33.8 gm; 0.107 mole or 100% yield; 97.1% assay). The zinc pyridine-2-thiol-N-oxide had the following color designation: L, 92.0; a, -3.5; b, 4.9. (Hunterlab Tristimulus Colorimeter, Model D25A-2, Reston, Va. 22090).
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH3:7])[O:5][C:4](=[O:8])[CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O>>[C:9]([C:3]1[C:4](=[O:8])[O:5][CH:6]([CH3:7])[C:2]=1[OH:1])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1OC(=O)C=C1O
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Product: CC1OC(=O)C(C(C)(C)C)=C1O
Temperature: 40 °C
Yield: 13 %

Procedure:
4-Hydroxy-5-methyl-5H-furan-2-one (15.9 g, 0.14 mol) was dissolved in tert-butanol (13.9 ml, 0.147 mol) with concentrated sulfuric acid (7.8 ml, 0.147 mol) and heated at 40° C. for 4 days. The reaction mixture was allowed to cool and was partitioned between water (75 ml) and diethyl ether (75 ml). The organic layer was separated and dried (Na2SO4), filtered and concentrated under vacuum. Chromatography on silica gel with diethyl ether as eluent gave a crude product which was further purified by chromatography on silica gel with dichloromethane as eluent then triturated with diethyl ether to give 3-tert-butyl-4-hydroxy-5-methyl-5H-furan-2-one (3.1 g) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.34 (9H, s), 1.46 (3H, d, J=6.7 Hz), 4.69 (1H, q, J=6.7 Hz).
Reaction SMILES: N#N.N[C@@H](CC1C=CC=CC=1)[C@H](O)C[C@@:7]1([C:16]([NH2:18])=[O:17])[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([CH3:15])([CH3:14])[CH3:13].C(OC(N[C@H](C(O)=O)CSC)=O)C1C=CC=CC=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:16]([NH2:18])=[O:17])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccccc1)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 650 mg of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide and 538 mg of N-(benzyloxycarbonyl)-S-methyl-L-cysteine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 270 mg of hydroxybenzotriazole, 230 mg of N-ethylmorpholine and 412 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using System G for the elution to give 800 mg of N2 -[3(S) [N-(benzyloxycarbonyl)-S-methyl-L-cysteinyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide; MS: m/e 585 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:13]=[CH:12][C:5]2[CH2:6][C:7]([NH:9][C:10](=[O:11])[C:4]=2[CH2:3]1)=[O:8].[H-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O1CCCC1.CCCCCC>[Cl:17][C:18]([Cl:22])([Cl:21])[S:19][N:9]1[C:10](=[O:11])[C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH:13]=[CH:12][C:5]=2[CH2:6][C:7]1=[O:8]
Reactant: CC1(C)C=CC2=C(C1)C(=O)NC(=O)C2
Reactant: ClSC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)C=CC2=C(C1)C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To 4,4-dimethyl homophthalimide (5.6 g) in 200 ml dry tetrahydrofuran was added 1.73 g sodium hydride. The mixture was stirred for one hour, then 5.75 g (3.38 ml) trichloromethyl sulfenyl chloride was added dropwise. The mixture was refluxed overnight, stripped of solvent, slurried in hexane and decanted. The brown crystalline residue was purified by tlc and recrystallized in ethanol to yield 3.2 g of the brown crystalline product, m.p. 129°-130° C.
Reaction SMILES: [CH:1](O)=[O:2].N1C=CN=C1.C(N(CC)CC)C.C(Cl)(=O)C(Cl)=O.Cl.[CH2:23]([O:25][C:26](=[O:48])[C@@H:27]([O:45][CH2:46][CH3:47])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[CH:31][CH:30]=1)[CH3:24]>ClCCl.C(OCC)(=O)C.CCCCCCC.O>[CH2:23]([O:25][C:26](=[O:48])[C@@H:27]([O:45][CH2:46][CH3:47])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([NH:44][CH:1]=[O:2])=[CH:42][CH:43]=2)=[CH:31][CH:30]=1)[CH3:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Reactant: O=CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCCCC
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC=O)cc2)cc1)OCC
Yield: 47 %

Procedure:
Formic acid (0.0585 g, 1.27 mmole) was dissolved in dichloromethane (2 ml). Imidazole (0.0874 g; 1.27 mmole) was added into the solution, followed by addition of triethylamine (0.353 ml, 2.54 mmole). The mixture was stirred for a little while and then oxalyl chloride (0.161 g; 1.27 mmole) in dichloromethane (2 ml) was added slowly. The resulting mixture was stirred for 30 minutes. A mixture of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (0.5 g, 1.27 mmole) and triethylamine (0.176 ml; 1.27 mmole) in dichloromethane (3 ml) was added into the reaction mixture. The reaction mixture was stirred at room temperature overnight. Water was added and the phases were separated. The organic phase was washed with water, dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (isolute, SI) using heptane, then ethyl acetate/heptane (5%), followed by ethyl acetate/heptane (10%) and then ethyl acetate/heptane (25%) as eluants gave 0.230 g (47% yield) of 2-(S)-ethoxy-3-(4-{2-[4-(formylamino)phenyl]ethoxy}-phenyl)propanoic acid ethyl ester.